bmj open · for peer review only 3 abstract objectives: this article provides an overview of the...

For peer review only

Upper Limb International Spasticity Study: Rationale and protocol for a large international, multicentre prospective

cohort study investigating management and goal attainment following treatment with botulinum toxin-A in

real-life clinical practice

Journal: BMJ Open

Manuscript ID: bmjopen-2012-002230

Article Type: Research

Date Submitted by the Author: 16-Oct-2012

Complete List of Authors: Turner-Stokes, Lynne; Northwick Park Hospital, Regional Rehabilitation Unit Fheodoroff, Klemens; Gailtal-Klinik, Neurorehabilitation Jacinto, Jorge; Centro de Medicina de Reabilitaçãode Alcoitão, Serviço de Reabilitação de adultos 3 Maisonobe, Pascal; Ipsen Pharma, Biostatistics & Data Management Zakine, Benjamin; Ipsen Pharma, Global medical Affairs

<b>Primary Subject Heading</b>:

Rehabilitation medicine

Secondary Subject Heading: Neurology

Keywords: Rehabilitation, STROKE MEDICINE, MEDICAL EDUCATION & TRAINING

For peer review only - http://bmjopen.bmj.com/site/about/guidelines.xhtml

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Upper Limb International Spasticity Study: Rationale and protocol for a large

international, multicentre prospective cohort study investigating management and

goal attainment following treatment with botulinum toxin-A in real-life clinical practice

Lynne Turner-Stokes,1 Klemens Fheodoroff,2 Jorge Jacinto,3 Pascal Maisonobe,4 Benjamin

Zakine4

1School of Medicine, King’s College London, London, UK, 2Neurorehabilitation, Gailtal-Klinik,

Hermagor, Austria, 3Centro de Medicina de Reabilitaçãode Alcoitão, Serviço de Reabilitação

de adultos 3, Estoril, Portugal and 4Medical Affairs, Ipsen Pharma, 65 Quai Georges Gorse,

Boulogne-Billancourt 92100, France

Correspondence: Lynne Turner-Stokes, Regional Rehabilitation Unit, Northwick Park

Hospital, Watford Road, Harrow, Middlesex, HA1 3UJ, UK. E-mail: lynne.turner-

[email protected]; Tel: +44 (0)-208-869-2800; Fax+44 (0)-208-869-2803

Short title: Upper Limb International Spasticity (ULIS-II) Study

Keywords: botulinum toxin-A; goal attainment scaling (GAS); post-stroke spasticity; stroke

rehabilitation.

Word count (abstract)/limit: 288/300 words

Word count (text)/limit: 5500 words without figures and tables

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Copyright statement:

“The Corresponding Author has the right to grant on behalf of all authors and does grant on

behalf of all authors, an exclusive licence (or non-exclusive for UK Crown Employees) on a

worldwide basis to the BMJ Publishing Group Ltd, and its Licensees to permit this article (if

accepted) to be published in BMJ Open and any other BMJPGL products and to exploit all

subsidiary rights, as set out in our licence.”

Previous publications:

Poster presentation, ‘Validation of individual person-centred goal statements for goal

attainment scaling (GAS) in a large international cohort study of botulinum toxin-A (BoNT-A)

for upper limb spasticity following stroke: The Upper Limb International Spasticity Study

(ULIS-II)’ at the American Academy of Physical Medicine and Rehabilitation, 17–20

November, 2011. Poster 269.

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ABSTRACT

Objectives: This article provides an overview of the Upper Limb International Spasticity

(ULIS) programme, which aims to develop a common core dataset for evaluation of real-life

practice and outcomes in the treatment of upper limb spasticity with botulinum toxin-A

(BoNT-A). Here we present the study protocol for ULIS-II, a large international cohort study,

to describe the rationale and steps to ensure validity of goal attainment scaling (GAS) as the

primary outcome measure.

Methods and analysis: Design: An international, multicentre, observational, prospective,

before-and-after study, conducted in 84 centres from 22 countries across three continents.

Participants: Four hundred and sixty-eight adults presenting with post-stroke upper limb

spasticity in whom a decision had already been made to inject BoNT-A, (five to 12

consecutive subjects recruited per centre).

Interventions: Physicians were free to choose targeted muscles, BoNT-A preparation,

injected doses/technique, and timing of follow-up in accordance with their usual practice and

the goals for treatment. Primary outcome measure: GAS. Secondary outcomes:

measurements of spasticity, standardised outcome measures and global benefits.

Steps to ensure validity included: a) Targeted training of all investigators in use of GAS; b)

Within study validation of goal statements; and c) Establishment of an electronic case report

form with an in-built tracking facility for separation of baseline/follow-up data.

Analysis: Efficacy population: all subjects who had a) BoNT-A injection and b) subsequent

assessment of GAS. Primary efficacy variable: percentage (95% confidence interval)

achievement of the primary goal from GAS following one BoNT-A injection cycle.

Ethics and dissemination: This non-interventional study is conducted in compliance with

Guidelines for Good Pharmacoepidemiology Practices. Appropriate ethical approvals were

obtained according to local regulations. ULIS-II will provide important information regarding

treatment and outcomes from BoNT-A in real-life upper limb spasticity management. The

results will be published separately.

Registration: ClinicalTrials.gov identifier: NCT01020500

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ARTICLE SUMMARY

Article focus

• To provide an overview of the Upper Limb International Spasticity (ULIS) programme

and the rationale and protocol of the ULIS-II study

• To outline the steps taken in ULIS-II to ensure the quality of goal statements and

support the validity of goal attainment scaling (GAS) as the primary outcome

measure for the trial

Key messages

• Evaluation of goals statements part-way through this study has assisted participating

centres to improve the quality and function-related focus of goal statements

Strengths and limitations of this study

• This methodology helps to support the validity of GAS as the primary outcome

measure for the efficacy analysis

• This large international cohort study represents a diverse sample of practice across

three continents

• However, the limited number of subjects per centre (five to 12) could lead to some

selection bias

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INTRODUCTION

Spasticity is a common sequel of stroke, with an incidence ranging from 17% to 38%.[1-5] It

is more prevalent in younger patients,[2] and most commonly affects the upper limb.[6]

Upper limb spasticity is often painful. It interferes with upper limb movement, and limits

use of the limb for active functional tasks. It can cause involuntary movements (associated

reactions) that impact on mobility (gait, balance, walking speed, etc). In severe cases, it can

also impede ‘passive function’, such as washing, dressing and caring for the affected limb,

therefore increasing the burden on caregivers.[7 8]

There is now a well-established body of evidence demonstrating that botulinum toxin-A

(BoNT-A) is a safe and effective focal intervention for the reduction of spasticity, and it is

widely recommended for use in standard clinical practice.[7-9] Controlled clinical trials

(CCTs)[10-18] have confirmed the benefits of BoNT-A at the level of impairment, but

functional change has been harder to demonstrate, particularly where impact on active

function is limited by underlying motor dysfunction. Nevertheless, on an individual level,

clinical experience suggests that some patients make substantial functional gains.

Whilst CCTs may be helpful for establishing the overall clinical efficacy of an

intervention, they do not answer important clinical questions such as which patients are most

likely to benefit and in what way; or which treatment approaches work best in clinical

practice. For these, we need large, multicentre, longitudinal, cohort studies conducted in the

course of routine clinical practice.[19] If the findings are to be generalisable across different

health cultures, these studies need to have wide geographical representation across the

international health community.

Measuring the effectiveness of BoNT-A treatment is challenging in the context of upper

limb spasticity because of wide diversity in patient presentation, potential for rehabilitation

and goals for treatment. Timing of assessment is also important due to the need for time to

practice and develop new skills in the hemiparetic arm after the spasticity has been

relieved,[20 21]. Current guidelines for the use of BoNT-A in the management of spasticity,

advocate the application of focused outcome evaluations, targeted on the attainment of

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priority goals that are relevant to the treatment intentions and important to the individual.[7 8]

Depending on the nature of the goals set, the individual clinical presentation and any

underlying trajectory towards recovery/deterioration, the timescale for expected goal

achievement will vary from person to person. Cohort study design in this context must

therefore be flexible enough to account for all this variation.

Goal attainment scaling (GAS) is a method of assimilating achievement in a number of

individually-set goals into a single ‘goal attainment score’, in order to capture outcomes

across a diverse range of goal areas. Originally described by Kiresuk and Sherman in the

1960s,[22] it is increasingly recognised as a sensitive method for recording patient-centred

outcomes in this context.[23-26] In addition to providing a semi-quantitative (ordinal)

assessment of goal attainment, GAS offers potentially useful qualitative information

regarding the patient’s priority goals for treatment. Moreover, the process of goal setting and

rating itself offers an opportunity for dialogue and negotiation between the patient and the

treating team,[27] which may help to establish mutual agreement of expectations for

outcome. However, this requires knowledge and experience, and it is important to recognize

that GAS is not a measure of outcome per se, but a measure of the achievement of

intention. It therefore does not replace standardised measures, but is a useful adjunct to use

alongside them.[28]

The use of GAS as a primary outcome measure for research is still somewhat

controversial. Concerns have been raised in some quarters about the validity of GAS; in

particular, the non-linearity of the scaling and lack of uni-dimensionality[29] and some

authors have proposed the development of standardized goals or ‘item banks’.[29 30] The

World Health Organization (WHO) International Classification of Functioning, Disability and

Health (ICF)[31] provides a useful common language for categorising goals into different

domains of personal experience. A previous secondary analysis of a multicentre CCT from

Australia[24] mapped a total of 165 goals onto ICF domains, to identify the key goal areas

impacting on quality of life to inform the future development of standardised goal sets. The

authors recommended further research with a priori categorisation of goals in large,

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prospective, cohort studies is required to describe the full value of BoNT-A in the

management of upper limb spasticity.

From the studies conducted to date, we know that there is considerable individual

variation in response. We also know that there is considerable variation in the approach of

clinicians with respect to selection of muscle, injection technique, follow-up therapy etc,

which appears to have more to do with clinician bias than patient presentation.[32] It is now

time to extend the field of investigation in this area to understand how BoNT-A is used in

routine clinical practice, to gain a better understanding of how to select those most likely to

respond and what works best for which types of presentation. To do this, we will need to

build a consistent body of data that captures clinically important changes at an individual

level and is of sufficient size and generalisability to interrogate for future answers to these

critical questions. The challenge lies in how to engage clinicians from across the globe, to

engage in a single common approach to data collection.

The Upper Limb International Spasticity (ULIS) study programme represents the first

steps towards this aim. This manuscript provides an overview of the programme and

presents the rationale and protocol for the ULIS-II study. The study results for ULIS-II will be

presented separately.

OVERVIEW OF THE ULIS PROGRAMME AND RATIONALE

The ULIS programme consists of a series of international, observational studies to describe

current clinical practice in the application of BoNT-A in the management of upper limb

spasticity. The ultimate aim is to work towards the development of a common core dataset

for prospective systematic recording of longitudinal outcomes that could inform development

of a large, international database of sufficient size and breadth to support future interrogation

and subset analysis.

A founding principle of establishing common datasets is to embed them as closely as

possible in real-life current clinical practice.

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• The first stage of the programme (ULIS-I) [33] was an international, cross-sectional,

survey, which set out to document clinical practice across four continents with respect to

treatment and outcome evaluation.

• The second stage (ULIS-II) (described here) is a large, before-and-after, prospective,

observational, cohort study to record goal attainment as a primary outcome following 1

cycle of BoNT-A. This has also served to develop expertise in GAS and refine an

electronic case report form (e-CRF). ULIS-II has recently completed recruitment and is

now in the process of analysis.

• Following further refinement of the dataset and tools, a third stage is planned to expand

the cohort, and to capture the broader benefits of treatment in a fully generalisable

sample. This is currently in the planning and pre-investigation phase.

How ULIS-I informed the rationale for ULIS-II

ULIS-I was an international, cross-sectional, non-interventional survey to document

(from review of current practice and reported intentions) the clinical profiles, treatment goals

and reported outcome evaluation in consecutive adults attending treatment with BoNT-A for

upper limb spasticity.[33] Over a 6-month period, a total of 974 consecutive patients were

recruited from 122 investigational centres in 31 countries spanning the European Union,

Pacific Asia, Eastern Europe, the Middle East and South America.

The findings demonstrated wide diversity in clinical practice with respect to both the

method of intervention and the use of assessment and outcome measures.[33] Most

frequently recorded were impairment measures, including range of movement (90%) and

spasticity – mainly using the Modified Ashworth Scale (MAS) (83%). Although 36% said they

routinely recorded at least one measure of active function, there was wide variation in the

instruments used and insufficient commonality to allow pooling of data.

Goal setting on the other hand was very common (78%). However, although the large

majority of clinicians reported that they set goals, the way by which they used these to

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monitor the effects of treatment varied widely. Formal application of GAS was used by only a

handful of participating centres (5%).

The findings suggested that goal attainment offered the most widely applicable common

outcome measure, and for this reason, it was selected as the principal outcome measure for

the next stage of the programme (ULIS-II). However, it was first necessary to establish a

consistent approach to the recording of goals and goal attainment. It was also important that

the method was simple and practical to apply across the wide international spectrum of

clinical practice in upper limb spasticity management.

ULIS-II STUDY PROTOCOL – METHODS AND ANALYSIS

Study objectives

The primary objective of the ULIS-II study was to assess the responder rate (as defined by

the achievement of the primary goal from GAS) following one BoNT-A injection cycle

delivered in the context of routine clinical practice.

Secondary objectives were to:

• Describe the baseline characteristics, including demographics, duration and pattern of

spasticity, concomitant therapies/medication, etc.

• Assess the overall attainment of treatment goals using GAS.

• Describe injection practices (muscle identification, dosage, dilution and injection points)

and additional treatment strategies (therapies and other modalities).

• Document the use of standardised outcome measures and their results.

• Assess the global benefits as perceived by the investigator and the patient (or

guardian).

Exploratory objectives, addressed through the analysis plan, were

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• To describe the common goal areas for treatment and to identify those in which goals

were most often achieved

• To identify any prognostic factors for response.

Study design and setting

ULIS-II was an 18-month, post-marketing, international, multicentre, observational,

prospective, longitudinal study, conducted in 84 centres in 22 countries (European Union,

Pacific Asia, Eastern Europe and South America). Figure 1 shows the geographical

distribution of participating centres.

Study participants

The main inclusion criteria were:

• Adults ≥18 years with post-stroke upper limb spasticity in whom a decision had already

been made to inject BoNT-A.

• No previous treatment with BoNT-A or BoNT-B within the last 12 weeks

• Agreement on an achievable goal set and ability to comply with the prescribed treatment.

Exclusions were any contraindications to BoNT-A or failure to consent to participate.

Recruitment

To limit the potential bias that might be introduced by over-recruiting sites, the number of

patients was limited to 5–12 patients per treatment centre. Participating centres represented

a range of experience to mirror clinical practice. However, in order to capture the

approaches to treatment that are borne of clinical experience, recruitment at less

experienced centres (n=59) was restricted to five patients only, whilst more experienced

centres (n=25) could recruit up to 12 patients. This approach also offers the potential for

future subanalysis of differences between experienced and less experienced injectors.

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Centres were asked to include consecutive patients attending the clinics over a

specified period. If consecutive inclusions were not feasible (e.g. due to administrative

constraints in a busy clinic setting), investigators were authorised to space the inclusions

(e.g. one per every two to three patients), until their recruitment target was achieved.

A total of 468 patients were recruited, 226 in more experienced (48.3%) and 242 in

(51.7%) less experienced centres, confirming more or less equal distribution. Figure 2 shows

the disposition of patients and table 1 shows the breakdown by country.

Table 1 Disposition of patients by country

Country Enrolled = treated

subjects

Discontinued

subjects

Completed subjects

Australia 44 (9.4%) 0 44 (9.6%)

Austria 14 (3.0%) 0 14 (3.1%)

Belgium 25 (5.3%) 1 (8.3%) 24 (5.3%)

Taiwan 10 (2.1%) 0 10 (2.2%)

Czech Republic 10 (2.1%) 0 10 (2.2%)

Denmark 5 (1.1%) 0 5 (1.1%)

Finland 13 (2.8%) 1 (8.3%) 12 (2.6%)

France 48 (10.3%) 1 (8.3%) 47 (10.3%)

Germany 45 (9.6%) 2 (16.7%) 43 (9.4%)

China 5 (1.1%) 0 5 (1.1%)

Italy 33 (7.1%) 2 (16.7%) 31 (6.8%)

South Korea 29 (6.2%) 1 (8.3%) 28 (6.1%)

Malaysia 6 (1.3%) 0 6 (1.3%)

Mexico 10 (2.1%) 0 10 (2.2%)

Philippines 10 (2.1%) 0 10 (2.2%)

Portugal 27 (5.8%) 0 27 (5.9%)

Russia 41 (8.8%) 0 41 (9.0%)

Singapore 10 (2.1%) 0 10 (2.2%)

Spain 14 (3.0%) 0 14 (3.1%)

Sweden 14 (3.0%) 0 14 (3.1%)

Thailand 10 (2.1%) 0 10 (2.2%)

United Kingdom 45 (9.6%) 4 (33.3%) 41 (9.0%)

Total 468 (100.0%) 12 (2.6%) 456 (97.4%)

Study schedule

Baseline evaluation (Time 1)

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On inclusion into the study the following assessments were recorded by the investigator on

the e-CRF:

• Demography and history of the stroke including type, location and time since onset.

• The pattern of impairment in the affected upper limb (motor function, sensation and

contractures) and the presence of any generalised impairments that may affect outcome

(including cognitive, emotional and behavioural function) were recorded using a

modified version of the Neurological Impairment Scale.[34]

• Previous/concomitant treatments for upper limb spasticity, including therapies and

medication.

• Clinical examination, including a list of measurements of spasticity and other

standardised outcome measures, as normally routinely performed in that centre e.g.:

– Measurements of spasticity (MAS, Tardieu scale)

– Visual analogue and verbal rating scales for symptoms such as pain, ease of care,

etc

– Standardised scales for active and/or passive function (e.g. the Leeds Adult

Spasticity Impact Scale[11] or the Arm Activity scale[35 36])

– Measures of involuntary movement, e.g. the Associated Reaction Rating Scale.[37]

• Goal-setting and GAS was applied using the ‘GAS-light’ method [28] as detailed below

with emphasis on setting SMART (specific, measurable, achievable, realistic and timed)

goals agreed between investigator, the patient and treating team

One primary and up to two secondary goals were set and assigned to one of seven goal

categories.

Injection of BoNT-A

To reflect real-life practice in this non-interventional observational study, physicians were

free to choose targeted muscles, BoNT-A preparation, injected doses, number of points and

volume for each point, and use of EMG/electrical stimulation in accordance with their usual

practice, local Summary of Product Characteristics and therapeutic guidelines.

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Follow-up evaluation (Time 2)

The timing of follow-up was at the discretion of the investigator, based on their usual practice

and the nature of the goals set – usually between Months 3–5 after injection.

At the follow-up evaluation (end of study), the following were recorded:

• Achievement of primary and secondary GAS goals rated on a 6-point verbal rating scale,

and transcribed within the computer software to the 5-point numerical scale (range –2 to

+2), and the GAS T-score ( see details below).

• Any concomitant treatments for upper limb spasticity given since baseline

• Clinical examination including measurements of spasticity as normally routinely

performed. Change on any standardised measures performed was recorded as ‘the

same’, ‘better’ or ‘worse’

• Global assessment of benefits were rated by the investigator and patient as either: ‘great

benefit’; ‘some benefit’; ‘same’; ‘worse’; or ‘much worse’

• Related adverse events (AEs): as this was a non-interventional study, this followed the

regulations for reporting of related spontaneous AEs

• The next therapeutic strategy – including information on any planned re-injection with

BoNT-A – whether using the same agent and protocol or an adjusted one.

Sample size calculation

The sample size calculation was based upon an estimate that 60% of patients would achieve

their primary goal following their first BoNT-A injection cycle. Using a 0.05 two-sided

significance level, with a power of 80%, 450 patients were needed to allow estimation of this

proportion with a precision of 4.5%. This sample size also allowed the detection of potential

prognostic factors to response (based on detection of odds ratio larger or equal to two).

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Analysis

Statistical evaluations will be performed using Statistical Analysis System (SAS)® (version 8

or later versions).

All analyses will be conducted on the efficacy population that includes all subjects who

received one BoNT-A injection and who underwent a post-injection visit including an

assessment of the GAS. For the primary statistical analysis, ‘Responders’ are those who

achieve their primary goal (GAS score 0, 1 or 2) (primary statistical analysis). Patient

demographics, baseline characteristics and efficacy evaluations for secondary variables will

be presented as descriptive statistics, including 95% confidence intervals where relevant.

Exploratory analysis used a stepwise logistic regression model in order to identify

potential prognostic factors for response. A backward elimination analysis was followed

using a significance level of 0.2 to retain variables in the model. The Hosmer and Lemeshow

goodness-of-fit test [38] was used and 95% confidence intervals for the OR estimated by the

logistic model were calculated. Descriptive analysis will also be carried out to evaluate any

possible country effect if considered relevant.

Statistical evaluations will be performed using Statistical Analysis System (SAS)®

(version 8 or later versions).

Method for recording GAS

We used the simplified ‘GAS-Light’ approach described by Turner-Stokes,[28] which is

based on the original method described by Kiresuk and Sherman,[22] but designed to be

timely and practical for use in a busy clinic setting.

• At the baseline visit, the investigator (in conjunction with their multidisciplinary team

where possible) interviewed the patient and identified the main problem areas. An

agreed set of goals (one primary and up to two secondary goals) was defined.

• A single SMART goal statement was recorded in free text box in the e-CRF to describe

the intended outcome for each goal (as opposed to predefining levels for each score).

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• Each primary and secondary goal was assigned to one of seven goal categories (‘pain’,

‘passive function’, ‘active function’, ‘mobility’ [balance, gait], ‘involuntary movement’ [i.e.

associated reaction], ‘impairment’ [e.g. range of movement] and ‘other’).

• There was an option to complete two goal weighting categories for each goal:

‘importance’ (rated by patient and/or family) and ‘difficulty’ (rated by the multidisciplinary

team), using 0 = not at all, 1 = a little, 2 = moderately and 3 = very. Weight = importance

x difficulty.[28] If no goal weighting was recorded a default value of 1 was entered.

• A baseline score was chosen:’ some function’ or ‘no function’ (as bad as they could be)

with respect to each goal.

• At the follow-up visit, goal attainment for each goal was recorded by the treating team, in

conjunction with the patient, based on the review of the detailed goal statement.

• Attainment was rated on a 6-point verbal rating scale as:

– ‘Achieved’ (with subcategories: ‘a lot more’, ‘a little more’ or ‘as expected’), or

– ‘Not achieved’ (with subcategories: ‘partially achieved’, ‘no change’ or ‘got worse’)

– These verbal descriptions align with how clinicians normally think about and

describe goal attainment

– The verbal ratings were transcribed to the 5-point numerical scale (–2 to +2), and a

standard formula applied to derive an assimilated GAS T-score for each patient

[28].

RIGOUR - Steps to ensure validity of ULIS-II results

In view of the concerns raised about the use of GAS as noted above, a number of steps

were taken to ensure the validity of GAS as the primary outcome measure for ULIS-II, which

included:

• Selection of contributing centres.

• Training in SMART goal setting and the use of GAS prior to the study start.

• Within study validation of goal statements.

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• Establishment of an e-CRF with an inbuilt auditing facility for separation of Time 1

(baseline, before the BoNT-A treatment) and Time 2 (assessment after treatment cycle)

data.

Selection of contributing centres

Contributing centres were rigorously selected on the basis that:

• They demonstrated a reasonably high and consistent level of data recording and

outcome measurement as part of their routine clinical practice.

• They routinely collected at least one standardised measure of spasticity (Ashworth scale

or Tardieu scale).

• They were formally trained in the use of GAS prior to recruitment.

Training in SMART goal setting and the use of GAS

In preparation for the ULIS-II study, a comprehensive GAS training programme was carried

out across all participating centres. This programme not only educated clinicians who were

unfamiliar with the use of GAS, but also formed an essential part of the validation process for

the use of GAS in ULIS-II.

First, a common training programme was established, with a set of training tools,

including:

• The practical guide to GAS, outlining the GAS-Light method described above.[28]

(i) A set of standard training slides in the form of a Microsoft PowerPoint presentation.

(ii) A DVD of three case examples to illustrate goal setting and recording of goal attainment

in different scenarios.

(iii) A standard Microsoft Excel spreadsheet for recording goal ratings applying the formula

to derive a GAS T-score (as part of the learning process, this offered the opportunity for

the teams to calculate their mean T-scores, providing feedback on whether they were

over/under ambitious in their goal setting during the practice period).

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The training was organised through a series of national and regional workshops. A

network of regional trainers was established as the leads for GAS training within their

country/area. A series of initial ‘Train-the-trainer’ sessions was held to familiarise the local

trainers with the training materials and to ensure that they themselves were competent in the

use of GAS before training others. Thereafter, all investigators at the participating centres

attended GAS training (a total of 35 workshops) before recruiting patients.

Quality checks on goal setting

The ultimate focus of treatment for spasticity should be towards functional improvement,

even though this may be at the level of passive function (i.e. ease of caring for the affected

limb) as opposed to active function (i.e. active use of the limb in functional tasks). It is

therefore expected that the primary goal statements should be both SMART and function

related in the majority of cases.

If goals are set in an unbiased fashion so that the results exceed and fall short of

expectations in roughly equal proportions, the GAS T-score should be normally distributed at

around a mean of 50 with a standard deviation of around ± 10.[28] If a team attempts to

inflate their results by setting goals over-cautiously, the mean score will be >50. Similarly, if

they are consistently over ambitious, it will be <50. This provides a means for checking the

overall quality of goal setting.

Validation of GAS goal statements

As a further step to ensure the validity of GAS, an interim validation process was undertaken

part-way through the recruitment phase of the ULIS-II study. The purpose of this was to

check that clinicians were setting SMART function-related goals in accordance with the

training.

Goal statements for the primary goal in each patient were independently evaluated by

three lead clinical investigators (LTS, KF and JJ) in two rounds.[34] In Round 1 (September

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2010), 345 goals from 67 centres and in Round 2 (December 2010), 438 goals from 79

centres were evaluated.

Goal statements were examined on a centre-by-centre basis and investigators were

blinded to country and centre. They were assessed on two criteria: (i) the WHO ICF domain;

and (ii) the quality of the SMART description (Table 2). It was accepted that for some

patients, goal statements would be impairment related, e.g. prevention of contractures.

However, investigators expected that at least some goals from each centre would be related

to function. Some examples of SMART and non-SMART goals are shown in Table 3.

Table 2 Quality rating criteria for primary goal statements – WHO ICF domain and SMART

description used during ULIS-II validation process

Rating WHO ‘ICF’ domain, disability and

health

Example

A Some goal statements contain reference

to functional activities at the level of

disability or participation – may be

‘active’ or ‘passive’ function*

Reference to meaningful activities

such as ease of self-care, reduced

care burden, mobility, community-

based activities, work-related function,

etc

B Goal statements contain reference to

impairment only

Reference to movement, range, grip

strength, spasticity, clonus, etc

C Goal statements contain reference to

anatomical structures only

Reference to extension, flexion,

pronation, etc

Rating ‘SMART’ description Example

++ There is a SMART goal description,

sufficiently detailed and specific to make

accurate GAS rating

‘To be able to type a four-word

sentence with only a single typing error

using index fingers in 15 seconds’

+ There is some clear goal description ‘To be able to open and close hand, as

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sufficient to support GAS rating, but still

reliant on subjective interpretation

well as use fingers more in household

chores’

– No clear goal description ‘To use the hand more easily’

*‘Passive’ function includes tasks related to caring for the affected limb (whether by a carer or by the person

him/herself). ‘Active’ function refers to using the affected limb in some motor activity, preferably for an identified

functional purpose.

GAS, goal attainment scaling; ICF, International Classification of Functioning; SMART, specific, measurable,

achievable, realistic and timely; WHO, World Health Organization; ULIS, Upper Limb International Spasticity.

Table 3 Examples of SMART and function-related goals for GAS analysis

SMART goal statements Non-SMART goal statements

To ease passive upper body dressing

(< 25% assistance) 1 month after injection

To improve ease of dressing upper limb

Improve carry angle from 25° to 0° when

walking

Elbow extension

To reduce upper limb pain during rest and

passive range of motion (<4/10 on VAS)

1 month after injection

To improve pain

To relieve thumb in palm and ease nail

clipping (taking less than 20 minutes)

1 month after injection

Easier thumb and finger extensions

Sitting at the table, to grip fork and spoon to

move them to mouth and eat 1 month after

injection

To improve grasp and release function of

the hand

GAS, goal attainment scaling; SMART, specific, measurable, achievable, realistic and timely; VAS, visual

analogue scale.

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After independent evaluation, ratings were compared and an overall centre rating for the

WHO ICF domain (A, B or C) and SMART description (++, + or –) was reached by

consensus. Results were then fed back to centres. The goal was to have a rating of A+ or

A++. In order to improve quality of goal setting, centres with lower rates (B, C or –) were

invited to submit revised goal statements for those patients who had not yet received their

follow-up evaluation.

The results from the interim validation of GAS goal statements are shown in figure 3a. In

Round 1, 62.7% recorded function-related statements rated (‘A’ or ‘AB’) and 40.3% received

a SMART quality rating of ‘++’/‘+’. In Round 2, these figures rose to 70.9% and 46.8%,

respectively.

After the goal refinement process, 37 centres submitted revised goal statements (of

which 21 [56.8%] had improved their rating), and 12 centres (24%) had achieved a

maximum possible combined rating of ‘A++’. Even after this process, however, there was

residual heterogeneity between countries in the quality of goal setting, especially with

respect to ‘SMARTness’, as illustrated in figure 3b.

In any multicentre study reflecting real-life practice, one would expect a range of quality

in goal setting and we do not think that ULIS-II is unique in this respect. Therefore, we do not

plan to discard the goals that were not SMART from the primary analysis, but we will perform

a secondary analysis to examine the relationship between GAS and the quality of goal

setting, testing the hypothesis that goal achievement rates are lower for SMART goals. If a

significant difference is found, subset analyses will be conducted to correct for this.

Development of the e-CRF

A further purpose of ULIS-II was to develop and refine the e-CRF for capturing a

standardised dataset. In ULIS-I, we identified the most commonly used approaches to

recording assessment, treatment and outcome evaluation. Learning from this experience, we

addressed ways of reducing the information and making it understandable by investigators in

all countries. This was achieved through small international group workshop discussions with

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key investigators (including LTS, KF and JJ), followed by circulation and feedback on the

draft (CRF, prior to commencing development of the electronic version).

The e-CRF was presented in one language only (English) to avoid introducing variance

through translation. Investigators therefore needed to be adequately proficient in the English

language to complete the form, although goal statements could be completed in the native

language. Site monitors provided support for any interpretational queries. The e-CRF was

posted on the internet to facilitate access to all participating countries. It was developed on

customised software that supported electronic and interactive data collection, as well as

online edit checks to ensure data accuracy and quality. Wherever possible, it included

dropdown value lists and check-box options to minimise ambiguity, and it also provided

automated calculation of the GAS T-Score.

Separation of Time 1 and Time 2 data

In this before-and-after study, Time 1 acts as the ‘within patient’ control. GAS rating requires

the investigator to be able to view the goals set at Time 1, so it was important to maintain the

independence of Time 1 and Time 2 data as far as possible. The e-CRF software did not

have the facility to lock the Time 1 data prior to completion of the follow-up form, in order to

avoid the opportunity for retrospective changes. However, it did have an inbuilt tracking

facility. Site monitors were responsible for reviewing the tracking log to ensure that no post-

hoc changes were made that could have influenced outcome evaluation.

STRENGTHS AND LIMITATIONS

The study builds on others that have used goal attainment to evaluate outcome from

interventions for upper limb spasticity.[23-26] It will expand our understanding of the types of

goals that are and are not likely to be achieved following treatment with BoNT-A. Importantly,

it sets in train a methodology that is practical for use in routine clinical practice, which will be

used in future studies to expand the clinical dataset to one of sufficient size to interrogate for

answers to the important questions including the:

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(i) Identification and selection of patients most likely to benefit from treatment.

(ii) Most effective approaches to muscle selection, injection technique, etc.

(iii) Most useful approaches to outcome measurement.

Goal setting is a complex process, which requires skill and experience on the part of

investigators – both to coin the SMART goal description and also to be able to predict the

likely outcome of the intervention and its timescale. This study has emphasised the need for

training in consistent goal-setting techniques as highlighted in other studies.[24] Our interim

goal validation study was an important step to ensure the rigour of goal setting in

participating centres. In future ULIS studies, demonstration of competency in high quality,

unbiased goal setting will be an essential prerequisite for centre participation. We

recommend that future trials using GAS in this context should adopt a similarly robust

approach.

The strengths of our approach include the following:

• The wide international representation of participating centres captures experience of

clinicians from around the globe, ensuring the generalisability of results.

• The use of goal setting and GAS in this context emphasises the assessment of

outcomes that are important to the patient.

• The simplified approach to GAS enabled its application in clinical practice and supported

the negotiation of realistic expectations for outcome.

• The comprehensive GAS training programme allowed investigators unfamiliar with this

method to be educated in goal setting prior to starting the study.

• The interim validation process assisted participating centres to improve the quality and

function-related focus of goal statements, supporting the eventual validity of GAS as the

primary outcome measure for this and future ULIS studies At first sight this might be

regarded as ‘cheating’. However, SMARTening goal statements would, if anything,

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make goals harder to achieve. For example, the broad goal statement ‘to improve pain’,

would be achieved with any improvement, whilst the SMART equivalent ‘to reduce

upper limb pain during rest and passive range of motion (<4/10 on the visual analogue

scale [VAS]) 1 month after injection’, would only be achieved if the specified targets

were achieved.

Recognised limitations

(i) Limiting recruits to five to 12 per centre may have introduced some selection bias

through under-representation of less common presentations of spasticity.

(ii) The e-CRF was not locked after Time 1 data entry, allowing for the possibility of

retrospective alteration (of the goal statement only) at Time 2. Using the e-CRF auditing

facility, no cases were found in which goal statements were retrospectively adjusted at

Time 2. In future studies, it will be important to use software with a locking facility.

In this study, it was not feasible to record raw data for outcome measures other than GAS

and spasticity (MAS). Aside from this, investigators were simply asked to record which

measures they had used and whether the results were ‘the same’, ‘better’ or ‘worse’ than at

baseline. Given the long list of measures used, it was not feasible or appropriate to compute

all of them within the e-CRF. However, this information will allow us to identify those

measures that are sensitive to change in the responder population that will assist in the

selection of an appropriate and feasible battery of standardised measures to record

alongside GAS in future ULIS studies.

SUMMARY

The importance of the ULIS programme lies in its staged approach to development, which

both educates participating centres and ensures that the final core dataset will capture the

cultural diversity of clinical practice in the various different corners of the world in which it will

be used. ULIS-II is not the final step, but marks an important phase in the development of

the programme.

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Despite the recognised limitations at this stage of development, ULIS-II will provide a

unique and important set of information regarding the treatment and outcomes from BoNT-A

in real-life management of post-stroke upper limb spasticity worldwide. Through the process

described above, we have developed a methodology that will not only help to ensure

credibility of results from ULIS-II, but will also underpin future studies and inform other

clinical trials and cohort studies in this context.

ETHICS AND DISSEMINATION

• Marketing authorisation for the use of BoNT-A in this context was ensured for each

participating country prior to the start of the study.

• As the study was non-interventional it did not fall under the scope of the EU Directive

2001/20/EC of the European Parliament. It was conducted in compliance with

Guidelines for Good Pharmacoepidemiology Practices

(http://www.pharmacoepi.org/resources/guidelines_08027.cfm)

• To reflect real-life practice in this observational study, physicians were free to choose

BoNT-A treatment (targeted muscles, preparation, injected doses and number of points

and volume for each point in accordance with their usual practice, and with their local

Summary of Product Characteristics and therapeutic guidelines).

• Ethical approval and written informed consent was obtained prior to anonymous data

collection in countries where this was required and the study protocol was approved by

an independent ethics committee at each participating site.

• Data protection: All personal information were collected at the investigational site and

protected according to local data protection law. Patients were identifiable only by

patient ID at investigational site.

• The results will be presented at international meetings and published in peer-reviewed

journals.

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Acknowledgements

This study was supported by Ipsen Pharma. The authors would like to acknowledge the

editorial assistance of Ogilvy Healthworld.

Contributor statement

All authors were involved in the planning of the study.

LTS was the lead investigator and wrote the first draft of this manuscript. LTS, KF and JJ

were involved in data collection and assembly of data for goal validation, manuscript review

and critique, and final approval of manuscript.

BZ and PM were involved in the concept and design, data analysis, manuscript writing,

manuscript review and critique, and final approval of manuscript.

Funding statement

Ipsen Pharma provided financial support for this study. Financial support for manuscript

preparation was also provided through the Dunhill Medical Trust.

Competing interests:

LTS, KF and JJ all received honoraria and conference attendance fees from Ipsen for the

undertaking of this research.

• LTS has a specific interest in outcomes evaluation and has published extensively on the

use of goal attainment scaling in this context, as well as a number of the other

standardized measures (including the Associated Reaction Scale, the Arm Activity Scale

and the Neurological Impairment Scale). All of these tools are freely available, however,

and she has no personal financial interest in any of the material mentioned in this article.

• KF has a specific interest in outcomes evaluation and the use of the International

Classification of Function in clinical settings. He has no personal financial interest in any

of the material mentioned in this article.

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• JJ has particular interest in spasticity clinical and instrumental evaluation methods, goal

setting, treatment strategies/techniques and outcome measurement. He has no

personal or financial interest in any of the material mentioned in this paper.

• PM is an employee of Ipsen and BZ was an employee of Ipsen at the time of this study.

Data Sharing

No data is available for sharing.

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FIGURE LEGENDS

Figure 1 World map showing geographical distribution of participating centres in ULIS-II

ULIS, Upper Limb International Spasticity.

Figure 2 Flow chart for recruitment

Figure 3a Percentage of centres achieving high quality ratings in Rounds 1 and 2 during

validation of GAS statements

See Table 1 for description of WHO ICF domains A, B and C, and SMART descriptor ratings ++, +, –.

Figure 3b Median quality rating of final goal statements by participating country

Goal quality ratings were derived from the WHO ICF domain rating (A = 4, A/B = 3, B = 2, C = 1) and

the SMART rating (‘++’ = 4, ‘+’ = 3, ‘+/–’ = 2, ‘–’ = 1). Each centre was assigned two goal quality

ratings and the graph shows the medians for each participating country.

GAS, goal attainment scaling; ICF, International Classification of Functioning; SMART, specific,

measurable, achievable, realistic and timely; WHO, World Health Organization.

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Italy (n=6/33)

Austria (n=2/14)

Czech Republic (n=2/10)

Germany (n=6/45)

Finland (n=3/13)

Sweden (n=2/14)

Denmark (n=1/5)

Belgium (n=4/25)

UK (n=5/45)

France (n=14/48)

Portugal (n=5/27)

Spain (n=3/14)

Russia (n=7/41)

Mexico (n=2/10)

South Korea (n=5/29)

Taiwan (n=2/10)

Philippines (n=2/10)

Thailand (n=2/10)

China (n=1/5)

Malaysia (n=2/6)

Singapore (n=2/10)

Australia (n=6/44)n = number of centres/ number of patients recruited

7712039_(7413247)_ULIS_II_Centre_Locations.indd 1 19/04/2012 14:34

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Upper Limb International Spasticity Study: Rationale and protocol for a large, international, multicentre prospective

cohort study investigating management and goal attainment following treatment with botulinum toxin-A in

real-life clinical practice

Journal: BMJ Open

Manuscript ID: bmjopen-2012-002230.R1

Article Type: Research

Date Submitted by the Author: 08-Feb-2013

Complete List of Authors: Turner-Stokes, Lynne; Northwick Park Hospital, Regional Rehabilitation Unit Fheodoroff, Klemens; Gailtal-Klinik, Neurorehabilitation Jacinto, Jorge; Centro de Medicina de Reabilitaçãode Alcoitão, Serviço de Reabilitação de adultos 3 Maisonobe, Pascal; Ipsen Pharma, Biostatistics & Data Management Zakine, Benjamin; Ipsen Pharma, Global medical Affairs

<b>Primary Subject Heading</b>:

Rehabilitation medicine

Secondary Subject Heading: Neurology

Keywords: Rehabilitation, STROKE MEDICINE, MEDICAL EDUCATION & TRAINING


BMJ Open on A

ugust 27, 2020 by guest. Protected by copyright.

http://bmjopen.bm

j.com/

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J Open: first published as 10.1136/bm

jopen-2012-002230 on 18 March 2013. D

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1

Upper Limb International Spasticity Study: Rationale and protocol for a large, international,

multicentre prospective cohort study investigating management and goal attainment following

treatment with botulinum toxin-A in real-life clinical practice

Lynne Turner-Stokes,1 Klemens Fheodoroff,

2 Jorge Jacinto,

3 Pascal Maisonobe,

4 Benjamin Zakine

4

1Cicely Saunders Institute, School of Medicine, King’s College London, London, UK,

2Neurorehabilitation, Gailtal-Klinik, Hermagor, Austria,

3Centro de Medicina de Reabilitaçãode Alcoitão, Serviço de Reabilitação de adultos 3, Estoril,

Portugal

4Medical Affairs, Ipsen Pharma, 65 Quai Georges Gorse, Boulogne-Billancourt 92100, France

Correspondence: Lynne Turner-Stokes, Regional Rehabilitation Unit, Northwick Park Hospital,

Watford Road, Harrow, Middlesex, HA1 3UJ, UK. E-mail: [email protected];

Tel: +44 (0)-208-869-2800; Fax+44 (0)-208-869-2803



rehabilitation.



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“The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf

of all authors, an exclusive licence (or non-exclusive for UK Crown Employees) on a worldwide basis

to the BMJ Publishing Group Ltd, and its Licensees to permit this article (if accepted) to be published

in BMJ Open and any other BMJPGL products and to exploit all subsidiary rights, as set out in our

licence.”


Poster presentation, ‘Validation of individual person-centred goal statements for goal attainment

scaling (GAS) in a large international cohort study of botulinum toxin-A (BoNT-A) for upper limb

spasticity following stroke: The Upper Limb International Spasticity Study (ULIS-II)’ at the American

Academy of Physical Medicine and Rehabilitation, 17–20 November, 2011. Poster 269.

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ABSTRACT

Objectives: This article provides an overview of the Upper Limb International Spasticity (ULIS)

programme, which aims to develop a common core dataset for evaluation of real-life practice and

outcomes in the treatment of upper limb spasticity with botulinum toxin-A (BoNT-A). Here we

present the study protocol for ULIS-II, a large, international cohort study, to describe the rationale

and steps to ensure validity of goal attainment scaling (GAS) as the primary outcome measure.

Methods and analysis: Design: An international, multicentre, observational, prospective, before-

and-after study, conducted at 84 centres in 22 countries across three continents.

Participants: Four hundred and sixty-eight adults presenting with post-stroke upper limb spasticity

in whom a decision had already been made to inject BoNT-A, (5–12 consecutive subjects recruited

per centre).

Interventions: Physicians were free to choose targeted muscles, BoNT-A preparation, injected

doses/technique, and timing of follow-up in accordance with their usual practice and the goals for

treatment. Primary outcome measure: GAS. Secondary outcomes: measurements of spasticity,

standardised outcome measures and global benefits.

Steps to ensure validity included: a) Targeted training of all investigators in the use of GAS; b)

Within-study validation of goal statements; and c) Establishment of an electronic case report form

with an in-built tracking facility for separation of baseline/follow-up data.

Analysis: Efficacy population: all subjects who had a) BoNT-A injection; and b) subsequent

assessment of GAS. Primary efficacy variable: percentage (95% confidence interval) achievement of

the primary goal from GAS following one BoNT-A injection cycle.

Ethics and dissemination: This non-interventional study is conducted in compliance with Guidelines

for Good Pharmacoepidemiology Practices. Appropriate ethical approvals were obtained according

to local regulations. ULIS-II will provide important information regarding treatment and outcomes

from BoNT-A in real-life upper limb spasticity management. The results will be published separately.


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ARTICLE SUMMARY

Article focus

• To provide an overview of the Upper Limb International Spasticity (ULIS) programme and the

rationale and protocol of the ULIS-II study.

• To outline the steps taken in ULIS-II to ensure the quality of goal statements and support the

validity of goal attainment scaling (GAS) as the primary outcome measure for the trial.

Key messages

• Evaluation of goals statements part-way through this study has assisted participating centres

to improve the quality and function-related focus of goal statements


• This methodology helps to support the validity of GAS as the primary outcome measure for

the efficacy analysis.

• This large international cohort study represents a diverse sample of practice across three

continents.

• However, the limited number of subjects per centre (5–12) could lead to some selection

bias.

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INTRODUCTION

Spasticity is a common sequela of stroke, with an incidence ranging from 17% to 38%.[1-5] It is more

prevalent in younger patients,[2] and most commonly affects the upper limb.[6]

Upper limb spasticity is often painful. It interferes with upper limb movement, and limits use of the

limb for active functional tasks. It can cause involuntary movements (associated reactions) that

impact on mobility (gait, balance, walking speed, etc). In severe cases, it can also impede ‘passive

function’, such as washing, dressing and caring for the affected limb, therefore increasing the burden

on caregivers.[7 8]

There is now a well-established body of evidence demonstrating that botulinum toxin-A (BoNT-A) is

a well-tolerated and effective focal intervention for the reduction of spasticity, and it is widely

recommended for use in standard clinical practice.[7-9] Controlled clinical trials (CCTs)[10-18] have

confirmed the benefits of BoNT-A at the level of impairment, but functional change has been harder

to demonstrate, particularly where impact on active function is limited by underlying motor

dysfunction. Nevertheless, on an individual level, clinical experience suggests that some patients

make substantial functional gains.

Whilst CCTs may be helpful for establishing the overall clinical efficacy of an intervention, they do

not answer important clinical questions such as which patients are most likely to benefit and in what

way; or which treatment approaches work best in real-life clinical care. For these, we need large,

multicentre, longitudinal, cohort studies conducted in the course of routine clinical practice.[19] If

the findings are to be generalisable across different health cultures, these studies need to have wide

geographical representation across the international health community.

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Measuring the effectiveness of BoNT-A treatment is challenging in the context of upper limb

spasticity because of wide diversity in patient presentation, potential for rehabilitation, and goals for

treatment. Timing of assessment is also important due to the need for time to practice and develop

new skills in the hemiparetic arm after the spasticity has been relieved.[20, 21] Current guidelines

for the use of BoNT-A in the management of spasticity advocate the application of focused outcome

evaluations, targeted on the attainment of priority goals that are both relevant to the treatment

intentions and important to the individual.[7, 8] Depending on the nature of the goals set, the

individual clinical presentation and any underlying trajectory towards recovery or deterioration, the

timescale for expected goal achievement will vary from person to person. Cohort study design in this

context must therefore be flexible enough to account for all this variation.

Goal attainment scaling (GAS) is a method of assimilating achievement of a number of individually

set goals into a single ‘goal attainment score’, in order to capture outcomes across a diverse range of

goal areas. Originally described by Kiresuk and Sherman in the 1960s,[22] it is increasingly

recognised as a sensitive method for recording patient-centred outcomes in this context.[23-26] In

addition to providing a semi-quantitative (ordinal) assessment of goal attainment, GAS offers

potentially useful qualitative information regarding the patient’s priority goals for treatment.

Moreover, the process of goal setting and rating itself offers an opportunity for dialogue and

negotiation between the patient and the treating team,[27] which may help to establish mutual

agreement of expectations for outcome. However, this requires knowledge and experience, and it is

important to recognise that GAS is not a measure of outcome per se, but a measure of the

achievement of intention. It therefore does not replace standardised measures, but is a useful

adjunct to use alongside them.[28]

The use of GAS as a primary outcome measure for research is still somewhat controversial. Concerns

have been raised in some quarters about the validity of GAS; in particular, the non-linearity of the

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scaling and lack of uni-dimensionality,[29] and some authors have proposed the development of

standardised goals or ‘item banks’.[29 30] The World Health Organization (WHO) International

Classification of Functioning, Disability and Health (ICF)[31] provides a useful common language for

categorising goals into different domains of personal experience. A previous secondary analysis of a

multicentre CCT from Australia[24] mapped a total of 165 goals onto ICF domains, to identify the key

goal areas impacting on quality of life, in order to inform the future development of standardised

goal sets. The authors recommended that further research with a priori categorisation of goals in

large, prospective, cohort studies is required to describe the full value of BoNT-A in the management

of upper limb spasticity.

From the studies conducted to date, we know that there is considerable individual variation in

response. We also know that there is variation in treatment with respect to selection of muscle,

injection technique, and concomitant therapy interventions (e.g. physiotherapy and/or occupational

therapy), and that these appear to have more to do with clinician bias and local availability of

services than with patient presentation.[32] It is now time to extend the field of investigation in this

area to explore how BoNT-A is used in routine clinical practice, in order to gain a better

understanding of how to select those most likely to respond and what works best for which types of

presentation. Horn and Gassaway (2007) argue that this type of ‘practice-based evidence’ is as

important it its own way for building the evidence base for clinical practice as the information that

derives from CCTs.[33]

To do this, however, we will need to build a consistent body of data that captures clinically

important changes at an individual level and is of sufficient size and generalisability to interrogate

for future answers to these critical questions. The challenge lies in how to engage clinicians across

the globe, to engage in a single common approach to data collection.

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The Upper Limb International Spasticity (ULIS) study programme represents the first steps towards

this aim. This manuscript provides an overview of the programme and presents the rationale and

protocol for the ULIS-II study. The study results for ULIS-II will be presented separately.


The ULIS programme consists of a series of international, observational studies to describe current

clinical practice in the application of BoNT-A in the management of upper limb spasticity. The

ultimate aim is to work towards the development of a common core dataset for prospective

systematic recording of longitudinal outcomes that could inform development of a large,

international database of sufficient size and breadth to support future interrogation and subset

analysis.

A founding principle of establishing common datasets is to embed them as closely as possible in

real-life current clinical practice.

• The first stage of the programme (ULIS-I) [34] was an international, cross-sectional, survey,

which was designed to document clinical practice across four continents with respect to



observational, cohort study to record goal attainment as a primary outcome following one cycle

of BoNT-A. This has also served to develop expertise in GAS and refine an electronic case report

form (e-CRF). ULIS-II has recently completed recruitment and is now in the process of analysis.

• Following further refinement of the dataset and tools, a third stage is planned to expand the

cohort, and to capture the broader benefits of treatment in a fully generalisable sample

recorded longitudinally over several cycles of treatment. This is currently in the planning and

pre-investigation phase.

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ULIS-I was an international, cross-sectional, non-interventional survey to document (from review of

current practice and reported intentions) the clinical profiles, treatment goals and reported outcome

evaluation in consecutive adults attending treatment with BoNT-A for upper limb spasticity.[34]

Over a 6-month period, a total of 974 consecutive patients were recruited from 122 investigational

centres in 31 countries spanning the European Union, Pacific Asia, Eastern Europe, the Middle East

and South America.

The findings demonstrated wide diversity in clinical practice with respect to both the method of

intervention and the use of assessment and outcome measures.[34] Most frequently recorded were

impairment measures, including range of movement (90%) and spasticity – mainly using the

Modified Ashworth Scale (MAS) (83%). Although 36% said they routinely recorded at least one

measure of active function, there was wide variation in the instruments used and insufficient

commonality to allow pooling of data.

Goal setting on the other hand was very common (78%). However, although the large majority of

clinicians reported that they set goals, the way by which they used these to monitor the effects of

treatment varied widely. Formal application of GAS was used by only a handful of participating

centres (5%).

The findings suggested that goal attainment offered the most widely applicable common outcome

measure, and for this reason, it was selected as the principal outcome measure for the next stage of

the programme (ULIS-II). However, it was first necessary to establish a consistent approach to the

recording of goals and goal attainment. It was also important that the method was simple and

practical to apply across the wide international spectrum of clinical practice in upper limb spasticity

management.

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Study objectives

The primary objective of the ULIS-II study was to assess the responder rate (as defined by the

achievement of the primary goal from GAS) following one BoNT-A injection cycle delivered in the

context of routine clinical practice.


• Describe the baseline characteristics, including (but not limited to) demographics, duration and

pattern of spasticity, concomitant therapies/medication.

• Describe injection practices (muscle identification, dosage, dilution and injection points) and

additional treatment strategies – including therapy intervention and different types of modality.

• Assess the achievement of secondary goals and the overall attainment of treatment goals using

the GAS T-score.


• Assess the global benefits as perceived by the investigator and the patient (or guardian).

Exploratory objectives, addressed through the analysis plan, were to:

• Describe the common goal areas for treatment and to identify those in which goals were most

often achieved.

• Identify any prognostic factors for response.


ULIS-II was an 18-month, post-marketing, international, multicentre, observational, prospective,

longitudinal study, conducted in 84 centres in 22 countries (European Union, Pacific Asia, Eastern

Europe and South America). Figure 1 shows the geographical distribution of participating centres.

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Study participants


• Adults ≥18 years with post-stroke upper limb spasticity in whom a decision had already been

made to inject BoNT-A.




Recruitment

To limit the potential bias that might be introduced by over-recruiting sites, the number of patients

was limited to 5–12 patients per treatment centre. Participating centres represented a range of

experience to mirror clinical practice. However, in order to capture the approaches to treatment

that are borne of clinical experience, recruitment at less experienced centres (n=59) was restricted

to five patients only, whilst more experienced centres (n=25) could recruit up to 12 patients. This

approach also offers the potential for future sub-analysis of the differences between experienced

and less experienced injectors.

Centres were asked to include consecutive patients attending the clinics over a specified period. If

consecutive inclusions were not feasible (e.g. due to administrative constraints in a busy clinic

setting), investigators were authorised to space the inclusions (e.g. one per every two to three

patients), until their recruitment target was achieved.

A total of 468 patients were recruited, 226 in more experienced (48.3%) and 242 in (51.7%) less

experienced centres, confirming more or less equal distribution. Figure 2 shows the disposition of

patients and Table 1 shows the breakdown by country, including completion rates. The 12-case

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attrition was primarily in Europe, but did not significantly affect geographic representation as the

European countries were the best represented to start with.

Table 1: Recruitment and attrition by country

Country No of

centres

Total

recruits Attrition

No cases

completed

(Efficacy

population)

% of total

efficacy

population*

Europe

Austria 2 14 0 14 3

Belgium 4 25 1 24 5

Czech Rep 2 10 0 10 2

Denmark 1 5 0 5 1

Finland 3 13 1 12 3

France 14 48 1 47 10

Germany 6 45 2 43 9

Italy 6 33 2 31 7

Portugal 5 27 0 27 6

Russia 7 41 0 41 9

Spain 3 14 0 14 3

Sweden 2 14 0 14 3

UK 5 45 4 41 9

60 334 11 (3.3%) 323 70%

Pacific Asia

South Korea 5 29 1 28 6

Singapore 2 10 0 10 2

Taiwan 2 10 0 10 2

Australia 6 44 0 44 10

China 1 5 0 5 1

Malaysia 2 6 0 6 1

Philippines 2 10 0 10 2

Thailand 2 10 0 10 2

22 124 1 (0.8%) 123 27%

South

America

Mexico 2 10 0 10 2

2 10 0 10 2%

n=22 n=84 n=468 n=12 (2.6%) n=456

*Due to rounding, percentages may not total 100%.

Table 2 shows the demographics of the efficacy population who completed the study per protocol.

Table 2: Demographics of the efficacy population

Parameter Values Range N / missing or

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untestable

Age (years)

Mean (SD)

56.7 (13.5)

18–88

456 / 0

Time since onset of stroke (months)

Mean (SD)

61.4 (69.1)

1–447

456 / 0

Gender, n (%)

Male

Female

266 (58.3%)

190 (41.7%)

456 / 0

Aetiology, n (%)

Infarct

Haemorrhage

Both

320 (70.2%)

139 (30.5%)

3 (0.7%)

456 / 0

Location of CVA, n (%)

Left hemisphere

Right hemisphere

Bilateral*

Posterior circulation

215 (47.1%)

235 (51.5%)

4 (0.9%)

13 (2.9%)

456 / 0

Study schedule


On inclusion into the study the following assessments were recorded by the investigator on the e-

CRF:

• Demography and history of the stroke including type, location and time since onset (Table 2).



(including cognitive, emotional and behavioural function) were recorded using a modified

version of the Neurological Impairment Scale.[35]

• Previous/concomitant treatments for upper limb spasticity, including therapies and medication.

• Clinical examination, including a list of measurements of spasticity and other standardised

outcome measures, as routinely performed in that centre e.g.:

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– Visual analogue and verbal rating scales for symptoms such as pain, ease of care, etc

– Standardised scales for active and/or passive function (e.g. the Leeds Adult Spasticity

Impact Scale[11] or the Arm Activity scale[36, 37])


• Goal-setting and GAS was applied using the ‘GAS-light’ method [28] as detailed below with

emphasis on setting SMART (specific, measurable, achievable, realistic and timed) goals agreed

between investigator, the patient and the treating team. One primary and up to three

secondary goals were set and assigned to one of seven goal categories.

Injection of BoNT-A

To reflect real-life practice in this non-interventional observational study, physicians were free to

choose targeted muscles, BoNT-A preparation, injected doses, number of points and volume for

each point, and use of EMG/electrical stimulation in accordance with their usual practice, local

Summary of Product Characteristics and therapeutic guidelines.


The timing of follow-up was at the discretion of the investigator, based on their usual practice and

the nature of the goals set – usually between Months 3–5 after injection. At Time 2 (end of study),

the following were recorded:

• Achievement of primary and secondary GAS goals rated on a 6-point verbal rating scale, and

transcribed within the computer software to the 5-point numerical scale (range –2 to +2), and

the GAS T-score (see details below).

• Any concomitant treatments for upper limb spasticity given since baseline.

• Clinical examination including measurements of spasticity as normally routinely performed.

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benefit’; ‘some benefit’; ‘same’; ‘worse’; or ‘much worse’.

• Change on any standardised measures performed was recorded on the same 5-point scale. (This

was for pragmatic reasons as it was not possible to accommodate the wide range of

standardised measures that were used by different centres on the electronic case report form

(e-CRF) without making it unwieldy).

• Related adverse events (AEs): as this was a non-interventional study, this followed the standard

regulations for reporting of related spontaneous AEs within each country.

• The next therapeutic strategy – including information on any planned re-injection with BoNT-A –

whether using the same agent and protocol or an adjusted one.


The sample size calculation was based upon an estimate that 60% of patients would achieve their

primary goal following their first BoNT-A injection cycle. Using a 0.05 two-sided significance level,

with a power of 80%, 450 patients were needed to allow estimation of this proportion with a

precision of 4.5%. This sample size also allowed the detection of potential prognostic factors to

response (based on detection of odds ratio larger or equal to two).

Analysis

Statistical evaluations will be performed using Statistical Analysis System (SAS)® (version 8 or later

versions).

All analyses will be conducted on the efficacy population that includes all subjects who received one

BoNT-A injection and who underwent a post-injection visit including an assessment of the GAS. For

the primary statistical analysis, ‘Responders’ are those who achieve their primary goal (GAS score 0,

1 or 2) (primary statistical analysis). Patient demographics, baseline characteristics and efficacy

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evaluations for secondary variables will be presented as descriptive statistics, including 95%

confidence intervals where relevant.

Relationships between GAS T-scores and other measures of outcome (e.g. measures of spasticity,

global benefit and other standardised measures) will be examined using Spearman rank correlation

coefficients. Stepwise logistic regression modelling will be used to identify potential prognostic

factors for response including the duration of spasticity, time interval to follow-up, presence of

confounding factors (including contractures, impaired cortical function, etc) and provision of

concomitant therapy.

Descriptive analysis will also be carried out to evaluate any possible country effect, if considered

relevant.


We used the simplified ‘GAS-Light’ approach described by Turner-Stokes,[28] which is based on the

original method described by Kiresuk and Sherman,[22] but designed to be timely and practical for

use in a busy clinic setting. The GAS-Light method uses a verbal rating scale, which reflects the way

clinicians usually record goals in routine practice. Verbal ratings are then translated into the 5-point

numerical scales as shown in Figure 3.

• At the baseline visit, the investigator (in conjunction with their multidisciplinary team where

possible) interviewed the patient and identified the main problem areas. An agreed set of goals

(one primary and up to three secondary goals) was defined.

• A single SMART goal statement was recorded in the free text box of the e-CRF to describe the

intended outcome for each goal (as opposed to predefining levels for each score).

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• Each primary and secondary goal was assigned to one of seven pre-defined goal categories

(‘pain’, ‘passive function’, ‘active function’, ‘mobility’ [balance, gait], ‘involuntary movement’

[associated reaction], ‘impairment’ [e.g. range of movement] and ‘other’).

• There was an option to weight goals for importance to the patient and/or family on a scale of 0

= not at all, 1 = a little, 2 = moderately, and 3 = very important.[28] If no goal weighting was

recorded, a default value of 1 was entered.

o A baseline score was chosen for each goal as either ‘some function’ (−1) or ‘no function’ (as bad

as they could be; −2).



• Attainment was rated on a 6-point verbal rating scale and transcribed to the 5-point GAS

numerical scale (−2 to +2), depending on the baseline rating as shown in Figure 3. [39]

• A composite GAS T-score for each patient was then derived from the product of their individual

goal achievement scores x goal weighting, using the following standard formula described by

Kiresuk and Sherman:[22]

• The overall GAS T-score was calculated by the following formula:

RIGOUR – Steps to ensure validity of ULIS-II results

In view of the concerns raised about the use of GAS as noted in the introduction, a number of steps


included:


T-Score = 50 + 10 x Σ(wi xi)

√(0.7 Σwi2

+ 0.3(Σwi) 2

)

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• Within-study validation of goal statements.

• Establishment of an e-CRF with an inbuilt auditing facility for separation of Time 1 (baseline,

before the BoNT-A treatment) and Time 2 (assessment after treatment cycle) data.



• They demonstrated a reasonably high and consistent level of data recording and outcome

measurement as part of their routine clinical practice.

• They routinely collected at least one standardised measure of spasticity (Ashworth scale or

Tardieu scale).



In preparation for the ULIS-II study, a comprehensive GAS training programme was carried out

across all participating centres. This programme not only educated clinicians who were unfamiliar

with the use of GAS, but also formed an essential part of the validation process for the use of GAS in

ULIS-II.

First, a common training programme was established, with a set of training tools, including:



(ii) A DVD of three case examples to illustrate goal setting and recording of goal attainment in

different scenarios.

(iii) A standard Microsoft Excel spreadsheet for recording goal ratings applying the formula to

derive a GAS T-score (as part of the learning process, this offered the opportunity for the

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teams to calculate their mean T-scores, providing feedback on whether they were


Further information about the GAS-light method, including copies of the practical guide and GAS T-

score calculator may be found on the Cicely Saunders Institute website http://www.csi.kcl.ac.uk/gas-

tool.html.

The training was organised through a series of national and regional workshops. A network of

regional trainers was established as the leads for GAS training within their country/area. A series of

initial ‘Train-the-trainer’ sessions was held to familiarise the local trainers with the training materials

and to ensure that they themselves were competent in the use of GAS before training others.

Thereafter, all investigators at the participating centres attended GAS training (a total of 35

workshops) before recruiting patients.


The ultimate focus of treatment for spasticity should be towards functional improvement, even

though this may be at the level of passive function (i.e. ease of caring for the affected limb) as

opposed to active function (i.e. active use of the limb in functional tasks). It is therefore expected

that the primary goal statements should be both SMART and function-related in the majority of

cases.

If goals are set in an unbiased fashion so that the results exceed and fall short of expectations in

roughly equal proportions, the GAS T-score should be normally distributed at around a mean of 50

with a standard deviation of around ±10.[28] If a team attempts to inflate their results by setting

goals over-cautiously, the mean score will be >50. Similarly, if they are consistently over ambitious, it

will be <50. This provides a means for checking the overall quality of goal setting.

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As a further step to ensure the validity of GAS, an interim validation process was undertaken part-

way through the recruitment phase of the ULIS-II study. The purpose of this was to check that

clinicians were setting SMART function-related goals in accordance with the training.

Goal statements for the primary goal in each patient were independently evaluated by three lead

clinical investigators (LTS, KF and JJ) in two rounds.[40] In Round 1 (September 2010), 345 goals from

67 centres and in Round 2 (December 2010), 438 goals from 79 centres were evaluated.

Goal statements were examined on a centre-by-centre basis and investigators were blinded to

country and centre. They were assessed on two criteria: (i) the WHO ICF domain; and (ii) the quality

of the SMART description (Table 3). It was accepted that for some patients, goal statements would

be impairment related, e.g. prevention of contractures. However, investigators expected that at

least some goals from each centre would be related to function. Some examples of comparative

SMART and non-SMART goals are shown in Table 4.

Table 3: Quality rating criteria for primary goal statements – WHO ICF domain and SMART


Rating WHO ‘ICF’ domain, disability and health Example

A Some goal statements contain reference to

functional activities at the level of disability

or participation – may be ‘active’ or ‘passive’

function*

Reference to meaningful activities such as

ease of self-care, reduced care burden,

mobility, community-based activities,

work-related function, etc


impairment only



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pronation, etc




accurate GAS rating

‘To be able to type a four-word sentence

with only a single typing error using index

fingers in 15 seconds’

+ There is some clear goal description



‘To be able to open and close hand, as


chores’


* ‘Active’ function refers to using the affected limb in some motor activity, preferably for an

identified functional purpose. ‘Passive’ function includes tasks related to caring for the affected limb

(whether by a carer or by the person him/herself).


measurable, achievable, realistic and timed; WHO, World Health Organization; ULIS, Upper Limb

International Spasticity.

Table 4: Examples of SMART and function-related goals for GAS analysis





Improve carry angle from 25° to 0° when walking

by 1 month after injection

Elbow extension

To reduce upper limb pain during rest and passive

range of motion (<4/10 on VAS) 1 month

after injection

To improve pain

To relieve thumb in palm and ease nail clipping

(taking less than 20 minutes) 1 month

after injection


Sitting at the table, to grip fork and spoon to move

them to mouth and eat 1 month after injection

To improve grasp and release function of the

hand

GAS, goal attainment scaling; SMART, specific, measurable, achievable, realistic and timed; VAS,

visual analogue scale.

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After independent evaluation, ratings were compared and an overall centre rating for the WHO ICF

domain (A, B or C) and SMART description (++, + or –) was reached by consensus. Results were then

fed back to centres. The goal was to have a rating of A+ or A++. In order to improve quality of goal

setting, centres with lower rates (B, C or –) were invited to submit revised goal statements for those

patients who had not yet received their follow-up evaluation.

The results from the interim validation of GAS goal statements are shown in Figure 4a. In Round 1,

62.7% recorded function-related statements rated (‘A’ or ‘AB’) and 40.3% received a SMART quality

rating of ‘++’/‘+’. In Round 2, these figures rose to 70.9% and 46.8%, respectively.

After the goal refinement process, 37 centres submitted revised goal statements (of which 21

[56.8%] had improved their rating), and 12 centres (24%) had achieved a maximum possible

combined rating of ‘A++’. Even after this process, however, there was residual heterogeneity

between countries in the quality of goal setting, especially with respect to ‘SMARTness’, as

illustrated in Figure 4b.

In any multicentre study reflecting real-life practice, one would expect a range of quality in goal

setting and we do not think that ULIS-II is unique in this respect. Therefore, we do not plan to discard

the goals that were not SMART from the primary analysis, but we will perform a secondary analysis

to examine the relationship between GAS and the quality of goal setting, testing the hypothesis that

goal achievement rates are lower for SMART goals (see below). If a significant difference is found,

subset analyses will be conducted to correct for this.


A further purpose of ULIS-II was to develop and refine the e-CRF for capturing a standardised

dataset. In ULIS-I, we identified the most commonly used approaches to recording assessment,

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treatment and outcome evaluation. Learning from this experience, we addressed ways of reducing

the information and making it understandable by investigators in all countries. This was achieved

through small international group workshop discussions with key investigators (including authors

LTS, KF and JJ), followed by circulation and feedback on the draft (case report form, prior to

commencing development of the electronic version).

The e-CRF was presented in one language only (English) to avoid introducing variance through

translation. Investigators therefore needed to be adequately proficient in the English language to

complete the form, although goal statements could be completed in the native language. Site

monitors provided support for any interpretational queries. The e-CRF was posted on the internet to

facilitate access to all participating countries. It was developed on customised software that

supported electronic and interactive data collection, as well as online edit checks to ensure data

accuracy and quality. Wherever possible, it included dropdown value lists and check-box options to

minimise ambiguity, and it also provided automated calculation of the GAS T-Score.


In this before-and-after study, Time 1 acts as the ‘within patient’ control. GAS rating requires the

investigator to be able to view the goals set at Time 1, so it was important to maintain the

independence of Time 1 and Time 2 data as far as possible. The e-CRF software did not have the

facility to lock the Time 1 data prior to completion of the follow-up form, which would have

prevented the opportunity for retrospective changes. However, it did have an inbuilt tracking facility.

Site monitors were responsible for reviewing the tracking log to ensure that no post-hoc changes

were made that could have influenced outcome evaluation.


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The study builds on others that have used goal attainment to evaluate outcome from interventions

for upper limb spasticity.[23-26] It will expand our understanding of the types of goals that are and

are not likely to be achieved following treatment with BoNT-A. Importantly, it sets in train a

methodology that is practical for use in routine clinical practice, which will be used in future studies

to expand the clinical dataset to one of sufficient size to interrogate for answers to the important

questions including:

(i) The identification and selection of patients most likely to benefit from treatment.

(ii) The most effective approaches to muscle selection, injection technique, etc.

(iii) The most useful approaches to outcome measurement.

Goal setting is a complex process, which requires skill and experience on the part of investigators –

both to coin the SMART goal description and also to be able to predict the likely outcome of the

intervention and its timescale. This study has emphasised the need for training in consistent goal-

setting techniques as highlighted in other studies.[24] Our interim goal validation study was an

important step to ensure the rigour of goal setting in participating centres. In future ULIS studies,

demonstration of competency in high quality, unbiased goal setting will be an essential prerequisite

for centre participation. We recommend that future trials using GAS in this context should adopt a

similarly robust approach.


• The wide international representation of participating centres captures experience of clinicians

from around the globe, ensuring the generalisability of results.

• The use of goal setting and GAS in this context emphasises the assessment of outcomes that are

important to the patient.

• The simplified approach to GAS enabled its application in clinical practice and supported the

negotiation of realistic expectations for outcome.

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• The comprehensive GAS training programme allowed investigators unfamiliar with this method

to be educated in goal setting prior to starting the study.



primary outcome measure for this and future ULIS studies. At first sight this might be regarded

as ‘cheating’. However, SMARTening goal statements would, if anything, make goals harder to

achieve. For example, the broad goal statement ‘to improve pain’, would be achieved with any

improvement, whilst the SMART equivalent ‘to reduce upper limb pain during rest and passive

range of motion (<4/10 on the visual analogue scale [VAS]) 1 month after injection’, would only

be achieved if the specified targets were achieved.


(i) Limiting recruits to 5–12 per centre may have introduced some selection bias through under-

representation of less common presentations of spasticity.

(ii) The e-CRF was not locked after Time 1 data entry, allowing for the possibility of retrospective

alteration (of the goal statement only) at Time 2. Using the e-CRF auditing facility, no cases

were found in which goal statements were retrospectively adjusted at Time 2. In future studies,

it will be important to use software with a locking facility.

In this study, it was not feasible to record raw data for outcome measures other than GAS and

spasticity (MAS). Aside from this, investigators were simply asked to record which measures they

had used and whether the results were ‘the same’, ‘better’ or ‘worse’ than at baseline. Given the

long list of measures used, it was not feasible or appropriate to compute all of them within the e-

CRF. However, this information will allow us to identify those measures that are sensitive to change

in the responder population, which will assist in the selection of an appropriate and feasible battery

of standardised measures to record alongside GAS in future ULIS studies.

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SUMMARY

The importance of the ULIS programme lies in its staged approach to development, which both

educates participating centres and ensures that the final core dataset will capture the cultural

diversity of worldwide clinical practices in which it will be used. ULIS-II is not the final step, but marks

an important phase in the development of the programme.

Despite the recognised limitations at this stage of development, ULIS-II will provide a unique and

important set of information regarding the treatment and outcomes from BoNT-A in real-life

management of post-stroke upper limb spasticity worldwide. Through the process described above,

we have developed a methodology that will not only help to ensure credibility of results from ULIS-II,

but will also underpin future studies and inform other clinical trials and cohort studies in this

context.





2001/20/EC of the European Parliament. It was conducted in compliance with Guidelines for

Good Pharmacoepidemiology Practices


• To reflect real-life practice in this observational study, physicians were free to choose BoNT-A

treatment (targeted muscles, preparation, injected doses and number of points and volume for

each point in accordance with their usual practice, and with their local Summary of Product

Characteristics and therapeutic guidelines).

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• Ethical approval and written informed consent was obtained prior to anonymous data collection

in countries where this was required and the study protocol was approved by an independent

ethics committee at each participating site.

• Data protection: All personal information was collected at the investigational site and protected

according to local data protection law. Patients were identifiable only by patient ID at

investigational site.

• The results will be presented at international meetings and published in peer-reviewed journals.

Acknowledgements

This study was supported by Ipsen Pharma. The authors would like to also acknowledge the editorial

assistance of Suzanne Patel at Ogilvy Healthworld in the preparation of the manuscript.



LTS was the lead investigator and wrote the first draft of this manuscript. LTS, KF and JJ were

involved in data collection and assembly of data for goal validation, manuscript review and critique,

and final approval of manuscript.

BZ and PM were involved in the concept and design, data analysis, manuscript writing, manuscript

review and critique, and final approval of manuscript.

Funding statement

Ipsen Pharma provided financial support for this study. Financial support for manuscript preparation

was also provided through the Dunhill Medical Trust.

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LTS, KF and JJ all received honoraria and conference attendance fees from Ipsen for the undertaking

of this research.

• LTS has a specific interest in outcomes evaluation and has published extensively on the use of

goal attainment scaling (GAS) in this context, as well as a number of the other standardised

measures (including the Associated Reaction Rating Scale, the Arm Activity Scale and the

Neurological Impairment Scale). All of these tools are freely available, however, and she has no

personal financial interest in any of the material mentioned in this article.

• KF has a specific interest in outcomes evaluation and the use of the International Classification

of Function in clinical settings. He has no personal financial interest in any of the material

mentioned in this article.


setting, treatment strategies/techniques and outcome measurement. He has no personal or

financial interest in any of the material mentioned in this article.


Data Sharing


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39. Turner-Stokes L, Williams H. Goal attainment scaling: a direct comparison of alternative rating

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FIGURE LEGENDS




Figure 3 Converting the GAS-light verbal scoring system to a numerical 5-point scale (-2 to +2)

The verbal descriptions align with how clinicians normally think about and describe goal attainment.

They allow goal attainment to be recorded without reference to the numeric scores, and so avoid the

perceived negative connotations of zero and minus scores.

Figure 4a Percentage of centres achieving high quality ratings in Rounds 1 and 2 during validation

of GAS statements







measurable, achievable, realistic and timed; WHO, World Health Organization.

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Upper Limb International Spasticity Study: Rationale and protocol for a large, international,

multicentre prospective cohort study investigating management and goal attainment following

treatment with botulinum toxin-A in real-life clinical practice

Lynne Turner-Stokes,1 Klemens Fheodoroff,

2 Jorge Jacinto,

3 Pascal Maisonobe,

4 Benjamin Zakine

4

1Cicely Saunders Institute, School of Medicine, King’s College London, London, UK,

2Neurorehabilitation, Gailtal-Klinik, Hermagor, Austria,

3Centro de Medicina de Reabilitaçãode Alcoitão, Serviço de Reabilitação de adultos 3, Estoril,

Portugal

4Medical Affairs, Ipsen Pharma, 65 Quai Georges Gorse, Boulogne-Billancourt 92100, France

Correspondence: Lynne Turner-Stokes, Regional Rehabilitation Unit, Northwick Park Hospital,

Watford Road, Harrow, Middlesex, HA1 3UJ, UK. E-mail: [email protected];

Tel: +44 (0)-208-869-2800; Fax+44 (0)-208-869-2803



rehabilitation.



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“The Corresponding Author has the right to grant on behalf of all authors and does grant on behalf

of all authors, an exclusive licence (or non-exclusive for UK Crown Employees) on a worldwide basis

to the BMJ Publishing Group Ltd, and its Licensees to permit this article (if accepted) to be published

in BMJ Open and any other BMJPGL products and to exploit all subsidiary rights, as set out in our

licence.”


Poster presentation, ‘Validation of individual person-centred goal statements for goal attainment

scaling (GAS) in a large international cohort study of botulinum toxin-A (BoNT-A) for upper limb

spasticity following stroke: The Upper Limb International Spasticity Study (ULIS-II)’ at the American

Academy of Physical Medicine and Rehabilitation, 17–20 November, 2011. Poster 269.

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ABSTRACT

Objectives: This article provides an overview of the Upper Limb International Spasticity (ULIS)

programme, which aims to develop a common core dataset for evaluation of real-life practice and

outcomes in the treatment of upper limb spasticity with botulinum toxin-A (BoNT-A). Here we

present the study protocol for ULIS-II, a large, international cohort study, to describe the rationale

and steps to ensure validity of goal attainment scaling (GAS) as the primary outcome measure.

Methods and analysis: Design: An international, multicentre, observational, prospective, before-

and-after study, conducted at 84 centres in 22 countries across three continents.

Participants: Four hundred and sixty-eight adults presenting with post-stroke upper limb spasticity

in whom a decision had already been made to inject BoNT-A, (5–12 consecutive subjects recruited

per centre).

Interventions: Physicians were free to choose targeted muscles, BoNT-A preparation, injected

doses/technique, and timing of follow-up in accordance with their usual practice and the goals for

treatment. Primary outcome measure: GAS. Secondary outcomes: measurements of spasticity,

standardised outcome measures and global benefits.

Steps to ensure validity included: a) Targeted training of all investigators in the use of GAS; b)

Within-study validation of goal statements; and c) Establishment of an electronic case report form

with an in-built tracking facility for separation of baseline/follow-up data.

Analysis: Efficacy population: all subjects who had a) BoNT-A injection; and b) subsequent

assessment of GAS. Primary efficacy variable: percentage (95% confidence interval) achievement of

the primary goal from GAS following one BoNT-A injection cycle.

Ethics and dissemination: This non-interventional study is conducted in compliance with Guidelines

for Good Pharmacoepidemiology Practices. Appropriate ethical approvals were obtained according

to local regulations. ULIS-II will provide important information regarding treatment and outcomes

from BoNT-A in real-life upper limb spasticity management. The results will be published separately.


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ARTICLE SUMMARY

Article focus

• To provide an overview of the Upper Limb International Spasticity (ULIS) programme and the

rationale and protocol of the ULIS-II study.

• To outline the steps taken in ULIS-II to ensure the quality of goal statements and support the

validity of goal attainment scaling (GAS) as the primary outcome measure for the trial.

Key messages

• Evaluation of goals statements part-way through this study has assisted participating centres

to improve the quality and function-related focus of goal statements


• This methodology helps to support the validity of GAS as the primary outcome measure for

the efficacy analysis.

• This large international cohort study represents a diverse sample of practice across three

continents.

• However, the limited number of subjects per centre (5–12) could lead to some selection

bias.

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INTRODUCTION

Spasticity is a common sequela of stroke, with an incidence ranging from 17% to 38%.[1-5] It is more

prevalent in younger patients,[2] and most commonly affects the upper limb.[6]

Upper limb spasticity is often painful. It interferes with upper limb movement, and limits use of the

limb for active functional tasks. It can cause involuntary movements (associated reactions) that

impact on mobility (gait, balance, walking speed, etc). In severe cases, it can also impede ‘passive

function’, such as washing, dressing and caring for the affected limb, therefore increasing the burden

on caregivers.[7 8]

There is now a well-established body of evidence demonstrating that botulinum toxin-A (BoNT-A) is

a well-tolerated and effective focal intervention for the reduction of spasticity, and it is widely

recommended for use in standard clinical practice.[7-9] Controlled clinical trials (CCTs)[10-18] have

confirmed the benefits of BoNT-A at the level of impairment, but functional change has been harder

to demonstrate, particularly where impact on active function is limited by underlying motor

dysfunction. Nevertheless, on an individual level, clinical experience suggests that some patients

make substantial functional gains.

Whilst CCTs may be helpful for establishing the overall clinical efficacy of an intervention, they do

not answer important clinical questions such as which patients are most likely to benefit and in what

way; or which treatment approaches work best in real-life clinical care. For these, we need large,

multicentre, longitudinal, cohort studies conducted in the course of routine clinical practice.[19] If

the findings are to be generalisable across different health cultures, these studies need to have wide

geographical representation across the international health community.

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Measuring the effectiveness of BoNT-A treatment is challenging in the context of upper limb

spasticity because of wide diversity in patient presentation, potential for rehabilitation, and goals for

treatment. Timing of assessment is also important due to the need for time to practice and develop

new skills in the hemiparetic arm after the spasticity has been relieved.[20, 21] Current guidelines

for the use of BoNT-A in the management of spasticity advocate the application of focused outcome

evaluations, targeted on the attainment of priority goals that are both relevant to the treatment

intentions and important to the individual.[7, 8] Depending on the nature of the goals set, the

individual clinical presentation and any underlying trajectory towards recovery or deterioration, the

timescale for expected goal achievement will vary from person to person. Cohort study design in this

context must therefore be flexible enough to account for all this variation.

Goal attainment scaling (GAS) is a method of assimilating achievement of a number of individually

set goals into a single ‘goal attainment score’, in order to capture outcomes across a diverse range of

goal areas. Originally described by Kiresuk and Sherman in the 1960s,[22] it is increasingly

recognised as a sensitive method for recording patient-centred outcomes in this context.[23-26] In

addition to providing a semi-quantitative (ordinal) assessment of goal attainment, GAS offers

potentially useful qualitative information regarding the patient’s priority goals for treatment.

Moreover, the process of goal setting and rating itself offers an opportunity for dialogue and

negotiation between the patient and the treating team,[27] which may help to establish mutual

agreement of expectations for outcome. However, this requires knowledge and experience, and it is

important to recognise that GAS is not a measure of outcome per se, but a measure of the

achievement of intention. It therefore does not replace standardised measures, but is a useful

adjunct to use alongside them.[28]

The use of GAS as a primary outcome measure for research is still somewhat controversial. Concerns

have been raised in some quarters about the validity of GAS; in particular, the non-linearity of the

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scaling and lack of uni-dimensionality,[29] and some authors have proposed the development of

standardised goals or ‘item banks’.[29 30] The World Health Organization (WHO) International

Classification of Functioning, Disability and Health (ICF)[31] provides a useful common language for

categorising goals into different domains of personal experience. A previous secondary analysis of a

multicentre CCT from Australia[24] mapped a total of 165 goals onto ICF domains, to identify the key

goal areas impacting on quality of life, in order to inform the future development of standardised

goal sets. The authors recommended that further research with a priori categorisation of goals in

large, prospective, cohort studies is required to describe the full value of BoNT-A in the management

of upper limb spasticity.

From the studies conducted to date, we know that there is considerable individual variation in

response. We also know that there is variation in treatment with respect to selection of muscle,

injection technique, and concomitant therapy interventions (e.g. physiotherapy and/or occupational

therapy), and that these appear to have more to do with clinician bias and local availability of

services than with patient presentation.[32] It is now time to extend the field of investigation in this

area to explore how BoNT-A is used in routine clinical practice, in order to gain a better

understanding of how to select those most likely to respond and what works best for which types of

presentation. Horn and Gassaway (2007) argue that this type of ‘practice-based evidence’ is as

important it its own way for building the evidence base for clinical practice as the information that

derives from CCTs.[33]

To do this, however, we will need to build a consistent body of data that captures clinically

important changes at an individual level and is of sufficient size and generalisability to interrogate

for future answers to these critical questions. The challenge lies in how to engage clinicians across

the globe, to engage in a single common approach to data collection.

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The Upper Limb International Spasticity (ULIS) study programme represents the first steps towards

this aim. This manuscript provides an overview of the programme and presents the rationale and

protocol for the ULIS-II study. The study results for ULIS-II will be presented separately.


The ULIS programme consists of a series of international, observational studies to describe current

clinical practice in the application of BoNT-A in the management of upper limb spasticity. The

ultimate aim is to work towards the development of a common core dataset for prospective

systematic recording of longitudinal outcomes that could inform development of a large,

international database of sufficient size and breadth to support future interrogation and subset

analysis.

A founding principle of establishing common datasets is to embed them as closely as possible in

real-life current clinical practice.

• The first stage of the programme (ULIS-I) [34] was an international, cross-sectional, survey,

which was designed to document clinical practice across four continents with respect to



observational, cohort study to record goal attainment as a primary outcome following one cycle

of BoNT-A. This has also served to develop expertise in GAS and refine an electronic case report

form (e-CRF). ULIS-II has recently completed recruitment and is now in the process of analysis.

• Following further refinement of the dataset and tools, a third stage is planned to expand the

cohort, and to capture the broader benefits of treatment in a fully generalisable sample

recorded longitudinally over several cycles of treatment. This is currently in the planning and

pre-investigation phase.

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ULIS-I was an international, cross-sectional, non-interventional survey to document (from review of

current practice and reported intentions) the clinical profiles, treatment goals and reported outcome

evaluation in consecutive adults attending treatment with BoNT-A for upper limb spasticity.[34]

Over a 6-month period, a total of 974 consecutive patients were recruited from 122 investigational

centres in 31 countries spanning the European Union, Pacific Asia, Eastern Europe, the Middle East

and South America.

The findings demonstrated wide diversity in clinical practice with respect to both the method of

intervention and the use of assessment and outcome measures.[34] Most frequently recorded were

impairment measures, including range of movement (90%) and spasticity – mainly using the

Modified Ashworth Scale (MAS) (83%). Although 36% said they routinely recorded at least one

measure of active function, there was wide variation in the instruments used and insufficient

commonality to allow pooling of data.

Goal setting on the other hand was very common (78%). However, although the large majority of

clinicians reported that they set goals, the way by which they used these to monitor the effects of

treatment varied widely. Formal application of GAS was used by only a handful of participating

centres (5%).

The findings suggested that goal attainment offered the most widely applicable common outcome

measure, and for this reason, it was selected as the principal outcome measure for the next stage of

the programme (ULIS-II). However, it was first necessary to establish a consistent approach to the

recording of goals and goal attainment. It was also important that the method was simple and

practical to apply across the wide international spectrum of clinical practice in upper limb spasticity

management.

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Study objectives

The primary objective of the ULIS-II study was to assess the responder rate (as defined by the

achievement of the primary goal from GAS) following one BoNT-A injection cycle delivered in the

context of routine clinical practice.


• Describe the baseline characteristics, including (but not limited to) demographics, duration and

pattern of spasticity, concomitant therapies/medication.

• Describe injection practices (muscle identification, dosage, dilution and injection points) and

additional treatment strategies – including therapy intervention and different types of modality.

• Assess the achievement of secondary goals and the overall attainment of treatment goals using

the GAS T-score.


• Assess the global benefits as perceived by the investigator and the patient (or guardian).

Exploratory objectives, addressed through the analysis plan, were to:

• Describe the common goal areas for treatment and to identify those in which goals were most

often achieved.

• Identify any prognostic factors for response.


ULIS-II was an 18-month, post-marketing, international, multicentre, observational, prospective,

longitudinal study, conducted in 84 centres in 22 countries (European Union, Pacific Asia, Eastern

Europe and South America). Figure 1 shows the geographical distribution of participating centres.

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Study participants


• Adults ≥18 years with post-stroke upper limb spasticity in whom a decision had already been

made to inject BoNT-A.




Recruitment

To limit the potential bias that might be introduced by over-recruiting sites, the number of patients

was limited to 5–12 patients per treatment centre. Participating centres represented a range of

experience to mirror clinical practice. However, in order to capture the approaches to treatment

that are borne of clinical experience, recruitment at less experienced centres (n=59) was restricted

to five patients only, whilst more experienced centres (n=25) could recruit up to 12 patients. This

approach also offers the potential for future sub-analysis of the differences between experienced

and less experienced injectors.

Centres were asked to include consecutive patients attending the clinics over a specified period. If

consecutive inclusions were not feasible (e.g. due to administrative constraints in a busy clinic

setting), investigators were authorised to space the inclusions (e.g. one per every two to three

patients), until their recruitment target was achieved.

A total of 468 patients were recruited, 226 in more experienced (48.3%) and 242 in (51.7%) less

experienced centres, confirming more or less equal distribution. Figure 2 shows the disposition of

patients and Table 1 shows the breakdown by country, including completion rates. The 12-case

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attrition was primarily in Europe, but did not significantly affect geographic representation as the

European countries were the best represented to start with.

Table 1: Recruitment and attrition by country

Country No of

centres

Total

recruits Attrition

No cases

completed

(Efficacy

population)

% of total

efficacy

population*

Europe

Austria 2 14 0 14 3

Belgium 4 25 1 24 5

Czech Rep 2 10 0 10 2

Denmark 1 5 0 5 1

Finland 3 13 1 12 3

France 14 48 1 47 10

Germany 6 45 2 43 9

Italy 6 33 2 31 7

Portugal 5 27 0 27 6

Russia 7 41 0 41 9

Spain 3 14 0 14 3

Sweden 2 14 0 14 3

UK 5 45 4 41 9

60 334 11 (3.3%) 323 70%

Pacific Asia

South Korea 5 29 1 28 6

Singapore 2 10 0 10 2

Taiwan 2 10 0 10 2

Australia 6 44 0 44 10

China 1 5 0 5 1

Malaysia 2 6 0 6 1

Philippines 2 10 0 10 2

Thailand 2 10 0 10 2

22 124 1 (0.8%) 123 27%

South

America

Mexico 2 10 0 10 2

2 10 0 10 2%

n=22 n=84 n=468 n=12 (2.6%) n=456

*Due to rounding, percentages may not total 100%.

Table 2 shows the demographics of the efficacy population who completed the study per protocol.

Table 2: Demographics of the efficacy population

Parameter Values Range N / missing or

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untestable

Age (years)

Mean (SD)

56.7 (13.5)

18–88

456 / 0

Time since onset of stroke (months)

Mean (SD)

61.4 (69.1)

1–447

456 / 0

Gender, n (%)

Male

Female

266 (58.3%)

190 (41.7%)

456 / 0

Aetiology, n (%)

Infarct

Haemorrhage

Both

320 (70.2%)

139 (30.5%)

3 (0.7%)

456 / 0

Location of CVA, n (%)

Left hemisphere

Right hemisphere

Bilateral*

Posterior circulation

215 (47.1%)

235 (51.5%)

4 (0.9%)

13 (2.9%)

456 / 0

Study schedule


On inclusion into the study the following assessments were recorded by the investigator on the e-

CRF:

• Demography and history of the stroke including type, location and time since onset (Table 2).



(including cognitive, emotional and behavioural function) were recorded using a modified

version of the Neurological Impairment Scale.[35]

• Previous/concomitant treatments for upper limb spasticity, including therapies and medication.

• Clinical examination, including a list of measurements of spasticity and other standardised

outcome measures, as routinely performed in that centre e.g.:

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– Visual analogue and verbal rating scales for symptoms such as pain, ease of care, etc

– Standardised scales for active and/or passive function (e.g. the Leeds Adult Spasticity

Impact Scale[11] or the Arm Activity scale[36, 37])


• Goal-setting and GAS was applied using the ‘GAS-light’ method [28] as detailed below with

emphasis on setting SMART (specific, measurable, achievable, realistic and timed) goals agreed

between investigator, the patient and the treating team. One primary and up to three

secondary goals were set and assigned to one of seven goal categories.

Injection of BoNT-A

To reflect real-life practice in this non-interventional observational study, physicians were free to

choose targeted muscles, BoNT-A preparation, injected doses, number of points and volume for

each point, and use of EMG/electrical stimulation in accordance with their usual practice, local

Summary of Product Characteristics and therapeutic guidelines.


The timing of follow-up was at the discretion of the investigator, based on their usual practice and

the nature of the goals set – usually between Months 3–5 after injection. At Time 2 (end of study),

the following were recorded:

• Achievement of primary and secondary GAS goals rated on a 6-point verbal rating scale, and

transcribed within the computer software to the 5-point numerical scale (range –2 to +2), and

the GAS T-score (see details below).

• Any concomitant treatments for upper limb spasticity given since baseline.

• Clinical examination including measurements of spasticity as normally routinely performed.

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benefit’; ‘some benefit’; ‘same’; ‘worse’; or ‘much worse’.

• Change on any standardised measures performed was recorded on the same 5-point scale. (This

was for pragmatic reasons as it was not possible to accommodate the wide range of

standardised measures that were used by different centres on the electronic case report form

(e-CRF) without making it unwieldy).

• Related adverse events (AEs): as this was a non-interventional study, this followed the standard

regulations for reporting of related spontaneous AEs within each country.

• The next therapeutic strategy – including information on any planned re-injection with BoNT-A –

whether using the same agent and protocol or an adjusted one.


The sample size calculation was based upon an estimate that 60% of patients would achieve their

primary goal following their first BoNT-A injection cycle. Using a 0.05 two-sided significance level,

with a power of 80%, 450 patients were needed to allow estimation of this proportion with a

precision of 4.5%. This sample size also allowed the detection of potential prognostic factors to

response (based on detection of odds ratio larger or equal to two).

Analysis

Statistical evaluations will be performed using Statistical Analysis System (SAS)® (version 8 or later

versions).

All analyses will be conducted on the efficacy population that includes all subjects who received one

BoNT-A injection and who underwent a post-injection visit including an assessment of the GAS. For

the primary statistical analysis, ‘Responders’ are those who achieve their primary goal (GAS score 0,

1 or 2) (primary statistical analysis). Patient demographics, baseline characteristics and efficacy

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evaluations for secondary variables will be presented as descriptive statistics, including 95%

confidence intervals where relevant.

Relationships between GAS T-scores and other measures of outcome (e.g. measures of spasticity,

global benefit and other standardised measures) will be examined using Spearman rank correlation

coefficients. Stepwise logistic regression modelling will be used to identify potential prognostic

factors for response including the duration of spasticity, time interval to follow-up, presence of

confounding factors (including contractures, impaired cortical function, etc) and provision of

concomitant therapy.

Descriptive analysis will also be carried out to evaluate any possible country effect, if considered

relevant.


We used the simplified ‘GAS-Light’ approach described by Turner-Stokes,[28] which is based on the

original method described by Kiresuk and Sherman,[22] but designed to be timely and practical for

use in a busy clinic setting. The GAS-Light method uses a verbal rating scale, which reflects the way

clinicians usually record goals in routine practice. Verbal ratings are then translated into the 5-point

numerical scales as shown in Figure 3.

• At the baseline visit, the investigator (in conjunction with their multidisciplinary team where

possible) interviewed the patient and identified the main problem areas. An agreed set of goals

(one primary and up to three secondary goals) was defined.

• A single SMART goal statement was recorded in the free text box of the e-CRF to describe the

intended outcome for each goal (as opposed to predefining levels for each score).

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• Each primary and secondary goal was assigned to one of seven pre-defined goal categories

(‘pain’, ‘passive function’, ‘active function’, ‘mobility’ [balance, gait], ‘involuntary movement’

[associated reaction], ‘impairment’ [e.g. range of movement] and ‘other’).

• There was an option to weight goals for importance to the patient and/or family on a scale of 0

= not at all, 1 = a little, 2 = moderately, and 3 = very important.[28] If no goal weighting was

recorded, a default value of 1 was entered.

o A baseline score was chosen for each goal as either ‘some function’ (−1) or ‘no function’ (as bad

as they could be; −2).



• Attainment was rated on a 6-point verbal rating scale and transcribed to the 5-point GAS

numerical scale (−2 to +2), depending on the baseline rating as shown in Figure 3. [39]

• A composite GAS T-score for each patient was then derived from the product of their individual

goal achievement scores x goal weighting, using the following standard formula described by

Kiresuk and Sherman:[22]

• The overall GAS T-score was calculated by the following formula:

RIGOUR – Steps to ensure validity of ULIS-II results

In view of the concerns raised about the use of GAS as noted in the introduction, a number of steps


included:


T-Score = 50 + 10 x Σ(wi xi)

√(0.7 Σwi2

+ 0.3(Σwi) 2

)

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• Within-study validation of goal statements.

• Establishment of an e-CRF with an inbuilt auditing facility for separation of Time 1 (baseline,

before the BoNT-A treatment) and Time 2 (assessment after treatment cycle) data.



• They demonstrated a reasonably high and consistent level of data recording and outcome

measurement as part of their routine clinical practice.

• They routinely collected at least one standardised measure of spasticity (Ashworth scale or

Tardieu scale).



In preparation for the ULIS-II study, a comprehensive GAS training programme was carried out

across all participating centres. This programme not only educated clinicians who were unfamiliar

with the use of GAS, but also formed an essential part of the validation process for the use of GAS in

ULIS-II.

First, a common training programme was established, with a set of training tools, including:



(ii) A DVD of three case examples to illustrate goal setting and recording of goal attainment in

different scenarios.

(iii) A standard Microsoft Excel spreadsheet for recording goal ratings applying the formula to

derive a GAS T-score (as part of the learning process, this offered the opportunity for the

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teams to calculate their mean T-scores, providing feedback on whether they were


Further information about the GAS-light method, including copies of the practical guide and GAS T-

score calculator may be found on the Cicely Saunders Institute website http://www.csi.kcl.ac.uk/gas-

tool.html.

The training was organised through a series of national and regional workshops. A network of

regional trainers was established as the leads for GAS training within their country/area. A series of

initial ‘Train-the-trainer’ sessions was held to familiarise the local trainers with the training materials

and to ensure that they themselves were competent in the use of GAS before training others.

Thereafter, all investigators at the participating centres attended GAS training (a total of 35

workshops) before recruiting patients.


The ultimate focus of treatment for spasticity should be towards functional improvement, even

though this may be at the level of passive function (i.e. ease of caring for the affected limb) as

opposed to active function (i.e. active use of the limb in functional tasks). It is therefore expected

that the primary goal statements should be both SMART and function-related in the majority of

cases.

If goals are set in an unbiased fashion so that the results exceed and fall short of expectations in

roughly equal proportions, the GAS T-score should be normally distributed at around a mean of 50

with a standard deviation of around ±10.[28] If a team attempts to inflate their results by setting

goals over-cautiously, the mean score will be >50. Similarly, if they are consistently over ambitious, it

will be <50. This provides a means for checking the overall quality of goal setting.

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As a further step to ensure the validity of GAS, an interim validation process was undertaken part-

way through the recruitment phase of the ULIS-II study. The purpose of this was to check that

clinicians were setting SMART function-related goals in accordance with the training.

Goal statements for the primary goal in each patient were independently evaluated by three lead

clinical investigators (LTS, KF and JJ) in two rounds.[40] In Round 1 (September 2010), 345 goals from

67 centres and in Round 2 (December 2010), 438 goals from 79 centres were evaluated.

Goal statements were examined on a centre-by-centre basis and investigators were blinded to

country and centre. They were assessed on two criteria: (i) the WHO ICF domain; and (ii) the quality

of the SMART description (Table 3). It was accepted that for some patients, goal statements would

be impairment related, e.g. prevention of contractures. However, investigators expected that at

least some goals from each centre would be related to function. Some examples of comparative

SMART and non-SMART goals are shown in Table 4.

Table 3: Quality rating criteria for primary goal statements – WHO ICF domain and SMART


Rating WHO ‘ICF’ domain, disability and health Example

A Some goal statements contain reference to

functional activities at the level of disability

or participation – may be ‘active’ or ‘passive’

function*

Reference to meaningful activities such as

ease of self-care, reduced care burden,

mobility, community-based activities,

work-related function, etc


impairment only



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pronation, etc




accurate GAS rating

‘To be able to type a four-word sentence

with only a single typing error using index

fingers in 15 seconds’

+ There is some clear goal description



‘To be able to open and close hand, as


chores’


* ‘Active’ function refers to using the affected limb in some motor activity, preferably for an

identified functional purpose. ‘Passive’ function includes tasks related to caring for the affected limb

(whether by a carer or by the person him/herself).


measurable, achievable, realistic and timed; WHO, World Health Organization; ULIS, Upper Limb

International Spasticity.

Table 4: Examples of SMART and function-related goals for GAS analysis





Improve carry angle from 25° to 0° when walking

by 1 month after injection

Elbow extension

To reduce upper limb pain during rest and passive

range of motion (<4/10 on VAS) 1 month

after injection

To improve pain

To relieve thumb in palm and ease nail clipping

(taking less than 20 minutes) 1 month

after injection


Sitting at the table, to grip fork and spoon to move

them to mouth and eat 1 month after injection

To improve grasp and release function of the

hand

GAS, goal attainment scaling; SMART, specific, measurable, achievable, realistic and timed; VAS,

visual analogue scale.

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After independent evaluation, ratings were compared and an overall centre rating for the WHO ICF

domain (A, B or C) and SMART description (++, + or –) was reached by consensus. Results were then

fed back to centres. The goal was to have a rating of A+ or A++. In order to improve quality of goal

setting, centres with lower rates (B, C or –) were invited to submit revised goal statements for those

patients who had not yet received their follow-up evaluation.

The results from the interim validation of GAS goal statements are shown in Figure 4a. In Round 1,

62.7% recorded function-related statements rated (‘A’ or ‘AB’) and 40.3% received a SMART quality

rating of ‘++’/‘+’. In Round 2, these figures rose to 70.9% and 46.8%, respectively.

After the goal refinement process, 37 centres submitted revised goal statements (of which 21

[56.8%] had improved their rating), and 12 centres (24%) had achieved a maximum possible

combined rating of ‘A++’. Even after this process, however, there was residual heterogeneity

between countries in the quality of goal setting, especially with respect to ‘SMARTness’, as

illustrated in Figure 4b.

In any multicentre study reflecting real-life practice, one would expect a range of quality in goal

setting and we do not think that ULIS-II is unique in this respect. Therefore, we do not plan to discard

the goals that were not SMART from the primary analysis, but we will perform a secondary analysis

to examine the relationship between GAS and the quality of goal setting, testing the hypothesis that

goal achievement rates are lower for SMART goals (see below). If a significant difference is found,

subset analyses will be conducted to correct for this.


A further purpose of ULIS-II was to develop and refine the e-CRF for capturing a standardised

dataset. In ULIS-I, we identified the most commonly used approaches to recording assessment,

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treatment and outcome evaluation. Learning from this experience, we addressed ways of reducing

the information and making it understandable by investigators in all countries. This was achieved

through small international group workshop discussions with key investigators (including authors

LTS, KF and JJ), followed by circulation and feedback on the draft (case report form, prior to

commencing development of the electronic version).

The e-CRF was presented in one language only (English) to avoid introducing variance through

translation. Investigators therefore needed to be adequately proficient in the English language to

complete the form, although goal statements could be completed in the native language. Site

monitors provided support for any interpretational queries. The e-CRF was posted on the internet to

facilitate access to all participating countries. It was developed on customised software that

supported electronic and interactive data collection, as well as online edit checks to ensure data

accuracy and quality. Wherever possible, it included dropdown value lists and check-box options to

minimise ambiguity, and it also provided automated calculation of the GAS T-Score.


In this before-and-after study, Time 1 acts as the ‘within patient’ control. GAS rating requires the

investigator to be able to view the goals set at Time 1, so it was important to maintain the

independence of Time 1 and Time 2 data as far as possible. The e-CRF software did not have the

facility to lock the Time 1 data prior to completion of the follow-up form, which would have

prevented the opportunity for retrospective changes. However, it did have an inbuilt tracking facility.

Site monitors were responsible for reviewing the tracking log to ensure that no post-hoc changes

were made that could have influenced outcome evaluation.


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The study builds on others that have used goal attainment to evaluate outcome from interventions

for upper limb spasticity.[23-26] It will expand our understanding of the types of goals that are and

are not likely to be achieved following treatment with BoNT-A. Importantly, it sets in train a

methodology that is practical for use in routine clinical practice, which will be used in future studies

to expand the clinical dataset to one of sufficient size to interrogate for answers to the important

questions including:

(i) The identification and selection of patients most likely to benefit from treatment.

(ii) The most effective approaches to muscle selection, injection technique, etc.

(iii) The most useful approaches to outcome measurement.

Goal setting is a complex process, which requires skill and experience on the part of investigators –

both to coin the SMART goal description and also to be able to predict the likely outcome of the

intervention and its timescale. This study has emphasised the need for training in consistent goal-

setting techniques as highlighted in other studies.[24] Our interim goal validation study was an

important step to ensure the rigour of goal setting in participating centres. In future ULIS studies,

demonstration of competency in high quality, unbiased goal setting will be an essential prerequisite

for centre participation. We recommend that future trials using GAS in this context should adopt a

similarly robust approach.


• The wide international representation of participating centres captures experience of clinicians

from around the globe, ensuring the generalisability of results.

• The use of goal setting and GAS in this context emphasises the assessment of outcomes that are

important to the patient.

• The simplified approach to GAS enabled its application in clinical practice and supported the

negotiation of realistic expectations for outcome.

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• The comprehensive GAS training programme allowed investigators unfamiliar with this method

to be educated in goal setting prior to starting the study.



primary outcome measure for this and future ULIS studies. At first sight this might be regarded

as ‘cheating’. However, SMARTening goal statements would, if anything, make goals harder to

achieve. For example, the broad goal statement ‘to improve pain’, would be achieved with any

improvement, whilst the SMART equivalent ‘to reduce upper limb pain during rest and passive

range of motion (<4/10 on the visual analogue scale [VAS]) 1 month after injection’, would only

be achieved if the specified targets were achieved.


(i) Limiting recruits to 5–12 per centre may have introduced some selection bias through under-

representation of less common presentations of spasticity.

(ii) The e-CRF was not locked after Time 1 data entry, allowing for the possibility of retrospective

alteration (of the goal statement only) at Time 2. Using the e-CRF auditing facility, no cases

were found in which goal statements were retrospectively adjusted at Time 2. In future studies,

it will be important to use software with a locking facility.

In this study, it was not feasible to record raw data for outcome measures other than GAS and

spasticity (MAS). Aside from this, investigators were simply asked to record which measures they

had used and whether the results were ‘the same’, ‘better’ or ‘worse’ than at baseline. Given the

long list of measures used, it was not feasible or appropriate to compute all of them within the e-

CRF. However, this information will allow us to identify those measures that are sensitive to change

in the responder population, which will assist in the selection of an appropriate and feasible battery

of standardised measures to record alongside GAS in future ULIS studies.

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SUMMARY

The importance of the ULIS programme lies in its staged approach to development, which both

educates participating centres and ensures that the final core dataset will capture the cultural

diversity of worldwide clinical practices in which it will be used. ULIS-II is not the final step, but marks

an important phase in the development of the programme.

Despite the recognised limitations at this stage of development, ULIS-II will provide a unique and

important set of information regarding the treatment and outcomes from BoNT-A in real-life

management of post-stroke upper limb spasticity worldwide. Through the process described above,

we have developed a methodology that will not only help to ensure credibility of results from ULIS-II,

but will also underpin future studies and inform other clinical trials and cohort studies in this

context.





2001/20/EC of the European Parliament. It was conducted in compliance with Guidelines for

Good Pharmacoepidemiology Practices


• To reflect real-life practice in this observational study, physicians were free to choose BoNT-A

treatment (targeted muscles, preparation, injected doses and number of points and volume for

each point in accordance with their usual practice, and with their local Summary of Product

Characteristics and therapeutic guidelines).

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• Ethical approval and written informed consent was obtained prior to anonymous data collection

in countries where this was required and the study protocol was approved by an independent

ethics committee at each participating site.

• Data protection: All personal information was collected at the investigational site and protected

according to local data protection law. Patients were identifiable only by patient ID at

investigational site.

• The results will be presented at international meetings and published in peer-reviewed journals.

Acknowledgements

This study was supported by Ipsen Pharma. The authors would like to also acknowledge the editorial

assistance of Suzanne Patel at Ogilvy Healthworld in the preparation of the manuscript.



LTS was the lead investigator and wrote the first draft of this manuscript. LTS, KF and JJ were

involved in data collection and assembly of data for goal validation, manuscript review and critique,

and final approval of manuscript.

BZ and PM were involved in the concept and design, data analysis, manuscript writing, manuscript

review and critique, and final approval of manuscript.

Funding statement

Ipsen Pharma provided financial support for this study. Financial support for manuscript preparation

was also provided through the Dunhill Medical Trust.

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LTS, KF and JJ all received honoraria and conference attendance fees from Ipsen for the undertaking

of this research.

• LTS has a specific interest in outcomes evaluation and has published extensively on the use of

goal attainment scaling (GAS) in this context, as well as a number of the other standardised

measures (including the Associated Reaction Rating Scale, the Arm Activity Scale and the

Neurological Impairment Scale). All of these tools are freely available, however, and she has no

personal financial interest in any of the material mentioned in this article.

• KF has a specific interest in outcomes evaluation and the use of the International Classification

of Function in clinical settings. He has no personal financial interest in any of the material

mentioned in this article.


setting, treatment strategies/techniques and outcome measurement. He has no personal or

financial interest in any of the material mentioned in this article.


Data Sharing


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FIGURE LEGENDS




Figure 3 Converting the GAS-light verbal scoring system to a numerical 5-point scale (-2 to +2)

The verbal descriptions align with how clinicians normally think about and describe goal attainment.

They allow goal attainment to be recorded without reference to the numeric scores, and so avoid the

perceived negative connotations of zero and minus scores.

Figure 4a Percentage of centres achieving high quality ratings in Rounds 1 and 2 during validation

of GAS statements







measurable, achievable, realistic and timed; WHO, World Health Organization.

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