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For peer review only

LiMA: A study protocol for a randomised, double blind,

placebo controlled trial of lisdexamfetamine for the

treatment of methamphetamine dependence

Journal: BMJ Open

Manuscript ID bmjopen-2017-020723

Article Type: Protocol

Date Submitted by the Author: 15-Mar-2018

Complete List of Authors: Ezard, Nadine; St Vincents Hospital; University of New South Wales - Randwick Campus Dunlop, Adrian; Hunter New England Local Health District, Drug and

Alcohol Clinical Services; University of Newcastle Hall, Michelle; Hunter New England Local Health District, Drug and Alcohol Clinical Services Ali, Robert; University of Adelaide McKetin, Rebecca; Curtin University Australia-Asia-Pacific Institute Bruno, Raimondo; University of Tasmania Nghi, Phung; Western Sydney Local Health District Carr, Andrew; St. Vincent's Hospital White, Jason; University of South Australia Clifford, Brendan; St. Vincent's Hospital; University of Sydney Liu, Zhixin; University of New South Wales - Randwick Campus Shanahan , Marian Shanahan ; National Drug and Alcohol Research Centre

Dolan, Kate; National Drug and Alcohol Research Centre Baker, Amanda; University of Newcastle, Lintzeris, Nicholas; South East Sydney Local Health District, The Langton Centre; University of Sydney

Keywords: Methamphetamine, Study protocol, Lisdexamfetamine, Pharmacotherapy, Stimulant use disorder

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

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ctober 29, 2020 by guest. Protected by copyright.

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TITLE PAGE

Title of article

LiMA: a study protocol for a randomised, double blind, placebo controlled trial of lisdexamfetamine for the


Corresponding author

Michelle Hall

Newcastle Community Health Centre

Drug and Alcohol Clinical Services

Level 3, 670 Hunter St

Newcastle, 2300, NSW

T: + 61 2 40164781

E: [email protected]

Co-authors

Nadine Ezard1,2

, Adrian Dunlop3,4

, Michelle Hall3, Robert Ali

6,2 , Rebecca McKetin

5, Raimondo Bruno

8, , Nghi

Phung7, Andrew Carr

1,2, Jason White

8, Brendan Clifford

1,11, Zhixin Liu

2 Marian Shanahan

10, Kate Dolan

10,

Amanda Baker4, Nicholas Lintzeris11,12

1St. Vincent's Hospital, Sydney, NSW, Australia

2UNSW, Sydney, NSW, Australia

3Hunter New England Drug and Alcohol Clinical Services, Newcastle, NSW, Australia

4 School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia

5Curtin University, Perth, WA, Australia

6University of Adelaide, Adelaide, SA, Australia

7Western Sydney Local Health District, Sydney, NSW, Australia

8University of South Australia, Adelaide, SA, Australia

9University of Tasmania, Hobart, TAS, Australia

10National Drug and Alcohol Research Centre, UNSW Sydney, NSW, Australia

11University of Sydney, Sydney, NSW and

12South East Sydney Local Health District, Sydney, NSW, Australia

Key Words

Methamphetamine, Study protocol, Lisdexamphetamine, Pharmacotherapy, Stimulant use disorder

Word count

4100 (excluding title page, abstract, references, figures and tables)

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ABSTRACT

Introduction

Methamphetamine dependence is a growing public health concern. There is currently no pharmacotherapy

approved for methamphetamine dependence. Lisdexamfetamine dimesylate, used in the treatment of

Attention-Deficit Hyperactivity Disorder (ADHD) and binge eating disorder, has potential as an agonist

therapy for methamphetamine dependence, and possible benefits of reduced risk of aberrant use due to its

novel formulation.

Methods and analysis

A double-blind randomised controlled trial will be used to evaluate the efficacy of lisdexamfetamine in

reducing methamphetamine use. The target sample is 180 participants with methamphetamine

dependence of ≥ 2 years, using ≥ 14 days out of the previous 28, who have previously attempted but not

responded to treatment for methamphetamine use. Participants will be randomly assigned to receive either

a 15-week intervention consisting of induction (1 week of 150mg lisdexamfetamine (LDX) or placebo),

maintenance (12 weeks of 250mg LDX or placebo) and reduction (1 week of 150mg LDX or placebo and 1

week of 50mg LDX or placebo). All participants will be given access to 4 sessions of CBT as treatment-as-

usual and receive a 4-week follow up appointment. The primary outcomes are efficacy (change from

baseline in days of methamphetamine use by self-report for the last 28 days at week 13, and urinalyses

confirmation of methamphetamine use) and safety (treatment related adverse events). Secondary outcomes

are total number of days of self-report MA use over the 12 week active treatment, longest period of

abstinence during treatment period, percentage of achieving >= 21 days abstinence, craving, withdrawal,

dependence, retention, blood borne virus transmission risk behaviour, criminal behaviour, as well measures

of abuse liability, physical and mental health, other substance use, cognitive performance, psychosocial

functioning, treatment retention and satisfaction. Additionally, the study will assess the cost effectiveness of

lisdexamfetamine relative to the placebo control.

Discussion

This will be the first Phase III trial of lisdexamfetamine for methamphetamine dependence. If successful the

intervention will provide a much needed therapeutic adjunct for people who are dependent on

methamphetamine.

Ethics and Dissemination

The study has been approved by the Human Research Ethics Committee of St. Vincent’s Hospital, Sydney,

Australia (HREC/16/SVH/222). Contact the corresponding author for the full trial protocol.

ARTICLE SUMMARY

Strengths and limitations of this study

• First Phase III trial of lisdexamfetamine for methamphetamine dependence.

• If successful the intervention will provide a much needed therapeutic adjunct for people who are

dependent on methamphetamine.

• The design is for a fixed dose (with option for one dose decrease): if efficacious, further dose-response

relationship studies may be indicated

• The duration of active treatment is limited to 12 weeks, if efficacious further studies will be needed to

explore optimum duration of treatment and a reducing regimen

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BACKGROUND

Methamphetamine is a synthetic stimulant of growing global public health importance and an important

contributor to the global burden of disease (1). There are an estimated 34 million people worldwide who use

the drug, and an estimated 17 million who are dependent on methamphetamine (2).

Australia has one of the highest documented rates of methamphetamine dependence in the world, with

160,000 people estimated to be dependent during 2013/14 (1). Methamphetamine dependence is

estimated to cost Australia around $5 billion a year, an economic impact which could be reduced by effective

treatments (3, 4). Methamphetamine dependence is associated with a range of negative health outcomes

including psychosis, depression, anxiety, blood-borne virus transmission, sexually transmissible infections,

and cardiovascular and cerebrovascular events (5). These problems are most prevalent among people who

use methamphetamine on a heavy or regular basis (6), highlighting the need for effective treatments for this

group.

There is no approved medication for the treatment of methamphetamine dependence. The current

standard treatment for methamphetamine dependence relies on psychosocial interventions, primarily

Cognitive Behaviour Therapy (CBT)-based approaches (7). Such approaches produce small to medium

reductions in methamphetamine use in controlled studies (d = 0.53 (8)). However, CBT approaches require a

substantial investment by trained therapists, there is often poor engagement with counselling by

methamphetamine users, and cognitive impairment associated with severe methamphetamine dependence

may limit CBT effectiveness (7). Poorer treatment outcomes are seen in methamphetamine users who use

frequently (those using methamphetamine at least 15 days out of the previous 30 days at treatment entry),

than in less frequent users (9), highlighting the need for more effective treatment approaches for such

individuals.

Many authors have highlighted the potential role of substitution agonist treatment for methamphetamine

dependence (10). The theoretical base for agonist prescription is consistent with the rationale for existing

agonist substitution for nicotine and opioid dependence. Agonist substitution therapies aim to replace

harmful drug use with safer alternatives in terms of dose, route of administration and adverse effects. Long-

acting agonists can reduce amphetamine withdrawal (11), craving (12), and decrease the euphoriant and

reinforcing effects of extra (illicit) stimulant use due to cross-tolerance (13). Agonist treatment also provides

a framework for regular ongoing healthcare and psychosocial interventions with this high-risk population,

enabling patients to distance themselves from illicit drug networks and related crime.

Agonist therapies for methamphetamine dependence show promise. A number of ‘weak’ stimulant agonist

therapies have been studied, including methylphenidate and modafinil (14). A recent systematic review

showed no benefit over placebo for any of these medications, noting limitations in retention and power of

published studies (15). Dexamphetamine, a more direct monoamine agonist that more closely mimics the

effects of methamphetamine, has been used clinically for amphetamine and methamphetamine dependence

in the United Kingdom (in doses ranging from 20mg to 200mg) for some time (16, 17), and in New South

Wales, Australia, since 2006, at doses up to 80mg (18). This experience suggests dexamphetamine

substitution treatment may be useful in retaining a difficult to engage group of severely dependent

methamphetamine users who do not respond to stand-alone psychosocial interventions. Previous studies

from methamphetamine dependent (19-21) subjects found no serious consequences of dexamphetamine in

doses from 30 - 110mg/day (22).

While a statistically significant benefit on methamphetamine use has not been established with

dexamphetamine pharmacotherapy, feasibility has been demonstrated with 60mg dexamphetamine/day

(equivalent to 150mg lisdexamfetamine) (19). Studies with sustained-release dexamphetamine (SR-DXA)

formulations have shown increased retention in treatment at up to 110mg SR-DXA/daily (mean dose of

80mg SR-DXA daily) (20), and decreased craving and withdrawal symptoms in a study using 60mg SR-DXA

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(21). This latter study (n=60) with a treatment duration of 8 weeks concluded that further studies should

test a longer treatment duration, that higher doses of dexamphetamine could be warranted due to possible

physiological tolerance, and that larger sample sizes are required (21).

Lisdexamfetamine, a pharmacologically inactive prodrug, is absorbed after oral administration and is

hydrolysed to inactive l-lysine and active dexamphetamine by red blood cells (23). It has a slower onset,

lower peak concentration, and longer duration of action than dexamphetamine (24). It is metabolised

rapidly to dexamphetamine: the peak plasma concentration occurs 3 hours after dosing. The plasma half-life

(t½) of dexamphetamine is 10 hours (25), with plasma dexamphetamine concentrations reaching steady

state at day 5 of once-daily lisdexamfetamine dosing (24). There is no plasma accumulation of

lisdexamfetamine (26). The conversion time from lisdexamfetamine to dexamphetamine results in a more

blunted effect on brain dopamine than immediate release dexamphetamine (27) and, as a consequence, it

has a more moderate reinforcing effect in self-administration studies due to the slower onset of peak effects

than other stimulant drugs (28).

Abuse liability studies of lisdexamfetamine with doses of up to 150mg indicate it has significantly less

propensity for abuse-related ‘liking’ when compared to dexamphetamine or diethylpropion (29). The lower

abuse liability of lisdexamfetamine, due to its rate-limited hydrolysis, attenuated onset and intensity of

amphetamine-like effects, and more moderate reinforcing properties thus reduce the need for supervised

dosing.

There have been no published randomised controlled trials of lisdexamfetamine for methamphetamine

dependence. Mooney et al (30) were unable to show a significant change in cocaine use, though the study

used a lower dose of 70mg lisdexamfetamine, and failed to reach its planned sample size. The maintenance

dose of 250mg lisdexamfetamine represents equivalence to current dexamphetamine regimes for

methamphetamine dependence (31). This dose has also been tolerated by non-methamphetamine

dependent volunteers in a pharmacokinetic study (32), as well as in a study in participants with

schizophrenia receiving anti-psychotic pharmacotherapy (33). A recent safety dose-escalating trial of

methamphetamine dependent participants with high frequency of use (34) successfully escalated 14 out of

16 participants to 250mg lisdexamfetamine (35)].

OBJECTIVES

The objective of the current trial was to test the efficacy of lisdexamfetamine for reducing

methamphetamine use among people with methamphetamine dependence, who had not previously

responded to psychosocial treatments.

We hypothesise that treatment with oral lisdexamfetamine will result in significantly reduced

methamphetamine use at 13 weeks compared to placebo in people who are dependent on

methamphetamine. The primary objectives of the study are efficacy and safety of 250mg of

lisdexamfetamine in reducing methamphetamine use after 13 weeks of treatment. Secondary objectives are

to examine the changes in physical and mental health, cognitive and psychosocial functioning and well-being

between lisdexamfetamine and placebo groups, as well as differences in retention rates, craving and

withdrawal symptoms, and severity of dependence. Other secondary objectives are to examine differences

in blood borne virus transmission risk behaviour, criminality, and in use of alcohol and other drugs between

groups, as well as the abuse liability profile of lisdexamfetamine and the cost effectiveness of


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METHODS

Trial Design

This project is a randomised double-blind placebo controlled fixed dose parallel design comparing a 12-week

maintenance course of 250mg lisdexamfetamine daily to placebo.

Sample Size

The sample size calculation is based on data from the existing NSW Stimulant Treatment Program clients (31)

who meet inclusion criteria. Such clients showed a reduction from a mean of 19 day of use out of 28 days at

pre-treatment to a mean of 9 days /28 days with standard deviation (SD) of 9 days at 12 weeks post-

treatment. To detect a mean difference of 4.5 days (9 days in control vs. 4.5 days in the lisdexamfetamine

group out of 28 days) at week 13 (12 weeks post treatment), assuming a pooled SD of 9 days (i.e. d=0.5, a

median clinically relevant effect size), with over 80% power at two-sided significance level of 0.05, a sample

size of 126 (63 per group) is required (10). Conservatively estimating a 30% attrition from research follow-up

(previous trials have achieved follow-up of 81% at 12 weeks (27), 90 participants per group will be recruited

– 180 in total.

Participants

The study population is treatment seeking adults with long-standing (≥12 months) methamphetamine

dependence who have failed to respond to previous methamphetamine treatment attempts. Participants

will be aged 18 to 65 years, meet ICD-10 criteria for methamphetamine dependence and self-report

methamphetamine use of ≥14 days out of the previous 28. Prior use of methamphetamine will be verified

by urinalysis. Failure to respond to previous treatment is defined as relapse to dependent use within one

month of completing treatment. Participants must be willing and able to comply with study requirements,

be able to store study medications securely, and be able to provide written, informed consent.

Exclusion criteria are sensitivity or previous adverse reaction to lisdexamfetamine, concurrent use or use

within the previous 14 days of medications with possible interaction with lisdexamfetamine. Known

contraindications for lisdexamfetamine are also exclusion criteria. Individuals with severe medical disorders,

including cardiovascular disease, untreated hypertension and peripheral vascular disease, will be ineligible,

as will those with severe psychiatric disorders. Those currently in counselling for methamphetamine

dependence or who have been prescribed dexamphetamine or modafinil (in the four weeks prior to

assessment) will be ineligible. Other exclusion criteria are dependent use of alcohol or other drugs,

exposure to another investigational drug within the 4 weeks prior to screening, unavailability for follow-up,

pregnant or lactating women and receipt of current pharmacotherapy treatment for opioid dependence.

Four specialist outpatient stimulant treatment centres in New South Wales and South Australia will recruit

participants. Potential participants will be pre-screened in person or by telephone by a researcher, and if

potentially eligible invited to attend for a formal eligibility assessment by a specialist in addiction medicine.

The assessment schedule, including eligibility assessments, is outlined in Table 1.

Table 1. Assessments and procedures: Eligible participants will be required to attend the clinic daily for the

first five days of treatment. On day 5 they will be provided with 2 days’ supply of study medication to take at

home.

For the remainder of the treatment period participants will attend the clinic twice a week for supervised

dosing, safety assessments, provision of urine sample and collection of take home dioses. Research visits will

occur every four weeks until week 19.

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Demographics and Baseline Assessments

Demographics Screening

Medical Screening Screening

Substance Use History and Treatment Screening

Columbia Suicide Severity Rating Scale – Screening (CSSRS) (36) Screening

Enriched Social Support Inventory (ESSI) Week 1

Wender-Utah Rating Scale (WURS)(37) Week 1

Intervention and counselling

Lisdexamfetamine or Placebo Weeks 1 to 15

Baker et al. 4 session CBT (38) Weeks 2 to 13 (4 sessions at least 2 weeks apart)

Efficacy and Safety Measures

Time Line Follow Back (All drugs - Past 28 days) (39) Screening and Weeks 1, 5, 9, 13, 19

Time Line Follow Back (Methamphetamine only - Past 7 days) Weeks 2, 3, 4, 6, 7, 8, 10, 11, 12, 14, 15

Medication Adherence (40) Weeks 1 to 15 (twice weekly)

Treatment Satisfaction Questionnaire (TSQM) (41) plus testing blind Weeks 5, 9, 13, 19

Adverse Events Weeks 1 to 15 (twice weekly) and Week 19

Urine Drug Screen Screening and Weeks 1 to 15 (twice weekly)

Vital signs (temperature, blood pressure, heart rate, respiratory rate) Screening and Weeks 1 to 15 (twice weekly)

Concomitant Medications Screening and Weeks 1 to 15 (twice weekly)

Electrocardiogram Screening and Weeks 5, 9, 13

Pregnancy testing (if applicable) Screening and Weeks 1, 5, 9, 13

Medical Assessment – Since last visit Screening and Weeks 1, 5, 9, 13, 19

Columbia Suicide Severity Rating Scale – Since last visit (CSSRS)(36) Screening and Weeks 1, 5, 9, 13, 19

Brief Psychiatric Rating Scale – 4 items (BPRS) (42) Screening and Weeks 1, 5, 9, 13, 19

Review by study doctor Weeks 1, 5, 9, 13 and last day of treatment

Measures of physical and mental health and cognitive and psychosocial functioning

Patient Health Questionnaire – 15 (PHQ15)(43) Weeks 1, 5, 9, 13, 19

Depression & Anxiety Survey Scale (DASS21)(44) Weeks 1, 5, 9, 13, 19

World Health Organization Quality of Life (WHOQOL-BREF) Weeks 1, 5, 9, 13, 19

Insomnia Severity Index (ISI) (45) Weeks 1, 5, 9, 13, 19

Neurocognitive testing batteries (combinations of the following):

(MOCA) (46), (WTAR) (47), RAVLT (48-50) RVIP (50, 51), N-Back (52), Trail

making test (53-56), Flankers (51, 57), Digit-Symbol (58, 59)

Screening and Weeks 1, 5, 9, 13, 19

Measures of cravings, withdrawal and severity of dependence

Amphetamine Withdrawal Questionnaire (AWQ) (60) Weeks 1, 5, 9, 13, 19

Visual Analogue Scale for Cravings (61) Weeks 1, 5, 9, 13, 19

Severity of Dependence Scale (SDS) (62) Weeks 1, 5, 9, 13, 19

Measures of abuse liability, other drug use, risk behaviour and crime

Drug Evaluation Questionnaire (DEQ5) Weeks 1, 5, 9, 13, 19


Urine Drug Screen Weeks 1 to 15 (twice weekly)

Opiate Treatment Index - Injecting Practices (OTI-I) Weeks 1, 5, 9, 13, 19

Opiate Treatment Index - Crime (OTI-C) Weeks 1, 5, 9, 13, 19

Substance Use and Sex Index (SUSI) Weeks 1, 5, 9, 13, 19

Measures for the Cost Effectiveness Analysis

EuroQol- 5D (EQ5D) (63) Weeks 1, 5, 9, 13, 19

Health Service Utilisation Weeks 1, 5, 9, 13, 19

Work Productivity Questionnaire (64) Weeks 1, 5, 9, 13, 19

Opiate Treatment Index – Crime (OTI-C) – additional questions Weeks 1, 5, 9, 13, 19

Travel Time and Costs Week 5

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Randomisation

Eligible participants will be randomised to receive either the lisdexamfetamine or a placebo medication (see

Figure 1). A computer-generated randomisation schedule has been developed by an independent statistician

and uploaded to the study database. Randomisation will be performed by the trial site pharmacist within the

study database. The randomisation component of the database has been safe guarded with specific user

rights allowing only the trial site pharmacist, the statistician and the chair of the Independent Data Safety

Monitoring Committee (IDSMC) to access randomisation allocations. Study participants, investigators, clinical

and research staff will be blinded to the treatment condition allocated to reduce the risk of bias. Emergency

unbinding will be permitted if required for safety of a participant, ongoing safe conduct of the trial or in the

case of pregnancy.

Intervention

Oral lisdexamfetamine dimesylate 50 mg capsules will be used to make up the prescribed study dose. Trial

medications will be obtained, prepacked in child resistant blister packs, stored and transported to

participating sites by a contracted Good Manufacturing Practice registered facility in accordance with the

Poisons and Therapeutic Goods Act 1966 and the Poisons and Therapeutic Goods Regulation 2008.

The active drug (lisdexamfetamine dimesylate) and the placebo shall be provided in identical capsules to

ensure the study blind.

Eligible participants enrolled in the study will commence with 7 days of 150mg lisdexamfetamine or placebo

daily (the induction phase) (34, 35). They will attend the clinic for the first five days for supervised

administration of the study medication, recording of blood pressure, pulse and temperature, monitoring of

adverse events and medication adherence counselling. On the fifth day the participant will be provided with

two additional doses self-administer orally once a day. If the induction phase is tolerated, the participant

will progress to the 250mg lisdexamfetamine/placebo 12-week maintenance phase.

During the maintenance phase, participants will visit the clinic twice per week for a nursing review where

vital signs will be recorded, adverse events monitored and medication adherence counselling undertaken.

On the visit days, the administration of the dose for that day will be observed by the study nurse and

participants will be provided with two or three days’ supply of the lisdexamfetamine/placebo to take home

for self-administration until the next clinic visit. Participants will be required to return study medication

packs for pill counts. A urine sample will be provided at each of the twice-weekly visits, one of which will be

randomly selected according to a predetermined randomised schedule and sent for testing at the end of the

study for the presence of methamphetamine, and the other stored for future use. Once each week study

personnel will collect self-reported methamphetamine use for the previous week.

Participants will undergo a medical review every four weeks during the maintenance phase (weeks 5, 9 and

13), as well as neurocognitive testing and questionnaire completion as outlined in Table 1.

If the participant experiences a grade 2 or 3 adverse event at any time that is considered to be related to the

study drug, the study doctor shall consult with the Trial Chairperson about the option of withholding one

dose. If a dose is withheld the participant will be reviewed by the study doctor the following day, or sooner

as clinically indicated. If the adverse event is resolved the following day, the dose can be recommenced and

the participant will be reviewed the subsequent day. If the adverse event is not resolved or recurs after

recommencing, the study doctor will then consult with the Trial Chairperson with regards to ceasing the

medication and withdrawing the participant from the treatment component of the study.

During the reduction phase the dose will be tapered so as to minimise any drug discontinuation effects. The

dose will be reduced to 150mg lisdexamfetamine or placebo daily for 1 week, then 50mg lisdexamfetamine

or placebo daily for one week and then ceased.

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Lisdexamfetamine will not be available for the management of methamphetamine dependence following

completion of the study. However, ongoing treatment will be individualised to the participant and outlined

in a treatment plan which will be developed at Week 13 by the study doctor.

Subjects will have a follow-up visit 4 weeks after cessation of the reduction phase (week 19).

Participants will be reimbursed with a supermarket voucher (that cannot be spent on alcohol or cigarettes)

at weeks 1, 5, 9, 13 and 19. Reimbursements will start at $20 and increase by $10 each month until the

follow-up visit.

All participants will be offered counselling representing best practice treatment as usual. This will consist of

four sessions of CBT of up to one hour per session (38), specially designed for and validated in the study

population and delivered by trained therapist who will receive supervision monthly.

In addition to safety concerns (including acute psychosis, suicidal or homicidal ideation) or pregnancy,

participants may be withdrawn from the study if they are absent from study treatment for more than 2

consecutive weeks. They will also be withdrawn from the study if they become subject to drug testing for

legal or occupational reasons (due to the risk of unblinding to group allocation).

Statistical Methods

All efficacy analyses will use an intention-to-treat (ITT) approach. ITT will be defined as all randomized

patients who received at least one dose of the prescribed medication. The primary efficacy measure is the

change from baseline in days of methamphetamine use self-reported for the last 28 days at week 13. A

likelihood-based mixed model repeated measures (MMRM) approach will be used for the primary efficacy

analysis. The difference between two groups at week 13 will be the primary comparison, and differences at

week 5, 9 and 19 will also be examined. No imputation of missing data will be performed under MMRM

approach, the MMRM analysis makes use of all available data and is reliable for effect and standard error

estimates under missing at random (MAR) assumption(65). Sensitivity analysis including baseline observation

carried forward imputation will be performed to investigate the robustness of results to the departure from

MAR assumption.

Secondary measures of the intervention effect will include total number of days of self-report MA use over

the 12 week active treatment period; longest period of abstinence during treatment period; percentage of

achieving >= 21 days abstinence; percentage of MA negative urines 4 weeks prior to week 12; craving,

withdrawal, dependence, retention, blood borne virus transmission risk behaviour, criminal behaviour, as

well measures of abuse liability, physical and mental health, other substance use, cognitive performance,

psychosocial functioning, and treatment satisfaction. Statistical analysis strategies (t-test, Mann–Whitney U

test, Chi-square test, linear/generalised linear regression, and mixed model analysis) will be used for

secondary outcomes based on the type and distribution of the outcome measures. Kaplan-Merrier curve, log

rank test and Cox proportional hazard model will be applied in the time to event data analysis.

Analysis of urine drug screen (UDS) results will follow established techniques for similar drug trials

(Treatment Effectiveness Score (66)), calculated as a proportion (%) of UDS negative for methamphetamine

out of total of 12 possible UDS (with missing tests counted as positive).

All patients enrolled in the study will be evaluated with respect to safety-related outcomes. Safety data will

be analysed according to the treatment that the patients actually received. Safety analyses will include

summaries of the incidence of all adverse events that are possibly or probably treatment related, that occur

during the study treatment period or within 30 days of the last dose of study treatment.

Additionally, the study will assess the cost effectiveness of lisdexamfetamine relative to the placebo control.

The primary outcome will be Quality Adjusted Life Years measured by the EQ-5D-5L. Costs will include

clinical resources, other health care, crime, productivity and personal costs. The costs will be summed and

combined with the outcome measure, and the incremental cost-effectiveness ratio calculated.

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All tests of the treatment effect will be conducted at a two-sided alpha level of 0.05.

Interim analyses will be performed when the 50th patient has completed treatment or 6 months after the

commencement of recruitment, whichever comes first.

An Independent Data Safety Monitoring Committee (IDSMC) will monitor the progress of the study with the

aim of safeguarding trial participants by assessing the safety and efficacy of the drug being investigated in

the trial. The IDSMC may recommend stopping the trial if the number and/or severity of adverse events

justify discontinuation of the study; on the basis of a positive efficacy result only when the primary endpoint

(methamphetamine use) data are truly compelling and the risk of a false positive conclusion is acceptably

low (p<0.001 for primary endpoint); if accrual rates are too low and/or that noncompliance is too great to

provide adequate power for identifying the specified benefit; it becomes clear that successful completion of

the study is not feasible.

Data Statement

Study data will be collected and managed using REDCap electronic data capture tools hosted at Hunter New

England Local Health District]. REDCap (67)1

(Research Electronic Data Capture) is a secure, web-based

application designed to support data capture for research studies, providing: 1) an intuitive interface for

validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated

export procedures for seamless data downloads to common statistical packages; and 4) procedures for

importing data from external sources.


Prior to an individual’s participation in the trial, he/she shall be fully informed about the research and given

ample time and opportunity to inquire about details and decide whether or not to participate. If they agree

to participate they will be asked to sign the study specific consent form. Participants will also be invited to

consent for their urine samples to be stored for future research

To ensure anonymity and to limit disclosure, participants will be assigned a unique identifier at the time of

randomisation. Results arising from the main study will be published in peer-reviewed journals, and

disseminated at international conferences. Results will be reported in such a manner that participants will

not be identifiable in any way.

All data will be considered the property of the Trial Chairperson who, in consultation with the Trial

Management Committee, will be responsible for presentations and publications arising from this trial.

Discussion

This is the first Phase III trial of lisdexamfetamine for methamphetamine dependence. The strength of this

study is in its proposed sample size, powered to detect a medium effect size in between group differences in

the primary outcome (days of methamphetamine use), using a higher dose of agonist medication (more than

triple) used typically for the treatment of ADHD. Participants will be closely monitored with twice weekly

clinic visits and nursing reviews and monthly medical reviews. Twice weekly dispensing will promote

retention in the study, and prevent high drop-out rates experienced in other studies (68). The study protocol

proposes to deliver the medication in an outpatient setting allowing participants take-home dosing to more

closely mimic the service delivery situations in which the medication may be used and provide some

indication. Limitations of the study include the fixed dose design, active treatment restricted to 12 weeks

and twice weekly observed dosing. If efficacious further dose-response relationship studies may be indicated

to explore optimum duration of treatment and a reducing regimen. If successful the intervention will provide

a much needed therapeutic adjunct for people who are dependent on methamphetamine.

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OTHER INFORMATION

Patient involvement

The initial concept of investigating the use of lisdexamfetamine in reducing methamphetamine use in

people who are dependent on methamphetamine was proposed by a patient who prefers to be unnamed.

No other patients were involved in setting the research question or the outcome measures, nor have they

been involved in developing plans for design or implementation of the study.

Author Contributions

The study was conceived and designed by NL, AD, NE and RA. Significant contributions to the development

and conceptualisation of the protocol was made by NE, AD, NL, RA, MH, BC, RM, RB, NP, AC, JW, ZL, MS and

AB. KD contributed to the design of the protocol. BC and MH wrote the first draft of the article with

significant input from NE. RM, ZL, MS and AB critically revised the article for intellectual content.

Acknowledgments

We thank Andrew Dawson (Royal Prince Alfred Hospital), Anthony Gill and Craig Rodgers (St. Vincent’s

Hospital Sydney, Australia), James Ward and Michael Farrell (UNSW Sydney, Australia), Mark Montebello

(Northern Sydney Local Health District Drug and Alcohol Service, St Leonards, Australia) and Ian Richards

and Will Liaw (Drug and Alcohol Services South Australia) for insightful comments on the protocol of the

study.

Funding

This study is funded largely by the National Health and Medical Research Council (NHMRC), Australia

(APP1109466) and the St Vincent’s Curran Foundation, Australia. The contents of the published material

are solely the responsibility of the individual authors and do not reflect the views of the NHMRC nor the

Curran Foundation.

Conflicts of Interests

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf.

(available on request from the corresponding author) and have the following declarations: AC reports

grants, personal fees and non-financial support from Gilead Sciences, grants, personal fees and nonfinancial

support from ViiV Healthcare, grants and personal fees from MSD and personal fees from Mayne

Healthcare, outside the submitted work; RB has received investigator-initiated untied educational grants

from Reckitt Benckiser/Indivior for the development of an opioid-related behavior scale and a study of

opioid substitution therapy uptake among chronic non-cancer pain patients and has received an untied

educational grant from Mundipharma for a post-market study of oxycodone. NL reports personal fees from

Indivior, personal fees from Mundipharma, grants from Braeburn Pharmaceuticals outside the submitted

work. AD reports grants from Braeburn Pharmaceuticals during the conduct of the study. All remaining

authors have nothing to declare and have no support from any organisation or any other relationships or

activities that could appear to have influenced the submitted work.

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Trial Registration number

Australian New Zealand Clinical Trials Registry: ACTRN12617000657325 (registered 08 May 2017)

Figure legend

Figure 1. Trial Schema: Potential participants will be screened for eligibility. Individuals that meet the

eligibility criteria and provide written informed consent to participate will be randomised to

lisdexamfetamine or a placebo medication. Treatment will be for 15 weeks with a follow visit 4 weeks post

treatment.

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Figure 1. Trial Schema: Potential participants will be screened for eligibility. Individuals that meet the eligibility criteria and provide written informed consent to participate will be randomised to lisdexamfetamine

or a placebo medication. Treatment will be for 15 weeks with a follow visit 4 weeks post treatment.

297x420mm (300 x 300 DPI)

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CONSORT 2010 checklist Page 1

CONSORT 2010 checklist of information to include when reporting a randomised trial*

Section/Topic Item No Checklist item

Reported on page No

Title and abstract

1a Identification as a randomised trial in the title 1

1b Structured summary of trial design, methods, results, and conclusions (for specific guidance see CONSORT for abstracts) 2

Introduction

Background and

objectives

2a Scientific background and explanation of rationale 3, 4

2b Specific objectives or hypotheses 4

Methods

Trial design 3a Description of trial design (such as parallel, factorial) including allocation ratio 4

3b Important changes to methods after trial commencement (such as eligibility criteria), with reasons n/a

Participants 4a Eligibility criteria for participants 5

4b Settings and locations where the data were collected 5

Interventions 5 The interventions for each group with sufficient details to allow replication, including how and when they were

actually administered

7

Outcomes 6a Completely defined pre-specified primary and secondary outcome measures, including how and when they

were assessed

8

6b Any changes to trial outcomes after the trial commenced, with reasons n/a

Sample size 7a How sample size was determined 5

7b When applicable, explanation of any interim analyses and stopping guidelines 9

Randomisation:

Sequence

generation

8a Method used to generate the random allocation sequence 7

8b Type of randomisation; details of any restriction (such as blocking and block size) 7

Allocation

concealment

mechanism

9 Mechanism used to implement the random allocation sequence (such as sequentially numbered containers),

describing any steps taken to conceal the sequence until interventions were assigned

7

Implementation 10 Who generated the random allocation sequence, who enrolled participants, and who assigned participants to

interventions

7

Blinding 11a If done, who was blinded after assignment to interventions (for example, participants, care providers, those 7

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CONSORT 2010 checklist Page 2

assessing outcomes) and how

11b If relevant, description of the similarity of interventions n/a

Statistical methods 12a Statistical methods used to compare groups for primary and secondary outcomes 8

12b Methods for additional analyses, such as subgroup analyses and adjusted analyses 8

Results

Participant flow (a

diagram is strongly

recommended)

13a For each group, the numbers of participants who were randomly assigned, received intended treatment, and

were analysed for the primary outcome

n/a

13b For each group, losses and exclusions after randomisation, together with reasons n/a

Recruitment 14a Dates defining the periods of recruitment and follow-up n/a

14b Why the trial ended or was stopped n/a

Baseline data 15 A table showing baseline demographic and clinical characteristics for each group n/a

Numbers analysed 16 For each group, number of participants (denominator) included in each analysis and whether the analysis was

by original assigned groups

n/a

Outcomes and

estimation

17a For each primary and secondary outcome, results for each group, and the estimated effect size and its

precision (such as 95% confidence interval)

n/a

17b For binary outcomes, presentation of both absolute and relative effect sizes is recommended n/a

Ancillary analyses 18 Results of any other analyses performed, including subgroup analyses and adjusted analyses, distinguishing

pre-specified from exploratory

n/a

Harms 19 All important harms or unintended effects in each group (for specific guidance see CONSORT for harms) n/a

Discussion

Limitations 20 Trial limitations, addressing sources of potential bias, imprecision, and, if relevant, multiplicity of analyses 9

Generalisability 21 Generalisability (external validity, applicability) of the trial findings n/a

Interpretation 22 Interpretation consistent with results, balancing benefits and harms, and considering other relevant evidence n/a

Other information

Registration 23 Registration number and name of trial registry 10

Protocol 24 Where the full trial protocol can be accessed, if available 10

Funding 25 Sources of funding and other support (such as supply of drugs), role of funders 10

*We strongly recommend reading this statement in conjunction with the CONSORT 2010 Explanation and Elaboration for important clarifications on all the items. If relevant, we also

recommend reading CONSORT extensions for cluster randomised trials, non-inferiority and equivalence trials, non-pharmacological treatments, herbal interventions, and pragmatic trials.

Additional extensions are forthcoming: for those and for up to date references relevant to this checklist, see www.consort-statement.org.

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LiMA: A study protocol for a randomised, double blind,

placebo controlled trial of lisdexamfetamine for the


Journal: BMJ Open

Manuscript ID bmjopen-2017-020723.R1

Article Type: Protocol

Date Submitted by the Author: 25-May-2018

Complete List of Authors: Ezard, Nadine; St Vincents Hospital; University of New South Wales - Randwick Campus Dunlop, Adrian; Hunter New England Local Health District, Drug and

Alcohol Clinical Services; University of Newcastle Hall, Michelle; Hunter New England Local Health District, Drug and Alcohol Clinical Services Ali, Robert; University of Adelaide McKetin, Rebecca; Curtin University Australia-Asia-Pacific Institute Bruno, Raimondo; University of Tasmania Nghi, Phung; Western Sydney Local Health District Carr, Andrew; St. Vincent's Hospital White, Jason; University of South Australia Clifford, Brendan; St. Vincent's Hospital; University of Sydney Liu, Zhixin; University of New South Wales - Randwick Campus Shanahan , Marian Shanahan ; National Drug and Alcohol Research Centre

Dolan, Kate; National Drug and Alcohol Research Centre Baker, Amanda; University of Newcastle, Lintzeris, Nicholas; South East Sydney Local Health District, The Langton Centre; University of Sydney

<b>Primary Subject Heading</b>:

Addiction

Secondary Subject Heading: Addiction

Keywords: Methamphetamine, Study protocol, Lisdexamfetamine, Pharmacotherapy, Stimulant use disorder


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Page 1 of 15

TITLE PAGE

Title of article

LiMA: a study protocol for a randomised, double blind, placebo controlled trial of lisdexamfetamine for the


Corresponding author

Michelle Hall

Newcastle Community Health Centre

Drug and Alcohol Clinical Services

Level 3, 670 Hunter St

Newcastle, 2300, NSW

T: + 61 2 40164781

E: [email protected]

Co-authors

Nadine Ezard1,2, Adrian Dunlop3,4, Michelle Hall3, Robert Ali6,2 , Rebecca McKetin5, Raimondo Bruno8, , Nghi

Phung7, Andrew Carr1,2, Jason White8, Brendan Clifford1,11, Zhixin Liu2 Marian Shanahan10, Kate Dolan10,

Amanda Baker4, Nicholas Lintzeris

11,12

1St. Vincent's Hospital, Sydney, NSW, Australia

2UNSW, Sydney, NSW, Australia

3Hunter New England Drug and Alcohol Clinical Services, Newcastle, NSW, Australia

4 School of Medicine and Public Health, University of Newcastle, Newcastle, NSW, Australia

5Curtin University, Perth, WA, Australia

6University of Adelaide, Adelaide, SA, Australia

7Western Sydney Local Health District, Sydney, NSW, Australia

8University of South Australia, Adelaide, SA, Australia

9University of Tasmania, Hobart, TAS, Australia

10National Drug and Alcohol Research Centre, UNSW Sydney, NSW, Australia

11University of Sydney, Sydney, NSW and

12South East Sydney Local Health District, Sydney, NSW, Australia

Key Words

Methamphetamine, Study protocol, Lisdexamphetamine, Pharmacotherapy, Stimulant use disorder

Word count

4474 (excluding title page, abstract, references, figures and tables)

ABSTRACT

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Introduction

Methamphetamine dependence is a growing public health concern. There is currently no pharmacotherapy

approved for methamphetamine dependence. Lisdexamfetamine dimesylate, used in the treatment of

Attention-Deficit Hyperactivity Disorder (ADHD) and binge eating disorder, has potential as an agonist

therapy for methamphetamine dependence, and possible benefits of reduced risk of aberrant use due to its

novel formulation.

Methods and analysis

A double-blind randomised controlled trial will be used to evaluate the efficacy of lisdexamfetamine in

reducing methamphetamine use. The target sample is 180 participants with methamphetamine

dependence of ≥ 2 years, using ≥ 14 days out of the previous 28, who have previously attempted but not

responded to treatment for methamphetamine use. Participants will be randomly assigned to receive

either a 15-week intervention consisting of induction (1 week of 150mg lisdexamfetamine (LDX) or

placebo), maintenance (12 weeks of 250mg LDX or placebo) and reduction (1 week of 150mg LDX or

placebo and 1 week of 50mg LDX or placebo). All participants will be given access to 4 sessions of CBT as

treatment-as-usual and receive a 4-week follow up appointment. The primary outcomes are efficacy

(change from baseline in days of methamphetamine use by self-report for the last 28 days at week 13, and

urinalyses confirmation of methamphetamine use) and safety (treatment related adverse events).

Secondary outcomes are total number of days of self-report MA use over the 12 week active treatment,

longest period of abstinence during treatment period, percentage of achieving >= 21 days abstinence,

craving, withdrawal, dependence, retention, blood borne virus transmission risk behaviour, criminal

behaviour, as well measures of abuse liability, physical and mental health, other substance use, cognitive

performance, psychosocial functioning, treatment retention and satisfaction. Additionally, the study will

assess the cost effectiveness of lisdexamfetamine relative to the placebo control.




Results arising from the main study will be published in peer-reviewed journals, and disseminated at

international conferences. Results will be reported in such a manner that participants will not be

identifiable in any way.

ARTICLE SUMMARY

Strengths and limitations of this study

• The study design is a prospective, randomised controlled trial

• Strength in methods include allocation concealment, blinding, compliance measuring, dropout

measuring and analyses of results by intention to treat.

• The fixed dose design is a limitation; if efficacious, further dose-response relationship studies may

be indicated

• The duration of active treatment is limited to 12 weeks, if efficacious further studies will be needed

to explore optimum duration of treatment and a reducing regimen

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BACKGROUND

Methamphetamine is a synthetic stimulant of growing global public health importance and an important

contributor to the global burden of disease (1). There are an estimated 34 million people worldwide who

use the drug, and an estimated 17 million who are dependent on methamphetamine (2).

Australia has one of the highest documented rates of methamphetamine dependence in the world, with

160,000 people estimated to be dependent during 2013/14 (1). Methamphetamine dependence is

estimated to cost Australia around $5 billion a year, an economic impact which could be reduced by

effective treatments (3, 4). Methamphetamine dependence is associated with a range of negative health

outcomes including psychosis, depression, anxiety, blood-borne virus transmission, sexually transmissible

infections, and cardiovascular and cerebrovascular events (5). These problems are most prevalent among

people who use methamphetamine on a heavy or regular basis (6), highlighting the need for effective

treatments for this group.

There is no approved medication for the treatment of methamphetamine dependence. The current

standard treatment for methamphetamine dependence relies on psychosocial interventions, primarily

Cognitive Behaviour Therapy (CBT)-based approaches (7). Such approaches produce small to medium

reductions in methamphetamine use in controlled studies (d = 0.53 (8)). However, CBT approaches require

a substantial investment by trained therapists, there is often poor engagement with counselling by

methamphetamine users, and cognitive impairment associated with severe methamphetamine

dependence may limit CBT effectiveness (7). Poorer treatment outcomes are seen in methamphetamine

users who use frequently (those using methamphetamine at least 15 days out of the previous 30 days at

treatment entry), than in less frequent users (9), highlighting the need for more effective treatment

approaches for such individuals.

Many authors have highlighted the potential role of substitution agonist treatment for methamphetamine

dependence (10). The theoretical base for agonist prescription is consistent with the rationale for existing

agonist substitution for nicotine and opioid dependence. Agonist substitution therapies aim to replace

harmful drug use with safer alternatives in terms of dose, route of administration and adverse effects.

Long-acting agonists can reduce amphetamine withdrawal (11), craving (12), and decrease the euphoriant

and reinforcing effects of extra (illicit) stimulant use due to cross-tolerance (13). Agonist treatment also

provides a framework for regular ongoing healthcare and psychosocial interventions with this high-risk

population, enabling patients to distance themselves from illicit drug networks and related crime.

Agonist therapies for methamphetamine dependence show promise. A number of ‘weak’ stimulant agonist

therapies have been studied, including methylphenidate and modafinil (14). A recent systematic review

showed no benefit over placebo for any of these medications, noting limitations in retention and power of

published studies (15). Dexamphetamine, a more direct monoamine agonist that more closely mimics the

effects of methamphetamine, has been used clinically for amphetamine and methamphetamine

dependence in the United Kingdom (in doses ranging from 20mg to 200mg) for some time (16, 17), and in

New South Wales, Australia, since 2006, at doses up to 80mg (18). This experience suggests

dexamphetamine substitution treatment may be useful in retaining a difficult to engage group of severely

dependent methamphetamine users who do not respond to stand-alone psychosocial interventions.

Previous studies from methamphetamine dependent (19-21) subjects found no serious consequences of

dexamphetamine in doses from 30 - 110mg/day (22).

While a statistically significant benefit on methamphetamine use has not been established with

dexamphetamine pharmacotherapy, feasibility has been demonstrated with 60mg dexamphetamine/day

(equivalent to 150mg lisdexamfetamine) (19). Studies with sustained-release dexamphetamine (SR-DXA)

formulations have shown increased retention in treatment at up to 110mg SR-DXA/daily (mean dose of

80mg SR-DXA daily) (20), and decreased craving and withdrawal symptoms in a study using 60mg SR-DXA

(21). This latter study (n=60) with a treatment duration of 8 weeks concluded that further studies should

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test a longer treatment duration, that higher doses of dexamphetamine could be warranted due to possible

physiological tolerance, and that larger sample sizes are required (21).

Lisdexamfetamine, a pharmacologically inactive prodrug, is absorbed after oral administration and is

hydrolysed to inactive l-lysine and active dexamphetamine by red blood cells (23). It has a slower onset,

lower peak concentration, and longer duration of action than dexamphetamine (24). It is metabolised

rapidly to dexamphetamine: the peak plasma concentration occurs 3 hours after dosing. The plasma half-

life (t½) of dexamphetamine is 10 hours (25), with plasma dexamphetamine concentrations reaching steady

state at day 5 of once-daily lisdexamfetamine dosing (24). There is no plasma accumulation of

lisdexamfetamine (26). The conversion time from lisdexamfetamine to dexamphetamine results in a more

blunted effect on brain dopamine than immediate release dexamphetamine (27) and, as a consequence, it

has a more moderate reinforcing effect in self-administration studies due to the slower onset of peak

effects than other stimulant drugs (28).

Abuse liability studies of lisdexamfetamine with doses of up to 150mg indicate it has significantly less

propensity for abuse-related ‘liking’ when compared to dexamphetamine or diethylpropion (29). The lower

abuse liability of lisdexamfetamine, due to its rate-limited hydrolysis, attenuated onset and intensity of

amphetamine-like effects, and more moderate reinforcing properties thus reduce the need for supervised

dosing.

There have been no published randomised controlled trials of lisdexamfetamine for methamphetamine

dependence. Mooney et al (30) were unable to show a significant change in cocaine use, though the study

used a lower dose of 70mg lisdexamfetamine, and failed to reach its planned sample size. The

maintenance dose of 250mg lisdexamfetamine represents equivalence to current dexamphetamine

regimes for methamphetamine dependence (31). This dose has also been tolerated by non-

methamphetamine dependent volunteers in a pharmacokinetic study (32), as well as in a study in

participants with schizophrenia receiving anti-psychotic pharmacotherapy (33). A recent safety dose-

escalating trial of methamphetamine dependent participants with high frequency of use (34) successfully

escalated 14 out of 16 participants to 250mg lisdexamfetamine (35)].

OBJECTIVES

The objective of the current trial was to test the efficacy of lisdexamfetamine for reducing

methamphetamine use among people with methamphetamine dependence, who had not previously

responded to psychosocial treatments.

We hypothesise that treatment with oral lisdexamfetamine will result in significantly reduced

methamphetamine use at 13 weeks compared to placebo in people who are dependent on

methamphetamine. The primary objectives of the study are efficacy and safety of 250mg of

lisdexamfetamine in reducing methamphetamine use after 13 weeks of treatment. Secondary objectives

are to examine the changes in physical and mental health, cognitive and psychosocial functioning and well-

being between lisdexamfetamine and placebo groups, as well as differences in retention rates, craving and

withdrawal symptoms, and severity of dependence. Other secondary objectives are to examine differences

in blood borne virus transmission risk behaviour, criminality, and in use of alcohol and other drugs between

groups, as well as the abuse liability profile of lisdexamfetamine and the cost effectiveness of


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METHODS

Trial Design

This project is a randomised double-blind placebo controlled fixed dose parallel design comparing a 12-

week maintenance course of 250mg lisdexamfetamine daily to placebo.

Sample Size

The sample size calculation is based on data from the existing NSW Stimulant Treatment Program clients

(31) who meet inclusion criteria. Such clients showed a reduction from a mean of 19 day of use out of 28

days at pre-treatment to a mean of 9 days /28 days with standard deviation (SD) of 9 days at 12 weeks

post-treatment. To detect a mean difference of 4.5 days (9 days in control vs. 4.5 days in the

lisdexamfetamine group out of 28 days) at week 13 (12 weeks post treatment), assuming a pooled SD of 9

days (i.e. d=0.5, a median clinically relevant effect size), with over 80% power at two-sided significance level

of 0.05, a sample size of 126 (63 per group) is required (10). Conservatively estimating a 30% attrition from

research follow-up (previous trials have achieved follow-up of 81% at 12 weeks (27), 90 participants per

group will be recruited – 180 in total.

Participants

This study is being conducted in sites experienced in delivering and evaluating interventions in people who

are dependent on methamphetamine. The participating sites are located in New South Wales (NSW) and

South Australia (SA).

The study population is treatment seeking adults with long-standing (≥12 months) methamphetamine

dependence who have failed to respond to previous methamphetamine treatment attempts. Participants

will be aged 18 to 65 years, meet ICD-10 criteria for methamphetamine dependence and self-report

methamphetamine use of ≥14 days out of the previous 28. Prior use of methamphetamine will be verified

by urinalysis. Failure to respond to previous treatment is defined as relapse to dependent use within one

month of completing treatment. Participants must be willing and able to comply with study requirements,

be able to store study medications securely, and be able to provide written, informed consent.

Exclusion criteria are sensitivity or previous adverse reaction to lisdexamfetamine, concurrent use or use

within the previous 14 days of medications with possible interaction with lisdexamfetamine. Known

contraindications for lisdexamfetamine are also exclusion criteria. Individuals with severe medical

disorders, including cardiovascular disease, untreated hypertension and peripheral vascular disease, will be

ineligible, as will those with severe psychiatric disorders. Those currently in counselling for

methamphetamine dependence or who have been prescribed dexamphetamine or modafinil (in the four

weeks prior to assessment) will be ineligible. Other exclusion criteria are dependent use of alcohol or other

drugs, exposure to another investigational drug within the 4 weeks prior to screening, unavailability for

follow-up, pregnant or lactating women and receipt of current pharmacotherapy treatment for opioid

dependence.

Four specialist outpatient stimulant treatment centres in New South Wales and South Australia will recruit

participants. Potential participants will be pre-screened in person or by telephone by a researcher, and if

potentially eligible invited to attend for a formal eligibility assessment by a specialist in addiction medicine.

The assessment schedule, including eligibility assessments, is outlined in Table 1.

Table 1. Assessments and procedures: Eligible participants will be required to attend the clinic daily for the

first five days of treatment. On day 5 they will be provided with 2 days’ supply of study medication to take

at home.

For the remainder of the treatment period participants will attend the clinic twice a week for supervised

dosing, safety assessments, provision of urine sample and collection of take home doses. Research visits

will occur every four weeks until week 19.

Demographics and Baseline Assessments

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Demographics Screening

Medical Screening Screening

Substance Use History and Treatment Screening

Columbia Suicide Severity Rating Scale – Screening (CSSRS) (36) Screening

Enriched Social Support Inventory (ESSI) Week 1

Wender-Utah Rating Scale (WURS)(37) Week 1

Intervention and counselling

Lisdexamfetamine or Placebo Weeks 1 to 15

Baker et al. 4 session CBT (38) Weeks 2 to 13 (4 sessions at least 2 weeks apart)

Efficacy and Safety Measures


Time Line Follow Back (Methamphetamine only - Past 7 days) Weeks 2, 3, 4, 6, 7, 8, 10, 11, 12, 14, 15

Medication Adherence (40) Weeks 1 to 15 (twice weekly)

Treatment Satisfaction Questionnaire (TSQM) (41) plus testing blind Weeks 5, 9, 13, 19

Adverse Events Weeks 1 to 15 (twice weekly) and Week 19

Urine Drug Screen Screening and Weeks 1 to 15 (twice weekly)

Vital signs (temperature, blood pressure, heart rate, respiratory rate) Screening and Weeks 1 to 15 (twice weekly)

Concomitant Medications Screening and Weeks 1 to 15 (twice weekly)

Electrocardiogram Screening and Weeks 5, 9, 13

Pregnancy testing (if applicable) Screening and Weeks 1, 5, 9, 13

Medical Assessment – Since last visit Screening and Weeks 1, 5, 9, 13, 19

Columbia Suicide Severity Rating Scale – Since last visit (CSSRS)(36) Screening and Weeks 1, 5, 9, 13, 19

Brief Psychiatric Rating Scale – 4 items (BPRS) (42) Screening and Weeks 1, 5, 9, 13, 19

Review by study doctor Weeks 1, 5, 9, 13 and last day of treatment

Measures of physical and mental health and cognitive and psychosocial functioning

Patient Health Questionnaire – 15 (PHQ15)(43) Weeks 1, 5, 9, 13, 19

Depression & Anxiety Survey Scale (DASS21)(44) Weeks 1, 5, 9, 13, 19

World Health Organization Quality of Life (WHOQOL-BREF) Weeks 1, 5, 9, 13, 19

Insomnia Severity Index (ISI) (45) Weeks 1, 5, 9, 13, 19

Neurocognitive testing batteries (combinations of the following):

(MOCA) (46), (WTAR) (47), RAVLT (48-50) RVIP (50, 51), N-Back (52), Trail

making test (53-56), Flankers (51, 57), Digit-Symbol (58, 59)

Screening and Weeks 1, 5, 9, 13, 19

Measures of cravings, withdrawal and severity of dependence

Amphetamine Withdrawal Questionnaire (AWQ) (60) Weeks 1, 5, 9, 13, 19

Visual Analogue Scale for Cravings (61) Weeks 1, 5, 9, 13, 19

Severity of Dependence Scale (SDS) (62) Weeks 1, 5, 9, 13, 19

Measures of abuse liability, other drug use, risk behaviour and crime

Drug Evaluation Questionnaire (DEQ5) Weeks 1, 5, 9, 13, 19


Urine Drug Screen Weeks 1 to 15 (twice weekly)

Opiate Treatment Index - Injecting Practices (OTI-I) Weeks 1, 5, 9, 13, 19

Opiate Treatment Index - Crime (OTI-C) Weeks 1, 5, 9, 13, 19

Substance Use and Sex Index (SUSI) Weeks 1, 5, 9, 13, 19

Measures for the Cost Effectiveness Analysis

EuroQol- 5D (EQ5D) (63) Weeks 1, 5, 9, 13, 19

Health Service Utilisation Weeks 1, 5, 9, 13, 19

Work Productivity Questionnaire (64) Weeks 1, 5, 9, 13, 19

Opiate Treatment Index – Crime (OTI-C) – additional questions Weeks 1, 5, 9, 13, 19

Travel Time and Costs Week 5

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Randomisation

Eligible participants will be randomised to receive either the lisdexamfetamine or a placebo medication

(see Figure 1). A computer-generated randomisation schedule has been developed by an independent

statistician and uploaded to the study database. Randomisation will be performed by the trial site

pharmacist within the study database. The randomisation component of the database has been safe

guarded with specific user rights allowing only the trial site pharmacist, the statistician and the chair of the

Independent Data Safety Monitoring Committee (IDSMC) to access randomisation allocations. Study

participants, investigators, clinical and research staff will be blinded to the treatment condition allocated to

reduce the risk of bias. Emergency unbinding will be permitted if required for safety of a participant,

ongoing safe conduct of the trial or in the case of pregnancy.

Intervention

Oral lisdexamfetamine dimesylate 50 mg capsules will be used to make up the prescribed study dose. Trial

medications will be obtained, prepacked in child resistant blister packs, stored and transported to

participating sites by a contracted Good Manufacturing Practice registered facility in accordance with the

Poisons and Therapeutic Goods Act 1966 and the Poisons and Therapeutic Goods Regulation 2008.

The active drug (lisdexamfetamine dimesylate) and the placebo shall be provided in identical capsules to

ensure the study blind.

Eligible participants enrolled in the study will commence with 7 days of 150mg lisdexamfetamine or

placebo daily (the induction phase) (34, 35). They will attend the clinic for the first five days for supervised

administration of the study medication, recording of blood pressure, pulse and temperature, monitoring of

adverse events and medication adherence counselling. On the fifth day the participant will be provided

with two additional doses self-administer orally once a day. If the induction phase is tolerated, the

participant will progress to the 250mg lisdexamfetamine/placebo 12-week maintenance phase.

During the maintenance phase, participants will visit the clinic twice per week for a nursing review where

vital signs will be recorded, adverse events monitored and medication adherence counselling undertaken.

On the visit days, the administration of the dose for that day will be observed by the study nurse and

participants will be provided with two or three days’ supply of the lisdexamfetamine/placebo to take home

for self-administration until the next clinic visit. Participants will be required to return study medication

packs for pill counts. A urine sample will be provided at each of the twice-weekly visits, one of which will

be randomly selected according to a predetermined randomised schedule and sent for testing at the end of

the study for the presence of methamphetamine, and the other stored for future use. Once each week

study personnel will collect self-reported methamphetamine use for the previous week.

Participants will undergo a medical review every four weeks during the maintenance phase (weeks 5, 9 and

13), as well as neurocognitive testing and questionnaire completion as outlined in Table 1.

If the participant experiences a grade 2 or 3 adverse event at any time that is considered to be related to

the study drug, the study doctor shall consult with the Trial Chairperson about the option of withholding

one dose. If a dose is withheld the participant will be reviewed by the study doctor the following day, or

sooner as clinically indicated. If the adverse event is resolved the following day, the dose can be

recommenced and the participant will be reviewed the subsequent day. If the adverse event is not

resolved or recurs after recommencing, the study doctor will then consult with the Trial Chairperson with

regards to ceasing the medication and withdrawing the participant from the treatment component of the

study.

During the reduction phase the dose will be tapered so as to minimise any drug discontinuation effects. The

dose will be reduced to 150mg lisdexamfetamine or placebo daily for 1 week, then 50mg lisdexamfetamine

or placebo daily for one week and then ceased.

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Lisdexamfetamine will not be available for the management of methamphetamine dependence following

completion of the study. However, ongoing treatment will be individualised to the participant and outlined

in a treatment plan which will be developed at Week 13 by the study doctor.

Subjects will have a follow-up visit 4 weeks after cessation of the reduction phase (week 19).

Participants will be reimbursed with a supermarket voucher (that cannot be spent on alcohol or cigarettes)

at weeks 1, 5, 9, 13 and 19. Reimbursements will start at $20 and increase by $10 each month until the

follow-up visit.

All participants will be offered counselling representing best practice treatment as usual. This will consist of

four sessions of CBT of up to one hour per session (38), specially designed for and validated in the study

population and delivered by trained therapist who will receive supervision monthly.

In addition to safety concerns (including acute psychosis, suicidal or homicidal ideation) or pregnancy,

participants may be withdrawn from the study if they are absent from study treatment for more than 2

consecutive weeks. They will also be withdrawn from the study if they become subject to drug testing for

legal or occupational reasons (due to the risk of unblinding to group allocation).

Participants that have discontinued protocol treatment will be offered the opportunity continue to

participate in all remaining research interviews and assessments. For those participants that revoke their

consent for the entire study, no further data will be collected from the participant.

Statistical Methods

All efficacy analyses will use an intention-to-treat (ITT) approach. ITT will be defined as all randomized

patients who received at least one dose of the prescribed medication. The primary efficacy measure is the

change from baseline in days of methamphetamine use self-reported for the last 28 days at week 13. A

likelihood-based mixed model repeated measures (MMRM) approach will be used for the primary efficacy

analysis. The difference between two groups at week 13 will be the primary comparison, and differences at

week 5, 9 and 19 will also be examined. No imputation of missing data will be performed under MMRM

approach, the MMRM analysis makes use of all available data and is reliable for effect and standard error

estimates under missing at random (MAR) assumption(65). Sensitivity analysis including baseline

observation carried forward imputation will be performed to investigate the robustness of results to the

departure from MAR assumption.

Secondary measures of the intervention effect will include total number of days of self-report MA use over

the 12 week active treatment period; longest period of abstinence during treatment period; percentage of

achieving >= 21 days abstinence; percentage of MA negative urines 4 weeks prior to week 12; craving,

withdrawal, dependence, retention, blood borne virus transmission risk behaviour, criminal behaviour, as

well measures of abuse liability, physical and mental health, other substance use, cognitive performance,

psychosocial functioning, and treatment satisfaction. Statistical analysis strategies (t-test, Mann–Whitney U

test, Chi-square test, linear/generalised linear regression, and mixed model analysis) will be used for

secondary outcomes based on the type and distribution of the outcome measures. Kaplan-Merrier curve,

log rank test and Cox proportional hazard model will be applied in the time to event data analysis.

Analysis of urine drug screen (UDS) results will follow established techniques for similar drug trials

(Treatment Effectiveness Score (66)), calculated as a proportion (%) of UDS negative for methamphetamine

out of total of 12 possible UDS (with missing tests counted as positive).

All patients enrolled in the study will be evaluated with respect to safety-related outcomes. Safety data will

be analysed according to the treatment that the patients actually received. Safety analyses will include

summaries of the incidence of all adverse events that are possibly or probably treatment related, that occur

during the study treatment period or within 30 days of the last dose of study treatment.

Additionally, the study will assess the cost effectiveness of lisdexamfetamine relative to the placebo

control. The primary outcome will be Quality Adjusted Life Years measured by the EQ-5D-5L. Costs will

include clinical resources, other health care, crime, productivity and personal costs. The costs will be

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summed and combined with the outcome measure, and the incremental cost-effectiveness ratio

calculated.

All tests of the treatment effect will be conducted at a two-sided alpha level of 0.05.

Interim analyses will be performed when the 50th patient has completed treatment or 6 months after the

commencement of recruitment, whichever comes first.

An Independent Data Safety Monitoring Committee (IDSMC) will monitor the progress of the study with the

aim of safeguarding trial participants by assessing the safety and efficacy of the drug being investigated in

the trial. The IDSMC may recommend stopping the trial if the number and/or severity of adverse events

justify discontinuation of the study; on the basis of a positive efficacy result only when the primary

endpoint (methamphetamine use) data are truly compelling and the risk of a false positive conclusion is

acceptably low (p<0.001 for primary endpoint); if accrual rates are too low and/or that noncompliance is

too great to provide adequate power for identifying the specified benefit; it becomes clear that successful

completion of the study is not feasible.

Data Statement

Study data will be collected and managed using REDCap electronic data capture tools hosted at Hunter New

England Local Health District]. REDCap (67)1

(Research Electronic Data Capture) is a secure, web-based

application designed to support data capture for research studies, providing: 1) an intuitive interface for

validated data entry; 2) audit trails for tracking data manipulation and export procedures; 3) automated

export procedures for seamless data downloads to common statistical packages; and 4) procedures for

importing data from external sources.




Prior to an individual’s participation in the trial, he/she shall be fully informed about the research and given

ample time and opportunity to inquire about details and decide whether or not to participate. If they agree

to participate they will be asked to sign the study specific consent form. Participants will also be invited to

consent for their urine samples to be stored for future research

To ensure anonymity and to limit disclosure, participants will be assigned a unique identifier at the time of

randomisation. Results arising from the main study will be published in peer-reviewed journals, and

disseminated at international conferences. Results will be reported in such a manner that participants will

not be identifiable in any way.

All data will be considered the property of the Trial Chairperson who, in consultation with the Trial

Management Committee, will be responsible for presentations and publications arising from this trial.

Patient involvement

The initial concept of investigating the use of lisdexamfetamine in reducing methamphetamine use in

people who are dependent on methamphetamine was proposed by a patient who prefers to be unnamed.

No other patients were involved in setting the research question or the outcome measures, nor have they

been involved in developing plans for design or implementation of the study.

Discussion

This is the first Phase III trial of lisdexamfetamine for methamphetamine dependence. The strength of this

study is in its proposed sample size, powered to detect a medium effect size in between group differences

in the primary outcome (days of methamphetamine use), using a higher dose of agonist medication (more

than triple) used typically for the treatment of ADHD. Participants will be closely monitored with twice

weekly clinic visits and nursing reviews and monthly medical reviews. Twice weekly dispensing will promote

retention in the study, and prevent high drop-out rates experienced in other studies (68). The study

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protocol proposes to deliver the medication in an outpatient setting allowing participants take-home

dosing to more closely mimic the service delivery situations in which the medication may be used and

provide some indication. Limitations of the study include the fixed dose design, active treatment restricted

to 12 weeks and twice weekly observed dosing. If efficacious further dose-response relationship studies

may be indicated to explore optimum duration of treatment and a reducing regimen. If successful the

intervention will provide a much needed therapeutic adjunct for people who are dependent on

methamphetamine.

OTHER INFORMATION

Author Contributions

The study was conceived and designed by NL, AD, NE and RA. Significant contributions to the development

and conceptualisation of the protocol was made by NE, AD, NL, RA, MH, BC, RM, RB, NP, AC, JW, ZL, MS and

AB. KD contributed to the design of the protocol. BC and MH wrote the first draft of the article with

significant input from NE. RM, ZL, MS and AB critically revised the article for intellectual content.

Acknowledgments

We thank Andrew Dawson (Royal Prince Alfred Hospital), Anthony Gill and Craig Rodgers (St. Vincent’s

Hospital Sydney, Australia), James Ward and Michael Farrell (UNSW Sydney, Australia), Mark Montebello

(Northern Sydney Local Health District Drug and Alcohol Service, St Leonards, Australia) and Ian Richards

and Will Liaw (Drug and Alcohol Services South Australia) for insightful comments on the protocol of the

study.

Funding

This study is funded largely by the National Health and Medical Research Council (NHMRC), Australia

(APP1109466) and the St Vincent’s Curran Foundation, Australia. The contents of the published material

are solely the responsibility of the individual authors and do not reflect the views of the NHMRC nor the

Curran Foundation.

Conflicts of Interests

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf.

(available on request from the corresponding author) and have the following declarations: AC reports

grants, personal fees and non-financial support from Gilead Sciences, grants, personal fees and nonfinancial

support from ViiV Healthcare, grants and personal fees from MSD and personal fees from Mayne

Healthcare, outside the submitted work; RB has received investigator-initiated untied educational grants

from Reckitt Benckiser/Indivior for the development of an opioid-related behavior scale and a study of

opioid substitution therapy uptake among chronic non-cancer pain patients and has received an untied

educational grant from Mundipharma for a post-market study of oxycodone. NL reports personal fees from

Indivior, personal fees from Mundipharma, grants from Braeburn Pharmaceuticals outside the submitted

work. AD reports grants from Braeburn Pharmaceuticals during the conduct of the study. All remaining

authors have nothing to declare and have no support from any organisation or any other relationships or

activities that could appear to have influenced the submitted work.

Trial Registration number

Australian New Zealand Clinical Trials Registry: ACTRN12617000657325 (registered 08 May 2017)

Figure legend

Figure 1. Trial Schema: Potential participants will be screened for eligibility. Individuals that meet the

eligibility criteria and provide written informed consent to participate will be randomised to

lisdexamfetamine or a placebo medication. Treatment will be for 15 weeks with a follow visit 4 weeks post

treatment.

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Figure 1. Trial Schema: Potential participants will be screened for eligibility. Individuals that meet the eligibility criteria and provide written informed consent to participate will be randomised to lisdexamfetamine

or a placebo medication. Treatment will be for 15 weeks with a follow visit 4 weeks post treatment.

297x420mm (300 x 300 DPI)

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SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents*

Section/item Item No

Description Addressed on page number

Administrative information

Title 1 Descriptive title identifying the study design, population, interventions, and, if applicable, trial acronym __1__(Pg1 Manuscript)

Trial registration 2a Trial identifier and registry name. If not yet registered, name of intended registry __6__(Pg10 Manuscript)

2b All items from the World Health Organization Trial Registration Data Set __6,7__(N/A Manuscript)

Protocol version 3 Date and version identifier __All__(N/A Manuscript)

Funding 4 Sources and types of financial, material, and other support __6_(Pg13 Manuscript)

Roles and responsibilities

5a Names, affiliations, and roles of protocol contributors __6_( Pgs1,11 Manuscript)

5b Name and contact information for the trial sponsor __6__(N/A Manuscript)

5c Role of study sponsor and funders, if any, in study design; collection, management, analysis, and interpretation of data; writing of the report; and the decision to submit the report for publication, including whether they will have ultimate authority over any of these activities

__N/A (Included in CTRA_

5d Composition, roles, and responsibilities of the coordinating centre, steering committee, endpoint adjudication committee, data management team, and other individuals or groups overseeing the trial, if applicable (see Item 21a for data monitoring committee)

__38__(N/A Manuscript)

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Introduction

Background and rationale

6a Description of research question and justification for undertaking the trial, including summary of relevant studies (published and unpublished) examining benefits and harms for each intervention

_9 - 11_ Pgs3,4 Manuscript)

6b Explanation for choice of comparators __11__(Pg4 Manuscript)

Objectives 7 Specific objectives or hypotheses __12__(Pg4 Manuscript)

Trial design 8 Description of trial design including type of trial (eg, parallel group, crossover, factorial, single group), allocation ratio, and framework (eg, superiority, equivalence, noninferiority, exploratory)

__13__(Pg5 Manuscript)

Methods: Participants, interventions, and outcomes

Study setting 9 Description of study settings (eg, community clinic, academic hospital) and list of countries where data will be collected. Reference to where list of study sites can be obtained


Eligibility criteria 10 Inclusion and exclusion criteria for participants. If applicable, eligibility criteria for study centres and individuals who will perform the interventions (eg, surgeons, psychotherapists)

_13 - 14_(Pg5 Manuscript)

Interventions 11a Interventions for each group with sufficient detail to allow replication, including how and when they will be administered

27 - 28_(Pgs7,8 Manuscript)

11b Criteria for discontinuing or modifying allocated interventions for a given trial participant (eg, drug dose change in response to harms, participant request, or improving/worsening disease)

29 - 31_ (Pgs7,8 Manuscript)

11c Strategies to improve adherence to intervention protocols, and any procedures for monitoring adherence (eg, drug tablet return, laboratory tests)


11d Relevant concomitant care and interventions that are permitted or prohibited during the trial _13 - 14_(Pg5 Manuscript)

Outcomes 12 Primary, secondary, and other outcomes, including the specific measurement variable (eg, systolic blood pressure), analysis metric (eg, change from baseline, final value, time to event), method of aggregation (eg, median, proportion), and time point for each outcome. Explanation of the clinical relevance of chosen efficacy and harm outcomes is strongly recommended

_29 - 31_ (Pg6 Manuscript)

Participant timeline 13 Time schedule of enrolment, interventions (including any run-ins and washouts), assessments, and visits for participants. A schematic diagram is highly recommended (see Figure)

_20 - 22_ (Pg6 Manuscript)

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Sample size 14 Estimated number of participants needed to achieve study objectives and how it was determined, including clinical and statistical assumptions supporting any sample size calculations


Recruitment 15 Strategies for achieving adequate participant enrolment to reach target sample size __14__(N/A Manuscript)

Methods: Assignment of interventions (for controlled trials)

Allocation:

Sequence generation

16a Method of generating the allocation sequence (eg, computer-generated random numbers), and list of any factors for stratification. To reduce predictability of a random sequence, details of any planned restriction (eg, blocking) should be provided in a separate document that is unavailable to those who enrol participants or assign interventions


Allocation concealment mechanism

16b Mechanism of implementing the allocation sequence (eg, central telephone; sequentially numbered, opaque, sealed envelopes), describing any steps to conceal the sequence until interventions are assigned


Implementation 16c Who will generate the allocation sequence, who will enrol participants, and who will assign participants to interventions


Blinding (masking) 17a Who will be blinded after assignment to interventions (eg, trial participants, care providers, outcome assessors, data analysts), and how


17b If blinded, circumstances under which unblinding is permissible, and procedure for revealing a participant’s allocated intervention during the trial


Methods: Data collection, management, and analysis

Data collection methods

18a Plans for assessment and collection of outcome, baseline, and other trial data, including any related processes to promote data quality (eg, duplicate measurements, training of assessors) and a description of study instruments (eg, questionnaires, laboratory tests) along with their reliability and validity, if known. Reference to where data collection forms can be found, if not in the protocol

23 - 26 (Pgs6,9 Manuscript)

18b Plans to promote participant retention and complete follow-up, including list of any outcome data to be collected for participants who discontinue or deviate from intervention protocols

_24,31_(Pg8 Manuscript)

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Data management 19 Plans for data entry, coding, security, and storage, including any related processes to promote data quality (eg, double data entry; range checks for data values). Reference to where details of data management procedures can be found, if not in the protocol


Statistical methods 20a Statistical methods for analysing primary and secondary outcomes. Reference to where other details of the statistical analysis plan can be found, if not in the protocol


20b Methods for any additional analyses (eg, subgroup and adjusted analyses) ____N/A_______

20c Definition of analysis population relating to protocol non-adherence (eg, as randomised analysis), and any statistical methods to handle missing data (eg, multiple imputation)


Methods: Monitoring

Data monitoring 21a Composition of data monitoring committee (DMC); summary of its role and reporting structure; statement of whether it is independent from the sponsor and competing interests; and reference to where further details about its charter can be found, if not in the protocol. Alternatively, an explanation of why a DMC is not needed


21b Description of any interim analyses and stopping guidelines, including who will have access to these interim results and make the final decision to terminate the trial


Harms 22 Plans for collecting, assessing, reporting, and managing solicited and spontaneously reported adverse events and other unintended effects of trial interventions or trial conduct


Auditing 23 Frequency and procedures for auditing trial conduct, if any, and whether the process will be independent from investigators and the sponsor

__35__(N/A Manuscript)

Ethics and dissemination

Research ethics approval

24 Plans for seeking research ethics committee/institutional review board (REC/IRB) approval _38_ (Pg9 Manuscript)

Protocol amendments

25 Plans for communicating important protocol modifications (eg, changes to eligibility criteria, outcomes, analyses) to relevant parties (eg, investigators, REC/IRBs, trial participants, trial registries, journals, regulators)

_38_(N/A Manuscript)

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Consent or assent 26a Who will obtain informed consent or assent from potential trial participants or authorised surrogates, and how (see Item 32)


26b Additional consent provisions for collection and use of participant data and biological specimens in ancillary studies, if applicable

_43,46_(N/A Manuscript)

Confidentiality 27 How personal information about potential and enrolled participants will be collected, shared, and maintained in order to protect confidentiality before, during, and after the trial

_38_ (Pg9 Manuscript)

Declaration of interests

28 Financial and other competing interests for principal investigators for the overall trial and each study site _N/A_ (Pg10 Manuscript)

Access to data 29 Statement of who will have access to the final trial dataset, and disclosure of contractual agreements that limit such access for investigators


Ancillary and post-trial care

30 Provisions, if any, for ancillary and post-trial care, and for compensation to those who suffer harm from trial participation

_38_(N/A Manuscript)

Dissemination policy 31a Plans for investigators and sponsor to communicate trial results to participants, healthcare professionals, the public, and other relevant groups (eg, via publication, reporting in results databases, or other data sharing arrangements), including any publication restrictions


31b Authorship eligibility guidelines and any intended use of professional writers _38_(N/A Manuscript)

31c Plans, if any, for granting public access to the full protocol, participant-level dataset, and statistical code ____N/A_______

Appendices

Informed consent materials

32 Model consent form and other related documentation given to participants and authorised surrogates _Separate document_

Biological specimens

33 Plans for collection, laboratory evaluation, and storage of biological specimens for genetic or molecular analysis in the current trial and for future use in ancillary studies, if applicable

_23_(Pg7 Manuscript)

*It is strongly recommended that this checklist be read in conjunction with the SPIRIT 2013 Explanation & Elaboration for important clarification on the items. Amendments to the protocol should be tracked and dated. The SPIRIT checklist is copyrighted by the SPIRIT Group under the Creative Commons “Attribution-NonCommercial-NoDerivs 3.0 Unported” license.

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