Agenda

8:00-8:10 Welcome and review of INTERACT1 (Tom Robinson)

8:10-8:30 INTERACT2: protocol, website, worldwide update (Emma Heeley)

8:30-8:40 INTERACT2 in the UK(Tom Robinson)

8:40-8:50 Discussion 

INTERACT pilot results

Tom Robinson

Aimed to assess the safety and efficiency of intensive BP lowering in acute ICH

In 404 patients, results showed that early intensive BP lowering was: Safe Feasible Produced modest reduction in haematoma growth at 24

hours - appeared to limit ongoing bleeding by about 20-30% (~2ml, or about ½ teaspoon) in intracerebral haemorrhage

(Lancet Neurology 2008; 7:391-399)

Lancet Neurology 2008 May;7(5):391-399

INTERACT1: pilot studyAcute spontaneous ICH

onset < 6 hoursSBP ≥150 and ≤220 mmHg

No definite indications or contraindications to treatmentAble to be actively managed

Provide informed consent

Repeat CT scans 24 + 72 hrsVital signs and BP over 7 days28 day and 3 month follow-up

Intensive BP loweringTarget systolic BP 140 mmHg within 1 hour and for 24+ hrs

Standard BP managementAHA Guideline-based

(treatment if systolic BP >180 mmHg)

RStandard

best practice stroke

unit care

INTERACT1- Adjusted mean absolute and relative increase in haematoma volume

Absolute increase in haematoma volume

Guideline Intensive Guideline Intensive

6

2

-2

30

10

-5

0

4 20

0

P=0.13 P=0.06

Δ-10%Δ-1.7ml

ml %

Relative increase in haematoma volume

Consistency of P >0.05 for heterogeneity in subgroups

36% (-19 to 65%)36% (-24 to 67%)

57% (-3 to 82%)24% (-28 to 55%)

15% (-73 to 50%) 47% (6 to 70%)

38% (-24 to 69%)30% (-25 to 61%)

37% (-3 to 62%)31% (-93 to 76%)

24% (-45 to 61%)45% (-2 to 70%)

Age <65 years 65+ years

Time to randomization <3 hours 3+ hours

Baseline systolic BP mean >mean

Baseline diastolic BP mean >mean

History of hypertension Yes No

Baseline NIHSS median >median

13 (15%) 23 (23%) 13 (15%) 17 (23%)

6 (12%) 14 (27%)20 (16%) 26 (22%)

12 (13%) 14 (15%) 14 (17%) 26 (32%)

12 (12%) 16 (20%)14 (19%) 24 (27%)

21 (16%) 32 (25%) 5 (13%) 8 (18%)

22 (15%) 18 (20%)13 (15%) 22 (28%)

Favoursstandard

Favoursintensive

Relative riskReduction (95% CI)

Number (%) of patients with eventIntensive(n=201)

Standard(n=203)

0.1 1.0 2.1Rate ratio

INTERACT1 – Adverse events to 90 days (%)

INTERACT1 – Clinical outcomes at 90 days

INTERACT2

Emma Heeley

New design : simpler, easier, quicker

Option of second CT scans600 patients to investigate haematoma growth

Reduced in-hospital assessments but assessment of ICU stay and use of renal dialysis

Option of telephone based outcome assessments at 28 and 90 days

INTERACT2: main studyAcute spontaneous ICH

onset < 6 hoursSBP ≥150 and ≤220 mmHg

No definite indications or contraindications to treatmentAble to be actively managed

Provide informed consent

Repeat CT scans 24 hrs in selected patients

Vital signs and BP over 7 days28 day and 3 month follow-up

Intensive BP loweringTarget systolic BP 140 mmHg within 1 hour and for 24+ hrs

Conservative BP managementAHA Guideline-based

(treatment if systolic BP >180 mmHg)

RStandard

best practice stroke

unit care

Inclusion Criteria Age 18 years or more Acute spontaneous ICH (history and CT) At least 2 Systolic BP 150-220 mmHg, recorded

2 or more minutes apart Able to be randomly assigned BP lowering

therapy within 6 hours of stroke onset Able to receive active (‘intensive’) care in a

monitored facility

Exclusion Criteria

Known definite contraindication to intensive BP lowering

Known definite indication to intensive BP lowering

ICH due to secondary to structural abnormality

Ischemic stroke in last 30 days High likelihood of death within 24 hours

(GCS 3-5)

Exclusion Criteria cont’d

Known advanced dementia or significant pre-stroke disability

Concomitant medical illness Planned early surgical intervention Participation in other trial Unlikely to adhere to treatment or follow-up

INTERACT2 BP Management

Evaluation of a management policy and NOT of a single agent

Pragmatic approach to treatment Agents readily available in hospitals Agents approved for clinical use Lower study costs

Inclusion of BP lowering management protocols for key available agents

Schedule of Assessments

Prior to Randomisation Day

Evaluation 1 7(b) 28(c) 90(c)

Eligibility X CT scan X X* Fevers to be recorded X X BP/Heart rate X

BP x 2 X **

q 15 min 1 h hourly 2-6h

6 hourly 6-24h

Consent (a) X Clinical history prior medications X Physical exam GCS/NIHSS X X X Functional assessment with mRS X X X

HRQoL assessment with EQ 5D X X Standard care & routine blood tests X X BP lowering treatment X X X X

Standard stroke care X X X X Hospitalised or not X X X X Contact details for Follow-up X X

INTERACT 2 Website

Internet-based randomisation and data collection system

24-hour password protected website using encryption software

An internet connection from the study centre (eg ED or stroke unit)

2 Website Addresses

1. TESThttps://test.thegeorgeinstitute.org/interact2

2. LIVEhttps://studies.thegeorgeinstitute.org/interact2

Each site has:- Separate user names and passwords- Distinguished by different colours.

TEST website is purple/yellow LIVE website is purple/white

Electronic Signature

Authorised study staff will electronically sign all computerised forms

All changes will have a complete audit trail

Data can be accessed and edited at any time

Query generation and resolution performed instantly

An Authorised Signature Form is required to obtain a username & password

Accessing INTERACT Website

1. Go to the website address 2. Type in User Name & Password in the Login box3. Click on the Login button

Prior to Randomisation

Confirm eligibility Complete hard copy of Form A To be eligible for INTERACT2: All inclusion criteria questions must be answered

“YES” All exclusion criteria questions must be answered

as “NO” Randomisation is performed on the website

Test Randomisation

TEST website:

https://test.thegeorgeinstitute.org/interact2

Successful RandomisationNotified of : Unique patient study number

Randomised to either: intensive BP lowering treatment or control current guideline-based management of BP

Patients will be stratified according to: time since stroke onset (0-4 vs. 4-6 hours), site and country of recruitment

Important to write these details in patient medical records and print a copy for your file

Screen shots of randomisation

8 Electronic CRFs Form A (Randomisation Form) Form B (Baseline & Medical History) Form C (Day 1 Assessment) Form D (Day 7 Assessment) Form E (BP Assessments) Form F (Day 28 Assessment) Form G (Day 90 Assessment) Form X (SAE or Outcome)

Electronic Case Report Forms

Review of INTERACT Database

Test database https://test.thegeorgeinstitute.org/interact2

Live database https://studies.thegeorgeinstitute.org/interact2

Form B Baseline & Medical History

Screening log Simplified Only for 1 month of each year

Any questions regarding the website?

INTERACT2 – Current Network

Recruitment

Oct-08Dec-

08Feb

-09Ap

r-09Jun

-09Au

g-09Oct-

09Dec-

09Feb

-10Ap

r-10Jun

-10Au

g-10Oct-

10Dec-

10Feb

-11Ap

r-11Jun

-11Au

g-11Oct-

11Dec-

11Feb

-12Ap

r-12Jun

-12Au

g-12Oct-

12Dec-

120

500

1000

1500

2000

2500

3000

Num

ber o

f pat

ient

s ran

dom

ised

RecruitmentRegion Randomised Patients*Australia 43China 1178India 22Pakistan 3Chile 2Austria 43Belgium 2France 101Germany 54Italy 14Portugal 6Spain 10

*as of 26/Nov/2010

Comparison of recruitment in INTERACT2 and other ICH trials (analysis 01/Nov/2010)

Name Date Duration (months)

Centres Sponsor Patients Recruitment rate

per month

Recruitment rate per

centre

INTERACT2 2008 25 83 NHMRC 1408 56.3 17STICH 1995-

2003 156 107 MRC 1033 6.6 9.6

FAST 2005-2007

40 122 NovoNordisk 841 21 6.8CHANT 2003-

2005 29 133 AstraZeneca 607 20.9 4.6

INTERACT1 2005-2007

18 44 NHMRC 404 22.4 9.2NovoSeven 2002-

2004 20 73 NovoNordisk 399 20 5.5

Comparison baseline characteristics INTERACT1 and 2

INTERACT1 (n= 404)

INTERACT2 ( n= 1223)

Median time from ICH onset to hospital presentation (hours)

1h30 (50min – 2h30)

1h20 †(45min – 2h10)

Median time form ICH onset to randomisation (hours)

3h40 (2h53 – 4h50)

3h40 (2h48 – 4h35)

Mean age (years)* 62 (12) 63 (12)

Females 35% 37%

Country of residence Asia 97% 87%‡

Other 3% 13%

‡

‡ p <0.001

INTERACT2 - Mean systolic BP time trendsΔ13 mmHg at 1 hour; Δ10 mmHg at 24 hours

rando

misatio

n(1)

rando

misatio

n (2)

15min

30min

45min 1hr 6hr 12h

r18h

r24h

r

day2,a

m

day2,p

m

day3,a

m

day3,p

m

day4,a

m

day4,p

m

day5,a

m

day5,p

m

day6,a

m

day6,p

m

day7,a

m

day7,p

m0

20

40

60

80

100

120

140

160

180

200

Control GroupIntensive Group

Time of SBP Measurement

Mean SBP Worldwide

Mea

n SB

P W

orld

wid

e

Analysis completed on 01/Nov/2010

Comparison Between Regions: mean systolic BP differences at 1 hour

Australia China Europe India Pakistan South America0

50

100

150

200

250

171 165 164172

162170

150 153144 139

210

138

Control GroupIntensive Group

Mean SBP per Region

Mea

n SB

P

RegionAnalysis completed on 01/Nov/2010

INTERACT2 important reminders: Form E

Day 1 is the day of randomisation regardless of the time the patient is randomised. Therefore, if a patient was randomised at 11:00 PM on Day 1, Day 2 blood pressure data entries may overlap with blood pressure data entries within the first 24 hours of randomisation.

In addition, if a patient has died prior to Day 7, some BP fields might be left empty

Form E Blood Pressure Assessment Form

Study Number: I__I__I__I - I__I__I__I Centre number Pt number

Patient Initials: I__I__I__I__I

INTERACT2

Blood pressure (Use Worksheet C) Time from randomisation 15min 30min 45min 1h 6h 12h 18h 24h

Systolic BP, mmHg I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I Diastolic BP, mmHg I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I

Blood pressure (Use Worksheet D1) Time from randomisation Day 2 Day 3 Day 4 Day 5 Day 6 Day 7

am pm am pm am pm am pm am pm am Pm Systolic BP, mmHg I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I Diastolic BP, mmHg I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I I__I__I__I

Signature of the investigator I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I__I Investigator name

I________________________________________________________________I Investigator signature

I__I__I / I__I__I / I_2_I_0_I__I__| d d m m y y y y Date signed

INTERACT2 important reminders: Outcome assessment (days 28 and 90)

Day 28 and day 90 outcome assessments are to be undertaken by an investigator who was not involved in the clinical management of the patient, and blind to the randomised treatment allocation.

These assessments can be conducted at 28±3 days and 90±7 days, by telephone interview or at a face-to-face outpatient consultation.

Progress over the past year Data Safety Monitoring Board (DSMB) interim analysis (~1300 patients with 90 day outcomes) on 26/Aug/2010. Recommended to continue the trial with no protocol changesFurther network expansion into South America, Northern Europe and UKHalf-way recruitment (1,400 patients) met on 29/Oct/2010

INTERACT2 in the UK

Tom Robinson

Update on progress Ethics University of Leicester UK sponsor Monitor/CRA based at University of

Leicester

Update on progress Ethics University of Leicester UK sponsor Monitor/CRA based at University of

Leicester

Ethics Nottingham REC 1 12 Oct 2010

Conditional Approval (subject to Chair action), Reply 01 Nov 2010 Short Version PIS/ RIS Clarification of 2 CT Head scans (1

routine clinical, 1 study specific) Context of 3% IS risk with BP reduction GP IS Results Lay Summary (SRN website)

Sponsorship Main Sponsor ICC, Sydney

UK Sponsor UoL Insurance Document available Division of responsibility between Main

and UK sponsor to be agreed

Monitor Based within UoL

JD being finalised

Advert/ Interview/ In Post

UK Up to 15 centres

Over 100 patients

Recruitment period ………….

FPI ……………..

INTERACT2 Discussion

Thank you very much!

Tom Robinson: tgr2@leicester.ac.uk

International Coordinating Centre: interact@george.org.au

Emma Heeley: eheeley@george.org.au Michelle Leroux: mleroux@george.org.au