agenda 8:00-8:10welcome and review of interact1 (tom robinson) 8:10-8:30 interact2: protocol,...
TRANSCRIPT
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 study
Acute spontaneous ICHonset < 6 hours
SBP ≥150 and ≤220 mmHgNo definite indications or contraindications to treatment
Able to be actively managedProvide 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)
R
Standard 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 scans
600 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 study
Acute spontaneous ICHonset < 6 hours
SBP ≥150 and ≤220 mmHgNo definite indications or contraindications to treatment
Able to be actively managedProvide 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)
R
Standard 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 box
3. 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 Randomisation
Notified 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-0
8
Dec-0
8
Feb-
09
Apr-0
9
Jun-
09
Aug-0
9
Oct-0
9
Dec-0
9
Feb-
10
Apr-1
0
Jun-
10
Aug-1
0
Oct-1
0
Dec-1
0
Feb-
11
Apr-1
1
Jun-
11
Aug-1
1
Oct-1
1
Dec-1
1
Feb-
12
Apr-1
2
Jun-
12
Aug-1
2
Oct-1
2
Dec-1
20
500
1000
1500
2000
2500
3000
Num
ber
of
pati
ents
ran
dom
ised
RecruitmentRegion Randomised Patients*
Australia 43
China 1178
India 22
Pakistan 3
Chile 2
Austria 43
Belgium 2
France 101
Germany 54
Italy 14
Portugal 6
Spain 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 17
STICH 1995-2003
156 107 MRC 1033 6.6 9.6
FAST 2005-2007
40 122 NovoNordisk 841 21 6.8
CHANT 2003-2005
29 133 AstraZeneca 607 20.9 4.6
INTERACT1 2005-2007
18 44 NHMRC 404 22.4 9.2
NovoSeven 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
rand
omisa
tion(
1)
rand
omisa
tion
(2)
15m
in
30m
in
45m
in 1hr
6hr
12hr
18hr
24hr
day2
,am
day2
,pm
day3
,am
day3
,pm
day4
,am
day4
,pm
day5
,am
day5
,pm
day6
,am
day6
,pm
day7
,am
day7
,pm
0
20
40
60
80
100
120
140
160
180
200
Control GroupIntensive Group
Time of SBP Measurement
Mean SBP Worldwide
Mean
SB
P
Worl
dw
ide
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
171165 164
172162
170
150 153144
139
210
138
Control GroupIntensive Group
Mean SBP per Region
Mean
S
BP
Region
Analysis 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 changes
Further network expansion into South America, Northern Europe and UK
Half-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: [email protected]
International Coordinating Centre: [email protected]
Emma Heeley: [email protected] Michelle Leroux: [email protected]