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CTRI Number  CTRI/2023/08/056550 [Registered on: 16/08/2023] Trial Registered Prospectively
Last Modified On: 23/12/2023
Post Graduate Thesis  No 
Type of Trial  Interventional 
Type of Study   Drug 
Study Design  Randomized, Parallel Group, Placebo Controlled Trial 
Public Title of Study   A randomized controlled trial of Prevention of severe thromboembolism in Indian patients presenting with severe brain injury 
Scientific Title of Study   PROphylaxis for venous ThromboEmbolism in severe Traumatic brain injury (the PROTEST RCT) 
Trial Acronym   
Secondary IDs if Any  
Secondary ID  Identifier 
NIL  NIL 
 
Details of Principal Investigator or overall Trial Coordinator (multi-center study)  
Name  Dr BK Misra 
Designation  MBBS, DNB, MCh Neurosurgery 
Affiliation  PD Hinduja Hospital, Mahim, Mumbai 
Address  Ground floor, Gamma knife centre, OPD building PD Hinduja hospital, Veer Sawarkar Marg, Mahim, Mumbai.

Mumbai (Suburban)
MAHARASHTRA
400016
India 
Phone  9224874632  
Fax    
Email  drbkmisraresearch@gmail.com  
 
Details of Contact Person
Scientific Query  
Name  Dr BK Misra 
Designation  MBBS, DNB, MCh Neurosurgery 
Affiliation  PD Hinduja Hospital, Mahim, Mumbai 
Address  Ground floor, Gamma knife centre, OPD building PD Hinduja hospital, Veer Sawarkar Marg, Mahim, Mumbai

Mumbai (Suburban)
MAHARASHTRA
400016
India 
Phone  9224874632  
Fax    
Email  drbkmisraresearch@gmail.com  
 
Details of Contact Person
Public Query  
Name  Dr BK Misra 
Designation  MBBS, DNB, MCh Neurosurgery 
Affiliation  PD Hinduja Hospital, Mahim, Mumbai 
Address  Ground floor, Gamma knife centre, OPD building PD Hinduja hospital, Veer Sawarkar Marg, Mahim, Mumbai.

Mumbai (Suburban)
MAHARASHTRA
400016
India 
Phone  9224874632  
Fax    
Email  drbkmisraresearch@gmail.com  
 
Source of Monetary or Material Support  
Canadian Institutes of Health Research 160 Elgin Street, 10th Floor Address Locator 4809A Ottawa ON K1A 0W9 Canada 
 
Primary Sponsor  
Name  Sunnybrook Research Institute 
Address  2075 Bayview Ave. Toronto, Ontario M4N 3M5 CANADA Phone No. 416-480-5632 Email ID Email: cctsqualityassurance@sunnybrook.ca AND PROTEST@sunnybrook.ca 
Type of Sponsor  Research institution and hospital 
 
Details of Secondary Sponsor  
Name  Address 
NIL  NIL 
 
Countries of Recruitment     India  
Sites of Study  
No of Sites = 1  
Name of Principal Investigator  Name of Site  Site Address  Phone/Fax/Email 
DR BK MISRA  PD HINDUJA HOSPITAL & MRC  Ground floor, Gamma knife centre, OPD building PD Hinduja hospital, Veer Sawarkar Marg, Mahim, Mumbai.
Mumbai (Suburban)
MAHARASHTRA 		 9224874632

drbkmisraresearch@gmail.com 
 
Details of Ethics Committee
Modification(s)  
No of Ethics Committees= 2  
Name of Committee  Approval Status 
P D Hinduja Hospital and MRC Institutional Ethics Committee (IEC)  Approved 
P D Hinduja Hospital and MRC Institutional Ethics Committee (IEC)  Approved 
 
Regulatory Clearance Status from DCGI  
Status 
Not Applicable 
 
Health Condition / Problems Studied  
Health Type  Condition 
Patients  (1) ICD-10 Condition: S069||Unspecified intracranial injury,  
 
Intervention / Comparator Agent  
Type  Name  Details 
Intervention  1.inj Dalteparin 2.Sequential compression device.  This pragmatic RCT will directly compare the effectiveness and safety of two VTE thromboprophylaxis strategies during the critical first week after severe TBI: (1) SCD plus placebo versus (2) SCD plus study drug (Dalteparin) for 7 days. Participants who are admitted to participating ICUs after traumatic injury will be screened for eligibility and randomized within 2 calendar days after injury. SCDs will be applied to all participants according to usual practice, and then worn continuously until the Day 8 outcome evaluation unless the patient is mobile or develops a complication related to their use. The study drug will be started on Day 1 and administered daily until Day 7 or ICU discharge unless deemed unsafe by criteria (previously outlined in Section 2.3). Enrolled participants will be randomly allocated to one of the following two groups: 1. SCD plus Placebo: SCDs will be applied according to usual practice. A placebo subcutaneous injection administered daily if safety criteria are satisfied. This placebo contains colorless normal saline, prepared by the inpatient pharmacy and supplied in sealed syringes. 2. SCD plus LMWH: (Dalteparin): SCDs will be applied according to usual practice. A prophylactic dose of LMWH will be administered daily if safety criteria are satisfied. The LMWH will be prepared by the site pharmacy and supplied in sealed syringes. The doses administered will be 5000 IU once daily of dalteparin delivered subcutaneously. 
Comparator Agent  Not applicable  Not applicable 
 
Inclusion Criteria  
Age From  12.00 Year(s)
Age To  99.00 Year(s)
Gender  Both 
Details  Patients with severe and moderate acute TBI defined as:

a. GCS of ≤8 or

b. GCS of 9-12 (moderate) with any intracranial hemorrhage seen on CT
scan (patients with only subarachnoid hemorrhage are excluded)
ii) Upon randomization patient can receive the first dose of study drug in the first
3 calendar days of the time of injury (within 72 hours after injury).
ii) ≥ 18 years of age 
 
ExclusionCriteria 
Details  All participants meeting any of the following exclusion criteria at baseline will be
excluded from participation in this study:

i) Known Hypersensitivity to FRAGMIN (Dalteparin), or its constituents including
benzyl alcohol or to other low molecular weight heparins and/or heparins or
pork products

ii) Known history of confirmed or suspected immunologically-mediated heparininduced thrombocytopenia (delayed-onset severe thrombocytopenia), and/or
in patients with a known history of a positive in vitro platelet-aggregation test
in the presence of FRAGMIN (Dalteparin) is positive

iii) Known septic endocarditis

iv) Uncontrollable active bleeding

v) Known major blood clotting disorders

vi) Known acute gastroduodenal ulcer (with active bleeding)

vii) Severe uncontrolled hypertension (i.e. BP>210 despite medications)

viii) Known diabetic or hemorrhagic retinopathy

ix) Anticipated to be unable to receive SCD on at least one lower extremity due to nature of injuries for duration of intervention period

x) Presence of another confounding factor that can adequately explain the poor
GCS at time of presentation (e.g. drug toxicity, seizure).

xi) Known presence of irreversible coagulopathies.

xii) Known Pregnancy

xiii) Participants extremely low weight (<45 kg), or extremely high weight (>120kg)


xiv) Not expected to survive more than 48 hours from admission

If it is determined after enrolment that if an enrolled patient had an exclusion criterion at
the time of randomization which was not previously identified, the study drug will be
discontinued. In these situations, the steering committee will review each case to
determine whether the patient should also be excluded from the intention to treat
analysis. 
 
Method of Generating Random Sequence   Stratified randomization 
Method of Concealment   Centralized 
Blinding/Masking   Participant, Investigator, Outcome Assessor and Date-entry Operator Blinded 
Primary Outcome  
Outcome  TimePoints 
1. Symptomatic, objectively-confirmed PE.
2. Symptomatic, objectively-confirmed, proximal leg DVT. In this case,
symptomatic would suggest that the patient has developed leg swelling or
signs of venous stasis that can be directly attributed to a DVT during the first
7 study days, and this DVT would need to be objectively confirmed (for
example using Doppler ultrasound).
3. Asymptomatic proximal leg DVT on Doppler ultrasound on Day 8-1 or +2 days
(at Day 7, 8, 9 or 10) after Initiation of study drug. In this case, the DVT is
detected during our routine screening on Day 8-1 or +2 days (at Day 7, 8, 9 or
10), and need not be associated with symptoms 		 30 days, 180 days 
 
Secondary Outcome  
Outcome  TimePoints 
Secondary Outcomes

1. Objectively confirmed new or progressing ICB on radiology assessed by
comparing the baseline brain CT usually about 24 h after admission to that
performed on Day 8 1 or 2 days at Day 7 8 9 or 10 or most recent prior to
death This will be confirmed by volumetric measurements by a central
neuroradiologist blinded to treatment allocation We have developed a protocol for
quantitatively measuring changes in brain blood volume this approach has high
interrater reliability

Symptomatic VTE at Day 8 ie excluding those diagnosed based on radiology
alone

Any clinically important VTE occurring between Day 8 to Day 30 detected by
treating clinicians

Composite endpoint of either death or clinically important VTE at Day 8 after study
drug initiation

All mortalities at 8 days, 30 days & 180 days

Glasgow Outcome Scale Extended GOSE at Day 30±5 and Day 180±14 by phone
interview

7 EQ5D at Day 30±5 and Day 180±14 by phone interview 		 30 days 180 days 
 
Target Sample Size   Total Sample Size="200"
Sample Size from India="200" 
Final Enrollment numbers achieved (Total)= "Applicable only for Completed/Terminated trials"
Final Enrollment numbers achieved (India)="Applicable only for Completed/Terminated trials" 
Phase of Trial   Phase 3 
Date of First Enrollment (India)   01/09/2023 
Date of Study Completion (India) Applicable only for Completed/Terminated trials 
Date of First Enrollment (Global)  Date Missing 
Date of Study Completion (Global) Applicable only for Completed/Terminated trials 
Estimated Duration of Trial   Years="5"
Months="6"
Days="0" 
Recruitment Status of Trial (Global)   Open to Recruitment 
Recruitment Status of Trial (India)  Not Yet Recruiting 
Publication Details   N/A 
Individual Participant Data (IPD) Sharing Statement

Will individual participant data (IPD) be shared publicly (including data dictionaries)?  

Response - NO
Brief Summary  
Authorship on study publications will adhere to the Uniform Requirements for Manuscripts Submitted to Biomedical Journals of the International Committee of Medical Journal Editors. These Requirements state “Authorship credit should be based on:
1) Substantial contributions to conception and design, acquisition of data, or analysis and interpretation of data; 
2) Drafting the article or revising it critically for important intellectual content; and 
3) Final approval of the version to be published. 
Authors should meet conditions 1, 2, and 3. Where journal policies permit, all study site investigators who played a contributing role in the trial, including to its accrual, will be included in an Acknowledgement section.

 
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