Dalteparin for Traumatic Brain Injury

(PROTEST Trial)

Recruiting at 12 trial locations

Overseen By Jim Kutsogiannis, MD, MHS, FRCPC

Age: 18+

Sex: Any

Trial Phase: Phase 3

Sponsor: Sunnybrook Health Sciences Centre

Must not be taking: Heparins

Disqualifiers: Severe hypertension, Pregnancy, others

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: Unknown

Duration: 1 week

1100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests the effectiveness of Dalteparin, a blood thinner, for people with traumatic brain injuries (TBI). The goal is to determine if it improves recovery compared to a placebo, such as saline. Participants include those with serious brain injuries requiring intensive care, especially if they are on a breathing machine or have worsening brain bleeds on scans. Individuals with severe brain injuries meeting these conditions may qualify for the study. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants the opportunity to contribute to potentially groundbreaking treatment advancements.

Will I have to stop taking my current medications?

The trial information does not specify if you need to stop taking your current medications. It's best to discuss this with the trial coordinators or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that dalteparin is generally safe for people. Many adults have used it for various health issues, and extensive safety information is available. Studies indicate that most researchers consider dalteparin safe for preventing blood clots after a traumatic brain injury (TBI). One study specifically found dalteparin safe for TBI patients, particularly those with stable brain bleeding.

Overall, research suggests that dalteparin is well-tolerated and rarely causes serious side effects. However, more evidence is needed to fully understand its effectiveness in preventing blood clots in TBI patients. ^{1 2 3 4 5}

Why do researchers think this study treatment might be promising for TBI?

Unlike the standard treatments for traumatic brain injury, which often focus on managing symptoms and preventing complications, Dalteparin is an anticoagulant that aims to reduce the risk of blood clots. This is significant because traumatic brain injuries can increase the likelihood of clots, which can lead to further complications or even stroke. Researchers are excited about Dalteparin because it is delivered via a subcutaneous injection, allowing for consistent dosing and potentially better outcomes. Additionally, it has a well-known safety profile, making it a promising option for improving recovery in patients with traumatic brain injuries.

What evidence suggests that Dalteparin might be an effective treatment for traumatic brain injury?

Research has shown that dalteparin can help prevent blood clots in people with traumatic brain injuries (TBI). In this trial, participants will receive either dalteparin or a saline placebo. One study found that dalteparin was as effective as enoxaparin, another blood thinner, in real-life trauma cases. A review of several studies indicates that starting blood thinners like dalteparin 72 hours after a TBI is generally safe and can lower the risk of venous thromboembolism (VTE), a type of blood clot. Another review found that using blood thinners after a TBI, when head scans are stable or improving, reduced the chance of VTE without increasing the risk of further injury. These findings suggest that dalteparin might help prevent complications from blood clots in TBI patients. ^{1 3 4 5 6}

Who Is on the Research Team?

Farhad Pirouzmand, MD, MSc, FRCSC

Principal Investigator

Sunnybrook Health Sciences Centre

Damon Scales, MD

Principal Investigator

Sunnybrook Health Sciences Centre

Are You a Good Fit for This Trial?

This trial is for adults over 18 with severe to moderate traumatic brain injury (TBI), evidenced by a Glasgow Coma Scale score of ≤12, who are in ICU and need mechanical ventilation. They must be able to start the treatment within 3 days of injury. Excluded are those with hypersensitivity to Dalteparin or pork products, certain blood disorders, uncontrollable bleeding, extreme weights (<45kg or >120kg), or other factors affecting consciousness.

Inclusion Criteria

I have a moderate brain injury, need a machine to help me breathe, and have bleeding in my brain.

My severe brain injury score is 8 or less.

I can start the trial medication within 3 days of my injury.

Exclusion Criteria

I have a permanent blood clotting disorder.

My weight is either below 45 kg or above 120 kg.

Known Pregnancy

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

1-2 weeks

Treatment

Participants receive either Saline (placebo) or Dalteparin sodium for 7 days upon randomization after hospital admission

1 week

Daily administration in hospital

Follow-up

Participants are monitored for safety and effectiveness, including VTE and neurological outcomes

30 days

Phone interviews and clinical assessments

Extended Follow-up

Participants' functional neurological outcomes and quality of life are assessed at 180 days

180 days

Phone interviews

What Are the Treatments Tested in This Trial?

Interventions

• Dalteparin

Trial Overview The PROTEST study is testing the effectiveness of Dalteparin versus Saline in preventing blood clots in patients with severe TBI. It's a phase III trial where participants are randomly assigned to receive either Dalteparin or Saline without knowing which one they're getting (double blind).

How Is the Trial Designed?

Group I: Anticoagulant Active Control 1 Intervention

Dalteparin sodium (at a dose of 5000 IU once daily by subcutaneous injection) for 7 days upon randomization after hospital admission.

Group II: Saline Placebo Group 1 Intervention

Saline (0.2 mL) once daily by subcutaneous injection for 7 days upon randomization after hospital admission.

Dalteparin is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Fragmin for:

• Prevention of deep vein thrombosis
• Treatment of deep vein thrombosis
• Prevention of pulmonary embolism
• Treatment of unstable angina and non-Q-wave myocardial infarction

Approved in United States as Fragmin for:

• Prevention of deep vein thrombosis
• Treatment of acute deep vein thrombosis
• Extended treatment of deep vein thrombosis
• Prevention of ischemic complications in unstable angina and non-Q-wave myocardial infarction

Approved in Canada as Fragmin for:

• Prevention of deep vein thrombosis
• Treatment of deep vein thrombosis
• Prevention of pulmonary embolism

Who Is Running the Clinical Trial?

Sunnybrook Health Sciences Centre

Lead Sponsor

Trials

693

Recruited

1,569,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

Sunnybrook Research Institute

Collaborator

Trials

33

Recruited

216,000+

Published Research Related to This Trial

Dalteparin sodium is a low molecular weight heparin that offers improved bioavailability and prolonged antithrombotic activity compared to unfractionated heparin, allowing for once-daily administration.

It has been extensively studied in randomized clinical trials for various thrombotic disorders and is approved for multiple clinical uses, including the prevention of thromboembolic events after surgery and the long-term treatment of deep vein thrombosis, although further research is needed for some applications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dalteparin sodium. Pineo, GF., Hull, RD.[2019]

Dalteparin sodium, a low molecular weight heparin, offers improved pharmacokinetics over unfractionated heparin, allowing for once-daily subcutaneous dosing and greater inhibition of factor Xa, making it effective for preventing blood clots.

Clinical studies indicate that dalteparin sodium is at least as effective as unfractionated heparin in preventing deep vein thrombosis and managing established DVT, with a similar or lower incidence of bleeding complications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dalteparin sodium. A review of its pharmacology and clinical use in the prevention and treatment of thromboembolic disorders. Dunn, CJ., Sorkin, EM.[2018]

Dalteparin, a low molecular weight heparin, is as effective as unfractionated heparin for preventing blood clots, with a simpler once-daily subcutaneous administration that enhances patient compliance and reduces hospital costs.

It has been shown to have a lower risk of bleeding complications compared to unfractionated heparin, making it a safer option for both surgical thromboprophylaxis and the treatment of conditions like deep vein thrombosis and unstable coronary artery disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Dalteparin: an update of its pharmacological properties and clinical efficacy in the prophylaxis and treatment of thromboembolic disease. Dunn, CJ., Jarvis, B.[2018]

In a study of 287 moderate-to-severe traumatic brain injury (TBI) patients, VTE prophylaxis started 48-72 hours post-trauma resulted in a VTE occurrence rate of only 7.3%, indicating effective prevention of venous thromboembolic events.

The risk of symptomatic expansion of intracranial hemorrhages (ICH) while on VTE prophylaxis was extremely low, with only one case reported, suggesting that current prophylactic regimens are safe for TBI patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Early venous thromboembolic event prophylaxis in traumatic brain injury with low-molecular-weight heparin: risks and benefits. Dudley, RR., Aziz, I., Bonnici, A., et al.[2013]

Implementing an anti-Xa monitoring protocol for adjusting dalteparin doses in high-risk trauma patients significantly reduced the incidence of venous thromboembolism (VTE) from 13% to 7%.

The study found that many patients receiving once-daily dalteparin had suboptimal anti-Xa levels (less than 0.1 IU/mL), which were linked to higher rates of VTE, indicating that more frequent dosing may be necessary for effective prophylaxis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effect of a dalteparin prophylaxis protocol using anti-factor Xa concentrations on venous thromboembolism in high-risk trauma patients. Droege, ME., Mueller, EW., Besl, KM., et al.[2014]

Dalteparin is effective for both the prevention and treatment of venous thromboembolism (VTE) in pediatric patients, with an overall response rate of 83% for thrombus resolution based on a retrospective review of 166 children.

Infants required significantly higher weight-based doses of dalteparin to achieve therapeutic levels compared to older children and adolescents, highlighting the need for age-based dosing adjustments and careful monitoring of anti-Xa activity to minimize bleeding risks.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A retrospective analysis of outcomes of dalteparin use in pediatric patients: a single institution experience. Warad, D., Rao, AN., Mullikin, T., et al.[2022]

In a study of 95 patients with acute spinal cord injury, both dalteparin and enoxaparin showed similar rates of deep venous thrombosis (6% for enoxaparin vs. 4% for dalteparin) and bleeding (4% for dalteparin vs. 2% for enoxaparin), indicating comparable safety profiles for both medications.

Patients found dalteparin more convenient due to its once-daily injection compared to enoxaparin's twice-daily regimen, which also resulted in lower medication costs ($750/month for dalteparin vs. $1101/month for enoxaparin).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of dalteparin and enoxaparin for deep venous thrombosis prophylaxis in patients with spinal cord injury. Chiou-Tan, FY., Garza, H., Chan, KT., et al.[2022]

In a study of 119 patients with deep venous thrombosis (DVT), treatment with low molecular weight heparin (Fragmin) was found to be as effective as standard heparin (SH) in improving venous conditions, with 76% of Fragmin patients showing improvement compared to 61% in the SH group after 5-7 days.

Fragmin demonstrated a better safety profile, with no major bleeding incidents reported, while the SH group had two cases of major bleeding, suggesting that Fragmin may be a safer option for DVT treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Two daily subcutaneous injections of fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis (DVT). Bratt, G., Aberg, W., Johansson, M., et al.[2006]

In a pilot study of 100 patients undergoing craniotomy, both unfractionated heparin and dalteparin were found to be safe for preventing venous thromboembolism, with no significant differences in postoperative complications like DVT or hemorrhage.

The study indicated that the combination of either heparin or dalteparin with intermittent pneumatic compression devices effectively reduced the incidence of venous thromboembolism, suggesting both medications are viable options for prophylaxis in this surgical context.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Randomized, pilot study of intermittent pneumatic compression devices plus dalteparin versus intermittent pneumatic compression devices plus heparin for prevention of venous thromboembolism in patients undergoing craniotomy. Macdonald, RL., Amidei, C., Baron, J., et al.[2019]

In a study involving 5,880 trauma patients, the rates of venous thromboembolism (VTE) were similar between those receiving enoxaparin and those receiving dalteparin, suggesting that both low-molecular-weight heparins are equally effective for thromboprophylaxis.

The study indicates that switching from enoxaparin to dalteparin did not change the VTE rates, which remained stable, highlighting the need for further research on how the timing and consistency of prophylaxis might influence the effectiveness of these medications.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparative Effectiveness of Enoxaparin vs Dalteparin for Thromboprophylaxis After Traumatic Injury. Miano, TA., Cuker, A., Christie, JD., et al.[2019]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC5812768/

Comparative Effectiveness of Enoxaparin vs Dalteparin for ... Conclusions. Our results suggest that dalteparin has an effectiveness similar to that of enoxaparin in real-world trauma patients. Future research should ...

2. withpower.com withpower.com/trial/phase-3-venous-thromboembolism-6-2018-cec71

Dalteparin for Traumatic Brain Injury (PROTEST Trial) Trial Overview The PROTEST study is testing the effectiveness of Dalteparin versus Saline in preventing blood clots in patients with severe TBI. It's a phase ...

3. thejns.org thejns.org/view/journals/j-neurosurg/142/4/article-p1046.xml

a systematic review and meta-analysis. A military traumatic ... The review of the literature shows that VTE chemoprophylaxis 72 hours after TBI is considered safe by the majority of authors.

4. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4282634/

A Systematic Review of the Benefits and Risks ... The authors concluded that PTP in TBI patients with stable or improved head CT after 24 hours of injury reduced the incidence of VTE without increasing the risk ...

5. sciencedirect.com sciencedirect.com/science/article/abs/pii/S0022480424002440

National Analysis of Outcomes for Adult Trauma Patients ... VTE prophylaxis later than 24 h is associated with a reduced risk of in-hospital mortality in patients with severe isolated blunt TBI, as opposed to VTE ...

6. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/20939698/

Early venous thromboembolic event prophylaxis in ... Moreover, the group treated with dalteparin was more severely injured (higher Injury Severity Score [p = 0.002]), had lower Glasgow Coma Scale (GCS) scores (p = ...