Dalteparin for Traumatic Brain Injury

(PROTEST Trial)

Recruiting at 11 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

Trial Summary

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.

What data supports the effectiveness of the drug Dalteparin for traumatic brain injury?

Research shows that Dalteparin, a low-molecular-weight heparin, is effective in preventing blood clots in patients with traumatic brain injury, with a low risk of worsening brain bleeding. It is as effective as another similar drug, Enoxaparin, in preventing these clots. ^{1 2 3 4 5}

Is Dalteparin safe for use in humans?

Dalteparin, also known as Fragmin, is generally considered safe for use in humans, with extensive safety data available from its use in adults for various conditions. In patients with traumatic brain injury, it has been used to prevent blood clots with a low risk of causing further bleeding in the brain. ^{1 2 6 7 8}

How does the drug Dalteparin differ from other treatments for traumatic brain injury?

Dalteparin is a low molecular weight heparin (LMWH) that offers improved bioavailability and a longer duration of action compared to unfractionated heparin (UFH), allowing for once-daily subcutaneous administration. This makes it potentially more convenient and effective for preventing blood clots in patients with traumatic brain injury, who are at high risk for venous thromboembolic events. ^{1 2 7 9 10}

What is the purpose of this trial?

This is a phase III, multi-centre, double blind, randomized controlled trial of patients with traumatic brain injury (TBI).

Research Team

Farhad Pirouzmand, MD, MSc, FRCSC

Principal Investigator

Sunnybrook Health Sciences Centre

Damon Scales, MD

Principal Investigator

Sunnybrook Health Sciences Centre

Eligibility Criteria

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.

Known Pregnancy

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

Timeline

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

Treatment Details

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).

Participant Groups

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+

Findings from Research

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]

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]

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]

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]

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]

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 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 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]

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]

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]

References

1. England pubmed.ncbi.nlm.nih.gov

Dalteparin sodium. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Early venous thromboembolic event prophylaxis in traumatic brain injury with low-molecular-weight heparin: risks and benefits. [2013]

3. United States pubmed.ncbi.nlm.nih.gov

Comparison of dalteparin and enoxaparin for deep venous thrombosis prophylaxis in patients with spinal cord injury. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Effect of a dalteparin prophylaxis protocol using anti-factor Xa concentrations on venous thromboembolism in high-risk trauma patients. [2014]

5. United States pubmed.ncbi.nlm.nih.gov

Comparative Effectiveness of Enoxaparin vs Dalteparin for Thromboprophylaxis After Traumatic Injury. [2019]

6. United States pubmed.ncbi.nlm.nih.gov

A retrospective analysis of outcomes of dalteparin use in pediatric patients: a single institution experience. [2022]

7. United States 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. [2019]

8. Germany 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). [2006]

9. New Zealand pubmed.ncbi.nlm.nih.gov

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

10. New Zealand pubmed.ncbi.nlm.nih.gov

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