aPCC-Emicizumab Safety for Hemophilia A

(SAFE Trial)

Recruiting at1 trial location

Overseen by Robert Sidonio, MD

Age: Any Age

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Emory University

Must be taking: Emicizumab

Must not be taking: Immunomodulators

Disqualifiers: Thromboembolic disease, HIV, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial uses a special blood-clotting medicine along with emicizumab to help control bleeding in children and adults with hemophilia A who have inhibitors. The treatment works by helping the blood to clot better. Emicizumab is approved for regular use in patients with severe hemophilia A with and without inhibitors.

Do I need to stop my current medications to join the trial?

The trial protocol does not specify if you need to stop taking your current medications. However, if you are using systemic immunomodulators, you cannot participate in the study.

What data supports the effectiveness of the drug emicizumab for treating hemophilia A?

Emicizumab has been shown to effectively reduce the frequency of bleeding episodes in patients with hemophilia A, both with and without inhibitors, as demonstrated in phase 1/2 and phase 3 clinical studies. It is approved for routine prophylaxis in several countries, indicating its effectiveness in managing this condition. ^{1 2 3 4 5}

Is aPCC-emicizumab treatment safe for humans?

Emicizumab is generally well-tolerated, but when used with activated prothrombin complex concentrate (aPCC) at high doses, it can lead to thrombotic events (blood clots) and thrombotic microangiopathy (a condition affecting small blood vessels). Recombinant activated factor VII (rFVIIa) used with emicizumab does not show these risks. ^{2 4 5 6 7}

What makes the aPCC-Emicizumab treatment unique for Hemophilia A?

The aPCC-Emicizumab treatment is unique for Hemophilia A because it combines aPCC (activated prothrombin complex concentrate) with Emicizumab, a bispecific antibody that mimics the function of factor VIII, which is missing or defective in Hemophilia A patients. This combination offers a novel approach by providing both a bypassing agent and a factor VIII mimetic, potentially improving bleeding control compared to traditional treatments. ^{8 9 10 11 12}

Research Team

Robert Sidonio, MD

Principal Investigator

Emory University

Eligibility Criteria

The SAFE Study is for children and adults over 6 years old with severe hemophilia A and inhibitors, who have not responded to standard treatments. Participants must have good blood, liver, and kidney function but cannot join if they have other bleeding disorders, high risk of clotting or bleeding conditions, HIV with low CD4 counts, a history of thromboembolic disease or significant reactions to monoclonal antibody therapies.

Inclusion Criteria

I have had two tests showing high inhibitor levels in the past 2 years.

I am 6 years old or older.

Parent/guardian (caregiver henceforth) or patient has provided written informed consent

Exclusion Criteria

I am not using and do not plan to use immune system medications during the study.

I am HIV positive with a CD4 count below 200, or I am under 35 years old.

Participants who are at high risk for TMA (for example, have a previous medical/family history of TMA), in the investigator's judgment

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a personalized dose of aPCC-emicizumab during acute bleeding events or prior to procedures

Up to 72 hours per event

As needed for acute events

Follow-up

Participants are monitored for safety and effectiveness after treatment

up to 2 years

Treatment Details

Interventions

• aPCC-emicizumab (Coagulation Factor Replacement Therapy)
• FEIBA (Coagulation Factor Replacement Therapy)
• rFVIIa (Coagulation Factor Replacement Therapy)
• SEVENFACT (Coagulation Factor Replacement Therapy)

Trial Overview This study tests the safety and effectiveness of personalized doses of aPCC in combination with emicizumab during acute bleeding events or before procedures in those on emicizumab prophylaxis. It aims to understand how well this treatment works for people with hemophilia A who also have inhibitors.

Participant Groups

Group I: Experimental treatment Experimental Treatment 3 Interventions

Participants will have a first/baseline thrombin generation assay (TGA) sample (to be processed within 60 minutes), followed by an infusion at 15 U/kg dose of aPCC, and provide a second TGA sample 15-30 minutes after to be processed within 60 minutes. If required, a subsequent TGA sample will be obtained upon a 25 U/kg dose of aPCC to be processed within 60-90 minutes.

aPCC-emicizumab is already approved in Japan, Canada for the following indications:

Approved in Japan as Hemlibra for:

• Hemophilia A with or without factor VIII inhibitors

Approved in Canada as Hemlibra for:

• Hemophilia A with or without factor VIII inhibitors

Who Is Running the Clinical Trial?

Emory University

Lead Sponsor

Trials

1,735

Recruited

2,605,000+

Dr. R. Donald Harvey

Emory University

Chief Medical Officer

MD from Emory University School of Medicine

Dr. George Painter

Emory University

Chief Executive Officer since 2013

PhD in Synthetic Organic Chemistry from Emory University

Takeda Pharmaceuticals North America, Inc.

Industry Sponsor

Trials

59

Recruited

109,000+

Christophe Weber

Takeda Pharmaceuticals North America, Inc.

Chief Executive Officer since 2015

MBA from INSEAD

Dr. Andrew Plump

Takeda Pharmaceuticals North America, Inc.

Chief Medical Officer since 2015

MD from Harvard Medical School

Findings from Research

Emicizumab-kxwh (Hemlibra®) is a bispecific monoclonal antibody that effectively restores the function of missing activated FVIII in patients with hemophilia A, facilitating better blood clotting.

It is approved in the USA for routine prophylaxis to prevent bleeding episodes in hemophilia A patients with FVIII inhibitors, and is currently undergoing phase 3 trials for those without FVIII inhibitors, indicating its potential broad application in hemophilia treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Emicizumab-kxwh: First Global Approval. Scott, LJ., Kim, ES.[2019]

Emicizumab, a bispecific antibody for hemophilia A, has shown a favorable safety profile and encouraging efficacy in phase 1/2 studies with once-weekly subcutaneous administration, even in patients with anti-FVIII inhibitors.

While emicizumab is an effective first-line therapy for hemophilia A, caution is advised when used with activated prothrombin complex concentrates (aPCC) due to potential thrombotic risks, highlighting the need for careful patient selection and management strategies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Spotlight on emicizumab in the management of hemophilia A: patient selection and special considerations. Yada, K., Nogami, K.[2020]

Emicizumab, a factor VIII mimetic used for treating Hemophilia A, has a unique mechanism of action that alters the results of standard coagulation tests, necessitating specific laboratory guidelines for monitoring.

The UKHCDO guidelines provide essential recommendations for clinical and laboratory staff on how to accurately measure factor VIII levels and emicizumab itself, ensuring effective treatment and monitoring for patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Laboratory coagulation tests and emicizumab treatment A United Kingdom Haemophilia Centre Doctors' Organisation guideline. Jenkins, PV., Bowyer, A., Burgess, C., et al.[2020]

In a review of data from the HAVEN clinical trials involving patients with congenital hemophilia A, the use of recombinant activated factor VII (rFVIIa) alongside emicizumab did not lead to any serious adverse events or thrombotic complications, indicating a favorable safety profile.

The standard dosing practices for rFVIIa were maintained during treatment of bleeding episodes, with no changes in safety outcomes when used in conjunction with emicizumab, supporting its continued use in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: Experience from the HAVEN clinical program. Levy, GG., Asikanius, E., Kuebler, P., et al.[2023]

In a study involving 11 patients with severe hemophilia A on emicizumab, higher concentrations of activated prothrombin complex concentrate (aPCC) led to excessive thrombin generation, raising concerns about thrombotic complications.

The findings suggest that aPCC could potentially be used safely with emicizumab at lower doses than typically prescribed, indicating a need for further clinical studies to explore this approach.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Comparison of bypassing agents in patients on emicizumab using global hemostasis assays. Kizilocak, H., Marquez-Casas, E., Phei Wee, C., et al.[2021]

Emicizumab can effectively manage bleeding events in patients with hemophilia A, allowing for minor bleeding and low-risk procedures to be treated without factor replacement therapy.

For major bleeding events and high-risk surgeries, additional factor VIII replacement is necessary, especially in the initial days, while continuing emicizumab treatment throughout the procedure and recovery.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of bleeding events and invasive procedures in patients with haemophilia A without inhibitors treated with emicizumab. Fontana, P., Alberio, L., Albisetti, M., et al.[2021]

In a phase IIIb study involving 402 female patients with breast cancer, intravenous (IV) NEPA was found to be highly effective in preventing chemotherapy-induced nausea and vomiting (CINV) with complete response rates of 73.0% for IV NEPA and 77.3% for oral NEPA during the first cycle.

IV NEPA demonstrated a favorable safety profile, with no reports of hypersensitivity or injection-site reactions, distinguishing it from other IV NK1 receptor antagonists that have been associated with such adverse effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase IIIb Safety and Efficacy of Intravenous NEPA for Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Patients with Breast Cancer Receiving Initial and Repeat Cycles of Anthracycline and Cyclophosphamide (AC) Chemotherapy. Schwartzberg, L., Navari, R., Clark-Snow, R., et al.[2021]

The recombinant human parvovirus B19 vaccine (MEDI-491) was found to be safe and well-tolerated in a phase 1 trial involving 24 parvovirus B19-seronegative adults.

All participants developed neutralizing antibodies that peaked after the third dose and remained elevated for at least one year, indicating strong immunogenicity of the vaccine.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and immunogenicity of a recombinant parvovirus B19 vaccine formulated with MF59C.1. Ballou, WR., Reed, JL., Noble, W., et al.[2013]

HTX-019, a new injectable formulation of aprepitant, has shown a tolerable safety profile in cancer patients when administered via both a 30-minute IV infusion and a 2-minute IV injection, with no treatment-emergent adverse events occurring within 30 minutes of administration.

In a study of 135 patients undergoing chemotherapy, both administration methods were well tolerated, and while some adverse events were reported during chemotherapy, none were directly related to HTX-019, indicating its potential as a safe option for preventing chemotherapy-induced nausea and vomiting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Crossover safety study of aprepitant: 2-min injection vs 30-min infusion in cancer patients receiving emetogenic chemotherapy. Navari, RM., Mosier, MC.[2020]

Rolapitant, a neurokinin-1 receptor antagonist, has been shown to effectively control chemotherapy-induced nausea and vomiting (CINV) in patients with various cancer types, including breast, gastrointestinal, and lung cancers, based on randomized controlled trials.

Unlike other NK-1 receptor antagonists, rolapitant has a long half-life and does not affect CYP3A4 metabolism, making it safer for use with other medications, although caution is advised with CYP2D6 substrates.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Recent developments in the clinical pharmacology of rolapitant: subanalyses in specific populations. Rapoport, BL., Aapro, M., Chasen, MR., et al.[2019]

References

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

Emicizumab-kxwh: First Global Approval. [2019]

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

Spotlight on emicizumab in the management of hemophilia A: patient selection and special considerations. [2020]

3. England pubmed.ncbi.nlm.nih.gov

Laboratory coagulation tests and emicizumab treatment A United Kingdom Haemophilia Centre Doctors' Organisation guideline. [2020]

4. England pubmed.ncbi.nlm.nih.gov

Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: Experience from the HAVEN clinical program. [2023]

5. England pubmed.ncbi.nlm.nih.gov

Safety of FEIBA and emicizumab (SAFE): Dose escalation study evaluating the safety of in vivo administration of activated prothrombin complex concentrate in haemophilia A patients on emicizumab. [2023]

6. England pubmed.ncbi.nlm.nih.gov

Comparison of bypassing agents in patients on emicizumab using global hemostasis assays. [2021]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Management of bleeding events and invasive procedures in patients with haemophilia A without inhibitors treated with emicizumab. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Phase IIIb Safety and Efficacy of Intravenous NEPA for Prevention of Chemotherapy-Induced Nausea and Vomiting (CINV) in Patients with Breast Cancer Receiving Initial and Repeat Cycles of Anthracycline and Cyclophosphamide (AC) Chemotherapy. [2021]

9. Germany pubmed.ncbi.nlm.nih.gov

Rolapitant improves quality of life of patients receiving highly or moderately emetogenic chemotherapy. [2019]

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

Safety and immunogenicity of a recombinant parvovirus B19 vaccine formulated with MF59C.1. [2013]

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

Crossover safety study of aprepitant: 2-min injection vs 30-min infusion in cancer patients receiving emetogenic chemotherapy. [2020]

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

Recent developments in the clinical pharmacology of rolapitant: subanalyses in specific populations. [2019]