aPCC-Emicizumab Safety for Hemophilia A

(SAFE Trial)

Recruiting at 1 trial location

Overseen By Robert Sidonio, MD

Age: Any Age

Sex: Any

Trial Phase: Phase 3

Sponsor: Emory University

Must be taking: Emicizumab

Must not be taking: Immunomodulators

Disqualifiers: Thromboembolic disease, HIV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

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

Compensation: Varies

Number of Visits: Unknown

Duration: Up to 72 hours per event

5 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for individuals with hemophilia A, a condition where blood doesn’t clot properly, who have also developed inhibitors (antibodies that block standard treatment). Researchers aim to determine how well a specific combination of medications aids blood clotting. Participants will receive a low, personalized dose of aPCC (activated prothrombin complex concentrate) while already on another medication, emicizumab. Those with moderately severe hemophilia A who have struggled with inhibitor issues are well-suited for this trial. As a Phase 3 trial, this study represents the final step before FDA approval, offering participants a chance to contribute to a potentially groundbreaking treatment.

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.

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

Research has shown that emicizumab, a component of the aPCC-emicizumab treatment, is generally safe. Over ten years of data reveal no major new safety issues. Emicizumab is already approved to prevent bleeding in people with Hemophilia A, indicating its safety.

Specific data for the aPCC component is not provided here. However, its inclusion in a Phase 3 trial means earlier studies found it safe enough to continue testing. Phase 3 trials typically indicate the treatment was well-tolerated in earlier phases.

Overall, the safety data for emicizumab is strong, and aPCC's presence in a Phase 3 trial suggests it is safe enough for this stage of research. Participants can feel reassured that the treatment has undergone thorough testing before reaching this point. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the aPCC-emicizumab treatment for Hemophilia A because it introduces a novel mechanism by combining aPCC with emicizumab to improve blood clotting without relying on traditional factor VIII replacement. Emicizumab acts as a bridge between factors IXa and X, mimicking the function of missing factor VIII, while aPCC provides additional clotting factors to boost the process. This combination could offer a more effective and potentially safer alternative to current treatments like factor VIII infusions, especially for patients who have developed inhibitors against factor VIII, making it a promising option for those with this challenging condition.

What evidence suggests that this trial's treatments could be effective for hemophilia A?

Research has shown that emicizumab reduces bleeding in people with hemophilia A, especially those with inhibitors. Studies have found that regular use of emicizumab significantly decreases bleeding compared to non-use. Long-term results from studies like HAVEN 3 and 4 have demonstrated that emicizumab continues to control bleeding effectively over several years. In this trial, researchers are examining the combination of emicizumab with aPCC (a treatment that helps blood clot) to determine if it can further improve results. Early findings suggest this combination might benefit those needing better bleeding control. ^{6 7 8 9 10}

Who Is on the Research Team?

Robert Sidonio, MD

Principal Investigator

Emory University

Are You a Good Fit for This Trial?

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

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• aPCC-emicizumab
• FEIBA
• rFVIIa
• SEVENFACT

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.

How Is the Trial Designed?

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 United States, European Union, Japan, Canada for the following indications:

Approved in United States as Hemlibra for:

• Hemophilia A with or without factor VIII inhibitors

Approved in European Union as Hemlibra for:

• Hemophilia A with or without factor VIII inhibitors

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+

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

Published Research Related to This Trial

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]

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]

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 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]

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]

In phase 3 trials involving patients receiving highly or moderately emetogenic chemotherapy, the addition of rolapitant to standard antiemetic therapy significantly improved quality of life, as measured by the Functional Living Index-Emesis (FLIE).

Rolapitant not only enhanced overall FLIE scores but also specifically reduced nausea and vomiting scores, with a higher percentage of patients reporting no impact on daily life compared to those receiving placebo.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rolapitant improves quality of life of patients receiving highly or moderately emetogenic chemotherapy. Chasen, M., Urban, L., Schnadig, I., et al.[2019]

In a study involving nine patients with severe hemophilia A on emicizumab, the in vitro results indicated that low doses of activated prothrombin complex concentrate (aPCC) could lead to excessive thrombin generation, raising concerns about safety when used together with emicizumab.

However, the in vivo results showed that most patients maintained normal thrombin generation levels at approved doses of aPCC, suggesting that while caution is necessary, low doses of aPCC may be safe for managing breakthrough bleeding in these patients.

NCBI (Pubmed)

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. Kizilocak, H., Marquez-Casas, E., Malvar, J., et al.[2023]

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]

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]

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, 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]

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]

Citations

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Long-term outcomes with emicizumab in hemophilia A ... With nearly 5 years of emicizumab exposure across the HAVEN 3 and 4 studies in people with HA without inhibitors, these data indicate continued bleed control.

2. nejm.org nejm.org/doi/full/10.1056/NEJMoa1703068

Emicizumab Prophylaxis in Hemophilia A with Inhibitors Emicizumab prophylaxis was associated with a significantly lower rate of bleeding events than no prophylaxis among participants with hemophilia A with ...

3. icer.org icer.org/wp-content/uploads/2020/10/ICER_Hemophilia_Final_Evidence_Report_041618.pdf

Emicizumab for Hemophilia A with Inhibitors: Effectiveness ... Foluso Agboola led the systematic review and authorship of the comparative clinical effectiveness section. Varun Kumar and Rick Chapman were ...

4. hemlibra.com hemlibra.com/about/clinical-trial-results.html

HEMLIBRA® (emicizumab-kxwh) Clinical Trial Results View study results and discover how HEMLIBRA® (emicizumab-kxwh) may help people with hemophilia A with or without factor VIII inhibitors.

5. hemlibra-hcp.com hemlibra-hcp.com/efficacy/clinical-trial-results.html

Clinical Trials | HEMLIBRA® (emicizumab-kxwh) HAVEN 1-4 LONG-TERM DATA · The ABR‡II (95% CI) over the entire study was 1.4 (1.1; 1.7). Median efficacy period (IQR) of 120.4 weeks (89.0; 164.4) · No new safety ...

6. emicizumabinfo.com emicizumabinfo.com/patient/scientific-data/safety-information.html

Safety Information - Hemlibra® (emicizumab-kxwh) Emicizumab Prophylaxis in People With Haemophilia A: Summary of 10 Years of Safety Data on Thromboembolic Events and Thrombotic Microangiopathy. Sarouei K, ...

7. hemlibra-hcp.com hemlibra-hcp.com/side-effects/important-safety-information.html

Important Safety Information | HEMLIBRA® (emicizumab-kxwh) HEMLIBRA is indicated for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients ages newborn and older ...

8. hemlibra.com hemlibra.com/

HEMLIBRA® (emicizumab-kxwh) | Hemophilia A Treatment ... Safety · For US Healthcare Professionals. PROVEN AND TRUSTED. BY THE HEMOPHILIA A COMMUNITY FOR 7 YEARS AND COUNTING. See the Data. First approved in 2017* | ...

9. sciencedirect.com sciencedirect.com/science/article/pii/S2531137925001178

Efficacy, safety and satisfaction of using emicizumab in ... Emicizumab represents a significant advancement in hemophilia A treatment, offering superior efficacy, safety, and patient satisfaction compared to traditional ...

10. roche.com roche.com/investors/updates/inv-update-2020-07-13b

New data from phase IIIb study reinforces safety profile of ... In the STASEY study, Hemlibra was effective with no new safety signals identified in adults and adolescents with haemophilia A with factor VIII ...