Study of Emicizumab Prophylaxis in Participants With Hemophilia A With or Without Inhibitors Undergoing Minor Surgical Procedures

Study Overview
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Brief Summary
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This Phase IV, multicenter study will evaluate whether participants with Hemophilia A (PwHA) with or without inhibitors receiving emicizumab prophylaxis can safely undergo minor surgical procedures without additional prophylactic bypassing agents (BPA; for participants with inhibitors) or factor VIII (FVIII; for participants without inhibitors).

Official Title
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A Phase IV, Multicenter, Single-Arm, Open-Label Study of Emicizumab Prophylaxis in Patients With Hemophilia A With or Without Inhibitors Undergoing Minor Surgical Procedures

Conditions
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Hemophilia A

Intervention / Treatment
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* Drug: Emicizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Any age (newborn and older) Ability to comply with the study protocol, in the investigator's judgment Diagnosis of hemophilia A and current or history of an inhibitor (Bethesda titer ≥0.6 Bethesda units) and currently using bypassing agents (BPAs) for breakthrough bleeds (for PwHA with inhibitors) Diagnosis of hemophilia A and no history of an inhibitor (Bethesda titer <0.6 Bethesda units), or a history of an inhibitor that has been tolerized for >5 years and using FVIII for breakthrough bleeds (for PwHA without inhibitors) Plan to receive at least 4 loading doses of emicizumab and been adherent to emicizumab prophylaxis by the time of surgery Undergoing minor surgery within 60 days of study enrollment. Other minor surgical procedures could be included upon consultation and approval of Medical Monitor, but examples include central venous catheter insertion/removal/replacement, simple dental extractions, colonoscopy, cystoscopy, or endoscopy with biopsy, excisional skin biopsy Must plan to continue emicizumab prophylaxis for at least 1 month after surgery For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraceptive methods that result in a failure rate of <1% per year during the study period Exclusion Criteria: Diagnosis of a bleeding disorder other than hemophilia A Participants who have been tolerized to Factor VIII products (for PwHA with inhibitors) Tolerized to FVIII products for <5 years (for PwHA without inhibitors) Using FVIII products to treat breakthrough bleeds (for PwHA with inhibitors) Treatment with BPAs or FVIII within 24 hours prior to surgical procedure Undergoing a major surgical procedure Previous (in the past 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or current signs of thromboembolic disease Other conditions (e.g., certain autoimmune diseases, including but not limited to diseases such as systemic lupus erythematosus, inflammatory bowel disease, and antiphospholipid syndrome) that may increase the risk of bleeding or thrombosis Patients who are at high risk for thrombotic microangiopathy (TMA), e.g., have a previous medical or family history of TMA, in the investigator's judgment Would refuse treatment with blood or blood products, if necessary Any serious medical condition or abnormality in clinical laboratory tests that, in the investigator's judgment, precludes the participant's safe participation in and completion of the study Pregnant or lactating, or intending to become pregnant during the study; women of childbearing potential must have a negative serum pregnancy test result within 7 days before Study Day 1 Treatment with any of the following: An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration before Study Day 1; A non-hemophilia-related investigational drug within the last 30 days or 5 half-lives before Study Day 1 (whichever is longer); An investigational drug concurrently History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection Known human immunodeficiency virus (HIV) infection with CD4 count < 200 cells/microlitre within 24 weeks prior to enrollment
Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PwHA With Inhibitors, Emicizumab: Surgery Not Performed Cohort<br>This cohort included participants with Hemophilia A (PwHA) with inhibitors that were enrolled but did not have surgery. All participants received emicizumab via subcutaneous (SC) injection at a loading dose of 3 milligrams of medication per kilogram of body weight (mg/kg) once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as they continued to derive sufficient benefit. Participants must have received all loading doses prior to surgery and planned to continue emicizumab for a minimum of 1 month after surgery. | Drug: Emicizumab<br>* Emicizumab via SC injection at a loading dose 3 mg/kg once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as the participant continues to derive sufficient benefit. Dosing was to be adjusted if the participant had a significant change in body weight.<br>* Other names: RG6013;|
| Experimental: PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort<br>This cohort included participants with Hemophilia A (PwHA) with inhibitors that were enrolled and had surgery for central venous access device (CVAD) removal. All participants received emicizumab via subcutaneous (SC) injection at a loading dose of 3 milligrams of medication per kilogram of body weight (mg/kg) once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as they continued to derive sufficient benefit. Participants must have received all loading doses prior to surgery and planned to continue emicizumab for a minimum of 1 month after surgery. | Drug: Emicizumab<br>* Emicizumab via SC injection at a loading dose 3 mg/kg once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as the participant continues to derive sufficient benefit. Dosing was to be adjusted if the participant had a significant change in body weight.<br>* Other names: RG6013;|
| Experimental: PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort<br>This cohort included participants with Hemophilia A (PwHA) with inhibitors that were enrolled and had surgery for simple dental extraction. All participants received emicizumab via subcutaneous (SC) injection at a loading dose of 3 milligrams of medication per kilogram of body weight (mg/kg) once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as they continued to derive sufficient benefit. Participants must have received all loading doses prior to surgery and planned to continue emicizumab for a minimum of 1 month after surgery. | Drug: Emicizumab<br>* Emicizumab via SC injection at a loading dose 3 mg/kg once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as the participant continues to derive sufficient benefit. Dosing was to be adjusted if the participant had a significant change in body weight.<br>* Other names: RG6013;|
| Experimental: PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort<br>This cohort included participants with Hemophilia A (PwHA) without inhibitors that were enrolled and had surgery for central venous access device (CVAD) removal. All participants received emicizumab via subcutaneous (SC) injection at a loading dose of 3 milligrams of medication per kilogram of body weight (mg/kg) once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as they continued to derive sufficient benefit. Participants must have received all loading doses prior to surgery and planned to continue emicizumab for a minimum of 1 month after surgery. | Drug: Emicizumab<br>* Emicizumab via SC injection at a loading dose 3 mg/kg once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as the participant continues to derive sufficient benefit. Dosing was to be adjusted if the participant had a significant change in body weight.<br>* Other names: RG6013;|
| Experimental: PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort<br>This cohort included participants with Hemophilia A (PwHA) without inhibitors that were enrolled and had surgery for simple dental extraction. All participants received emicizumab via subcutaneous (SC) injection at a loading dose of 3 milligrams of medication per kilogram of body weight (mg/kg) once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as they continued to derive sufficient benefit. Participants must have received all loading doses prior to surgery and planned to continue emicizumab for a minimum of 1 month after surgery. | Drug: Emicizumab<br>* Emicizumab via SC injection at a loading dose 3 mg/kg once weekly for the first 4 weeks, followed by 1.5 mg/kg once weekly, or by any other approved maintenance regimen, as long as the participant continues to derive sufficient benefit. Dosing was to be adjusted if the participant had a significant change in body weight.<br>* Other names: RG6013;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Without Excessive Bleeding at Surgical Sites and Did Not Require BPA/FVIII Use for Bleeding Related to the Surgery, From the Start of Surgery Until Discharge, as Measured by the ISTH Hemostatic Efficacy Scale | The International Society on Thrombosis and Haemostasis (ISTH) Assessment of Hemostatic Response for Surgical Procedures scale (see reference PubMed ID:25059285) has four categories, listed here in order of best to worst response: Excellent, Good, Fair, and Poor. The participant's bleeding related to surgery was evaluated by the healthcare professional who performed the procedure using the hemostatic efficacy scale, with an absence of excessive bleeding at the surgical site indicated by a good to excellent rating. The endpoint was met when the response to Intraoperative and/or postoperative blood loss increased over expectation for the non-hemophilic patient determined at the time of discharge was 0 to <10% or 10% to < 25% AND the response to the question Did the patient use any bypassing agent (BPA)/factor VIII (FVIII) for the surgery before the discharge? was No. | Determined at the time of discharge (within approximately 48 hours after surgery) | 
| Percentage of Participants With Excessive Bleeding at Surgical Sites and Required BPA/FVIII Use for Treating Bleeding Related to the Surgery, From the Start of Surgery Until Discharge, as Measured by the ISTH Hemostatic Efficacy Scale | The ISTH Assessment of Hemostatic Response for Surgical Procedures scale (see reference PubMed ID:25059285) has four categories, listed here in order of best to worst response: Excellent, Good, Fair, and Poor. The participant's bleeding related to surgery was evaluated by the healthcare professional who performed the procedure using the hemostatic efficacy scale, with excessive bleeding at the surgical site indicated by a fair to poor rating. The endpoint was met when the response to Intraoperative and/or postoperative blood loss increased over expectation for the non-hemophilic patient determined at the time of discharge was 25% to <50% or ≥50% AND the response to the question Did the patient use any bypassing agent (BPA)/factor VIII (FVIII) for the surgery before the discharge? was Yes. The percentage of participants by type and dose of BPA/FVIII used to treat the bleeding is also reported. rFVIIa = recombinant activated human factor VII (eptacog alfa [activated]) | Determined at the time of discharge (within approximately 48 hours after surgery) | 
| Percentage of Participants Who, After Being Discharged From Surgery, Experienced Bleeds That Were Either Related or Unrelated to Surgery and Also Required BPA/FVIII Use | Post-surgical bleeding information was self-reported by participants (or the participant's legally authorized representative) on the Bleed and Medication Diary. Bypassing agents (BPAs)/factor VIII (FVIII) used to treat excessive bleeding were also self-reported by participants if it was self-administered. BPAs/FVIII administered by the investigators to treat the bleeding were reported on the Concomitant Medications case report form page. The percentage of participants by type and dose of BPA/FVIII used to treat the bleeding is also reported. rFVIIa = recombinant activated human factor VII (eptacog alfa [activated]) | Within 48 hours (if discharged home), and 8 and 28 days after surgery | 
| Emicizumab Plasma Concentration on the Day of Surgery | Enrolled participants received a minimum of four loading doses of emicizumab prior to their surgical procedure. Pharmacokinetic blood samples were obtained at study sites 24 hours before the procedures in order to describe emicizumab plasma concentration on the day of surgery for each of the inhibitor and non-inhibitor cohorts. | Approximately 24 hours prior to surgery | 
| Safety Summary of the Number of Participants With at Least One Adverse Event | All adverse events (AEs) that occurred after informed consent was obtained were coded using the Medical Dictionary for Regulatory Activities (MedDRA) v23.0, summarized by severity according to the World Health Organization (WHO) toxicity grading scale (Grade 1 is mild; Grade 2 is moderate; Grade 3 is severe; Grade 4 is life-threatening; and Grade 5 is death related to AE), and tabulated by body system and preferred term (PT) for individual events within each system organ class (SOC). For each AE, the investigator independently assessed its severity and seriousness, and whether it was considered to be related to the study drug. | From Baseline up to 30 days after surgery | 
| Percentage of Participants With Surgical Complications Requiring Hospitalization or Return to Surgery | This safety endpoint was a composite endpoint. Surgical complications were entered as adverse events on the case report form page with Other suspected causes marked as Study Surgery or Procedure. This endpoint was met when response to It required or prolonged inpatient hospitalization was checked OR response to Was procedure/surgery performed? was Yes. | Within 48 hours after surgery, and 8 and 28 days after initial surgery | 
| Percentage of Participants Who Needed Blood/Blood Product Transfusions During Surgery | The percentage of participants who needed blood or blood product transfusions (e.g., platelets, plasma, etc.) during surgery was evaluated. | Within 48 hours after surgery, and 8 and 28 days after initial surgery |