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
试验速览
- 阶段
- 4 期
- 状态
- 终止
- 入组人数
- 14
- 试验地点
- 8
- 主要终点
- 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
研究概览
简要总结
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
排除标准
- •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
研究组 & 干预措施
PwHA With Inhibitors, Emicizumab: Surgery Not Performed Cohort
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.
干预措施: Emicizumab (Drug)
PwHA With Inhibitors, Emicizumab: CVAD Removal Cohort
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.
干预措施: Emicizumab (Drug)
PwHA With Inhibitors, Emicizumab: Simple Dental Extraction Cohort
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.
干预措施: Emicizumab (Drug)
PwHA Without Inhibitors, Emicizumab: CVAD Removal Cohort
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.
干预措施: Emicizumab (Drug)
PwHA Without Inhibitors, Emicizumab: Simple Dental Extraction Cohort
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.
干预措施: Emicizumab (Drug)
结局指标
主要结局
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
时间窗: Determined at the time of discharge (within approximately 48 hours after surgery)
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".
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
时间窗: Determined at the time of discharge (within approximately 48 hours after surgery)
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 \[activated\])
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
时间窗: Within 48 hours (if discharged home), and 8 and 28 days after surgery
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 \[activated\])
Percentage of Participants With Surgical Complications Requiring Hospitalization or Return to Surgery
时间窗: Within 48 hours after surgery, and 8 and 28 days after initial 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".
Percentage of Participants Who Needed Blood/Blood Product Transfusions During Surgery
时间窗: Within 48 hours after surgery, and 8 and 28 days after initial surgery
The percentage of participants who needed blood or blood product transfusions (e.g., platelets, plasma, etc.) during surgery was evaluated.
Emicizumab Plasma Concentration on the Day of Surgery
时间窗: Approximately 24 hours prior to 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.
Safety Summary of the Number of Participants With at Least One Adverse Event
时间窗: From Baseline up to 30 days after surgery
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.
次要结局
未报告次要终点