E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hemophilia A with or without inhibitors |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia A is a genetic deficiency in blood clotting factor VIII, which causes increased bleeding. Inhibitors, however, prevent replacement factor VIII concentrates from controlling bleeds. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053753 |
E.1.2 | Term | Hemophilia A without inhibitors |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10053751 |
E.1.2 | Term | Hemophilia A with anti factor VIII |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
-To evaluate the efficacy and safety of emicizumab in preventing surgery-related bleeding in patients with Hemophilia A with and without inhibitors undergoing minor surgical procedures |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal 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 |
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E.4 | Principal 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Percentage of patients without excessive bleeding at surgical sites and did not require BPA/FVIII use for bleeding related to the surgery, from the start of the surgery until the patient is discharged from the surgery.
2. Percentage of patients with excessive bleeding at surgical sites and required BPA/FVIII use for bleeding related to the surgery, from the start of the surgery until the patient is discharged from the surgery. Dose and schedule (including number of doses, total dose, and frequency) of BPAs/FVIII used per bleed will be summarized.
3. Percentage of patients who, after being discharged from surgery, experienced bleeds that were either related or unrelated to the surgery and also required BPA/FVIII use. Dose and schedule (including number of doses, total dose, and frequency) of BPAs/FVIII used per bleed will be summarized.
4. Incidence and severity of all adverse events
5. Percentage of patients with surgical complications requiring hospitalization or return to surgery
6. Percentage of patients who need blood/blood product transfusions (i.e., platelets, plasma, etc.) during surgery |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. and 2. From the start of the surgery until the patient is discharged from the surgery (within 48 hours)
3. From discharge up to 30 days after surgery
4. From Baseline up to 30 days after surgery
5. From surgery up to 30 days after surgery
6. From the start of the surgery until the patient is discharged from the surgery (within 48 hours) |
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E.5.2 | Secondary end point(s) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | Yes |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | No |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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The end of this study is defined as the date when the last patient, last visit (LPLV) occurs or the date at which the last data point required for statistical analysis or safety follow-up is received from the last patient, whichever occurs later. The end of a patient’s participation in the study is expected to occur after Study Day 28. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 6 |