E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia A is a genetic disorder that impairs the body's ability to control blood clotting or coagulation, which is used to stop bleeding. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
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 | 10060613 |
E.1.2 | Term | Hemophilia A (Factor VIII) |
E.1.2 | System Organ Class | 100000004850 |
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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 | 100000004850 |
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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 |
The primary objective of the study is to describe the time to tolerance (I.e., ITI succes) with rFVIIIFc in subjects within a maximum of 48weeks (12 months) of ITI treatment. |
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E.2.2 | Secondary objectives of the trial |
•To describe the outcome of ITI treatment
•To describe the relapse rate over the 48-week (12-month) period following successful ITI performed with rFVIIIFc
•To describe the intercurrent bleeding during ITI and during the 48-week (12-month) period after successful ITI performed with rFVIIIFc
•To describe the safety and tolerability of rFVIIIFc when used for ITI
•To evaluate the impact of ITI treatment with rFVIIIFc on health economics and adherence
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Ability of the subject or his legally authorized representative (e.g., parent or legal guardian) to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information in accordance with national and local subject privacy regulations.
2.Male subjects of any age diagnosed with severe hemophilia A (as confirmed from the medical record).
3.Currently diagnosed with high titer inhibitors (historical peak ≥5 BU/mL, according to medical records)
4.Previously treated with any plasma-derived or recombinant conventional or Extended Half-Life FVIII. |
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E.4 | Principal exclusion criteria |
1. Other coagulation disorder(s) in addition to hemophilia A.
2. Previous ITI
3. History of hypersensitivity or anaphylaxis associated with any rFVIIIFc administration.
4. Planned major surgery scheduled during the study unless deferred until after study completion (minor surgery such as tooth extraction or insertion/replacement of central venous access device is allowed)
5. Abnormal renal function (serum creatinine >1.5 mg/dL or 2x upper limit of normal (ULN) for subject age based on local laboratory range) as
assessed by local laboratory.
6. Serum alanine aminotransferase or aspartate aminotransferase >5 × upper limit of normal (ULN) as assessed by local laboratory.
7. Serum total bilirubin >3 × ULN as assessed by local laboratory
8. Current enrollment or a plan to enroll in any interventional clinical study in which an investigational treatment or approved therapy, other than rFVIIIFc, for investigational use is administered within 30 days (or 5 half-lives of the agent, whichever is longer) prior to the Baseline Visit.
9. Inability to comply with study requirements.
10. Presence of any medical or psychological condition or laboratory result that in the opinion of the Investigator can interfere with the subject's ability to comply with the protocol requirements or make the subject not appropriate for inclusion to the study and treatment with Elocta/Eloctate (rFVIIIFc)
11. Other unspecified reasons that, in the opinion of the Investigator or Sponsor, make the subject unsuitable for enrollment.
12. Unwillingness or inability to comply with the requirements of the protocol, including the presence of any condition (physical, mental, or social) that prevents the subject from participating in visits as scheduled or entering required information into the EPD in a timely manner
13. Concurrent systemic treatment with immunosuppressive drugs within 12 weeks (3 months) prior to Screening. Exceptions to this include: ribavirin for treatment of hepatitis C virus (HCV), and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days within 12 weeks [3 months] prior to Day 1) and/or inhaled steroids
14. High risk of cardiovascular, cerebrovascular, or other thromboembolic events, as judged by the Investigator
The following criteria refer to tests performed within 26 weeks (6.5 months) prior to Screening. If not available, a new test will be drawn at
the Screening visit.
15. Cluster of differentiation 4 (CD4) lymphocytes <200 mm3 at Screening, if known as human immunodeficiency virus (HIV) antibody
positive based on medical history or HIV testing
16. Viral load of >400 copies/mL at Screening, if known as HIV antibody positive, based on medical history. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint of this study is time to tolerization with a maximum of 48 weeks (12 months) ITI treatment offered in the study. (Tolerization defined as inhibitor titer <0.6BU/ml, rFVIIIFc incremental recovery [IR] ≥ 66% of the expected IR, and t1/2 of ≥7hrs) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint of time to tolerization with a maximum of 12 months (48 weeks) of ITI treatment, will be summarized descriptively using minimum, mean, standard deviation, median, 25th and 75th quartiles, and maximum. A Kaplan-Meier plot showing percentage of subjects who are tolerized against time from the first ITI infusion will also be generated. Subjects not achieving ITI success during the 12 month (48-week) ITI period will be censored at the last observed time for this analysis. The ITIFAS will be used for this analysis |
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E.5.2 | Secondary end point(s) |
•ITI success
oConfirmed negative titers consisting of 2 consecutive negative inhibitor assessments within 2 weeks (+/-3 days) based on local laboratory results <0.6 BU/mL by the Nijmegen-modified Bethesda assay; determination of negative titer based on the Bethesda assay is acceptable at sites that have not yet adopted the Nijmegen-modified Bethesda assay oIR) ≥1.32 IU/dL per IU/kg in 2 consecutive assessments representing ≥66% of the expected IR 2 IU/dL per IU/kg (SmPC;USPI).
o t1/2 ≥7 hours
•Occurrence of relapse( defined as confirmed positive inhibitor titer ≥ 0.6 BU/mL), abnormal recovery after tolerance is achieved, and t½ <7 hours) during the Tapering or Follow-Up Periods
•Number of bleeding episodes during ITI and during the 48-week (12-month) period after successful ITI performed with rFVIIIFc
•Adverse events (AEs) and serious adverse events (SAEs)
•Number of days away from work or school
•Number of hospitalization days
•Adherence (defined as percentage of administered doses versus planned doses)
•Consumption of rFVIIIFc (measured in total rFVIIIFc use) |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
After Baseline Visit which is the start of ITI treatment, subjects will be seen at Week 2 and every fourth week until subjects acheive a negative inhibitor titer (<0.6 BU/mL). Starting at time of first negative inhibitor titer until ITI success OR 48 weeks (12 months) of treatment, subjects will be seen every 2nd week. With ITI success (3 success criteria met) and continuing for 16 weeks (Tapering period), subjects will have assessment visits after 2 weeks, 4 weeks and then every 4th week thereafter. Follow-up Period constitutes the time period in which subject returns to prophylactic dosing regimen and will be approximately 32 weeks (8 months) in duration. |
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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 | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | No |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
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 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 22 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 22 |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
Belgium |
Canada |
European Union |
France |
Germany |
Italy |
Japan |
Spain |
United Kingdom |
United States |
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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 study is last subject, last visit for final collection of data. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 8 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |