| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Severe Haemophilia A Patients with Inhibitors who have Failed Previous Immune Tolerance Induction Therapies |
|
| E.1.1.1 | Medical condition in easily understood language |
| patients with haemophilia A who have developed inhibitors towards factor VIII replacement therapy and has not been helped by previous attempts to erradicate the inhibitors |
|
| 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 | 10018937 |
| E.1.2 | Term | Haemophilia A |
| E.1.2 | System Organ Class | 100000004850 |
|
| 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 describe the outcome of ITI treatment performed with rFVIIIFc within a timeframe of 60 weeks in patients who failed previous attempts at tolerization including use of immunosuppressants |
|
| E.2.2 | Secondary objectives of the trial |
To describe time to tolerization of ITI (i.e. ITI success) performed with rFVIIIFc within a timeframe of 60 weeks in patients who failed previous attempts at tolerization including use of immunosuppressants.
To describe the relapse rate over a 48-week period following successful ITI performed with rFVIIIFc.
To describe the intercurrent bleeding during ITI and during the 48-week period after successful ITI performed with rFVIIIFc.
To describe safety and tolerability of rFVIIIFc when used for ITI.
To describe the impact of ITI treatment with rFVIIIFc on health economy.
To describe adherence of rFVIIIFc when used for ITI.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated informed consent provided by the patient, or the patient's legally authorized representative for patients under the legal age. Assent should be obtained from pediatric patients according to local regulations
2. Male patients of any age diagnosed with severe haemophilia A, as confirmed from the medical record
3. Previously treated with any plasma-derived or recombinant conventional or extended half-life FVIII
4. Diagnosed with high titer inhibitors (historical peak ≥5 BU/mL according to medical records)
5. Inhibitor titer ≥ 0.6 BU at screening
6. Failed previous ITI attempt(s) with any plasma-derived or recombinant conventional or extended half-life FVIII product including the use of immunosuppressant The attempt should be documented in the medical records and have the following characteristics:
• A minimum FVIII dose equivalent to the low dose arm of the International ITI study (50 IU/kg, 3 times/week)
• A minimum ITI treatment period of 33 months or
• Shorter than 33 months if no downward trend of at least 20% in the inhibitor titer in a 6-month period after the initial 3 months of the ITI treatment
7. All patients must assure to practice effective contraception during the study and for 3 months after their last dose of study treatment
Acceptable forms of birth control include barrier method (e.g. male condom, female condom, cervical cap, diaphragm, contraceptive sponge). |
|
| E.4 | Principal exclusion criteria |
1. Other coagulation disorder(s) in addition to haemophilia A
2. History of hypersensitivity reactions associated with any rFVIIIFc administration
3. High risk of cardiovascular, cerebrovascular, or other thromboembolic events, as judged by the investigator
4. Planned major surgery to be deferred after study completion. Minor surgery such as tooth extraction or insertion/replacement of central venous access device is allowed.
5. Concurrent systemic treatment with immunosuppressive drugs within 12 weeks prior to screening. Exceptions to this include: ribavirin for treatment of HCV, and/or systemic steroids (a total of 2 courses of pulse treatments lasting no more than 7 days within 12 weeks prior to Day 1) and/or inhaled steroids
6. Abnormal renal function (serum creatinine >1.5 mg/dL or 2× upper limit of normal (ULN) for subject age based on local laboratory range) as assessed by local laboratory
7. Serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5 × ULN as assessed by local lab
8. Serum total bilirubin >3 × ULN as assessed by local lab
9. CD4 lymphocytes ≤200 mm3 if known as HIV antibody positive at Screening
10. Viral load of ≥400 copies/mL if known as HIV antibody positive at Screening
11. Patients with a documented history of alcohol or substance abuse within 12 months prior to randomization
12. Previous enrollment in this study (rescreening is allowed)
13. Participation in another concurrent clinical interventional study within 30 days of screening or intake of an investigational drug within five half-lives of that investigational drug has passed
14. Foreseeable inability to cooperate with given instructions or study procedures
15. Presence of any medical or psychological condition or laboratory result that in the opinion of the investigator can interfere with the patient’s ability to comply with the protocol requirements or makes the patient not appropriate for inclusion to the study and treatment with rFVIIIFc
16. Concurrent treatment with emicizumab or previous use of emicizumab within five half-lives of emicizumab has passed unless laboratory analysis shows the level of emicizumab < lower level of detection
Exclusion criteria 9 and 10 refer to tests performed within 26 weeks prior to Screening. If results are not available, a new test should be drawn at the screening visit and analyzed locally prior to inclusion.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
ITI success defined as achieving all 3 of the following criteria:
• Negative titer for inhibitor (<0.6 BU/mL by the Nijmegen-modified Bethesda assay) at 2 consecutive visits
• FVIII incremental recovery (IR) >66% of the expected IR at 2 consecutive visits
• FVIII elimination half-life (t½) ≥7 hours
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Time to ITI success
Occurrence of relapse during a 48-week period following successful ITI treatment
Number of bleedings during ITI treatment
Bleeding rate during a 48-week period following successful ITI treatment
Adverse events
Consumption of rFVIIIFc
Number of days missed school or work during ITI treatment
Number of days missed school or work during a 48-week period following successful ITI treatment
Number of hospitalizations during ITI treatment
Number of hospitalizations during a 48-week period following successful ITI treatment
Adherence
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
60 weeks for the following secondary endpoints -
- Time to ITI success
- Number of bleedings during ITI treatment
- Time to ITI Success
- Number of days missed school or work during ITI treatment
- ITI treatment Adherence
108 weeks for the following secondary endpoint
- Occurrence of relapse during a 48-week period following successful ITI
- Bleeding rate during a 48-week period following successful ITI
- treatment
- Adverse events
- Consumption of rFVIIIFc
- Number of days missed school or work during a 48-week period
- following successful ITI treatment
- Number of hospitalizations during a 48-week period following successful
|
|
| 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 | Yes |
| 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 | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | Yes |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Germany |
| Ireland |
| Italy |
| Slovenia |
| Sweden |
| United Kingdom |
| United States |
|
| 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
|
| the date of the last patient’s last visit |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 2 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
