E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Hemophilia A or Hemophilia B |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia is an inherited bleeding disorder in which the blood does not clot normally and can result in internal bleeding into the muscles and joints. |
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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 | 10060614 |
E.1.2 | Term | Hemophilia B (Factor IX) |
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 |
To evaluate the efficacy of fitusiran compared to on-demand treatment with BPAs (bypassing agents), as determined by the frequency of bleeding episodes |
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E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of fitusiran compared to on-demand treatment with BPAs, as determined by the frequency of spontaneous bleeding
episodes, the frequency of joint bleeding episodes, and health related quality of life (HRQOL) in patients ≥ 17 years of age
To determine the frequency of bleeding episodes during the onset period
To determine the safety and tolerability of fitusiran |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Males ≥12 years of age.
Severe hemophilia A or B with inhibitors evidenced by:
a.A central laboratory measurement or documented medical record evidence of FVIII <1% or FIX level ≤2% at Screening.
b.On-demand use of BPAs to manage bleeding episodes for at least the last 6 months prior to Screening, and meet one of the following Nijmegen-modified Bethesda assay results criteria:
Inhibitor titer of ≥0.6 BU/mL at Screening, or
Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of 2 consecutive titers ≥0.6 BU/mL, or
Inhibitor titer of <0.6 BU/mL at Screening with medical record evidence of anamnestic response
A minimum of 6 bleeding episodes requiring BPA treatment within the last 6 months prior to Screening.
Willing and able to comply with the study requirements and to provide written informed consent and assent in the case of patients under the age of legal consent, per local and national requirements.
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E.4 | Principal exclusion criteria |
Patients with known co-existing bleeding disorders other than hemophilia A or B
Patients with clinically significant liver disease
Patients known to be HIV positive and have a CD4 count <200 cells/μL
Patients with a history of arterial or venous thromboembolism
Estimated glomerular filtration rate ≤45 mL/min/1.73m2 (using the Modification of Diet in Renal Disease [MDRD] formula)
Patients with a co-existing thrombophilic disorder
Patients with a history of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc
Patients with a history of intolerance to SC injection(s)
Patients with an anticipated or planned need for surgery during the study
Any other conditions or comorbidities that would make the patient unsuitable for enrollment or could interfere with participation in or completion of the study, per Investigator judgement |
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E.5 End points |
E.5.1 | Primary end point(s) |
Annualized bleeding rate (ABR) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
ABR in the treatment period
Annualized spontaneous bleeding rate in the efficacy period
Annualized joint bleeding rate in the efficacy period
Change in Haem-A-QOL physical health score and total score in the treatment period
ABR in the onset period |
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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 | Yes |
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) | Yes |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
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) | Yes |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | Yes |
E.8.2.3.1 | Comparator description |
Rescue therapy per standard of Care |
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E.8.2.4 | Number of treatment arms in the trial | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 17 |
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 |
Australia |
Bulgaria |
Canada |
China |
Denmark |
France |
Germany |
Hungary |
India |
Israel |
Italy |
Japan |
Korea, Republic of |
Malaysia |
Netherlands |
Portugal |
Russian Federation |
South Africa |
Spain |
Taiwan |
Turkey |
Ukraine |
United Kingdom |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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Last Patient Last Visit (LPLV) |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | |
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 | 4 |