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 characterize the frequency of bleeding episodes while receiving fitusiran treatment, relative to the frequency of bleeding episodes while receiving factor or bypassing agent prophylaxis. |
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E.2.2 | Secondary objectives of the trial |
To characterize the following while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis: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 characterize the frequency of bleeding episodes during the onset period in patients receiving fitusiran
To characterize the safety and tolerability of fitusiran
To characterize the annualized weight-adjusted consumption of factor/BPA while receiving fitusiran treatment, relative to receiving factor or BPA prophylaxis
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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 as evidenced by: a.A central laboratory measurement or documented medical record evidence of FVIII <1% or FIX level ≤2% at Screening.
A minimum of 2 bleeding episodes requiring BPA treatment within the last 6 months prior to Screening. for patients with inhibitory antibodies to factor VIII or factor IX (Cohort A). A minimum of 1 bleeding episode requiring factor treatment within the last 12 months prior to Screening for patients without inhibitory antibodies to factor VIII or factor IX (Cohort B).
Must meet either the definition of inhibitor or non-inhibitor patient as below: Inhibitor: Use of BPAs for prophylaxis and for any 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 The subgroup of patients in Cohort A patients must additionally meet the following criteria to be eligible to start treatment with fitusiran directly after the screening period: - Hemophilia B with inhibitory antibody to Factor IX as defined above - Not responding adequately to BPA treatment (historical ABR =20) prior to enrollment - In the opinion of the Investigator, with approval of Sponsor Medical Monitor, 6-month BPA prophylaxis period should be omitted.
Non-inhibitor: Use of factor concentrates for prophylaxis and for any bleeding episodes for at least the last 6 months prior to Screening, and meet each of the following criterion: Nijmegen-modified Bethesda assay inhibitor titer of <0.6 BU/mL at Screening and No use of bypassing agents to treat bleeding episodes for at least the last 6 months prior to Screening and No history of immune tolerance induction therapy within the past 3 years prior to Screening.
Prescribed prophylactic treatment (documented in the medical or pharmacy records) of hemophilia with factor concentrates or BPAs for at least 6 months prior to Screening; the regimen must be consistent with the approved prescribing information for the product or local recommendations, allowing for adjustment to individual patient response, and designed to decrease spontaneous bleeding.
Adherent to the prescribed prophylactic therapy for at least 6 months prior to Screening per Investigator assessment.
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) in the fitusiran efficacy period and the factor or BPA prophylaxis period |
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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) |
Annualized spontaneous bleeding rate in the fitusiran efficacy period and the factor or BPA prophylaxis period
Annualized joint bleeding rate in the fitusiran efficacy period and the factor or BPA prophylaxis period
Change in Haem-A-QOL physical health score and total score in the fitusiran treatment period and the factor or BPA prophylaxis period
ABR in the fitusiran onset period
ABR in fitusiran treatment period
Annualized weight-adjusted consumption of factor/BPA |
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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 | 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 | Yes |
E.8.1.7.1 | Other trial design description |
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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 | 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 | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
Australia |
Canada |
China |
Israel |
Japan |
Korea, Republic of |
Malaysia |
Russian Federation |
Taiwan |
Turkey |
Ukraine |
United States |
Bulgaria |
Denmark |
France |
Germany |
Hungary |
Ireland |
Italy |
Portugal |
Spain |
Switzerland |
United Kingdom |
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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.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |