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 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 bypassing agents, as determined by the frequency of spontaneous bleeding episodes, the frequency of joint bleeding episodes in patients, and health related quality of life (HRQOL) in patients receiving 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 (evidenced by a central laboratory FVIII <1% or FIX level ≤2% at Screening)
with inhibitors (evidenced by inhibitor titer of ≥0.6 BU/mL or as evidenced by medical records)
AT activity ≥60% at Screening
A minimum of 6 bleeding episodes requiring bypassing agent treatment within the last 6 months
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
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E.4 | Principal exclusion criteria |
1. Known co-existing bleeding disorders other than hemophilia A or B, ie, Von Willebrand's disease, additional factor deficiencies, or platelet disorders.
2. Current participation in immune tolerance induction therapy (ITI)
3. Current use of bypassing agents as regularly administered prophylaxis designed to prevent spontaneous bleeding episodes.
4. AT activity <60% at Screening, as determined by central laboratory measurement.
5. Presence of clinically significant liver disease, or as indicated by any of the conditions below:
a. INR >1.2
b. ALT and/or AST >1.5× upper limit of normal reference range (ULN);
c. Total bilirubin >ULN (>1.5 ULN in patients with Gilbert's Syndrome);
d. History of portal hypertension, esophageal varices, or hepatic encephalopathy;
e. Presence of ascites by physical exam
6. Hepatitis C virus antibody positive, except patients with a history of HCV infection who meet both conditions a. and b.:
a. Completed curative treatment at least 12 weeks prior to enrollment and attained sustained virologic response as documented by a negative HCV RNA at screening, or they have spontaneously cleared infection as documented by negative HCV RNA at Screening.
b. No evidence of cirrhosis according to one of the following assessments:
- FibroScan <12.5 kPa (where available), or
- FibroTest score <0.75 and APRI <2 (if FibroScan unavailable)
7. Presence of acute hepatitis, ie, hepatitis A, hepatitis E.
8. Presence of acute or chronic hepatitis B infection (IgM anti-HBc antibody positive or HBsAg positive).
9. Platelet count ≤100,000/μL.
10. Presence of acute infection at Screening.
11. Known to be HIV positive with CD4 count <200 cells/μL.
12. Estimated glomerular filtration rate ≤45 mL/min/1.73m2 (using the Modification of Diet in Renal Disease [MDRD] formula).
13. Co-existing thrombophilic disorder, as determined by presence of any of the below as identified at central laboratory (or via historical results, where available):
a. FV Leiden mutation (homozygous or heterozygous)
b. Protein S deficiency
c. Protein C deficiency
d. Prothrombin mutation (G20210A; homozygous or heterozygous)
14. History of antiphospholipid antibody syndrome.
15. History of arterial or venous thromboembolism, atrial fibrillation, significant valvular disease, myocardial infarction, angina, transient ischemic attack, or stroke. Patients who have experienced thrombosis associated with indwelling venous access may be enrolled.
16. Had a malignancy within 2 years, except for basal or squamous cell carcinoma of the skin that has been successfully treated.
17. Any condition (eg, medical concern), which in the opinion of the Investigator, would make the patient unsuitable for dosing on Day 1 or which could interfere with the study compliance, the patient's safety and/or the patient's participation in the completion of the treatment period of the study. This includes significant active and poorly controlled
(unstable) cardiovascular, neurologic, gastrointestinal, endocrine, renal or psychiatric disorders unrelated to hemophilia identified by key laboratory abnormalities or medical history.
18. At Screening, anticipated need of surgery during the study or planned surgery scheduled to occur during the study.
19. Completion of a surgical procedure within 14 days prior to Screening, or currently receiving additional bypassing agent infusion for postoperative hemostasis.
20. History of multiple drug allergies or history of allergic reaction to an oligonucleotide or GalNAc.
21. Inadequate venous access, as determined by the Investigator, to allow the blood draws required by the study protocol.
22. History of intolerance to SC injection(s).
23. Current or future participation in another clinical study, scheduled to
occur during this study, involving an investigational product other than fitusiran or an investigational device; in order to participate in this study, patient must discontinue the investigational product or investigational device at least 30 days (or 5× the investigational product halflife, whichever is longer) prior to dosing (Day 1).
24. Current or prior participation in a gene therapy trial.
25. History of alcohol abuse within the 12 months before Screening. Alcohol abuse is defined as regular weekly intake of more than 14 units (unit: 1 glass of wine [approximately 125 mL] = 1 measure of spirits (approximately 1 fluid ounce) = ½ pint of beer [approximately 284 mL]). |
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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 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 |
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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 | 1 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 19 |
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 |
Brazil |
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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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 |