A Phase 3 Study to Evaluate the Efficacy and Safety of Fitusiran in Patients with Hemophilia A or B, with Inhibitory Antibodies to Factor VIII or IX
- Conditions
- Hemophilia A or B10064477
- Registration Number
- NL-OMON46748
- Lead Sponsor
- Alnylam Pharmaceuticals Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Withdrawn
- Sex
- Not specified
- Target Recruitment
- 2
Each patient must meet all of the following inclusion criteria to be eligible for enrollment in the study:
1. Males <=12 years of age.
2. 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 bypassing agents 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
3. A minimum of 6 bleeding episodes requiring bypassing agent treatment within the last
6 months prior to Screening.
4. 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.
Each patient must not meet any of the following exclusion criteria to be eligible for enrollment in the study:
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 planne
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Primary<br /><br>* Annualized Bleeding Rate (ABR) in the fitusiran efficacy period and the BPA<br /><br>prophylaxis period </p><br>
- Secondary Outcome Measures
Name Time Method <p>Secondary<br /><br>* Annualized spontaneous bleeding rate in the fitusiran efficacy period and<br /><br>the BPA prophylaxis period<br /><br>* Annualized joint bleeding rate in the fitusiran efficacy period and the BPA<br /><br>prophylaxis period<br /><br>* Change in Haem-A-QOL score in the fitusiran treatment period<br /><br>* ABR in the fitusiran onset period<br /><br>* ABR in fitusiran treatment period </p><br>