A study to look at the efficacy and safety of ALN TTRSC in patients with an inherited condition that causes certain protein molecules to deposit in the heart
- Conditions
- Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]Transthyretin (TTR) mediated familial amyloidotic cardiomyopathy (FAC)MedDRA version: 18.1Level: PTClassification code 10016202Term: Familial amyloidosisSystem Organ Class: 10010331 - Congenital, familial and genetic disorders
- Registration Number
- EUCTR2014-003835-20-BE
- Lead Sponsor
- Alnylam Pharmaceuticals, Inc.
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- ot Recruiting
- Sex
- All
- Target Recruitment
- 200
1. Are male or female of 18 to 90 years of age (inclusive).
2. Have a documented TTR mutation.
3. Amyloid deposits in cardiac or non-cardiac tissue confirmed by Congo Red (or equivalent) staining or technetium (99mTc) scintigraphy (99mTc-3,3-diphosphono-1,2- propanodicarboxylic acid [DPD-Tc] or 99mTc-pyrophosphate [PYP-Tc]) with Grade 2 or 3 cardiac uptake, centrally confirmed.
4. If patient has monoclonal gammopathy, TTR amyloidosis needs to be confirmed through TTR protein identification by immunohistochemistry or mass spectrometry.
5. Have a medical history of heart failure (HF) with at least 1 prior hospitalization for HF, which may include hospitalization for arrhythmia or pacemaker placement, OR clinical evidence of HF (as evidenced by one or more of the following: elevated jugular venous pressure, peripheral edema, shortness of breath or signs of pulmonary congestion on x-ray or auscultation) that either requires/required treatment with diuretics or is/was associated with an N terminal prohormone of B-type natriuretic peptide (NT-proBNP) >400 ng/L or B-type natriuretic peptide (BNP) >100 ng/L.
6. Have evidence of cardiac involvement by Screening/Baseline echocardiogram including an end-diastolic intraventricular septum thickness of =12 mm. For patients with an end-diastolic intraventricular septum thickness of <12mm, an endomyocardialbiopsy showing amyloid deposition is required.
7. Can walk =150 meters on a 6-minute walk test (6-MWT).
8. Have a Karnofsky performance status of =50%.
9. Symptoms of HF optimally managed with no CV hospitalizations within 4 weeks prior to consent or during Screening/Baseline.
10. Have adequate liver function, demonstrated by an AST and ALT = 2.0×ULN, albumin >3 g/dL (>4.35 µmol/L), and total bilirubin <2.0 mg/dL (34.2 µmol/L), unless elevation in total bilirubin is due to Gilbert's Syndrome.
11. No active infection with hepatitis B (HBV) or hepatitis C (HCV) by serology.
12. Women of child-bearing potential must have a negative pregnancy test, cannot be breastfeeding, and use 1 highly effective method of contraception in combination with a barrier method throughout study participation, and for 28 days after last dose of study drug.
13. Males with partners of child-bearing potential, must agree to use a condom, accompanied with spermicidal foam, gel, film, cream, or suppository, except in countries where spermicide is not available for use in combination with condom, throughout study participation and for 28 days after the last dose of study drug; males must also abstain from sperm donation after the first dose of study drug through study participation and for 28 days after the last dose of study drug.
14. Must be willing and able to comply with protocol-required visit schedule and visit requirements and provide informed consent or have a legal guardian who can provide informed consent.
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 100
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 100
1. Has estimated Glomerular Filtration Rate (eGFR) <30 mL/min/1.73m2 (using the Modification of Diet in Renal Disease [MDRD] formula)
2. Has known primary amyloidosis (AL), leptomeningeal amyloidosis, non- FAC hereditary cardiomyopathy, hypertensive cardiomyopathy, or cardiomyopathy due to valvular heart disease
3. Has non-amyloid diseases affecting exercise testing (e.g., severe chronic obstructive lung disease, severe arthritis, peripheral vascular disease affecting ambulation).
4. Has uncontrolled hypertension
5. Has uncontrolled ischemic heart disease
6. Has uncontrolled clinically significant cardiac arrhythmia
7. Had acute coronary syndrome within the past 3 months
8. Has a Polyneuropathy Disability score >2
9. Has untreated hypo- or hyperthyroidism
10. Has a New York Heart Association (NYHA) classification of IV
11. Has known or suspected systemic bacterial, viral, parasitic, or fungal infection
12. Has known human immunodeficiency virus (HIV) infection
13. Current, heavy alcohol use, defined as regular consumption of greater than 2 to 3 units/day for women and 3 to 4 units/day for men (a unit of alcohol equals 1 glass of wine [125 mL], 1 measure of spirits, or ½ pint of beer), or a known history of alcohol abuse within the past 2 years.
14. Has received an investigational agent or device within 30 days of anticipated study drug administration or 5 half-lives of the investigational drug, whichever is longer
15. Is currently taking diflunisal, tafamidis, doxycycline, or tauroursodeoxycholic acid; if previously on any of these agents, must have completed a 14-day wash-out prior to start of study drug administration in this study
16. Had metastatic cancer within the past 5 years
17. History of allergic reaction to an oligonucleotide or Nacetylgalactosamine (GalNAc).
18. Has a history of intolerance to SC injection
19. Has other medical conditions or comorbidities which, in the opinion of the Investigator, would interfere with study compliance or data interpretation
20. Has had a heart or liver transplant, or is being considered for a transplant during the study period.
21. Known history of clinically significant chronic liver disease in the opinion of the Investigator.
Study & Design
- Study Type
- Interventional clinical trial of medicinal product
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method Main Objective: To determine the efficacy of ALN-TTRSC in patients with FAC.;Secondary Objective: Not applicable;Primary end point(s): The co-primary endpoints of the study are to evaluate the difference between the ALN-TTRSC and placebo groups for:<br><br>1. Change in 6-MWD at 18 months compared to baseline<br><br>2. Percent reduction in serum TTR burden over 18 months;Timepoint(s) of evaluation of this end point: 1. At 18 months<br><br>2. Over 18 months
- Secondary Outcome Measures
Name Time Method Secondary end point(s): The secondary endpoints of the study are to determine the effect of ALN-TTRSC on various clinical parameters by assessing the difference between the ALN-TTRSC and placebo groups at 18 months for:<br><br>• Composite CV mortality and CV hospitalization<br>• Change in New York Heart Association (NYHA) class compared to baseline<br>• Change in Kansas City Cardiomyopathy Questionnaire (KCCQ) compared to baseline<br>• Cardiovascular (CV) mortality<br>• CV hospitalization<br>• All-cause mortality;Timepoint(s) of evaluation of this end point: • At 18 months