ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease MedDRA version: 19.1 Level: PT Classification code 10001806 Term: Alpha-1 anti-trypsin deficiency System Organ Class: 10010331 - Congenital, familial and genetic disorders
Conditions
Interventions
Product Name: ALN-AAT
Product Code: ALN-AAT
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ALN-61444
Current Sponsor c
Sponsors
Alnylam Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Inclusion Criteria for All Subjects and Patients in Parts A, B, and C: 1.Male and female subjects, aged 18 to 65 years, inclusive 2.12-lead ECG within normal limits or with no clinically significant abnormalities in the opinion of the Investigator 3.Body mass index (BMI) =18.0 kg/m2 and =30 kg/m2 4.Female subjects/patients of childbearing potential, cannot be pregnant, cannot be breastfeeding, and must agree to use one of the acceptable methods of contraception from the time of signing the informed consent until 3 months following administration of the last dose of study drug. 5. Male subjects/patients must agree to use acceptable methods of contraception if the male subject’s/patient’s partner could become pregnant from the time of the first dose of study drug until 3 months following administration of the last dose of study drug. 6.Non-smokers for at least 5 years before screening Additional Inclusion Criteria for Subjects in Parts A and B: 1. AAT levels within normal limits 2. Forced expiratory volume in 1 second =85% of predicted, and FEV1/forced vital capacity (FVC) ratio =0.7 Additional Inclusion Criteria for Patients in Part C: 1. Documented ZZ type AAT by phenotype or genotype 2. Liver histopathology consistent with ZZ liver disease 3. Post-bronchodilator FEV1 =70% of predicted and DLCO =50% of predicted 4. If on any maintenance medication regimen other than augmentation therapy, likely, in the opinion of the Investigator, to be able to remain on a stable medication regimen for the duration of the study (no new medications within 30 days prior to first dose of study drug) 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 64 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 2
Exclusion criteria
Exclusion criteria: Exclusion Criteria for All Subjects and Patients in Parts A, B, and C: 1.Any uncontrolled or serious disease, or any medical or surgical condition, that may either interfere with participation in the clinical study, and/or put the subject at significant risk (according to Investigator’s judgment) if he/she participates in the clinical study, with the exception of AAT deficiency for patients in Part C 2.An underlying known disease, or surgical or medical condition that, in the opinion of the Investigator, might interfere with interpretation of the clinical study results, with the exception of AAT deficiency for patients in Part C 3.Clinically significant illness within 7 days before the first dose of study drug 4.Systolic blood pressure =140 mmHg and a diastolic blood pressure of =90 mmHg after 10 minutes supine rest 5.Any clinical safety laboratory result considered clinically significant and unacceptable by the Investigator 6.Received an investigational agent within 90 days before the first dose of study drug or are active in the follow-up phase of another clinical study involving interventional treatment 7.Clinical laboratory evidence or clinical diagnosis of human immunodeficiency virus (HIV) infection, hepatitis C virus (HCV) infection, or chronic hepatitis B virus (HBV) infection (as shown by hepatitis B surface antigen [HBsAg] positivity). 8.Consume more than 14 (female) or 21 (male) units of alcohol per week (unit: 1 glass of wine [125 mL] = 1 measure of spirits = ½ pint of beer) 9.History or clinical evidence of alcohol abuse, within the 12 months before screening. Alcohol abuse is defined as regular weekly intake of more than 21 units for males and 14 units for females. 10.History or clinical evidence of drug abuse, within the 12 months before screening. Drug abuse is defined as compulsive, repetitive, and/or chronic use of drugs or other substances with or without problems related to their use and/or where stopping or a reduction in dose will lead to withdrawal symptoms. 11.History of intolerance to SC injection 12.Legal incapacity or limited legal capacity at screening 13.Any conditions which, in the opinion of the Investigator, would make the subject unsuitable for enrollment or could interfere with the subject’s participation in or completion of the study. Additional Exclusion Criteria for Subjects in Parts A and B: 1. History of asthma, or recurrent or chronic lung disease, excluding childhood asthma that has resolved 2. History of chronic liver disease from any cause 3. Alanine aminotransferase (ALT) and/or total bilirubin above the upper limit of normal (ULN; subjects with known Gilbert’s syndrome with unconjugated hyperbilirubinemia will be allowed) 4. Aspartate aminotransferase (AST), alkaline phosphatase (ALP), or gamma glutamyl transferase (GGT) > 2×ULN (no Investigator discretion); or, if AST, ALP, or GGT > ULN, but = 2×ULN and considered clinically relevant by the Investigator 5. Complete blood count clinical laboratory results that are considered clinically relevant and unacceptable by the Investigator at screening and Day -1 6. Donated more than 500 mL of blood within 90 days bef
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: To evaluate the safety and tolerability of single or multiple doses of ALN-AAT when administered to healthy adult subjects and PiZZ patients.; Secondary Objective: -To characterize the PK of ALN-AAT in healthy adult subjects and PiZZ patients -To assess the effect of ALN-AAT on serum levels of AAT protein in healthy adult subjects and PiZZ patients ;Primary end point(s): Safety: clinical laboratory tests (haematology, biochemistry, coagulation, and urinalysis), vital signs (oral body temperature, blood pressure, heart rate, and respiration rate), physical examinations, 12-lead ECGs, pulmonary function testing (spirometry), adverse event monitoring.; Timepoint(s) of evaluation of this end point: SAD phase: through day 70, or until serum AAT levels return to either >80% of mean pre-treatment value or are within the normal range of the local laboratory. MAD phase: through Day 154, or until serum AAT levels return to either >80% of mean pre-treatment value or are within the normal range of the local laboratory. MD phase: through Day 238, or until serum AAT levels return to either >80% of mean pre-treatment value or are within the normal range of the local laboratory. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): PK of ALN-AAT: maximum plasma concentration, time to reach maximum plasma concentration, area under the plasma concentration versus time curve, apparent terminal elimination half-life, fraction eliminated in the urine, and renal clearance. PD: Serum AAT levels ; Timepoint(s) of evaluation of this end point: SAD phase: through day 70, or until serum AAT levels return to either >80% of mean pre-treatment value or are within the normal range of the local laboratory. MAD phase: through Day 154, or until serum AAT levels return to either >80% of mean pre-treatment value or are within the normal range of the local laboratory. MD phase: through Day 238, or until serum AAT levels return to either >80% of mean pre-treatment value or are within the normal range of the local laboratory. | — |
Countries
United Kingdom, United States
Contacts
Public ContactClinical Trial Hotline
Alnylam Pharmaceuticals Inc
Outcome results
None listed