The First-in-Human Study of an Investigational Drug, ALN-AAT, in Healthy Subjects and Patients with ZZ Type Alpha 1 Antitrypsin Deficiency Liver Disease

• Register: EUCTR
• Last refreshed on: 28 February 2019
• Main ID: EUCTR2015-001297-18-GB
• Date of registration: 15/05/2015
• Prospective Registration: Yes
• Primary sponsor: Alnylam Pharmaceuticals, Inc.
• Public title: The First-in-Human Study of an Investigational Drug, ALN-AAT, in Healthy Subjects and Patients with ZZ Type Alpha 1 Antitrypsin Deficiency Liver Disease
• Scientific title: A Phase 1/2, Randomized, Single-Blind, Placebo-Controlled, Single-Ascending, and Multiple-Dose, Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics Study of Subcutaneously Administered ALN-AAT in Healthy Adult Subjects and Patients with ZZ Type Alpha 1 Antitrypsin Deficiency Liver Disease
• Date of first enrolment: 29/06/2015
• Target sample size: 66
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2015-001297-18
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: yes Double blind: no Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): yes Therapeutic exploratory (Phase II): yes Therapeutic confirmatory - (Phase III): no Therapeutic use (Phase IV): no

Countries of recruitment

United Kingdom, United States

Contacts

• Name: Clinical Trial Hotline
• Affiliation: Alnylam Pharmaceuticals Inc

• Name: Clinical Trial Hotline
• Affiliation: Alnylam Pharmaceuticals Inc

Key inclusion & exclusion 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 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

Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

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

Therapeutic area: Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]

Intervention(s)

Product Name: ALN-AAT
Product Code: ALN-AAT
Pharmaceutical Form: Solution for injection
INN or Proposed INN: ALN-61444
Current Sponsor code: ALN-61444
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 200-
Pharmaceutical form of the placebo: Solution for injection
Route of administration of the placebo: Subcutaneous use

Primary Outcome(s)

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.

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

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.

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 Outcome(s)

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.

Secondary ID(s)

ALN-AAT-001

Source(s) of Monetary Support

Alnylam Pharmaceuticals, Inc.

Ethics review

Status: Approved
Approval date:
Contact:

Results

• Results available: Yes
• Date Posted: 13/01/2019
• Date Completed: 03/01/2018
• URL: https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-001297-18/results