E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease |
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E.1.1.1 | Medical condition in easily understood language |
Liver disease associated with Alpha-1 antitrypsin deficiency |
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E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10001806 |
E.1.2 | Term | Alpha-1 anti-trypsin deficiency |
E.1.2 | System Organ Class | 10010331 - Congenital, familial and genetic disorders |
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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 safety and tolerability of single or multiple doses of ALN-AAT02 when administered to healthy adult subjects and patients with ZZ type of alpha-1 antitrypsin deficiency (PiZZ) AAT deficiency liver disease |
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E.2.2 | Secondary objectives of the trial |
- To assess the effect of ALN-AAT02 on serum levels of alpha-1 antitrypsin (AAT) protein in healthy adult subjects and PiZZ patients - To characterize the pharmacokinetics (PK) of ALN-AAT02 in healthy adult subjects and PiZZ patients
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Inclusion Criteria for All Participants in Part A and Part B - Male or female, aged 18 to 65 years, inclusive - Body mass index (BMI) ≥18.0 kg/m2 and ≤30 kg/m2 - Nonsmoker for at least 5 years before screening
Additional Inclusion Criteria for Subjects in Part A - AAT levels within normal limits - FEV1 ≥85% of predicted and FEV1/forced vital capacity ratio ≥0.7
Additional Inclusion Criteria for Patients in Part B - Documented ZZ type AAT by genotype - Liver biopsy performed within 90 days of the first dose of study drug demonstrating liver histopathology consistent with PiZZ AATD liver disease meeting the following criteria: a. Presence of diastase-resistant PAS-positive globules in hepatocytes b. Ishak fibrosis score of <4 - Post-bronchodilator FEV1 ≥70% of predicted and diffusing capacity of the lung for carbon monoxide ≥50% of predicted - Prior/Concomitant Therapy: If on any maintenance medication regimen, 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)
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E.4 | Principal exclusion criteria |
Exclusion Criteria for All Participants in Part A and Part B - Has known active human immunodeficiency virus (HIV) infection, or evidence of current or chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection - Has an estimated glomerular filtration of ≤45 mL/min/1.73 m2 at screening - Has any clinical safety laboratory result considered clinically significant and unacceptable by the Investigator during screening or on Day 1 - Received an investigational agent within 30 days or within 5 elimination half-lives, whichever is longer prior to the first dose of study drug, or are in follow-up of another clinical study prior to study enrollment - Is unwilling or unable to limit alcohol consumption throughout the course of the study. Alcohol intake of >2 units/day is excluded during the study - Has history of alcohol abuse, within the last 12 months before screening, in the opinion of the Investigator - Has known history or clinical evidence of drug abuse, within the 12 months before screening.
Additional Exclusion Criteria for Subjects in Part A - Is positive for the rs1303 single nucleotide polymorphism in the SERPINA1 gene - Has alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >upper limit of normal (ULN) at screening - Has total bilirubin above the ULN - Has history of asthma or recurrent or chronic lung disease, excluding childhood asthma that has resolved - Has history of chronic liver disease from any cause
Additional Exclusion Criteria for Patients in Part B - Has any of the following laboratory parameter assessments at screening: a. Alanine aminotransferase or AST ≥1.5× ULN b. Total bilirubin >ULN. Patients with elevated total bilirubin that is secondary to documented Gilbert’s syndrome are eligible. c. Serum albumin level ≤80% of the LLN d. Platelet count ≤100,000 per microliter e. International normalized ratio (INR) or prothrombin time (PT) >1.2 of the clinical laboratory reference range - Receiving augmentation therapy for AAT deficiency or who have received augmentation therapy within 8 weeks of first dose of study drug - Has history of chronic liver disease from any known cause other than ZZ type AAT deficiency - Has history of hepatic encephalopathy - Has history of gastrointestinal bleeding from esophageal or gastric varices complicating portal hypertension or ascites - Has any history of a bleeding disorder or inability to abstain from medications that may interfere with normal blood clotting such that the risk of bleeding following liver biopsy would be increased
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E.5 End points |
E.5.1 | Primary end point(s) |
Frequency of adverse events (AEs) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A: at specified time points through the last postdose follow-up visit (Day 85), or until serum AAT levels return to either ≥80% of mean pre-treatment values, or are within the normal range of the local laboratory, or until the subject has been followed for 12 months following the last dose of study drug and blood AAT values exceed 0.49 g/dL.
Part B: at specified time points through the last postdose follow-up visit (Day 85), or until serum AAT levels return to either ≥80% of mean pre-treatment values. |
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E.5.2 | Secondary end point(s) |
- Change from baseline in serum levels of AAT in healthy adult subjects and PiZZ patients over the course of the study - PK parameters of ALN-AAT02
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Part A: at specified time points through the last postdose follow-up visit (Day 85), or until serum AAT levels return to either ≥80% of mean pre-treatment values, or are within the normal range of the local laboratory, or until the subject has been followed for 12 months following the last dose of study drug and blood AAT values exceed 0.49 g/dL.
Part B: at specified time points through the last postdose follow-up visit (Day 85), or until serum AAT levels return to either ≥80% of mean pre-treatment values. |
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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 | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
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) | Yes |
E.7.1.1 | First administration to humans | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | Yes |
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) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 4 |
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 |
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E.8.7 | Trial has a data monitoring committee | No |
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 | 3 |
E.8.9.1 | In the Member State concerned months | 4 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 4 |
E.8.9.2 | In all countries concerned by the trial days | 0 |