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    Summary
    EudraCT Number:2015-001297-18
    Sponsor's Protocol Code Number:ALN-AAT-001
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-05-15
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedUK - MHRA
    A.2EudraCT number2015-001297-18
    A.3Full title of the trial
    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
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    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
    A.4.1Sponsor's protocol code numberALN-AAT-001
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAlnylam Pharmaceuticals, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportAlnylam Pharmaceuticals, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAlnylam Pharmaceuticals Inc
    B.5.2Functional name of contact pointClinical Trial Hotline
    B.5.3 Address:
    B.5.3.1Street Address300 Third Street
    B.5.3.2Town/ cityCambridge
    B.5.3.3Post codeMA 02142
    B.5.3.4CountryUnited States
    B.5.4Telephone number0018663300326
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameALN-AAT
    D.3.2Product code ALN-AAT
    D.3.4Pharmaceutical form Solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNALN-61444
    D.3.9.2Current sponsor codeALN-61444
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number200
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSolution for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    ZZ Type Alpha-1 Antitrypsin Deficiency Liver Disease
    E.1.1.1Medical condition in easily understood language
    Liver disease associated with Alpha-1 antitrypsin deficiency (AATD)
    E.1.1.2Therapeutic area Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    E.1.2Level PT
    E.1.2Classification code 10001806
    E.1.2Term Alpha-1 anti-trypsin deficiency
    E.1.2System Organ Class 10010331 - Congenital, familial and genetic disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety and tolerability of single or multiple doses of ALN-AAT when administered to healthy adult subjects and PiZZ patients.
    E.2.2Secondary objectives of the trial
    -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
    E.2.3Trial contains a sub-study No
    E.3Principal 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)
    E.4Principal 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 before the first dose of study drug
    7. Positive screen for alcohol or drugs of abuse (DOA)

    Additional Exclusion Criteria for Patients in Part C:
    1. History of chronic liver disease from any known cause other than ZZ type AAT deficiency
    2. History of hepatic encephalopathy
    3. History of gastrointestinal bleeding from esophageal or gastric varices complicating portal hypertension
    4. Post-bronchodilator FEV1 that has declined to <70% of predicted or by>15% relative to screening assessment
    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(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.
    E.5.2Secondary 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
    E.5.2.1Timepoint(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.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety Yes
    E.6.5Efficacy No
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) Yes
    E.7.1.1First administration to humans Yes
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind Yes
    E.8.1.4Double blind No
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned2
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    United States
    E.8.7Trial 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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 64
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state60
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 60
    F.4.2.2In the whole clinical trial 66
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    As per normal clinical practice
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2015-06-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-06-29
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2018-01-03
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