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    Summary
    EudraCT Number:2015-004360-10
    Sponsor's Protocol Code Number:ALN-HBV-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:2016-02-24
    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 number2015-004360-10
    A.3Full title of the trial
    A Phase 1/2, Randomized, Single-Blind, Placebo-Controlled, Single-Ascending and Multiple-Ascending Dose, Safety, Tolerability, Pharmacokinetics, and Antiviral Efficacy Study of Subcutaneously Administered ALN-HBV in Healthy Adult Subjects and Non-cirrhotic Patients with Chronic Hepatitis B Virus (HBV) Infection
    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-HBV, in Healthy Adult Subjects and Patients with Chronic Hepatitis B Virus (HBV) Infection
    A.4.1Sponsor's protocol code numberALN-HBV-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
    B.5.6E-mailclinicaltrials@alnylam.com
    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-HBV
    D.3.2Product code ALN-HBV
    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-66810
    D.3.9.2Current sponsor codeALN-66810
    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
    Chronic Hepatitis B virus (HBV) Infection
    E.1.1.1Medical condition in easily understood language
    Chronic Hepatitis B virus (HBV) Infection
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10008910
    E.1.2Term Chronic hepatitis B
    E.1.2System Organ Class 10021881 - Infections and infestations
    E.1.3Condition being studied is a rare disease No
    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-HBV in healthy adult subjects and non-cirrhotic patients with chronic HBV infection when administered as monotherapy or concomitantly with the anti-HBV nucleoside, entecavir, or the anti-HBV nucleotide, tenofovir
    E.2.2Secondary objectives of the trial
    - To characterize the PK of ALN-HBV in healthy adult subjects and non-cirrhotic patients with chronic HBV infection.
    - To assess the antiviral efficacy of ALN-HBV in non-cirrhotic patients with chronic HBV infection who are receiving anti-HBV NUC treatment (Parts B and C) or who are anti-HBV treatment naïve (Part D) as measured by changes in HBV DNA and HBsAg levels
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion Criteria for Parts A, B, C and D
    1. Age 18 (or age of legal consent, whichever is older) to 65 years, inclusive
    2. 12-lead electrocardiogram (ECG) within normal limits or with no clinically significant abnormalities at screening and Day -1 in the opinion of the Investigator.
    3. Women of child-bearing potential must have a negative pregnancy test, cannot be breast feeding, and must be willing to use a highly effective method of contraception 14 days before first dose, throughout study participation, and for 90 days after last dose administration.

    Additional Inclusion Criteria for Part A
    7. Body mass index (BMI) ≥18.0 kg/m2 and ≤30 kg/m2 as assessed at screening.

    Additional Inclusion Criteria for Parts B and C
    8. Body mass index (BMI) ≥18.0 kg/m2 and ≤32 kg/m2 as assessed at screening.
    10. Chronic HBV infection as evidenced by a screening HBsAg level > 500 IU/mL.
    11. A history of treatment with only one HBV polymerase inhibitor, entecavir or tenofovir.
    12. Taking entecavir or tenofovir for at least 12 months prior to screening without an interruption of 7 or more consecutive days over this time period.
    13. Screening HBV DNA below the lower limit of quantitation (<LLOQ) and without any viral load measure >100 IU/mL in the last 6 months. Only a single HBV DNA measure that is ≥LLOQ but ≤100 IU/mL in the last 6 months is permitted provided that the subsequent HBV DNA level is <LLOQ.

    Additional Inclusion Criteria for Part D
    14. Body mass index (BMI) ≥18.0 kg/m2 and ≤32 kg/m2 as assessed at Screening.
    16. Chronic HBV infection as evidenced by a screening HBV DNA level >2,000 IU/mL and screening HBsAg level that is >500 IU/mL.
    17. The patient has not previously received any anti-HBV treatment.
    E.4Principal exclusion criteria
    Exclusion Criteria for Parts A, B, C and D
    5. Systolic blood pressure >140 mmHg and a diastolic blood pressure of >90 mmHg after 10 minutes supine rest at screening.
    6. Indirect bilirubin > 1.5 × ULN and direct bilirubin > ULN at screening.
    9. Active infection with human immunodeficiency virus (HIV) infection or hepatitis C virus (HCV) infection and/or a history of delta virus hepatitis.
    11. History or clinical evidence of alcohol and/or drug abuse, within the 12 months before screening.
    13. Known hypersensitivity or contraindication to any medication or history of allergic reaction to an oligonucleotide or N-acetylgalactosamine (GalNAc).
    15. History of intolerance to SC injection or relevant abdominal scarring (surgical, burns, etc.).
    20. Estimated glomerular filtration rate (using MDRD equation) < 60 mL/min/1.73 m2 at screening.

    Additional Exclusion Criteria for Part A (Healthy Adult Subjects)
    21. Known history of chronic liver disease.
    22. Clinical laboratory evidence or clinical diagnosis of chronic hepatitis B virus (HBV) infection as shown by HBsAg positivity in blood.
    23. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) above the normal range; alkaline phosphatase (ALP), or albumin outside the reference range and considered clinically relevant in the opinion of the Investigator at screening.

    Additional Exclusion Criteria for Parts B and C
    27. History of chronic liver disease from any cause other than chronic HBV infection.
    28. History of cirrhosis.
    29. History of hepatic decompensation, including ascites, hepatic encephalopathy and/or esophageal or gastric varices.
    30. Screening ALT level >3×ULN.
    31. Serum albumin level < lower limit of normal at screening.
    32. Platelet count ≤100,000 per microliter at screening.
    33. Absolute neutrophil count (ANC) <1500 cells/μL at screening.
    34. International normalized ratio (INR) or prothrombin time (PT) above the upper limit of the normal reference range (as per the local laboratory reference range) at screening.

    Additional Exclusion Criteria for Part D
    35. History of chronic liver disease from any cause other than CHB.
    36. History of cirrhosis.
    37. History of hepatic decompensation including ascites, hepatic encephalopathy and/or esophageal or gastric varices.
    38. Screening ALT level >5×ULN.
    39. Serum albumin level < lower limit of normal at screening.
    40. Platelet count ≤100,000 per microliter at screening.
    41. ANC <1500 cells/μL at screening.
    42. INR or PT above the upper limit of the normal reference range (as per the local laboratory reference range) at screening.
    E.5 End points
    E.5.1Primary end point(s)
    - Incidence of adverse events
    - Clinical laboratory test results
    E.5.1.1Timepoint(s) of evaluation of this end point
    Part A: assessed throughout to Day 29.

    Part B: assessed throughout to Day 85 and up to Day 169, or until HBsAg level is <1 log10 IU/mL below the Day 1 value, whichever duration is shorter.

    Part C & D: assessed throughout to Day 176 and up to Day 260, or until HBsAg level is <1 log10 IU/mL below the Day 1 value, whichever duration is shorter.
    E.5.2Secondary end point(s)
    Secondary Endpoint for Parts A, B, C, and D (All Subjects)
    - Pharmacokinetic parameters of ALN-HBV and possible metabolites (may include, but not be limited to, 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)

    Secondary Endpoints for Parts B, C and D only (HBV Patients)
    - Change in the levels of HBsAg in blood
    - Change in the levels of HBV DNA in blood
    E.5.2.1Timepoint(s) of evaluation of this end point
    Part A: assessed throughout to Day 29.

    Part B: assessed throughout to Day 85 and up to Day 169, or until HBsAg level is <1 log10 IU/mL below the Day 1 value, whichever duration is shorter.

    Part C & D: assessed throughout to Day 176 and up to Day 260, or until HBsAg level is <1 log10 IU/mL below the Day 1 value, whichever duration is shorter.
    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 Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    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 trial3
    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
    Australia
    Hong Kong
    Korea, Republic of
    New Zealand
    Singapore
    Taiwan
    United Kingdom
    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 years2
    E.8.9.2In all countries concerned by the trial months0
    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: 142
    F.1.3Elderly (>=65 years) No
    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 state34
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 34
    F.4.2.2In the whole clinical trial 142
    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)
    Expected standard of care
    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 Decision2016-04-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-02-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-10-06
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