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    Summary
    EudraCT Number:2012-002489-11
    Sponsor's Protocol Code Number:GS-US-321-0106
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-01-28
    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 ConcernedGermany - PEI
    A.2EudraCT number2012-002489-11
    A.3Full title of the trial
    A Phase 2b, Dose-Ranging, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Safety and Efficacy of GS-6624, a Monoclonal Antibody Against Lysyl Oxidase-Like 2 (LOXL2), in Subjects with Compensated Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    An investigational study to assess the safety and efficacy of a new investigational drug in subjects with compensated liver cirrhosis secondary to non-alcoholic steatohepatitis (NASH)
    A.4.1Sponsor's protocol code numberGS-US-321-0106
    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 SponsorGilead Sciences 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 supportGilead Sciences Inc
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationGilead Sciences Inc
    B.5.2Functional name of contact pointMedical Monitor
    B.5.3 Address:
    B.5.3.1Street Address333 Lakeside Drive
    B.5.3.2Town/ cityFoster City
    B.5.3.3Post codeCA 94404
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1650574 3000
    B.5.5Fax number+1650578 9264
    B.5.6E-mailclinical.trials@gilead.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.3.2Product code GS-6624
    D.3.4Pharmaceutical form Solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNGS-6624
    D.3.9.2Current sponsor codeGS-6624
    D.3.9.4EV Substance CodeSUB33243
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Compensated Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH)
    E.1.1.1Medical condition in easily understood language
    Compensated Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH)
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level PT
    E.1.2Classification code 10053219
    E.1.2Term Non-alcoholic steatohepatitis
    E.1.2System Organ Class 10019805 - Hepatobiliary disorders
    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 whether simtuzumab (formerly referred to as GS-6624) can reduce portal venous pressure and incidence of clinical events in subjects with cirrhosis due to NASH.
    E.2.2Secondary objectives of the trial
    To assess whether simtuzumab can reverse fibrosis and lead to a regression of cirrhosis in subjects with cirrhosis due to NASH;
    To assess the safety of simtuzumab in subjects with compensated cirrhosis due to NASH
    To assess the immunogenicity of simtuzumab in this population;
    To assess whether baseline LOXL2 levels are predictive of response to therapy (active arms) or progression (placebo arm);
    To compare different efficacy assessment tools in this population;
    To determine whether non-invasive measures of fibrosis can predict regression of fibrosis and reversal of cirrhosis in this population.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    There will be two optional exploratory substudies - MRE Substudy and an Impedance Ultrasonography Substudy, performed as part of this study at sites that have the capability:
    - The MRE Substudy will consist of approximately 50 subjects from selected investigative sites with the ability to perform
    magnetic resonance elastography (MRE). Subjects will undergo a liver stiffness assessment by MRE at Baseline Visit and at Weeks 48, 96, 144, 192 and the End of Treatment Visit (Week 240 or its equivalent).

    - The Impedance Ultrasonography Substudy will consist of approximately 50 subjects from selected investigative sites with the ability to perform impedance ultrasonography (such as Fibroscan). Subjects will undergo a liver stiffness
    assessment by impedance ultrasonography at Baseline Visit and at Weeks 48, 96, 144, 192 and the End of Treatment Visit
    (Week 240 or its equivalent).
    E.3Principal inclusion criteria
    1. Males and females 18 - 65 years of age;
    2. Be willing and able to provide written informed consent;
    3. Cirrhosis of the liver defined as an Ishak fibrosis stage ≥ 5;
    4.Liver biopsy consistent with NASH or cryptogenic cirrhosis. If a liver biopsy has been performed within 3 months of the Screening Visit, tissue from that biopsy may be used as the screening biopsy. Slides would be re-cut from the existing tissue block and submitted for central reader assessment. If the subject is deemed ineligible for this study, the liver biopsy, if performed according to protocol specifications and is within 3 months of the screening visit, may be used to determine
    eligibility for the GS-US-321-0105 Study (another Gilead Sciences study part of the NASH program which must also be IRB/EC approved at participating centers). Note: For subjects with biopsies consistent with cryptogenic cirrhosis, at least one clinical feature suggestive of underlying NASH must be present. This may include diabetes, insulin resistance, obesity, hypercholesterolemia, hyperlipidemia, or hypertension;
    5. The liver biopsy sample must be determined to be adequate for evaluation by the central pathologist;
    6. Must be willing and able to comply with all study requirements;
    7. Must have AST and ALT ≤ 10 x clULN (refer to the central laboratory manual for normal ranges);
    8. Must have serum creatinine < 2.0 mg/dL;
    9. Female subjects of childbearing potential must have a negative serum pregnancy test prior to starting study treatment. For the purposes of this study, a female subject of child-bearing potential is a woman who has not had a hysterectomy, bilateral oophorectomy, or medically-documented ovarian failure. Women ≤ 50 years of age with amenorrhea of any duration will be considered to be of childbearing potential;
    10. All female subjects who are of childbearing potential must agree to use a highly effective
    method of contraception during heterosexual intercourse from the screening visit throughout the study period and for 90 days following the last dose of study drug. If females utilize hormonal agents as one of their contraceptive methods, the same hormonal method must have been used for at least 1 month before study dosing. Females on hormonal methods must utilize a barrier method as the other form of contraception;
    11. Lactating females must agree to discontinue nursing before starting study treatment.
    12. Male subjects, if not vasectomized, are required to use barrier contraception (condom plus spermicide) during heterosexual intercourse from the screening through the study completion and for 90 days following the last dose of study drug.
    E.4Principal exclusion criteria
    1. Pregnant or breast feeding;
    2. Any history of hepatic decompensation present, including ascites, hepatic encephalopathy, variceal bleeding;
    3. CPT score > 7;
    4. MELD score > 12;
    5. BMI < 18 kg/m2;
    6. Weight reduction surgery in the past 5 years;
    7. HCV RNA positive;
    8. HBsAg positive;
    9. Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1oz/25mL of alcohol is present in 1 12oz/300 mL beer, 1 4oz/125 mL glass of wine, and a 1 oz/25mL measure of 40% proof alcohol);
    10. Positive urine screen for amphetamines, cocaine or opiates (i.e., heroin, morphine) at Screening. Subjects on stable methadone or buprenorphine maintenance treatment for at least 6 months prior to screening may be included in the study. Subjects with a positive urine drug screen due to prescription opioid-based medication are eligible if the prescription and diagnosis are reviewed and approved by the investigator;
    11. Clinically significant cardiac disease;
    12. History of malignancy, other than non-melanomatous skin cancer, within 5 years prior to screening;
    13. Major surgical procedure within 30 days prior to Screening or the presence of an open wound;
    14. Known hypersensitivity to the investigation product or any of its formulation excipients;
    15. History of bleeding diathesis within 6 months of screening;
    16. Unavailable for follow-up assessment or concern for subject's compliance with the protocol procedures;
    17. Participation in an investigational trial of a drug or device within 30 days prior to Screening;
    18. History of prior solid-organ transplant;
    19. Poor venous access or requirement for permanent or semipermanent central vein catheter such as a portacath;
    20. Any other condition that in the opinion of the investigator renders the subject a poor risk for inclusion into the study.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint will be:
    The difference in the mean change from baseline in HVPG at Week 96 between simtuzumab and placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 96
    E.5.2Secondary end point(s)
    Clinical Efficacy Endpoint:
    - The clinical efficacy endpoint is event free survival (EFS). Subjects will be followed for up to 240 weeks. EFS is assessed by time to first liverrelated event or death (whichever occurs first).

    Liver-related events are:
    Liver transplantation
    Qualification for liver transplantation:
    — MELD ≥ 15
    Events indicative of hepatic decompensation
    — Esophageal variceal bleeding
    — Ascites
    — Hepatic Encephalopathy
    — ≥ 2 point increase in CPT score
    Newly diagnosed varices in a subject without prior varices

    Exploratory endpoints are:
    Portal Venous Pressure Endpoints:
    1. Mean change from baseline in HVPG at Week 48;
    2. Proportion of subjects with at least 10% reduction in HVPG from baseline at Weeks 48 and 96;
    3. Proportion of subjects with at least 20% reduction in HVPG from baseline at Weeks 48 and 96;
    4. Proportion of subjects with a baseline HVPG ≥ 12 mmHg who achieve at least a 20% reduction in HVPG or a reduction to <12 mmHg at Weeks 48 and 96;
    5. Proportion of subjects with a baseline HVPG < 10 mmHg who progress to an HVPG ≥ 10 mmHg at Weeks 48 and 96;

    Histology Endpoints:
    6. Mean change from baseline in MQC on liver biopsy at Weeks 48, 96, and 240;
    7. Change from baseline in modified Ishak fibrosis stage on liver biopsy at Weeks 48, 96, and 240;
    8. Change from baseline in Brunt/Kleiner {7937} fibrosis stage on liver biopsy at Weeks 48, 96, and 240;
    9. Change from baseline in NAS {7937} liver biopsy at Weeks 48, 96, and 240;
    10. Mean change from baseline in α-SMA on liver biopsy at Weeks 48, 96, and 240;

    Surrogate Marker Endpoints:
    11. Change from baseline in the MELD score at 4-week intervals;
    12. Mean change from baseline in serum LOXL2 levels at Weeks 4, 8, 12, then every 12 weeks until Week 96, and then every 24 weeks thereafter up to Week 240;
    13. Change from baseline in ELF test score and FibroSURE/FibroTest at Weeks 4, 8, 12, and every 12 weeks thereafter up to Week 240;

    Other Endpoints:
    14. Incidence of hepatocellular carcinoma (HCC);
    15. Change from baseline in ALT, AST, bilirubin, GGT and alkaline phosphatase at Weeks 4, 8, 12 and every 12 weeks thereafter;
    16. Mean change from baseline in HOMA-IR at Weeks 48, 96, 144, 192, and 240;
    17. Rate of cardiac adverse events;

    Substudies, which are subsets of approximately 50 subjects each, will
    evaluate the following efficacy endpoint respectively:
    1. Change from baseline in liver stiffness as measured by MRE at Weeks 48, 96, 144, 192, and 240;
    2. Change from baseline in liver stiffness as assessed by impedance
    ultrasonography at Weeks 48, 96, 144, 192, and 240

    Safety endpoints include extent of exposure, adverse events, laboratory evaluations, and immunogenicity.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The clinical efficacy endpoint is event free survival (EFS). Subjects will be followed for up to 240 weeks

    Exploratory endpoints:
    Portal Venous Pressure Endpoint evaluated at Week 96 and/or 48

    Histology Endpoints evaluated at Week 48, 96, and 240

    Surrogate Marker Endpoints:
    11. Change from baseline in the MELD score at 4-week intervals;
    12. Mean change from baseline in serum LOXL2 levels at Weeks 4, 8, 12, then every 12 weeks until Week 96, and then every 24 weeks thereafter up to Week 240;
    13. Change from baseline in ELF test score and FibroSURE/FibroTest at Weeks 4, 8, 12, and every 12 weeks thereafter up to Week 240;
    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 Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    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 No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA40
    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
    Canada
    India
    United States
    E.8.7Trial has a data monitoring committee Yes
    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
    Last Subject Last visit
    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 months7
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months11
    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: 225
    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 No
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 95
    F.4.2.2In the whole clinical trial 225
    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)
    None
    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 Decision2013-01-30
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-02-26
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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