E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced Liver Fibrosis Secondary to Non-Alcoholic Steatohepatitis (NASH) |
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E.1.1.1 | Medical condition in easily understood language |
Liver Fibrosis Secondary to Non-Alcoholic Steatohepatitis (NASH) |
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E.1.1.2 | Therapeutic area | Diseases [C] - Nutritional and Metabolic Diseases [C18] |
MedDRA Classification |
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 14.1 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10053219 |
E.1.2 | Term | Non-alcoholic steatohepatitis |
E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
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E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate whether GS-6624 is effective at preventing the progression of liver fibrosis in subjects with NASH. |
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E.2.2 | Secondary objectives of the trial |
To assess the safety of GS-6624 in subjects with NASH;
To assess the immunogenicity of GS-6624 in this population;
To assess whether baseline LOXL2 levels are predictive of response to GS-6624 therapy (active arms) and/or prognostic for disease 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 prevention of cirrhosis in this population. |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
MRE Substudy
The Magnetic Resonance Elastography (MRE) Substudy will consist of approximately 50 subjects from selected investigative sites with the ability to perform MRE. Subjects will undergo a liver stiffness assessment by MRE at Baseline Visit, Week 48 and the End of Treatment Visit (Week 96).
Impedance Ultrasonography Substudy
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, Week 48 and the End of Treatment Visit (Week 96). |
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E.3 | Principal inclusion criteria |
1. Males and females 18 - 65 years of age;
2. Be willing and able to provide written informed consent;
3. Have chronic liver disease due to NASH defined as macrovesicular steatosis involving >5% of hepatocytes on a liver biopsy with associated lobular inflammation;
4. Stage 3-4 fibrosis by Ishak score on a liver biopsy. 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-321-0106 study (another Gilead
Sciences NASH study that also must be IRB/EC approved at participating centers);
5. Exclusion of other causes of liver disease including viral hepatitis and alcoholic liver disease;
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 30 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 also utilize a barrier method as another
form of contraception (See Section 7.11.2);
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. |
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E.4 | Principal exclusion criteria |
1. Pregnant or breast feeding;
2. Cirrhosis of the liver;
3. Any evidence of hepatic decompensation present, including ascites, episodes of hepatic encephalopathy, variceal bleeding or a prolonged PT/INR;
4. Weight reduction surgery in the past 5 years;
5. HCV RNA positive;
6. HBsAg positive;
7. Alcohol consumption greater than 21oz/week for males or 14oz/week for females (1oz/25mL of alcohol is present in 1 12oz/300mL beer, 1 4oz/125mL glass of wine, and a 1 oz/25mL measure of 40% proof alcohol)
8. 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;
9. Clinically significant cardiac disease;
10. History of malignancy, other than non-melanomatous skin cancer, within 5 years prior to screening;
11. Major surgical procedure within 30 days prior to screening or the presence of an open wound;
12. Known hypersensitivity to the investigation product or any of its formulation excipients;
13. History of bleeding diathesis within 6 months of screening;
14. Unavailable for follow-up assessment or concern for subject’s compliance with the protocol procedures;
15. Participation in an investigational trial of a drug or device within 30 days prior to screening;
16. Any other condition that in the opinion of the investigator renders the subject a poor risk for inclusion into the study. |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be:
1. Prevention of progression of fibrosis as assessed by change from baseline in morphometric quantitative collagen on liver biopsy;
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Subjects will complete the 96 week treatment course with blinded study medication and will undergo repeat HbA1c liver biopsy at weeks 48 and 96 to assess the primary endpoint. |
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E.5.2 | Secondary end point(s) |
Exploratory efficacy endpoints will include:
1. Prevention of progression to cirrhosis as assessed by change from baseline in Ishak fibrosis stage on liver biopsy.
2. Prevention of progression of liver disease as assessed by change from baseline in the MELD score;
3. Reduction in the amount of activated hepatic stellate cells as assessed by change from baseline in α-smooth muscle actin on liver biopsy;
4. Reduction in fibrosis disease activity as assessed by change from baseline in serum LOXL2 levels;
5. Change from baseline in non-invasive markers of fibrosis including the ELF™ test score and
FibroSURE/FibroMAX/FibroTest;
6. Number of clinical events of hepatic decompensation occurring in each arm (including variceal bleeding, ascites, hepatic encephalopathy, development of hepatocellular carcinoma or
death);
7. Change from baseline on liver enzymes: ALT, AST, bilirubin, GGT and alkaline phosphatase;
8. Change from baseline in HOMA-IR.
Substudy endpoints will include:
1. Reduction in liver fibrosis as assessed by change from baseline in liver stiffness by MRE;
2. Reduction in liver fibrosis as assessed by change from baseline in liver stiffness by impedance ultrasonography.
Subgroup analyses will be conducted to assess:
• The effect of weight loss on the efficacy parameters. Subjects who lose at least 5% of their body weight will be compared to subjects who fail to lose this much weight across all of the above efficacy parameters. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary Endpoints:
Subjects will complete the 96 week treatment course with blinded study medication and will undergo repeat HbA1c liver biopsy and HVPG measurement at weeks 48 and 96. Repeat non-invasive markers of fibrosis and fibrogenesis will be assessed at Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96. Chemistry and hematology will be assessed every 4 weeks, allowing for the MELD score to be calculated at 4 week intervals. The HOMA-IR will be calculated at baseline, Week 48 and Week 96.
Subjects will undergo a liver stiffness assessment by MRE at the Baseline Visit, Week 48 and the End of Treatment Visit (Week 96).
Subjects will undergo a liver stiffness assessment by impedance ultrasonography at the Baseline Visit, Week 48 and the End of Treatment Visit (Week 96). |
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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 | Yes |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | Yes |
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) | No |
E.7.1.1 | First administration to humans | No |
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 | No |
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 | 3 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 | 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
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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 | 0 |
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 | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |