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 | 17.1 |
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 simtuzumab (formerly referred to as GS-6624 ) is effective at preventing the histologic progression of liver fibrosis and the clinical progression to cirrhosis in subjects with NASH. |
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E.2.2 | Secondary objectives of the trial |
To assess the safety of simtuzumab in subjects with NASH;
To assess the immunogenicity of simtuzumab in this population;
To assess whether baseline LOXL2 levels are predictive of response to simtuzumab 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 histologic regression of fibrosis and prevention of progression to 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 and at weeks 48, 96, 144, 192 and 240 or its equivalent End of Treatment Visit.
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, and at weeks 48, 96, 144, 192 and 240 or its equivalent End of
Treatment Visit. |
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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 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 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 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 history of hepatic decompensation, including ascites, hepatic encephalopathy, variceal bleeding;
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) |
Primary Efficacy Endpoint
The primary efficacy endpoint is change from baseline in morphometric quantitative collagen (MQC) on liver biopsy at Week 96.
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 progression to cirrhosis. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary efficacy end point is week 96
The clinical efficacy endpoint is event free survival (EFS). Subjects will be followed for up to 240 weeks. EFS is assessed by time to progression to cirrhosis. |
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E.5.2 | Secondary end point(s) |
Exploratory efficacy endpoints are:
- Change from baseline in modified Ishak fibrosis stage on liver biopsy at Weeks 48, 96 and 240;
- Change from baseline in Brunt/Kleiner fibrosis stage on liver biopsy at Week 48, 96 and 240;
- Change from baseline in NAS on liver biopsy at Week 48, 96 and 240; |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Liver biopsy at Weeks 48, 96 and 240 |
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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 | 3 |
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 | |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 10 |
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 |