E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Compensated Cirrhosis Secondary to Non-Alcoholic Steatohepatitis (NASH) |
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E.1.1.1 | Medical condition in easily understood language |
Compensated Cirrhosis 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 | 18.0 |
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) can reduce portal venous pressure and incidence of clinical events in subjects with cirrhosis due to NASH. |
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E.2.2 | Secondary 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. |
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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 |
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). |
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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. 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. |
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E.4 | Principal 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. |
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E.5 End points |
E.5.1 | Primary 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. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary 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. |
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E.5.2.1 | Timepoint(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; |
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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 | 40 |
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 |
Canada |
India |
United States |
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 7 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 11 |