E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Sclerosing Cholangitis |
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E.1.1.1 | Medical condition in easily understood language |
Primary Sclerosing Cholangitis |
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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 | 20.1 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10036732 |
E.1.2 | Term | Primary sclerosing cholangitis |
E.1.2 | System Organ Class | 100000004871 |
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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 |
The primary objective of this study is to evaluate the safety and tolerability of GS-9674 in subjects with primary sclerosing cholangitis (PSC). |
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E.2.2 | Secondary objectives of the trial |
The exploratory objectives of this study are as follows: -To evaluate changes in serum alkaline phosphatase (ALP) -To evaluate changes in serum bilirubin -To assess changes in markers of liver injury and function: ALT, AST, GGT, albumin, and INR -To assess changes in non-invasive markers of fibrosis including ELFTM test score and FibroSURE/FibroTest® -To evaluate changes in liver stiffness as measured by FibroScan® and by Magnetic Resonance Elastography (MRE) -To evaluate changes in biliary strictures as measured by Magnetic Resonance Cholangiopancreatography (MRCP) -To determine the effect of GS-9674 on metabolism and cardiovascular risk factors (insulin resistance, hyperlipidemia, obesity and blood pressure) -To evaluate the pharmacokinetics (PK) of GS-9674 -To evaluate the pharmacodynamic (PD) effects of GS-9674 as evidenced by changes in FGF19, C4, and bile acids -To determine the effects of GS-9674 on quality of life as assessed by QoL questionnaires |
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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 |
PK and PD Substudy For subjects who provide consent, plasma and serum samples will be collected relative to dosing of GS-9674 to measure concentrations of GS-9674 (and its metabolites, as applicable) and the PD biomarkers FGF19 and C4 for GS-9674. |
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E.3 | Principal inclusion criteria |
-Diagnosis of PSC based on cholangiogram (magnetic resonance cholangiopancreatography [MRCP], endoscopic retrograde cholangiopancreatography [ERCP], or percutaneous transhepatic cholangiogram [PTC]) within the previous 12 months;
-Serum ALP > 1.67 x ULN;
-For subjects on ursodeoxycholic acid (UDCA), the dose of UDCA must have been stable for at least 12 months prior to screening through the end of treatment. For subjects not on UDCA, no UDCA use for at least 12 months before screening through the end of treatment;
-For subjects being administered biologic treatments (eg, antitumor necrosis factor [TNF] or anti-integrin monoclonal antibodies), immunosuppressants or systemic corticosteroids, the dose must have been stable at least 3 months prior to screening and anticipated to remain stable throughout the trial;
-Screening FibroSURE/FibroTest® <0.75. |
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E.4 | Principal exclusion criteria |
-ALT > 10x ULN; -Total bilirubin > 2x ULN; -INR > 1.2 unless on anticoagulant therapy; -Serum albumin < 3.3 g/dL; -Cirrhosis of the liver as defined by any of the following: a) Historical liver biopsy demonstrating stage 4 fibrosis (e.g. Ludwig stage 4 or Ishak stage ≥5); b) History of decompensated liver disease, including ascites, hepatic encephalopathy or variceal bleeding; c) Liver stiffness > 14.4 kPa by FibroScan® -Small-duct PSC (histologic evidence of PSC with normal bile ducts on cholangiography); -Other causes of liver disease including secondary sclerosing cholangitis and viral, metabolic, alcoholic, and other autoimmune conditions. Subjects with hepatic steatosis may be included if there is no evidence of nonalcoholic steatohepatitis (NASH) in the opinion of the investigator or on liver biopsy; -Ascending cholangitis within 60 days of screening; -Presence of a percutaneous drain or bile duct stent; -Use of fibrates or obeticholic acid within 3 months prior to screening and through the end of treatment; -Current, active inflammatory bowel disease (IBD) defined as a partial Mayo score of > 1 and/or a score on the Rectal Bleeding Domain > 0. |
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E.5 End points |
E.5.1 | Primary end point(s) |
To evaluate the safety and tolerability of GS-9674 in subjects with PSC |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Blinded phase: Baseline/Day 1 and at Weeks 1, 2, 4, 8, and 12 Open Label phase: Baseline/Day 1 and at Weeks 1, 2, 4, 8, 12 and every 12 weeks thereafter |
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E.5.2 | Secondary end point(s) |
-Change in serum ALP concentration -Change in serum bilirubin concentration -Change from baseline in markers of liver injury and function: ALT, AST, GGT, INR, and albumin -Change from baseline in liver stiffness by FibroScan® and MRE -Change from baseline in biliary strictures as assessed by MRCP -Change from baseline in non-invasive markers of fibrosis including the ELF™ test score and FibroSURE/FibroTest® -Change from baseline in Mayo Risk Score and UK-PSC Risk Score -Change from baseline in health-related QoL measures -Change from baseline in measures of pruritus -Change from baseline in HOMA-IR, serum lipid profiles, and HbA1c levels -Change from baseline in Pooled Cohort Risk Score |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Blinded phase: Baseline/Day 1 and at Weeks 1, 2, 4, 8, and 12 Open Label phase: Baseline/Day 1 and at Weeks 1, 2, 4, 8, 12 and every 12 weeks thereafter |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
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 | Yes |
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 | 6 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 7 |
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 |
Austria |
Canada |
United Kingdom |
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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End of study is defined as when the last patient last visit (LPLV) for the OLE follow-up visit occurs 4 weeks after completing OLE treatment or the OLE ET follow-up visit, whichever occurs later. |
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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 | |
E.8.9.1 | In the Member State concerned months | 30 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 33 |