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 is a chronic disease which causes scarring of the bile ducts. This can block the flow of bile which can cause damage to the liver over time.
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E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
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 | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
To evaluate whether cilofexor (CILO, previously known as GS-9674) reduces the risk of fibrosis progression among non-cirrhotic subjects with primary sclerosing cholangitis (PSC) |
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E.2.2 | Secondary objectives of the trial |
-To assess the safety and tolerability of CILO -To evaluate changes in serum concentrations of alkaline phosphatase (ALP), gamma-glutamyl transferase (GGT), alanine aminotransferase (ALT), and bile acids -To evaluate whether CILO increases the proportion of subjects with ≥ 25% relative reduction in serum ALP concentration from baseline (biochemical response) and no worsening of fibrosis according to the Ludwig classification (histologic response) -To evaluate changes in liver fibrosis including hepatic collagen content, fibrosis stage improvement, progression to cirrhosis, and changes in noninvasive markers of fibrosis, including liver stiffness by FibroScan® and enhanced liver fibrosis test (ELF™ test) score -To evaluate changes in health-related quality of life (QoL) based on the disease-specific PSC patient-reported outcome (PSC-PRO) |
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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 |
Optional Intensive PK and PD Substudy All subjects will have the option to participate in the intensive PK and PD substudy. For subjects who agree to participate and provide their consent, the intensive PK and PD sampling will be performed once any time between Week 4 to Week 84 (inclusive). |
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E.3 | Principal inclusion criteria |
1) Diagnosis of large duct PSC based on cholangiogram (magnetic resonance cholangiopancreatography [MRCP], endoscopic retrograde cholangiopancreatography [ERCP], or percutaneous transhepatic cholangiogram [PTC]) 2) Liver biopsy at screening that is deemed acceptable for interpretation and demonstrates stage F0 – F3 fibrosis (according to the Ludwig classification) in the opinion of the central reader a. A historical liver biopsy within 6 months of the screening visit may be accepted as the screening biopsy if the sample is deemed acceptable for interpretation by the central reader. 3) Subject has the following laboratory parameters at the screening visit, as determined by the central laboratory: a. Platelet count ≥ 150,000/mm3 b. Estimated glomerular filtration rate (eGFR) ≥ 30 milliliter/minute (mL/min), as calculated by the Cockcroft-Gault equation c. ALT ≤ 8 x upper limit of normal (ULN) d. Total bilirubin < 2 mg/dL, unless the subject is known to have Gilbert’s syndrome or hemolytic anemia e. International normalized ratio (INR) ≤ 1.4, unless due to therapeutic anticoagulation f. Negative anti-mitochondrial antibody 4) For subjects on ursodeoxycholic acid (UDCA), the dose of UDCA must have been stable in the opinion of the investigator for at least 6 months before screening. For subjects not on UDCA, no UDCA use for at least 6 months prior to screening. |
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E.4 | Principal exclusion criteria |
1) Current or prior history of any of the following: a. Cirrhosis as defined by any of the following: i. Liver biopsy demonstrating stage F4 fibrosis according to the Ludwig classification (or equivalent) ii. Decompensated liver disease, including ascites, hepatic encephalopathy (HE), or variceal hemorrhage iii. Liver stiffness > 20.0 kPa by FibroScan® b. Liver transplantation c. Cholangiocarcinoma or hepatocellular carcinoma (HCC). If a dominant stricture has been identified, cholangiocarcinoma must be adequately excluded in the opinion of the investigator prior to Day 1. d. Ascending cholangitis within 30 days of screening 2) Presence of a percutaneous drain or biliary stent 3) Other causes of liver disease including immunoglobulin (IgG4)-related sclerosing cholangitis, autoimmune hepatitis/PSC overlap syndrome, secondary sclerosing cholangitis, small duct PSC (histologic evidence of PSC with normal bile ducts on cholangiography), and viral, metabolic, alcoholic, and other autoimmune conditions. Subjects with hepatic steatosis may be included if there is no evidence of nonalcoholic steatohepatitis (NASH) on liver biopsy in the opinion of the central reader 4) Current or prior history of any of the following: a. Malignancy within 5 years of screening with the following exceptions: i. Adequately treated carcinoma in situ of the cervix ii. Adequately treated basal or squamous cell cancer or other localized non-melanoma skin cancer. Subjects under evaluation for possible malignancy are not eligible. b. Unstable cardiovascular disease as defined by any of the following: i. Unstable angina, myocardial infarction, coronary artery bypass graft surgery or coronary angioplasty within 6 months prior to screening ii. Transient ischemic attack or cerebrovascular accident within 6 months prior to screening iii. Symptomatic obstructive valvular heart disease or hypertrophic cardiomyopathy iv. Symptomatic congestive heart failure v. Uncontrolled or recurrent ventricular tachycardia or other arrhythmia requiring an automatic implantable cardioverter defibrillator (AICD). Stable, controlled atrial fibrillation is allowed. c. Hypercoagulable condition or venous or arterial thromboembolic disease d. Intestinal resection or malabsorptive condition that may limit the absorption of CILO. Prior cholecystectomy and appendectomy are permitted. 5) Child-Pugh (CP) score > 6 at Screening, unless due to an alternative etiology such as Gilbert’s syndrome or therapeutic anticoagulation 6) Model for End-stage Liver Disease (MELD) score > 12 at Screening, unless due to an alternate etiology such as therapeutic anticoagulation 7) HIV infection (HIV antibody [Ab] and HIV RNA positive) 8) Chronic HBV infection (hepatitis B surface antigen [HBsAg] positive) 9) Chronic HCV infection (HCV Ab and HCV RNA positive). Subjects cured of HCV infection ≥ 2 years prior to screening are eligible. 10) Current moderate to severe inflammatory bowel disease (IBD) (including ulcerative colitis, Crohn’s disease, and indeterminate colitis) defined as a screening visit Partial Mayo score of > 4 and/or a score in the screening visit Rectal Bleeding domain > 1, unless bleeding is due to perianal disease Note: Subjects with IBD who currently have an external ostomy bag are not subject to this exclusion criterion and need not undergo Partial Mayo evaluation at screening 11) Habitual alcohol consumption greater than 21 oz/week for males or 14 oz/week for females (1 oz/30 mL of alcohol is present in one 12 oz/360 mL beer, one 4 oz/120 mL glass of wine, and a 1 oz/30 mL measure of 40% proof alcohol) 12) Use of antibiotics (eg, vancomycin, metronidazole, minocycline, etc.) for the treatment of PSC within 60 days of Screening. Antibiotic prophylaxis for ascending cholangitis is permitted if stable in the opinion of the investigator for at least 6 months prior to Screening 13) Use of any prohibited concomitant medications |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint is the proportion of subjects with progression of liver fibrosis, as defined by a ≥ 1-stage increase in fibrosis according to the Ludwig classification at Week 96 |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Baseline/Day 1 and at Week 96 |
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E.5.2 | Secondary end point(s) |
The secondary endpoints of this study are as follows: -Changes from baseline in serum concentrations of ALP, GGT, ALT, and bile acids at Week 96 -The proportion of subjects with ≥ 25% relative reduction in serum ALP concentration from baseline (biochemical response) and no worsening of fibrosis according to the Ludwig classification (histologic response) -Changes from baseline in liver fibrosis, including hepatic collagen content, fibrosis improvement, and progression to cirrhosis (according to the Ludwig classification), and noninvasive markers of fibrosis, including liver stiffness by FibroScan® and ELF™ test score, at Week 96 -Changes from baseline in health-related QoL based on the disease specific PSC-PRO at Week 96 |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Baseline/Day 1 and at 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 | No |
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 | 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) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
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 | 2 |
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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 80 |
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 |
Australia |
Austria |
Belgium |
Canada |
Denmark |
France |
Germany |
Israel |
Italy |
Japan |
Netherlands |
New Zealand |
Spain |
Sweden |
Switzerland |
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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Last patient last visit (LPLV) |
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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 | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 4 |
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 |