E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Primary Sclerosing Cholangitis (PSC) |
|
E.1.1.1 | Medical condition in easily understood language |
Primary Sclerosing Cholangitis (PSC) |
|
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 | LLT |
E.1.2 | Classification code | 10036732 |
E.1.2 | Term | Primary sclerosing cholangitis |
E.1.2 | System Organ Class | 100000004871 |
|
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 PSC. |
|
E.2.2 | Secondary objectives of the trial |
• To assess the safety of GS-6624 in subjects with PSC;
• To assess the immunogenicity of GS-6624 in this population;
• To assess whether baseline serum LOXL2 levels are predictive of response to GS-6624 therapy (active groups) and/or prognostic for disease progression (placebo group);
• 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. |
|
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). |
|
E.3 | Principal inclusion criteria |
1. Males and females 18 - 70 years of age;
2. Willing and able to provide informed, written consent;
3. Chronic cholestatic liver disease of at least 6 months’ duration;
4. Liver biopsy consistent with PSC; 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. Some subjects with PSC may have a normal liver biopsy, in the event of a normal liver biopsy, the subject must have an abnormal MRCP
5. MRCP consistent with PSC; some subjects with PSC may have a normal MRCP, in the event of a normal MRCP, the subject must have an abnormal liver biopsy;
6. Exclusion of other causes of liver disease including viral hepatitis, alcoholic liver disease, primary biliary cirrhosis and secondary sclerosing cholangitis;
7. Must be willing and able to comply with all study requirements;
8. Must have AST and ALT ≤ 10 x clULN;
9. Must have serum creatinine < 2.0 mg/dL;
10. 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 childbearing
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;
11. All sexually active 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 utilize a barrier method as the other form of contraception;
12. Lactating females must agree to discontinue nursing before study investigational medicinal product administration;
13. Male subjects, if not vasectomized, are required to use barrier contraception (condom plus spermicide) during intercourse from screening through to study completion and for 90 days from the last dose of study investigational medicinal product. |
|
E.4 | Principal exclusion criteria |
1. Pregnant or breast feeding;
2. Any evidence of hepatic decompensation past or present, including ascites, episodes of hepatic encephalopathy, variceal bleeding or a prolonged PT/INR;
3. HCV RNA positive;
4. HBsAg positive;
5. Positive anti-mitochondrial antibody;
6. Alcohol consumption greater than 21 oz/week for males or 14 oz/week for females;
7. Moderately active UC defined as either a partial Mayo score of > 4, bleeding score of >1, or current use of oral corticosteroid therapy and/or any inhibitor of TNF-α or α4β7 integrin antagonist
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 opiod-based medications are eligible if the prescription and diagnosis are reviewed and approved by the investigator.
9. Clinically significant cardiac disease;
10. History of cholangiocarcinoma. If a dominant stricture is found, cholangiocarcinoma must be ruled out by brush cytology or biopsy prior to randomization;
11. History of cancer, other than non-melanomatous skin cancer, within 5 years prior to screening;
12. Ascending cholangitis within 60 days of screening;
13. Presence of a percutaneous drain or bile duct stent;
14. Major surgical procedure within 30 days prior to screening or the presence of an open wound;
15. Known hypersensitivity to the investigational product or any
of its formulation excipients;
16. History of bleeding diathesis within 6 months of screening;
17. Unavailable for follow-up assessment or concern for subject’s compliance with the protocol procedures;
18. Participation in a clinical trial of an investigational drug or device within 30 days prior to screening;
19. Any other condition that in the opinion of the investigator renders the subject a poor risk for inclusion into the study
20. For France only: Subjects benefitting from a legal protection measure |
|
E.5 End points |
E.5.1 | Primary end point(s) |
The primary endpoint will be:
Change from baseline in morphometric quantitative collagen on liver biopsy at Week 96. |
|
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 liver biopsy at Week 96 |
|
E.5.2 | Secondary end point(s) |
Exploratory efficacy endpoints will include:
• Change from baseline in morphometric quantitative collagen on liver biopsy at Week 48;
• Change from Baseline in the Mayo risk score at 4 week intervals;
• Change from Baseline in the MELD score at 4 week intervals;
• Assess the rate of events related to progression of PSC in each treatment arm, including variceal bleeding, ascites, encephalopathy, ascending cholangitis, cholangiocarcinoma, hepatocellular carcinoma, transplant and death.
• Change from Baseline in serum alkaline phosphatase levels at 4 week intervals;
• Change from Baseline in the Ishak fibrosis stage on liver biopsy at weeks 48 and 96;
• Change from Baseline in α-smooth muscle actin on liver
biopsy at weeks 48 and 96;
• Change from Baseline on a VAS assessment of pruritus severity at weeks 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96;
• Change from baseline in serum LOXL2 levels at weeks 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96;
• Change from baseline in ELF™ test at Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96;
• Change from baseline in FibroSURE/FibroTest/FibroMAX at Weeks 4, 8, 12, 24, 36, 48, 60, 72, 84, and 96;
• MRCP as compared to Baseline at weeks 48 and 96;
• For a subset of approximately 50 subjects, change from baseline in liver stiffness as measured by MRE at weeks 48 and 96;
• For a subset of approximately 50 subjects, change from baseline in liver stiffness as measured by impedance ultrasonography at weeks 48 and 96. |
|
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 liver biopsy at week 96. Other endpoints will be assessed at weeks 4, 8, 12, 24, 36, 48, 60, 72, 84 and 96 as detailed in each specific endpoint
• For a subset of approximately 50 subjects, change from baseline in liver stiffness as measured by MRE at weeks 48 and 96;
• For a subset of approximately 50 subjects, change from baseline in liver stiffness as measured by impedance ultrasonography at weeks 48 and 96. |
|
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 | 5 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 30 |
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 |
Belgium |
Canada |
Denmark |
France |
Germany |
Italy |
Netherlands |
Norway |
Spain |
Sweden |
United Kingdom |
United States |
|
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
|
|
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 | 11 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 11 |