| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Patients with Non-Alcoholic Steatohepatitis (NASH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Accumulation of fat in the liver (Hepatic steatosis) associated with inflammation and liver cell injury at microscopic examination of liver biopsy. |
|
| 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 | 14.1 |
| 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 |
|
| 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 the efficacy of GFT505 80mg and GFT505 120mg once daily for 52 weeks versus placebo in reversing histological steatohepatitis without worsening of fibrosis.
Worsening of fibrosis is evaluated using NASH CRN fibrosis staging system and defined as:
- Progression to stage 3 or 4 for patients at stage 0, 1 or 2 on diagnostic liver biopsy,
- Progression to stage 4 for patients at stage 3 on diagnostic liver biopsy. |
|
| E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of GFT505 80mg and 120mg daily for 52 weeks vs. placebo in reversing histological steatohepatitis.
- To assess the improvement on NAS score.
- To assess the changes in individual histological scores of steatosis, and hepatic activity.
- To evaluate changes in area of fibrosis by morphometry.
- To assess changes in fibrosis by the NASH CRN fibrosis staging system.
- To assess changes in liver enzymes.
- To describe the changes in non-invasive markers of fibrosis and steatosis, in lipid parameters, in insulin resistance, in inflammatory markers, and in safety markers.
- To describe the variation in body weight.
- To evaluate the changes in cardiovascular risk profile.
- To determine PK parameters of GFT505 and GFT1007 after 52 weeks of treatment
- To assess the tolerability and safety of daily administration of GFT505 80mg and 120mg for 52 weeks.
- To constitute a Biobank for discovery and validation of biomarkers in NASH/NAFLD and related diseases. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide written informed consent prior to enrolment.
2. Males or females able to read.
3. Females participating in the study must be either of non-child bearing potential (surgically sterilized at least 6 months prior to screening or postmenopausal) or using an efficient double contraception: hormonal contraception (including patch, contraceptive ring, etc.), intra-uterine device or other mechanical contraception method + condom or diaphragm or spermicide for all the duration of the study. For male participants, contraceptive measures must be taken during the study, either by the male participant or his female partner.
4. Aged from 18 to 75 years inclusive at screening.
5. BMI ≤ 45 kg/m².
6. Patients agree to have one liver biopsy during the screening period for diagnostic purpose (if no historical biopsy within 9 months before randomization is available) and one at the end of the treatment period for assessment of the treatment effects.
7. For hypertensive patients, hypertension must be controlled by stable dose of anti-hypertensive medication for at least 2 months prior to screening (and the stable dose can be maintained throughout the study).
8. Patients treated with vitamin E (>400IU/d), or PUFAs (>2g/day) or Ursodeoxycholic acid can be included if drugs are stopped at least 3 months prior to diagnostic liver biopsy and up to the end of the study.
9. Histological confirmation of steatohepatitis on a diagnostic liver biopsy (biopsy obtained within 9 months prior to randomization or during the screening period). Histological diagnostic is confirmed by central reading of the slides (steatosis > 5% + lobular inflammation, any grade + ballooning, any amount).
10. For patients with Type 2 Diabetes, glycemia must be controlled (HbA1c≤8.5%). If glycemia is controlled by anti-diabetic drugs, qualitative change (i.e. implementation of a new antidiabetic drug) is not permitted within 6 months prior to randomization and should be avoided during the study. Treatments with metformin, DPPIV inhibitors, GLP1 agonists, sulfamides, insulin are authorised. Sulfamides and insulin are permitted if glycemia is self-monitored by the patient.
11. Patients agree to come to the study visits within the protocol-specified delay. |
|
| E.4 | Principal exclusion criteria |
1. Known heart failure (Grade I to IV of NYHA classification).
2. Weight loss of more than 5% within 6 months prior to randomization.
3. History of bariatric surgery.
4. Uncontrolled Blood Pressure (SBP> 160 mmHg and/or DBP>95 mmHg).
5. Type 1 diabetes patients.
6. Patients who had an acute cardiovascular episode within the 6 months prior to screening, or with a history of coronary angioplasty, history of stroke, TIA , Coronary Heart Disease (Angina pectoris, myocardial infarction, revascularisation procedures).
7. Compensated and uncompensated cirrhosis (clinical and/or histological evidence of cirrhosis). Notably, NASH patients with fibrosis stage = 4 according to the NASH CRN fibrosis staging system are excluded.
8. Known alcohol and/or any other drug abuse or dependence in the last five years. Alcohol consumption of more than 2 drink units per day for women and 3 drink units per day for men is considered abusive. One drink unit is defined as 30 mL distilled spirits, 120 mL wine, or 330 mL beer.
9. Patients who have donated blood or blood products within the previous month prior to screening or who plan to donate blood or blood products at any time during the trial and in the 3 months following the end of the study.
10. Pregnant or lactating females.
11. Other well documented causes of chronic liver disease according to standard diagnostic procedures including, but not restricted to: positive HBsAg, positive HCV RNA, suspicion of drug-induced liver disease, autoimmune hepatitis, Wilson’s disease, primary biliary cirrhosis, primary sclerosing cholangitis, genetic hemochromatosis documented by homozygosity for the C282Y HFE gene mutation.
12. Patients not covered by Health Insurance System and/or not in compliance with the recommendations of National Law in force.
13. When applicable and according to National Law in force, patient of legal age unable of giving consent or under legal protection or deprived of freedom by judicial or administrative decision.
14. Patients who cannot be contacted in case of emergency.
15. Known intolerance or contra-indication to the list of excipients of GFT505.
16. Patients are currently participating in, plan to participate in, or have participated in an investigational drug or medical device trial within 30 days or five half-lives, whichever is longer, prior to screening.
17. Glitazones (rosiglitazone and pioglitazone) are not permitted 6 months before diagnostic liver biopsy and up to the end of the study.
18. Non-statin lipid-lowering medications such as fibrates are not permitted 8 weeks before randomization and up to the end of the study. Non-statin lipid lowering medications can be washed-out during the screening period. Patients that used statins before screening may participate if the dosage has been kept constant for the past 3 months, and is kept constant and stable during the study.
19. Vitamin E (>400IU/day), PUFAs (>2g/day) and Ursodeoxycholic acid should have been stopped 3 months before diagnostic liver biopsy (and can be washed-out during the screening period in case of no available historical biopsy). They are not permitted up to the end of the study.
20. Currently taking drugs that can induce Steatosis/steatohepatitis: corticosteroids (parenteral administration only), amiodarone (Cordarone), Tamoxifen (Nolvadex), methotrexate (Rheumatrex, Trexall).
21. Currently taking any medication that could interfere with study medication absorption, distribution, metabolism or excretion or could lead to induction or inhibition of microsomal enzymes.
22. Antiplatelet or anticoagulant medications are not permitted one week before screening and to the end of the study.
23.Evidence of any other unstable or, untreated clinically significant immunological, neoplasic, endocrine, haematological, gastrointestinal, neurological or psychiatric disorder.
24. Patients who have serious or unstable medical or psychological conditions which, in the opinion of the Investigator, would lead the patient to be non-compliant or uncooperative during the study or would compromise the patient’s safety or successful participation in the study.
25. Positive HBsAg, Positive anti-HIV, positive HCV-RNA.
26. Uncontrolled hypothyroidism defined as TSH > 2X the upper limit of normal . Thyroid dysfunction controlled for at least 6 months prior to screening is permitted.
27. Significant renal disease, including nephritic syndrome, chronic renal failure .
28. Unexplained serum creatine phosphokinase (CPK) > 3X the upper limit of normal (ULN). Patients with a reason for CPK elevation may have the measurement repeated prior to randomization; a CPK retest > 3X ULN leads to exclusion . |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percentage of responders defined by the disappearance of steatohepatitis (i.e. patients no longer meeting the criteria for steatohepatitis) without worsening of fibrosis (evaluated using NASH CRN fibrosis staging system). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| from Baseline to Week 52. |
|
| E.5.2 | Secondary end point(s) |
1- Percentage of responders, defined by the disappearance of steatohepatitis (i.e. patients no longer meeting the criteria for steatohepatitis).
2- Change in NAS score.
3- Changes in stages of steatosis, hepatic activity (lobular inflammation + ballooning).
4- Changes in stages of fibrosis (NASH CRN scoring).
5- Changes in area of fibrosis by morphometry
6- Changes in liver enzymes.
7- Changes in non-invasive markers of fibrosis and steatosis.
8- Changes in lipid parameters.
9- Changes in body weight.
10- Changes in insulin resistance.
11- Changes in inflammatory markers.
12- Changes in safety markers (renal or cardiac function parameters).
13- Changes in cardiovascular risk profile.
14- To determine PK parameters of GFT505 and GFT1007 after 52 weeks of treatment.
15- SAE, AE, physical examination, vital signs, medical history, ECG. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
End points n°1 to 13 will be measured from Baseline to week 52.
End point n°14 will be measured at 2 time points post dosing at week 52.
End point n°15:
- collection of AE/SAE throughout the study ;
- ECG at baseline, week 26 and week 52 ;
- physical examination at each visit ;
- vital signs at each visit. |
|
| 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 | Yes |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 49 |
| 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 |
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 5 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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