| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| The study population included adult male and famele subjects, >= 18 years of age, with confirmed disgnosis of NASH and Stage 2 or Stage 3 fibrosis based upon the NASH Clinical Research Network (CRN) Histologic Scoring System and a Nonalcoholic Fatty Liver Disease (NAFLD) Activity Score (NAS) of 4 or higher, with a score of at least 1 for each of the three components (steatosis, hepatocellular ballooning, and lobular inflammation). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Confirmed diagnosis of NONALCOHOLIC STEATOHEPATITIS (NASH) and Stage 2 or Stage 3 of liver fibrosis. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| 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 the study is to evaluate the effect of oral CC-90001, administered once daily QD,
compared with placebo, on liver histology in subjects with NASH and Stage2 or Stage 3 fibrosis. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the effects of oral CC-90001, administered QD, compared with placebo, in subjects with NASH and Stage 2 or Stage 3 fibrosis, on:
- Additional Liver biopsy-based endpoints
- Liver biochemistry-based endpoints
- Metabolic parameters-based endpoints
- Dose response
- Safety and tolerability
- Pharmacokinetics (PK) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects must satisfy the following criteria to be enrolled in the study:
1. Subject is male or female ≥ 18 years of age at the time of signing the informed consent form (ICF).
2. Subject must understand and voluntarily sign an ICF prior to any study-related assessments/procedures being conducted.
3. Subject is willing and able to adhere to the study visit schedule and other protocol requirements.
4. Diagnosis of NASH with presence of Stage 2 or Stage 3 fibrosis based upon central reading of the NASH CRN Histologic Scoring System and a NAFLD Activity Score (NAS) of 4 or higher, with a score of at least 1 for each of the three components (steatosis scored 0 to 3, ballooning degeneration scored 0 to 2, and lobular inflammation scored 0 to 3) within 6 months prior to Screening or at Screening.
5. If histopathological specimens are submitted from a historical liver biopsy, the subject could not be on a therapy specifically for the treatment of NASH after liver biopsy and the subject’s weight must have been documented to be stable since the liver biopsy (ie, within 5% if the liver biopsy was obtained 4 to 6 months prior to Screening or within 2.5% if the liver biopsy was obtained less than 4 months prior to Screening).
6. If receiving any of the following agents, the doses must have been stable for 3 months prior to Screening and the subject must agree to maintain stable doses during the course of the study, unless required to adjust doses due to safety reasons: ursodeoxycholic acid, fibric acid derivatives (fibrates) (eg, gemfibrozil), metformin, sodium-glucose co-transporter 2 (SGLT2) inhibitors (eg, canagliflozin), dipeptidyl peptidase-4 inhibitors (‘gliptins’) (such as sitagliptin), glucagon peptide-1 (GLP-1) agonists (eg, liraglutide), anti-obesity medications (eg, orlistat, lorcaserin, liraglutide, phentermine-topiramate, or naltrexone-bupropion). Note: If historical liver biopsy is submitted, the doses of above medications must have been stable for 3 months prior to biopsy and stable doses should be maintained through screening and during the course of the study. If SGLT2 inhibitors, GLP-1 agonists and anti-obesity medications have been recently discontinued, the treatment must have been stopped for at least 3 months prior to Screening or historical biopsy used for Screening assessment.
7. If receiving thiazolidinediones (eg, pioglitazone) or vitamin E, the doses must have been stable for 3 months prior to Screening and the subject must agree to maintain stable doses during the course of the study. Note: If historical liver biopsy is submitted the doses of above medications must have been stable for 3 months prior to biopsy and stable doses should be maintained through screening and during the course of the study. If thiazolidinediones (eg, pioglitazone) or vitamin E have been recently discontinued, the treatment must have been stopped for at least 3 months prior to Screening or historical biopsy used for Screening assessment.
8. Females of childbearing potential (FCBP) must:
a. Have two negative pregnancy tests as verified by the Investigator prior to starting investigational product (IP). She must agree to ongoing pregnancy testing during the course of the study, and after end of study treatment. This applies even if the subject practices true abstinence* from heterosexual contact.
b. Either commit to true abstinence* from heterosexual contact (which must be reviewed on a monthly basis and source documented) or agree to use two forms of effective birth control (one of which is highly effective) at the same time, and be able to comply with, effective contraception without interruption, 28 days prior to starting IP, during the study therapy (including dose interruptions), and for 28 days after discontinuation of IP.
Approved options for birth control are:
• Any one of the following highly effective methods: Hormonal contraception (for example, birth control pills, intravaginal ring, transdermal patch, injection, implant); intrauterine device (IUD); tubal ligation (tying your tubes); or a partner with a vasectomy.
Note: Certain drugs may reduce the effectiveness of hormonal contraceptives during and up to one month after discontinuation of these concomitant therapies.
• Any effective method, for example, condoms.
9. Male subjects must:
Practice true abstinence* (which must be reviewed on a monthly basis) or agree to use a latex condom or nonlatex condom not made out of natural (animal) membrane (eg, polyurethane) during sexual contact with a pregnant female or a female of childbearing potential while participating in the study, during dose interruptions and for at least 28 days following IP discontinuation, even if he has undergone a successful vasectomy.
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|
| E.4 | Principal exclusion criteria |
1. Subject has any significant medical condition, laboratory abnormality (other than NASH related dyscrasias), or psychiatric illness that would confound the ability to interpret data, prevent the subject from participating or place the subject at unacceptable risk if he/she were to participate in the study.
2. History or evidence of decompensated liver disease, including clinical ascites, hepatic encephalopathy, or variceal bleeding.
3. Hepatitis and fibrosis more likely related to etiologies other than NASH such as, but not limited to, alcoholic steatohepatitis, autoimmune hepatitis, HBV infection, HCV infection, primary biliary cirrhosis, primary sclerosing cholangitis, Wilson's disease, alpha-1-antitrypsin deficiency, hemochromatosis or iron overload, and drug-induced liver disease.
4. Hemoglobin A1c (HbA1c) ≥ 9.5% at Screening.
5. Subject has evidence of worsening liver function based on two measurements of AST, ALT, alkaline phosphatase (ALP) and total bilirubin (TBL) during Screening period
6. Subject has a QTcF > 450 msec.
7. Subject has a history of liver transplantation or subject is likely to have liver transplantation during the study.
8. Current or history of recreational drug abuse or significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening. Significant alcohol consumption is defined as more than 14 oz (420 mL) per week in females and more than 21 oz (630 mL) per week in males, on average (1 oz/30 mL of alcohol is present in one 12 oz/360 mL beer, one 4 oz/120 mL glass of wine, or a 1.5 oz/45 mL measure of 40% proof alcohol).
9. Subject has urine ethyl glucuronide (EtG) > 500 ng/mL at Screening.
10. Use of any drugs that are known to cause hepatotoxicity, such as, but not limited to, acetaminophen (paracetamol) at dosages of > 3 grams/day and niacin at dosages of > 2 grams/day within 2 weeks of randomization.
11. Receiving immunomodulator agents (eg, tumor necrosis factor [TNF] inhibitors), or cytokine inhibitors (eg, tofacitinib) within 3 months of Screening.
12. History of recurrent bacterial, viral, fungal, mycobacterial or other infections (including, but not limited to, atypical mycobacterial disease and herpes zoster), or any major episode of infection requiring either hospitalization or treatment with IV or oral antibiotics within 4 weeks of the Screening Visit and at any time during the Screening Phase, up through the first dose of IP. Additionally, in the case of prior SARS-CoV-2 infection, symptoms must have completely resolved and based on investigator assessment in consultation with the clinical trial physician, there are no sequelae that would place the participant at a higher risk of receiving investigational treatment.
13. History of active or latent TB, unless there is medical record documentation of successful completion of a standard course of treatment considered appropriate, based on local prevalence of multi-drug resistant TB and consistent with World Health Organization guideline
14. Subject has had a household contact with a person with active TB and subject did not receive appropriate and documented prophylaxis for TB
15. History or positive screen for human immunodeficiency virus (HIV) infection or congenital or HIV-unrelated acquired immunodeficiencies (eg, common variable immunodeficiency [CVID]).
16. History or positive screen for hepatitis B (and/or hepatitis C.
17. History of cardiac valve replacement requiring chronic anticoagulation therapy
18. History of inflammatory bowel disease (IBD).
19. History of bleeding peptic ulcer or bleeding diverticular disease within the last 5 years.
20. Subjects with Type 1 DM.
21. History of malignancy within the last 5 years (exceptions: excised and cured basal/squamous cell skin carcinomas or cervical carcinoma in situ).
22. Use of any medications that are substrates of the transporters P-gp, BCRP, OAT3, OATP1B1, OATP1B3, and OCT2 (See Appendix B) and have a narrow therapeutic index (eg, digoxin) after Screening.
23. Use of strong CYP3A inhibitors (Refer to Appendix E and the following link for the list of strong CYP3A inhibitors: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers) after Screening.
24. Use of vitamin K antagonists (eg, warfarin) within 2 weeks prior to Screening.
25. Pregnancy or lactation.
26. Subject has a known hypersensitivity to CC-90001 or any ingredient in the investigational product.
27. Concurrent treatment with another IP, including through participation in an interventional trial for COVID-19. Prospective subjects may not participate in a concurrent IP study or have received an IP within 5 drug half-lives prior to screening.
28. Prior use of approved agents for treatment of NASH within 6 months prior to Screening or historical biopsy used for Screening.
PLEASE REFER TO PROTOCOL AMENDMNT 4 TO SEE COMPLETLE LIST OF EXCLUSION CRITERIA |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects who achieve a ≥1 stage improvement in liver fibrosis using the nonalcoholic steatohepatitis (NASH) clinical research network (CRN) Histological Scoring System |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Combined assessment of liver fibrosis score and steatohepatitis:Proportion of subjects who achieve a ≥ 1 stage improvement in liver fibrosis and no worsening of steatohepatitis (no worsening of lobular inflammation or hepatocellular ballooning score) (Subjects with Stage 2 or Stage 3 fibrosis only)
- Nonalcoholic fatty liver disease (NAFLD) activity score (NAS): Proportion of subjects with an improvement of ≥ 2 points in the total NAS in more than one category of steatosis, lobular inflammation, and hepatocellular ballooning, and no worsening of liver fibrosis (Subjects with Stage 2 or Stage 3 fibrosis only)
- Resolution of NASH: Proportion of subjects who demonstrate absence of ballooning, and lobular inflammation score of 0 or 1
- Resolution of NASH without worsening of liver fibrosis : Proportion of subjects who demonstrate absence of ballooning, and lobular inflammation score of 0 or 1 and no worsening of liver fibrosis (Subjects with Stage 2 or Stage 3 fibrosis only)
- Progression to cirrhosis: Proportion of subjects who progress to cirrhosis (Subjects with Stage 2 or Stage 3 fibrosis only)
Liver stiffness measurements (LSM) by 2 dimensional magnetic resonance elastography (MRE)
- Liver biochemistry: Proportion of subjects who achieve the following relative reductions in liver stiffness: 15%, 20%, 25%, and 30% (Subjects with Stage 2 or Stage 3 fibrosis only)Change from Baseline in serum aspartate aminotransferase (AST), alanine aminotransferase (ALT) and γ-glutamyl transferase (GGT)
- Metabolic parameters: Change from Baseline in total cholesterol, low density cholesterol (LDL) high density cholesterol (HDL), and triglycerides
- Dose response: Percentage change from Baseline in liver stiffness (Subjects with Stage 2 or Stage 3 fibrosis only)Dose-related changes in the primary and secondary endpoints
- Safety: Type, frequency, severity, and relationship of adverse events (AEs) to CC-90001; Laboratory, 12-lead electrocardiogram (ECG), physical examination or other changes and tolerability (Stage 2 or Stage 3 subjects; Stage 4 subjects; all subjects combined)
- Pharmacokinetics (PK): Maximum plasma concentration of drug (Cmax), area under the plasma concentration time-curve (AUC), time to peak (maximum) plasma concentration (Tmax), terminal half-life (t1/2), apparent total body clearance of the drug (CL/F), apparent volume of distribution (Vz/F), and accumulation index of CC-90001 (Stage 2 or Stage 3 subjects; Stage 4 subjects; all subjects combined)
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 52.
Liver biochemistry: Through week 52
Metabolic parameters: Through week 52
Dose response: throught Week 24 (secendary endpoints); throught Week 52 (primary and secondary endpoins)
Safety: through End of Study
|
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| The double blind placebo controlled phase is followed by double blind active treatment phase |
|
| 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 | 4 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 22 |
| 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 |
| Canada |
| Korea, Republic of |
| France |
| Germany |
| United Kingdom |
|
| 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
|
| The End of Trial is defined as either the date of the last visit of the last subject to complete the post-treatment follow-up, or the date of receipt of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 17 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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