E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Confirmed diagnosis of NASH and Stage 3 or Stage 4 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 3 or Stage 4 of liver fibrosis. |
|
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 QD,
compared with placebo, on liver histology in subjects with NASH and 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 3 fibrosis, on:
- Liver biopsy-based endpoints
- Liver imaging-based endpoints (magnetic resonance elastography [MRE], and
magnetic resonance imaging-proton density fat fraction [MRI-PDFF])
- Liver biochemistry
- Metabolic parameters
To evaluate the effects of oral CC-90001, administered QD, compared with placebo, in subjects with NASH and Stage 3 or Stage 4 fibrosis, and all subjects combined, on:
- Dose response
- Safety and tolerability
- Pharmacokinetics (PK)
Exploratory Objective(s)
To explore the effects of oral CC-90001, administered QD, compared with placebo, in
subjects with NASH and Stage 3 or Stage 4 fibrosis, and all subjects combined, on:
|
|
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 3 or Stage 4 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 of Screening. Note: Subjects who do not have pathological specimens from a prior liver biopsy obtained within 6 months of Screening and available for central reading, must undergo liver biopsy during Screening. Appendix B and Appendix C outline an algorithm to help determine which potential subjects may proceed to liver biopsy.
5. If histopathological specimens are submitted from a historical liver biopsy, the subject’s weight must have been documented to be stable since the liver biopsy (eg, 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 within 3 months prior to Screening and the subject agrees to maintain stable doses during the course of the study, unless required to adjust doses due to safety reasons: vitamin E, ursodeoxycholic acid, gemfibrozil, metformin, sodium-glucose co-transporter 2 (SGLT2) inhibitors (eg, canagliflozin), dipeptidyl peptidase-4 inhibitors (‘gliptins’) (such as sitagliptin), glucagon peptide-1 agonists (eg, liraglutide [1.2 mg or 1.8 mg QD] for indications other than weight loss).
7. If receiving thiazolidinediones (eg, pioglitazone), the doses must have been stable with 6 months prior to Screening.
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 methods (for example: birth control pills, condoms, etc.) (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 condomsa 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.
*True abstinence is acceptable when this is in line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception).
|
|
E.4 | Principal exclusion criteria |
1.Subject has any significant medical condition, laboratory abnormality (other than NASH related dyscrasias), or psychiatric illness 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, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, primary biliary cirrhosis, primary biliary cholangitis, Wilson's disease, alpha-1-antitrypsin deficiency, hemochromatosis or iron overload, drug-induced liver disease
4.Hemoglobin A1c (HbA1c)>8% at Screening
5.Subjects with evidence of worsening liver function based on two liver function tests during Screening period (refer Section 6.1)
6.Subject with a QTcF >450msec
7.Subject is likely to have liver transplantation or bariatric surgery 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 (420mL) per wk in females and more than 21 oz (630 mL) per wk in males, on average (1 oz/30mL of alcohol is present in one 12 oz/360mL beer, one 4 oz/120mL glass of wine, and a 1 oz/30mL measure of 40% proof alcohol).
9.Subject has urine ethyl glucuronide(EtG)>500ng/mL at Screening
10.Use of drugs historically associated with nonalcoholic fatty liver disease (NAFLD) for more than 2 consecutive wks within a year prior to randomization or any drugs that are known to cause hepatotoxicity, such as, but not limited to, acetaminophen at dosages of >3grams/day and niacin at dosages of >2grams/day within 2 wks of randomization
11.Receiving any biologic agents, or cytokine inhibitors within 3 months of Screening
12.Use of approved weight-loss medications within 3 months of Screening
13. Active or 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 hospitalization or treatment with IV or oral antibiotics within 4 wks of Screening Visit and at any time during the Screening Phase, up through the first dose of IP
14.History of active or latent or active tuberculosis (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 WHO guidelines.Note: If a subject has adequate documentation of successful treatment for either latent or active TB, the QuantiFERON-TB Gold test is not needed. Instead, a chest radiograph, obtained within the 12 wks prior to Screening, without changes suggestive of active TB infection as determined by a qualified radiologist, will be sufficient to permit further participation in the study for these subjects. Documentation of adequate treatment for TB must be obtained prior to randomization
15.Subject has had a household contact with a person with active TB and subject did not receive appropriate and documented prophylaxis for TB.Note: Household contact is a person who shared the same enclosed living space as the index case for one or more nights or for frequent or extended daytime periods during the 3 months before the start of current treatment
16.History for positive screen for human immunodeficiency virus infection or congenital or acquired immunodeficiencies
17.History of HBV and/or HCV
18.History of cardiac valve replacement requiring chronic anticoagulation therapy
19.History of inflammatory bowel disease
20.History of bleeding peptic ulcer or bleeding diverticular disease within the last 5 yrs
21.Subject has 2 positive fecal occult blood tests during Screening, collected at least 4wks apart
22.Subjects with Type 1 DM
23.History of malignancy (exceptions: excised and cured basal/squamous cell skin carcinomas & cervical carcinoma in situ with no recurrence in 5yrs)
24.Use of any medications that are substrates of the transporters P-gp, BCRP, OAT3, OATP1B1, OATP1B3, and OCT2 (See Appendix D) and have a narrow therapeutic index
25.Use of strong CYP3A inhibitors (Refer Appendix G and the following link: https://www.fda.gov/drugs/drug-interactions-labeling/drug-development-and-drug-interactions-table-substrates-inhibitors-and-inducers)
26.Use of vitamin K antagonists within 2 wks prior to Screening
27.Pregnancy or lactation
28.Subject has a known hypersensitivity to CC-90001 or any ingredient in the IP
29.Participation in any investigational study of an investigational drug within one month or 5PK or PD half-lives, whichever is longer, prior to Screening
30.Prior use of obeticholic acid or participation of obeticholic acid clinical trial
|
|
E.5 End points |
E.5.1 | Primary end point(s) |
Liver fibrosis score-Proportion of subjects who achieve a ≥1 stage improvement in liver fibrosis using the NASH clinical research network (CRN) Histological Scoring System (Stage 3 subjects only) |
|
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, Nonalcoholic fatty liver disease (NAFLD) activity score (NAS), Resolution of NASH, Progression to cirrhosis, Liver stiffness measurements (LSM) by 2 dimensional magnetic resonance elastography (MRE), Magnetic resonance imaging-proton density fat fraction (MRI-PDFF), Liver biochemistry, Metabolic parameters, Dose response, Safet, PK |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 52.
Safety through week 106.
PK: Day 1 and week 4.
Liver biochemistry and Metabolic parameters: Through week 52 |
|
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 | 7 |
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 |
France |
Germany |
Korea, Republic of |
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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 |