| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-alcoholic Steatohepatitis (NASH) Cirrhosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Chronic disease of the liver |
|
| 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 | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10009214 |
| E.1.2 | Term | Cirrhosis of liver without mention of alcohol |
| 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 determine the effect of randomized, once-daily, oral administration of 80 mg resmetirom versus matching placebo on patients as measured by time to experiencing a first adjudicated Composite Clinical Outcome event, defined as any of the following: all-cause mortality, liver transplant, and significant hepatic events including hepatic decompensation events (ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage) and confirmed increase of Model for End-stage Liver Disease (MELD) score from <12 to ≥15 |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objectives:
To determine the effect of randomized, once daily, oral administration of 80 mg resmetirom versus matching placebo on the:
1. Percent change from Baseline to Week 28 in low-density lipoprotein cholesterol (LDL-C)
2. Percent change from Baseline to Week 52 in hepatic fat fraction by magnetic resonance imaging proton density fat fraction (MRI-PDFF) in patients with baseline MRI-PDFF ≥5% |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Must be willing to participate in the study and provide written informed consent.
NOTE: Subjects must be affiliated to the social security regime or be a beneficiary of such a regime. (France only)
2. Male and female adults ≥18 years of age.
3. Female patients who:
a. are of reproductive potential and have a negative serum pregnancy test (beta human chorionic gonadotropin), are not parturient, not breastfeeding, and do not plan to become pregnant during the study and agree to use highly effective birth control methods during the study from Screening, throughout the study, and for at least 30 days after the last dose of study drug administration.
b. OR are not of child bearing potential (ie, surgically [permanent sterilization methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy] or naturally sterile [no menses for > 12 months without an alternative medical cause])
- Female patients must agree not to donate ovocytes for a period of 30 days after the last dose of study drug administration (France only)
4. Male patients who are sexually active with a partner of child-bearing potential and:
a. are sterile (vasectomy with history of a negative sperm count at least 90 days following the procedure)
b. OR practice total abstinence from sexual intercourse as the preferred lifestyle (periodic abstinence is not acceptable) OR
c. OR agree to use a birth control method during the study from the time of Screening until 30 days after the last dose of study drug administration.
- Male patients must agree not to donate sperm for a period of 30 days after the last dose of study drug administration.
5. Definitive (by histologic documentation) or probable NASH as causative agent for cirrhosis, following a modified version of the NASH Cirrhosis: Liver Forum Consensus Definitions for Clinical Trials, Noureddin 2020;
Historic Biopsy, Tissue available
A. On study centrally read as F4, historic biopsy is consistent with NASH cirrhosis
i) Continue in screening
B. On study centrally read as consistent with NASH with significant fibrosis
i) Biopsy must have been obtained six months or greater prior to prescreening date (to allow time for clinical progression to occur) and patient must now be presenting with clinical cirrhosis
ii) If screening FibroScan ≥ 15 kPa, must also have one of the following screening results:
(1) MRE ≥4.2 kPa
(2) ELF ≥10.25
(3) Fib-4 ≥3
(4) Platelet count <140,000 mm3
iii) If screening FibroScan < 15 kPa, must also have two of the following screening results:
(1) MRE ≥4.2 kPa
(2) ELF ≥10.25
(3) Fib-4 ≥3
(4) Platelet count <140,000 mm3
• Historic Biopsy, Tissue not available
A. Historical read as F4. If steatosis and ballooning and/or steatosis and inflammation are noted by the local pathologist, then the biopsy qualifies even if an NAS is not provided.
i) Continue in screening
B. Historical read as consistent with NASH with significant fibrosis
i) Biopsy must have been obtained six months or greater prior to prescreening date (to allow time for clinical progression to occur) and patient must now be presenting with clinical cirrhosis
ii) If screening FibroScan ≥ 15 kPa, must also have one of the following screening results:
(1) MRE ≥4.2 kPa
(2) ELF ≥10.25
(3) Fib-4 ≥3
(4) Platelet count <140,000 mm3
iii) If screening FibroScan < 15 kPa, must also have two of the following screening results:
(1) MRE ≥4.2 kPa
(2) ELF ≥10.25
(3) Fib-4 ≥3
(4) Platelet count <140,000 per mL
• No Biopsy – subject must be presenting with clinical cirrhosis
i) If screening FibroScan ≥ 15 kPa, must also have one of the following results:
(1) MRE ≥4.2 kPa
(2) ELF ≥10.25
(3) Fib-4 ≥3
(4) Platelet count <140,000 mm3
ii) If screening FibroScan <15 kPa, must also have two of the following screening results:
(1) MRE ≥4.2 kPa
(2) ELF ≥10.25
(3) Fib-4 ≥3
(4) Platelet count <140,000 mm3
• On study (not historic) biopsy (only obtained in rare instances and with preapproval from the Sponsor), or the biopsy was obtained less than six months prior to the screening date
A. On study (not historic) centrally read as F4, biopsy is consistent with NASH cirrhosis
i) Continue in screening
B. On study centrally read as consistent with NASH with significant fibrosis
i) Need screening FibroScan ≥ 15 kPa
ii) Must also have all of the following screening results:
(1) MRE ≥4.2 kPa
(2) ELF ≥10.25
(3) Fib-4 ≥3
(4) Platelet count <140,000 mm3
− NOTE: When possible, historical biopsies that are used for eligibility will be reviewed and confirmed as consistent with NASH cirrhosis by a central pathologist
− In the event of a conflicting read between historical biopsy report and central biopsy read, the central report will be used.
6. Well-compensated Child-Pugh A (score of 5–6) cirrhosis at Screening and Baseline AND no history of a hepatic decompensation event.
For full list of inclusion criteria please refer to the protocol.
|
|
| E.4 | Principal exclusion criteria |
1. Chronic liver diseases other than NASH cirrhosis:
a. Primary biliary cholangitis
b. Primary sclerosing cholangitis
c. Hepatitis B positive (as defined in Appendix 2)
d. Hepatitis C (as defined in Appendix 3)
e. History or evidence of current active autoimmune hepatitis
f. History or evidence of Wilson's disease
g. History or evidence of alpha-1-antitrypsin deficiency
h. History or evidence of genetic hemochromatosis (hereditary, primary)
i. Evidence of drug-induced liver disease, as defined on the basis of typical exposure and history
j. Known bile duct obstruction
k. Suspected or confirmed liver cancer
2. MELD score ≥12, due to liver disease at either screening OR baseline.
- NOTE: MELD of ≥12 as the result of liver disease is exclusionary, NOT including isolated lab abnormalities such as elevated creatinine due to chronic kidney disease, INR abnormality secondary to anticoagulants or lab error, or bilirubin elevation due to Gilbert’s syndrome. UGT1A1 allele testing to be performed at Screening on all patients (where permitted).
3. History of hepatic decompensation or impairment at either screening or baseline, defined as presence of any of the following:
a. History of variceal bleeding (NOTE: small to medium (Grade I-II) non-bleeding varices are allowed)
b. Ascites due to cirrhosis. Screening MRI or CT shows at least a 2 cm pocket of fluid in at least 2 of 5 abdominal stations, including the four abdominal quadrants and pelvis. NOTE: in situations where both MRI and CT are contraindicated, ultrasound is acceptable for evaluation of ascites.
c. Overt hepatic encephalopathy, lactulose treatment, or other treatment for hepatic encephalopathy
d. Serum albumin <3.5 g/dL, except as explained by non-hepatic causes
e. INR >1.4 unless due to therapeutic anticoagulants or laboratory error (NOTE: If laboratory error is suspected, retest to confirm INR ≤1.4 is required)
f. Total bilirubin ≥2 mg/dL
- NOTE: Patients with genetically confirmed Gilbert’s syndrome are eligible with a total bilirubin ≥2 mg/dL if reticulocyte count is within normal limits, hemoglobin is within normal limits unless due to chronic anemia and unrelated to hemolysis, and direct bilirubin is <20% of total bilirubin.
4. Diagnosis of hepatocellular carcinoma (HCC) at Screening or historically
5. Liver Imaging Reporting and Data System (LI-RADS) score ≥4 at Screening. NOTE: in situations where both MRI and CT are contraindicated, ultrasound is acceptable for evaluation of hepatocellular cancer.
6. Thyroid diseases, as defined by the following conditions:
a. Active hyperthyroidism.
- NOTE: Patients with a history of hyperthyroidism are eligible to participate.
b. Untreated clinical hypothyroidism defined by:
- Thyroid stimulating hormone (TSH) ≥7 IU/L with symptoms of hypothyroidism,
or
- TSH ≥10 IU/L without symptoms
• NOTE: TSH may be repeated once during Screening, and if still does not meet entry criteria, patients will be considered screen failures. Patients with clinical hypothyroidism newly treated with thyroxine may be rescreened once thyroxine dose is stabilized.
7. Has an active autoimmune disease, including actively treated lupus, rheumatoid arthritis, inflammatory bowel disease, or autoimmune hepatitis that requires systemic treatment within the past 12 weeks or a documented history of clinically severe autoimmune disease, including autoimmune liver disease, or a syndrome that requires systemic steroids or immunosuppressive agents.
- NOTE: Patients with vitiligo or resolved childhood asthma/atopy would be an exception to this rule. Patients that require intermittent use of bronchodilators, topical, inhaled, or intranasal corticosteroids, or local steroid injections are not excluded from the study.
- NOTE: Patients with autoimmune diseases such as rheumatoid arthritis who are on systemic therapies may be eligible on a case-by-case basis as long as the systemic therapy for the autoimmune disease is not specifically excluded (ie steroids or immunosuppressive agents).
8. Alcohol consumption of any type, frequency or amount is not allowed during the Screening or Treatment phase of the study
9. History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study
10. History of biliary diversion
11. Uncontrolled hypertension (either treated or untreated), defined as systolic blood pressure >170 mmHg or diastolic blood pressure >100 mmHg at Screening
12. New York Heart Association Class III or IV heart failure or known left ventricular ejection fraction <30%
13. Uncontrolled cardiac arrhythmia
14. Screening ECG shows uncontrolled cardiac arrythmia, or not previously diagnosed.
For a full list of exclusion criteria see protocol. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint is the effect of once-daily, oral administration of resmetirom versus matching placebo on NASH CP-A patients, as measured by the time to a confirmed adjudicated Composite Clinical Outcome event.
The composite clinical outcome event is composed of all-cause mortality, liver transplant, significant hepatic events including hepatic decompensation events [ascites, hepatic encephalopathy, or gastroesophageal variceal hemorrhage] and confirmed increase of MELD score from <12 to ≥15. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
1. Percent change from baseline in LDL-C at Week 28
2. Percent change from Baseline to Week 52 in hepatic fat fraction by MRI-PDFF in patients with baseline MRI-PDFF ≥8% |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| 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) | 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 43 |
| 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 |
| Canada |
| United Kingdom |
| United States |
| Belgium |
| France |
| Germany |
| Italy |
| Poland |
| Spain |
|
| 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
|
| Once a sufficient number of confirmed adjudicated Composite Clinical Outcome events has accrued (approximately 109 confirmed events), the Sponsor will conclude the study. Patients will be required to return to the site by the time of their next scheduled study visit to complete the EOS visit. A 28-Day Follow-up visit will occur after the EOS visit. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| 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 | 6 |
Print
