| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Non-Alcoholic Steatohepatitis (NASH) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Inflammation 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 | 24.1 |
| 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 |
Week 52 Dual Primary Objectives: To determine the effect of once-daily, oral administration of 80 or 100 mg MGL 3196 versus matching placebo on NASH, as measured by:
1. The resolution of NASH associated with an at least 2-point reduction in non alcoholic fatty liver disease (NAFLD) activity score (NAS) and without worsening of fibrosis by liver biopsy after 52 weeks of treatment (Week 52 Primary Endpoint) in the mITT-LB-W52 population.
Resolution includes:
• The total absence of ballooning (score = 0) and absent or mild lobular inflammation (score 0 to 1) (associated with an at least 2-point reduction in NAS).
• No worsening of fibrosis: worsening of fibrosis is defined as any progression ≥1 stage.
2. The histological improvement from Baseline demonstrated by at least
a 1-point improvement in fibrosis by liver biopsy with no worsening of
NAS at Week 52.
Month 54 Primary Objective:
Time to experiencing an adjudicated Composite Clinical Outcome event |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Objective:
For the week 52 analysis, the key secondary objective is to determine the effect of once-daily, oral administration of 80 or 100 mg MGL-3196 versus matching placebo on the percent change from Baseline at 24 weeks in directly measured low-density lipoprotein cholesterol (LDL-C). |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Only evaluate patients for study participation if they meet the Prescreening Criteria.
Patients who do not initially meet eligibility criteria may be retested, based on Investigator judgment. Patients who meet all of the following criteria will be eligible to participate in the study:
1. Must be willing to participate in the study and provide written informed consent.
2. Male and female adults ≥18 years of age.
3. Female patients are eligible if they are of reproductive potential and
have a negative serum pregnancy test (beta human chorionic gonadotropin), are not breastfeeding, and do not plan to become pregnant during the study and agree to use 2 highly effective birth control methods during the study OR if they are not of child bearing potential (ie, surgically [bilateral oophorectomy, hysterectomy, or tubal ligation] or naturally sterile [> 12 consecutive months without menses]). Highly effective birth control methods include condoms with spermicide, diaphragm with spermicide, hormonal and non-hormonal intrauterine device, hormonal contraception (estrogens stable ≥ 3 months), a vasectomized or sterile male partner, or sexual abstinence (defined as refraining from heterosexual intercourse), from Screening
throughout the study and for at least 30 days after study drug administration. Reliance on abstinence from heterosexual intercourse is acceptable only if it is subject`s habitual practice.
4. Male subjects who are sexually active with a partner of child-bearing
potential must either be sterile (vasectomy with history of a negative sperm count at least 90 days following the procedure); practice total abstinence from sexual intercourse as the preferred lifestyle (periodic abstinence is not acceptable); use a male condom with any sexual
activity; or agree to use a birth control method considered to be appropriate by the Investigator (such as one of the methods identified
above for female subjects of childbearing potential) from the time of Screening until 30 days after the last dose of study drug administration.
Male subjects must agree not to donate sperm for a period of 30 days after the last dose of study drug administration.
5. Suspected or confirmed diagnosis of NASH fibrosis suggested by the historical data.
Meet one of the following criteria that is consistent with NASH liver fibrosis:
• Historical biochemical test for fibrosis: PRO-C3 >14 ng/mL; or ELF ≥9 (ELF is based on a historic value and is not obtained at screening; PROC3 is based on the historic PRO-C3 and not the screening PRO-C3).
• FibroScan with transient elastography ≥8.5 kPa; and controlled attenuation parameter ≥280 dB.m-1 (FibroScan does not need to be repeated at screening if done at prescreening and/or a historical FibroScan was done in the prior 3 months).
• Historical liver biopsy obtained <2 years before expected randomization showing Stage 1B, 2 or 3 fibrosis with NASH based on existing pathology review, with no significant change in body weight >5% or medication that might affect NAS or fibrosis stage.
NOTE: A biopsy that was obtained >6 months before the time of anticipated randomization is not eligible for study entry; a biopsy done ≤6 months is potentially eligible for study entry as a baseline biopsy only after confirmation of eligibility based on Inclusion #7 by the central pathology reviewer. If a FibroScan is not used to meet Inclusion #5 (as in the case of historic eligible PRO-C3/ELF or liver biopsy), a baseline FibroScan should be obtained prior to randomization. If other criteria are used to meet inclusion #5 and the MRI-PDFF≥8%, OR an eligible historical liver biopsy (≤6 months) has been confirmed by the central reader, and with confirmed no significant change in metabolic status since the time of that biopsy, the baseline FibroScan can be KpA<8.5, CAP<280.
NOTE: Eligibility based on meeting Inclusion #5 should be determined based on historic medical and laboratory (PRO-C3/ELF, FibroScan, liver biopsy) data and should be determined prior to informed consent and screening visit.
6. MRI-PDFF fat fraction ≥8% obtained during the screening period (baseline MRI-PDFF).
NOTE: To be eligible to perform the screening MRI-PDFF (Baseline MRIPDFF)
a patient must first meet Criterion #5. An eligible MRI-PDFF with fat fraction ≥8% must be obtained prior to performing the baseline liver biopsy (Criterion #7). Patients with contraindications to an MRI-PDFF (e.g., metal prosthetics or uncontrolled claustrophobia) examination or screened at an investigative site where MRI-PDFF is not available are eligible for a liver biopsy if they have a FibroScan with CAP ≥280.
NOTE:A historical MRI-PDFF ≥8% is eligible as a baseline MRI-PDFF if obtained ≤8 weeks prior to randomization.
NOTE: In cases with an eligible historical biopsy (≤6 months) confirmed
by central reader, and with confirmed no significant change in metabolic
status since the time of the biopsy, MRI-PDFF <8% may be eligible |
|
| E.4 | Principal exclusion criteria |
Patients who meet any of the following criteria will be excluded from study participation. Patients who do not initially meet eligibility criteria may be retested or rescreened, based on Investigator judgment.
-- Regular use of drugs historically associated with NAFLD, which include but are not limited to the following: amiodarone, methotrexate, systemic oral glucocorticoids, tamoxifen, estrogens at doses greater than those used for hormone replacement or contraception, anabolic steroids except testosterone replacement, valproic acid, and known hepatotoxins for more than 4 weeks within the last 8 weeks prior to the initial Screening.
-- History of bariatric surgery or intestinal bypass surgery within the 5 years prior to randomization or planned during the conduct of the study
-- Weight gain or loss ≥5% total body weight within 12 weeks prior to randomization
-- Glucagon-like peptide 1 [GLP-1] agonist therapy (e.g., exenatide, liraglutide, lixisenatide, albiglutide, dulaglutide, semaglutide and albiglutide) unless stable dose for 24 weeks prior to biopsy. NOTE: GLP-1 therapeutics may not be initiated or doses increased during the first 52 weeks of the study.
-- Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis
-- Diagnosis of hepatocellular carcinoma (HCC)
-- Chronic liver diseases:
a. Primary biliary cholangitis
b. Primary sclerosing cholangitis
c. Hepatitis B positive
d. Hepatitis C as defined by presence of hepatitis C virus (HCV) antibody (HCV Ab) and positive HCV RNA (tested for known cured HCV infection, or positive HCV Ab at Screening). NOTE: Patients who are HCV antibody positive and HCV RNA negative who have a history of clearly documented HCV infection (history of positive HCV RNA) are eligible to participate if prior treatment for HCV was given, and they have a documented sustained virologic response (SVR) of at least two years prior to the baseline liver biopsy
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. 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 proven liver cancer.
-- Serum ALT >250 U/L
NOTE: Given the intrinsic variability in ALT and AST in NASH patients,
investigators should use the following guide in an attempt to establish a relatively stable baseline for ALT and AST. Investigator discretion is allowed. Documented historical (3 weeks to 6 months prior to study entry) ALT and AST levels consistent with the Screening ALT and AST
values may help establish a stable baseline, based on the following:
o If the historical and Screening ALT and AST values are both ≤1.5 × ULN, there is no limit to the difference between the values.
o Patients who do not have historical ALT and AST evaluations available will have their ALT and AST repeated during the Screening Period to help
to establish no worsening of >30% (both assessments during Screening period) with >2 weeks between assessments.
o If the historic ALT/AST are >1.5 × elevated and Screening ALT and AST are markedly improved (>50% decreased or normalized) relative to historic, then a third ALT/AST determination will be made during Screening to help establish a stable Baseline.
o If at least 1 of the values is >1.5 × ULN and the second value is greater than the first value, the difference in the mean of ALT and AST values must be ≤30%. If the second value is greater than the first value by >30%, a third value assessed >2 weeks after the second value should be determined to help establish a lack of worsening trend in ALT/AST. If a worsening trend is confirmed (3 consecutive worsening values with difference from first value and second value >30% and difference between second and third value >30%), patient will be a screen failure, but may be rescreened if ALT and AST stabilize.
-- Statins and/or other lipid-lowering therapies unless dose(s) is stable for ≥30 days prior to anticipated randomization. Statins must be taken in the evening for at least 2 weeks prior to randomization, and permitted statins include rosuvastatin up to 20 mg/day, atorvastatin up to 40 mg/day, pravastatin up to 40 mg/day, simvastatin up to 20 mg/day, pitavastatin up to 2 mg/day and lovastatin up to 40 mg/day.
Other stable dyslipidemia therapies not specifically listed as excluded or dose-restricted such as PCSK9 inhibitors are allowed. Higher doses and other statins are excluded. Stable doses of bile acid sequestrants are permitted only if taken 4 h after or 4 h before the study drug dose.
-- Pioglitazone >15 mg per day, stable treatment for ≥24 weeks prior to the eligible liver biopsy.
-- Platelet count <140,000/mm3. Patients with platelets <140,000 and
≥120,000 /mm3 are eligible if Fib-4<3.5
-- Uncontrolled cardiac arrhythmia |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Week 52 Dual Primary endpoints:
NASH Resolution Response at Week 52
Fibrosis ≥ 1 Stage Responder at Week 52
Time to Composite Clinical Outcome Event at Month 54 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Percent change from baseline in directly measured LDL-C
|
|
| 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 | 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 | 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) | 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 | 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 | 13 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 85 |
| 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 |
| Switzerland |
| Australia |
| Canada |
| Israel |
| Mexico |
| United Kingdom |
| United States |
| Austria |
| Belgium |
| France |
| Germany |
| Hungary |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
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