| 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 | 22.0 |
| 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 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 Week 52 population (defined as the first 900 F2 and F3 patients randomized, containing at least 450 F3 patients).
Resolution includes:
• The total absence of ballooning (score = 0) and absent or mild 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. Time to experiencing an adjudicated Composite Clinical Outcome event in all F2 and F3 patients; Final Primary Endpoint, at 54 months. |
|
| E.2.2 | Secondary objectives of the trial |
Key Secondary Objectives:
1. 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 low-density lipoprotein cholesterol (LDL-C).
2. To determine the effect of once-daily, oral administration of 80 or 100 mg MGL-3196 versus placebo for 52 weeks in patients with biopsy-proven NASH on the histological improvement from Baseline demonstrated by at least a 1-point improvement in fibrosis by liver biopsy with no worsening of NAS (total of three NAS components, ballooning, inflammation and steatosis) (Fibrosis ≥1 Stage Responder). |
|
| 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 highly effective birth control methods during the study and for at least 30 days after study drug administration OR if they are not of child bearing potential. A woman is considered of childbearing potential (WOCBP), ie, fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.
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 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 (all 3 components) 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 is >24 weeks at the time of anticipated randomization is not eligible for study entry; a biopsy ≤24 weeks 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 (≤24 weeks) 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 (≤24 weeks) 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.
2. Regular use of drugs historically associated with NAFLD, which include
but are not limited to the following: amiodarone, methotrexate, systemic
glucocorticoids at greater than 5 mg/day, 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.
4. History of bariatric surgery or intestinal bypass surgery within the 5
years prior to randomization or planned during the conduct of the study
5. Weight gain or loss ≥5% total body weight within 12 weeks prior to
randomization
7. 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. GLP-1
therapeutics may not be initiated or doses increased during the first 52 weeks of the study
9. Presence of cirrhosis on liver biopsy defined as stage 4 fibrosis
10. Diagnosis of hepatocellular carcinoma (HCC)
13. 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.
15. 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.
16. 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.
18 Pioglitazone >15 mg per day, stable treatment for ≥24 weeks prior
to the eligible liver biopsy.
19. Platelet count <140,000/mm3. Patients with platelets <140,000 and
≥120,000 /mm3 are eligible if Fib-4<3.5
24. Uncontrolled cardiac arrhythmia. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
NASH Resolution Response 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 LDL-C
Fibrosis = 1 Stage Responder
NASH Resolution Responder
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Week 24
Month 54
Week 52 andMonth 54 |
|
| 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 | 7 |
| 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 |
| Australia |
| Austria |
| Belgium |
| Canada |
| France |
| Germany |
| Hungary |
| Israel |
| Italy |
| Mexico |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| 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 | 11 |
| 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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