Clinical trial NCT02912260: Phase 2 Study of MGL-3196 in Patients With Non-Alcoholic Steatohepatitis (NASH)
Official title: A Phase 2, Multi-Center, Double-Blind, Randomized, Placebo-controlled Study of MGL-3196 in Patients With Non-alcoholic Steatohepatitis
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE2
Conditions: Non-alcoholic Steatohepatitis
Lead sponsor: Madrigal Pharmaceuticals, Inc.
Sponsor class: INDUSTRY
First posted: 2016-09-23
Enrollment: 125
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to determine the effect of once-daily oral MGL-3196 on the percent change in hepatic fat fraction from baseline in patients with biopsy-proven Non-alcoholic Steatohepatitis (NASH).


Eligibility criteria: Inclusion Criteria. Patients who meet all of the following criteria will be eligible to participate in the study:

* Must be willing to participate in the study and provide written informed consent;
* Male and female adults ≥18 years of age with a BMI \<45 kg/m\^2;
* Female patients of child bearing potential with negative serum pregnancy (beta human chorionic gonadotropin) tests who are not breastfeeding, do not plan to become pregnant during the study, and agree to use effective birth control (ie, condoms, diaphragm, non hormonal intrauterine device \[IUD\], or sexual abstinence \[only if this is in line with the patient's current lifestyle\]) throughout the study and for at least 1 month after study completion; hormonal contraception (estrogens stable ≥3 months) and hormonal IUDs are permitted if used with a secondary birth control measure (eg, condoms); OR female patients of non-child bearing potential (ie, surgically \[bilateral oophorectomy, hysterectomy, or tubal ligation\] or naturally sterile \[\>12 consecutive months without menses\]); Male patients who have sexual intercourse with a female partner of child bearing potential from the first dose of study drug until 1 month after study completion must be either surgically sterile (confirmed by documented azoospermia \>90 days after the procedure) OR agree to use a condom with spermicide. All male patients must agree not to donate sperm from the first dose of study drug until 1 month after study completion;
* Must have confirmation of ≥10% liver fat content on PDFF-MRI;
* Biopsy-proven NASH. Must have had prior liver biopsy within 180 days of randomization with fibrosis stage 1 to 3 and a NAS of ≥4 with at least a score of 1 in each of the following NAS components:

  * Steatosis (scored 0 to 3),
  * Ballooning degeneration (scored 0 to 2), and
  * Lobular inflammation (scored 0 to 3);
* Must have documented historical (3 weeks to 6 months prior to the study entry) ALT and AST levels consistent with the screening ALT and AST values.

Exclusion Criteria. Patients who meet any of the following criteria will be excluded from participation in the study:

Note: Unless otherwise specified, repeat testing may be performed in consultation with the Medical Monitor.

* History of significant alcohol consumption for a period of more than 3 consecutive months within 1 year prior to screening;
* Weight gain or loss \>5% in the 6 months prior to randomization or \>10% in the 12 months prior to screening;
* Hyperthyroidism;
* Patients on thyroid replacement therapy;
* Prior or planned (during the study period) bariatric surgery (eg, gastroplasty, roux-en-Y gastric bypass);
* Type 1 diabetes;
* Uncontrolled Type 2 diabetes defined as Hemoglobin A1c ≥ 9.5% at screening (patients with HbA1c ≥ 9.5% may be rescreened);
* Use of obeticholic acid, ursodeoxycholic acid (Ursodiol® and Urso®), high dose vitamin E (\>400 IU/day) unless on stable dose of vitamin E \>400 IU/day for at least 6 months at the time of liver biopsy, or pioglitazone within 90 days prior to enrollment or since screening biopsy, whichever is longer;
* Presence of cirrhosis on liver biopsy (stage 4 fibrosis);
* Platelet count \< 140,000/mm\^3;
* Clinical evidence of hepatic decompensation;
* Evidence of other forms of chronic liver disease;
* Active, serious medical disease with likely life expectancy \<2 years;
* Participation in an investigational new drug trial in the 30 days prior to randomization; or
* Any other condition which, in the opinion of the Investigator, would impede compliance, hinder completion of the study, compromise the well-being of the patient, or interfere with the study outcomes.

Primary outcomes:
measure: Change from baseline in hepatic fat fraction assessed by MRI-PDFF
timeFrame: 12 weeks
Secondary outcomes:
measure: Two-point reduction in Non-alcoholic fatty liver disease NASH CRN (NAFLD) activity score (NAS)
timeFrame: 36 weeks
measure: Resolution of Non-alcoholic steatohepatitis (NASH) (ballooning = 0; inflammation = 0 to 1) as determined by the NASH CRN NAS score
timeFrame: 36 weeks
measure: Improvement in fibrosis by at least 1 stage with no worsening of steatohepatitis
timeFrame: 36 weeks
measure: Change from baseline in hepatic fat fraction
timeFrame: 36 weeks
measure: Safety and tolerability of MGL-3196 based on Adverse Events and Changes in Laboratory Values
timeFrame: 12 and 36 weeks
measure: Effect on high-sensitivity C-reactive protein (hsCRP)
timeFrame: 12 and 36 weeks
measure: Effect on serum alanine aminotransferase (ALT)
timeFrame: 12 and 36 weeks
measure: Effect on aspartate aminotransferase (AST)
timeFrame: 12 and 36 weeks
measure: Effect on lipid parameters
timeFrame: 12 and 36 weeks
measure: Effect on NASH and fibrosis biomarkers
timeFrame: 12 and 36 weeks
Other outcomes:
Locations:
city: Dothan
country: United States
facility: Madrigal Research Site
state: Alabama
city: Tucson
country: United States
facility: Madrigal Research Site
state: Arizona
city: Coronado
country: United States
facility: Madrigal Research Site
state: California
city: Los Angeles
country: United States
facility: Madrigal Research Site
state: California
city: Rialto
country: United States
facility: Madrigal Research Site
state: California
city: San Diego
country: United States
facility: Madrigal Research Site
state: California
city: Ventura
country: United States
facility: Madrigal Research Site
state: California
city: Englewood
country: United States
facility: Madrigal Research Site
state: Colorado
city: Boca Raton
country: United States
facility: Madrigal Research Site
state: Florida
city: Lakewood Ranch
country: United States
facility: Madrigal Research Site
state: Florida
city: Lauderdale Lakes
country: United States
facility: Madrigal Research Site
state: Florida
city: Miami
country: United States
facility: Madrigal Research Site
state: Florida
city: New Port Richey
country: United States
facility: Madrigal Research Site
state: Florida
city: Kansas City
country: United States
facility: Madrigal Research Site
state: Kansas
city: Monroe
country: United States
facility: Madrigal Research Site
state: Louisiana
city: Baltimore
country: United States
facility: Madrigal Research Site
state: Maryland
city: Jackson
country: United States
facility: Madrigal Research Site
state: Mississippi
city: Saint Louis
country: United States
facility: Madrigal Research Site
state: Missouri
city: Albuquerque
country: United States
facility: Madrigal Research Site
state: New Mexico
city: New York
country: United States
facility: Madrigal Research Site
state: New York
city: Durham
country: United States
facility: Madrigal Research Site
state: North Carolina
city: Rapid City
country: United States
facility: Madrigal Research Site
state: South Dakota
city: Live Oak
country: United States
facility: Madrigal Research Site
state: Texas
city: San Antonio
country: United States
facility: Madrigal Research Site
state: Texas
city: Charlottesville
country: United States
facility: Madrigal Research Site
state: Virginia
city: Seattle
country: United States
facility: Madrigal Research Site
state: Washington
Study officials:
References:
citation: Younossi ZM, Stepanova M, Taub RA, Barbone JM, Harrison SA. Hepatic Fat Reduction Due to Resmetirom in Patients With Nonalcoholic Steatohepatitis Is Associated With Improvement of Quality of Life. Clin Gastroenterol Hepatol. 2022 Jun;20(6):1354-1361.e7. doi: 10.1016/j.cgh.2021.07.039. Epub 2021 Jul 27.
citation: Harrison SA, Bashir M, Moussa SE, McCarty K, Pablo Frias J, Taub R, Alkhouri N. Effects of Resmetirom on Noninvasive Endpoints in a 36-Week Phase 2 Active Treatment Extension Study in Patients With NASH. Hepatol Commun. 2021 Jan 4;5(4):573-588. doi: 10.1002/hep4.1657. eCollection 2021 Apr.
citation: Harrison SA, Bashir MR, Guy CD, Zhou R, Moylan CA, Frias JP, Alkhouri N, Bansal MB, Baum S, Neuschwander-Tetri BA, Taub R, Moussa SE. Resmetirom (MGL-3196) for the treatment of non-alcoholic steatohepatitis: a multicentre, randomised, double-blind, placebo-controlled, phase 2 trial. Lancet. 2019 Nov 30;394(10213):2012-2024. doi: 10.1016/S0140-6736(19)32517-6. Epub 2019 Nov 11.