Metabolic Interventions to Resolve Non-alcoholic Steatohepatitis (NASH) With Fibrosis (MIRNA)

Phase 2

Completed

Conditions: Nonalcoholic Fatty Liver Disease
Nonalcoholic Steatohepatitis With Liver Fibrosis

Interventions: Drug: PF-06865571
Drug: Placebo
Drug: PF-05221304

Registration Number: NCT04321031

Lead Sponsor: Pfizer

Brief Summary: The study aims to evaluate two, orally administered, investigational agents - PF-06865571 (DGAT2 inhibitor) and the coadministration of PF-06865571 with PF-05221304 (ACC inhibitor). This study is specifically designed to evaluate the effect of a range of doses of DGAT2i alone, and DGAT2i + ACCi, on resolution of NASH or improvement in liver fibrosis, as assessed histologically (via liver biopsy).

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 256

Inclusion Criteria

Biopsy proven NASH with either F2 or F3 fibrosis, per NASH CRN definition
BMI >/= 22.5kg/m2

Exclusion Criteria

Evidence of other causes of liver disease such as Alcoholic steatohepatitis, (de)compensated cirrhosis, active viral hepatitis
Any condition possibly affecting drug absorption -Unstable concomitant medical conditions, based on medical history or screening laboratory results including-
unstable liver function tests, recent cardiovascular event(s) significant malignancies,

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
PF-06865571 75 mg BID	PF-06865571	participants will receive medication for 48 weeks
PF-06865571 150 mg BID	PF-06865571	participants will receive medication for 48 weeks
Placebo	Placebo	participants will receive medication for 48 weeks
PF-06865571 25 milligrams (mg) twice daily (BID)	PF-06865571	participants will receive medication for 48 weeks
PF-06865571 300 mg BID	PF-06865571	participants will receive medication for 48 weeks
PF-06865571 (150 mg BID) + PF-05221304 (5 mg BID)	PF-06865571	participants will receive medication for 48 weeks
PF-06865771 (300 mg BID) + PF-05221304 (10 mg BID)	PF-06865571	participants will receive medication for 48 weeks
PF-06865571 (150 mg BID) + PF-05221304 (5 mg BID)	PF-05221304	participants will receive medication for 48 weeks
PF-06865771 (300 mg BID) + PF-05221304 (10 mg BID)	PF-05221304	participants will receive medication for 48 weeks

Primary Outcome Measures

Name	Time	Method
Mean Proportion of Participants Achieving Resolution of NASH Without Worsening/Improvement of Fibrosis by >=1 Stage Without Worsening of NASH/Both Based on Assessment by Sponsor-Identified Central Pathologist at Week 48:Bayesian Dose Response Model (BDRM)	Week 48	NASH resolution: disappearance of ballooning (Nonalcoholic Fatty Liver Disease \[NAFLD\] Activity Score \[NAS\] ballooning score=0;0=no ballooning,1=few balloon cells,2=many cells with prominent ballooning; higher scores(HS)=more disease activity \[DA\]),residual/no lobular inflammation(NAS lobular inflammation score 0/1,0=no foci,1= \<2 foci, 2=2-4 foci,3= \>4 foci; HS=more DA),NAS steatosis score 0,1,2,3; 0= \<5% hepatocytes involved (HI),1=5-33% HI ,2= 34-66% HI, 3= \>66% HI; HS=more DA. No worsening of fibrosis: no change/decrease of at least 1 stage in Brunt-Kleiner scale (BKS) compared to baseline (CTB). Improvement in fibrosis by \>=1 stage: decrease of at least 1 stage in BKS CTB. No worsening of NASH: no change/increase in NAS for ballooning, inflammation, steatosis CTB. BDRM utilized to characterize dose response across BID treatment groups, estimate posterior mean proportion (\& 90% credible interval \[CI\], indicated as 'confidence interval' below) for placebo and each BID dose studied.
Number of Participants Achieving Resolution of NASH Without Worsening or Improvement in Fibrosis by >= 1 Stage Without Worsening of NASH or Both Based on Assessment by Sponsor-Identified Central Pathologist at Week 48: Logistic Regression Model	Week 48	Resolution of NASH: disappearance of ballooning (NAS ballooning score= 0; where 0= no ballooning, 1= few balloon cells, 2= many cells with prominent ballooning; higher scores= more disease activity), residual or no lobular inflammation (NAS lobular inflammation score 0 or 1, where 0= no foci, 1= \<2 foci, 2= 2-4 foci, 3= \>4 foci; higher scores= more disease activity), NAS steatosis score 0, 1, 2, or 3, where 0= \<5% hepatocytes involved, 1= 5-33% hepatocytes involved, 2= 34-66% hepatocytes involved, 3= \>66% hepatocytes involved; higher scores= more disease activity. No worsening of fibrosis: no change or decrease of at least 1 stage in BKS compared to baseline. Improvement in fibrosis by \>=1 stage: decrease of at least 1 stage in BKS compared to baseline. No worsening of NASH: no change or increase in NAS for ballooning, inflammation, steatosis compared to baseline.

Secondary Outcome Measures

Name	Time	Method
Percent Change From Baseline in Liver Fat at Week 48: Bayesian Dose Response Model	Baseline, Week 48	Magnetic resonance imaging proton density fat fraction (MRI-PDFF) is an established method that enables quantification of fat content in the liver.
Mean Proportion of Participants Achieving Resolution of NASH, Without Worsening of Fibrosis Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Bayesian Dose Response Model	Week 48	Resolution of NASH: disappearance of ballooning (NAS ballooning score= 0; where 0= no ballooning, 1= few balloon cells, 2= many cells with prominent ballooning; higher scores= more disease activity), residual or no lobular inflammation (NAS lobular inflammation score 0 or 1, where 0= no foci, 1= \<2 foci, 2= 2-4 foci, 3= \>4 foci; higher scores= more disease activity), NAS steatosis score 0, 1, 2 or 3, where 0= \<5% HI, 1= 5-33% HI, 2= 34-66% HI, 3= \>66% HI; higher scores= more disease activity. No worsening of fibrosis: no change or decrease of at least 1 stage in BKS compared to baseline. BKS: scaling for fibrosis (0= none, 1= perisinusoidal/ periportal, 2= perisinusoidal, portal/ periportal, 3= bridging, 4= cirrhosis; higher scores= more disease activity). BDRM utilized to characterize dose response across BID treatment groups, estimate posterior mean proportion (\& 90% credible interval \[CI\], indicated as 'confidence interval' below) for placebo and each BID dose studied.
Number of Participants Achieving Resolution of NASH, Without Worsening of Fibrosis Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Pairwise Comparisons With Logistic Regression Model	Week 48	Resolution of NASH: disappearance of ballooning (NAS ballooning score= 0; where 0= no ballooning, 1= few balloon cells, 2= many cells with prominent ballooning; higher scores= more disease activity), residual or no lobular inflammation (NAS lobular inflammation score 0 or 1, where 0= no foci, 1= \<2 foci, 2= 2-4 foci, 3= \>4 foci; higher scores= more disease activity), NAS steatosis score 0, 1, 2 or 3, where 0= \<5% hepatocytes involved, 1= 5-33% hepatocytes involved, 2= 34-66% hepatocytes involved, 3= \>66% hepatocytes involved; higher scores= more disease activity. No worsening of fibrosis: no change or decrease of at least 1 stage in Brunt-Kleiner scale compared to baseline. Brunt-Kleiner scale included scaling for fibrosis (0= none, 1= perisinusoidal/ periportal, 2= perisinusoidal, portal/ periportal, 3= bridging, 4= cirrhosis; higher scores = more disease activity). Logistic Regression model included treatment and baseline fibrosis stage (F2/F3) as factors.
Mean Proportion of Participants Achieving Improvement in Fibrosis by >=1 Stage, Without Worsening of NASH Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Bayesian Dose Response Model	Week 48	Improvement in fibrosis by \>=1 stage: decrease of at least 1 stage in Brunt-Kleiner scale compared to baseline. No worsening of fibrosis: no change or decrease of at least 1 stage in Brunt-Kleiner scale compared to baseline. Brunt-Kleiner scale included scaling for fibrosis (0= none, 1= perisinusoidal/ periportal, 2= perisinusoidal, portal/ periportal, 3= bridging, 4= cirrhosis; higher scores = more disease activity). BDRM utilized to characterize dose response across BID treatment groups, estimate posterior mean proportion (\& 90% credible interval \[CI\], indicated as 'confidence interval' below) for placebo and each BID dose studied.
Number of Participants Achieving Improvement in Fibrosis by >=1 Stage, Without Worsening of NASH Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Pairwise Comparisons With Logistic Regression Model	Week 48	Improvement in fibrosis by \>=1 stage: decrease of at least 1 stage in Brunt-Kleiner scale compared to baseline. No worsening of fibrosis: no change/decrease of at least 1 stage in Brunt-Kleiner scale compared to baseline. Brunt-Kleiner scale included scaling for fibrosis (0= none, 1= perisinusoidal/ periportal, 2= perisinusoidal, portal/ periportal, 3= bridging, 4= cirrhosis; higher scores = more DA). Logistic Regression model included treatment and baseline fibrosis stage (F2/F3) as factors.
Mean Proportion of Participants Achieving Improvement in Fibrosis by >=2 Stage, Without Worsening of NASH Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Bayesian Dose Response Model	Week 48	Improvement in fibrosis by \>=2 stage: decrease of at least 2 points in total NAS compared to baseline, without progression of fibrosis. No worsening of NASH: no change or no increase in NAS for ballooning (NAS ballooning score= 0; where 0= no ballooning, 1= few balloon cells, 2= many cells with prominent ballooning; higher scores= more disease activity), inflammation (NAS lobular inflammation score 0 or 1, where 0= no foci, 1= \<2 foci, 2= 2-4 foci, 3= \>4 foci; higher scores= more disease activity), steatosis (NAS steatosis score 0, 1, 2, or 3, where 0= \<5% hepatocytes involved, 1= 5-33% hepatocytes involved, 2= 34-66% hepatocytes involved, 3= \>66% hepatocytes involved; higher scores=more disease activity) compared to baseline. BDRM utilized to characterize dose response across BID treatment groups, estimate posterior mean proportion (\& 90% credible interval \[CI\], indicated as 'confidence interval' below) for placebo and each BID dose studied.
Number of Participants Achieving Improvement in Fibrosis by >=2 Stage, Without Worsening of NASH Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Pairwise Comparisons With Logistic Regression Model	Week 48	Improvement in fibrosis by \>=2 stage: decrease of at least 2 points in total NAS compared to baseline, without progression of fibrosis. No worsening of NASH: no change or no increase in NAS for ballooning (NAS ballooning score= 0; where 0= no ballooning, 1= few balloon cells, 2= many cells with prominent ballooning; higher scores= more disease activity), inflammation (NAS lobular inflammation score 0 or 1, where 0= no foci, 1= \<2 foci, 2= 2-4 foci, 3= \>4 foci; higher scores= more disease activity), steatosis (NAS steatosis score 0, 1, 2 or 3, where 0= \<5% hepatocytes involved, 1= 5-33% hepatocytes involved, 2= 34-66% hepatocytes involved, 3= \>66% hepatocytes involved; higher scores= more disease activity) compared to baseline. Logistic Regression model included treatment and baseline fibrosis stage (F2/F3) as factors.
Mean Proportion of Participants Achieving Improvement of >=2 Points in Total NAS, Without Progression of Fibrosis Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Bayesian Dose Response Model	Week 48	Improvement of \>=2 points in Total NAS: decrease of at least 2 points in Total NAS compared to baseline, without progression of fibrosis. Total NAS ranged 0 to 8, higher scores= more disease activity and calculated as sum of scores of steatosis (0= \<5% hepatocytes involved, 1=5-33% hepatocytes involved, 2=34-66% hepatocytes involved, 3= \>66% hepatocytes involved; higher scores= more disease activity), lobular inflammation (0= no foci, 1= \<2 foci, 2= 2-4 foci, 3= \>4 foci; higher scores= more disease activity), ballooning (0= no ballooning, 1= few balloon cells, 2= many cells with prominent ballooning; higher scores= more disease activity). If sub-scale scores non evaluable or missing, total score was derived as missing. BDRM utilized to characterize dose response across BID treatment groups, estimate posterior mean proportion (\& 90% credible interval \[CI\], indicated as 'confidence interval' below) for placebo and each BID dose studied.
Number of Participants Achieving Improvement of >=2 Points in Total NAS Without Progression of Fibrosis Based on Assessment by Sponsor-Identified Central Pathologist(s) at Week 48: Pairwise Comparisons With Logistic Regression Model	Week 48	Improvement of \>=2 points in Total NAS: decrease of at least 2 points in Total NAS compared to baseline, without progression of fibrosis. Total NAS ranged from 0 to 8, higher scores= more DA and calculated as sum of scores of steatosis (0= \<5% hepatocytes involved, 1= 5-33% hepatocytes involved, 2= 34-66% hepatocytes involved, 3= \>66% hepatocytes involved; higher scores= more DA), lobular inflammation (0= no foci, 1= \<2 foci, 2= 2-4 foci, 3= \>4 foci; higher scores= more DA), ballooning (0= no ballooning, 1= few balloon cells, 2= many cells with prominent ballooning; higher scores= more DA). If any of the sub-scale scores were non evaluable/missing, then the total score was derived as missing. Logistic Regression model included treatment and baseline fibrosis stage (F2/F3) as factors.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	From first dose of study drug (Day 1) up to 4 weeks after last dose of study drug (maximum up to approximately 52 weeks)	An adverse event (AE) was any untoward medical occurrence in a participant/ clinical investigational participant administered a medicinal product and which does not necessarily have a causal relationship with this treatment. Serious adverse events (SAE) was any untoward medical occurrence at any dose that: resulted in death, was life threatening (risk of death), required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity (substantial disruption of the ability to conduct normal life functions), resulted in congenital anomaly/birth defect. AEs included both serious and all non-serious AEs. TEAEs were defined as newly occurring or worsening AE after the first dose of study drug.
Number of Participants With Laboratory Test Abnormalities	From first dose of study drug (Day 1) up to 4 weeks after last dose of study drug (maximum up to approximately 52 weeks)	Laboratory abnormalities included: Hematology (Hemoglobin \[hgb\], hematocrit, erythrocytes \[ery\]: \<0.8\lower limit of normal \[LLN\]; reticulocytes, reticulocytes/ery: \<0.5\LLN, \>1.5\upper LN \[ULN\]; ery mean corpuscular volume \[EMC\], EMC hgb: \<0.9\LLN, \>1.1\ULN; platelet: \>1.75 ULN; lymphocytes, neutrophils, basophils, eosinophils: \<0.8\ LLN, \>1.2\ULN; monocytes: \>1.2\ULN; activated partial thromboplastin time, prothrombin time: \>1.1\ULN); Clinical chemistry (Total/direct bilirubin, glucose:\>1.5\ULN; aspartate aminotransferase \[AT\], alanine AT, gamma glutamyl transferase: \>3.0\ULN; HDL cholesterol: \<0.8\LLN; urea nitrogen, creatinine, triglyceride, cholesterol, hgb A1C: \>1.3\ULN; urate: \>1.2\ULN; potassium: \<0.9\LLN, \>1.1\ULN; sodium: \<0.95\LLN; calcium, bicarbonate: \<0.9\LLN; creatine kinase: \>2.0\*ULN); Urinalysis (glucose, protein, hgb, ketones, nitrite, leukocyte esterase, urobilinogen, bilirubin: \>=1; ery, leukocytes: \>=20; granular, hyaline casts: \>1).
Number of Participants With Clinically Significant Abnormalities in Vital Signs	From first dose of study drug (Day 1) upto Week 48 (maximum up to approximately 50 weeks)	Number of participants with clinically significant vital signs were reported in this outcome measure. Vital signs included blood pressure, and heart rate. Clinical significance in vital signs abnormalities was judged by investigator.
Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters	From first dose of study drug (Day 1) upto Week 48 (maximum up to approximately 50 weeks)	Number of participants with clinically significant ECG abnormalities were reported in this outcome measure. ECG parameters included heart rate, PR interval, QRS interval and QTcF interval.
Percent Change From Baseline in Liver Fat at Week 48: Pairwise Comparisons With Analysis of Covariance (ANCOVA)	Baseline, Week 48	MRI-PDFF is an established method that enables quantification of fat content in the liver.

Trial Locations

Locations (286): Institute for Liver Health dba Arizona Liver Health
🇺🇸
Chandler, Arizona, United States
Comprehensive Interventional Care Centers (CICC)
🇺🇸
Sun City, Arizona, United States
The Institute for Liver Health
🇺🇸
Peoria, Arizona, United States
Institute for Liver Health DBA Arizona Liver Health
🇺🇸
Tucson, Arizona, United States
Hope Clinical Research
🇺🇸
Canoga Park, California, United States
Sharp Coronado Hospital
🇺🇸
Coronado, California, United States
Southern California Research Center
🇺🇸
Coronado, California, United States
Magnolia Surgery Center
🇺🇸
El Cajon, California, United States
Encino Hospital Medical Center
🇺🇸
Encino, California, United States
National Research Institute
🇺🇸
Huntington Park, California, United States
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Institute for Liver Health dba Arizona Liver Health
🇺🇸Chandler, Arizona, United States