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

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.

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.

Magnetic resonance imaging proton density fat fraction (MRI-PDFF) is an established method that enables quantification of fat content in the liver.

MRI-PDFF is an established method that enables quantification of fat content in the liver.

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.

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.

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.

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.

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.

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.

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.

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.

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.

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 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 ECG abnormalities were reported in this outcome measure. ECG parameters included heart rate, PR interval, QRS interval and QTcF interval.