Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis With Liver Fibrosis
Conditions
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).
Interventions
Sponsors
Pfizer
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Masking description
Double blind, double dummy, placebo controlled
Intervention model description
dose ranging, dose finding
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
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,
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
| 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. |
| 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. |
| 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. |
Countries
Bulgaria, Canada, China, Hong Kong, India, Japan, Poland, Puerto Rico, Slovakia, South Korea, Taiwan, United States
Participant flow
Recruitment details
A total of 256 participants with biopsy confirmed Non-alcoholic Steatohepatitis (NASH) with fibrosis state (F2-F3) were randomized, of which 255 were treated.
Pre-assignment details
F2: significant stage of fibrosis when scarring had occurred and extended outside liver area and F3: severe stage of fibrosis with spreading and forming bridges with other fibrotic liver areas.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Participants were randomized to receive 2 tablets of diacylglycerol acyltransferase 2 inhibitor (PF-06865571/DGAT2i) matching placebo and 1 tablet of acetyl-CoA carboxylase inhibitor (PF-05221304/ACCi) matching placebo twice a day (BID) for 48 weeks by oral administration. Participants were followed up to 52 weeks. | 34 |
| DGAT2i/PF-06865571 25 mg BID Participants were randomized to receive 1 tablet of DGAT2i 25 milligrams (mg) along with 1 tablet of DGAT2i and ACCi matching placebo BID for 48 weeks by oral administration. Participants were followed up to 52 weeks. | 35 |
| DGAT2i/PF-06865571 75 mg BID Participants were randomized to receive 1 tablet of DGAT2i 25 mg, 1 tablet of DGAT2i 50 mg and 1 tablet of ACCi matching placebo BID for 48 weeks by oral administration. Participants were followed up to 52 weeks. | 48 |
| DGAT2i/PF-06865571 150 mg BID Participants were randomized to receive 1 tablet of DGAT2i matching placebo, 1 tablet of DGAT2i 150 mg and 1 tablet of ACCi matching placebo BID for 48 weeks by oral administration. Participants were followed up to 52 weeks. | 42 |
| DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID Participants were randomized to receive 1 tablet of DGAT2i matching placebo, 1 tablet of DGAT2i 150 mg and 1 tablet of ACCi 5 mg BID for 48 weeks by oral administration. Participants were followed up to 52 weeks. | 35 |
| DGAT2i/PF-06865571 300 mg BID Participants were randomized to receive 2 tablets of DGAT2i 150 mg and 1 tablet of ACCi matching placebo BID for 48 weeks by oral administration. Participants were followed up to 52 weeks. | 31 |
| DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID Participants were randomized to receive 2 tablets of DGAT2i 150 mg and 1 tablet of ACCi 10 mg BID for 48 weeks by oral administration. Participants were followed up to 52 weeks. | 30 |
| Total | 255 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 2 | 2 | 2 | 2 | 0 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 | 0 | 2 | 1 |
| Overall Study | Non-compliance with study drug | 0 | 0 | 0 | 0 | 0 | 1 | 0 |
| Overall Study | Other | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 | 1 | 3 | 1 | 0 | 1 |
Baseline characteristics
| Characteristic | Placebo | DGAT2i/PF-06865571 25 mg BID | DGAT2i/PF-06865571 75 mg BID | DGAT2i/PF-06865571 150 mg BID | DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID | DGAT2i/PF-06865571 300 mg BID | DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 55.21 Years STANDARD_DEVIATION 12 | 56.54 Years STANDARD_DEVIATION 11.38 | 56.02 Years STANDARD_DEVIATION 12.67 | 55.95 Years STANDARD_DEVIATION 11.32 | 56.60 Years STANDARD_DEVIATION 10.23 | 59.65 Years STANDARD_DEVIATION 7.49 | 54.23 Years STANDARD_DEVIATION 11.32 | 56.28 Years STANDARD_DEVIATION 11.12 |
| Ethnicity (NIH/OMB) Ethnicity Hispanic or Latino | 8 Participants | 15 Participants | 13 Participants | 10 Participants | 6 Participants | 11 Participants | 8 Participants | 71 Participants |
| Ethnicity (NIH/OMB) Ethnicity Not Hispanic or Latino | 24 Participants | 20 Participants | 35 Participants | 29 Participants | 29 Participants | 18 Participants | 20 Participants | 175 Participants |
| Ethnicity (NIH/OMB) Ethnicity Unknown or Not Reported | 2 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 2 Participants | 9 Participants |
| Race (NIH/OMB) Race American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race Asian | 12 Participants | 10 Participants | 16 Participants | 14 Participants | 13 Participants | 11 Participants | 11 Participants | 87 Participants |
| Race (NIH/OMB) Race Black or African American | 0 Participants | 2 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) Race More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Race Unknown or Not Reported | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 2 Participants | 2 Participants | 1 Participants | 13 Participants |
| Race (NIH/OMB) Race White | 21 Participants | 20 Participants | 31 Participants | 24 Participants | 19 Participants | 17 Participants | 18 Participants | 150 Participants |
| Sex: Female, Male Female | 17 Participants | 19 Participants | 31 Participants | 28 Participants | 24 Participants | 20 Participants | 15 Participants | 154 Participants |
| Sex: Female, Male Male | 17 Participants | 16 Participants | 17 Participants | 14 Participants | 11 Participants | 11 Participants | 15 Participants | 101 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 34 | 0 / 35 | 0 / 48 | 0 / 42 | 0 / 35 | 0 / 31 | 0 / 30 |
| other Total, other adverse events | 21 / 34 | 21 / 35 | 28 / 48 | 22 / 42 | 19 / 35 | 19 / 31 | 15 / 30 |
| serious Total, serious adverse events | 1 / 34 | 1 / 35 | 5 / 48 | 1 / 42 | 5 / 35 | 4 / 31 | 2 / 30 |
Outcome results
Primary
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)
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.
Time frame: Week 48
Population: BKS: scaling for fibrosis (0=none,1=perisinusoidal/ periportal,2=perisinusoidal, portal/ periportal,3=bridging,4=cirrhosis; higher scores=more DA). Full analysis set (FAS):all randomized participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. This outcome measure was not planned to be analyzed in combination arms (DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID and DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | 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) | 0.38 Proportion of participants |
| DGAT2i/PF-06865571 25 mg BID | 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) | 0.45 Proportion of participants |
| DGAT2i/PF-06865571 75 mg BID | 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) | 0.48 Proportion of participants |
| DGAT2i/PF-06865571 150 mg BID | 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) | 0.50 Proportion of participants |
| DGAT2i/PF-06865571 300 mg BID | 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) | 0.51 Proportion of participants |
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the statistical analysis plan (SAP).90% CI: [-0.02, 0.2]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [-0.03, 0.24]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [-0.03, 0.26]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [-0.04, 0.28]
Primary
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
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.
Time frame: Week 48
Population: BKS: 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 F2/F3 as factors. Full analysis set included all randomized participants who took at least 1 dose of investigational product who had provided baseline data for the primary endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 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 | 13 Participants |
| DGAT2i/PF-06865571 25 mg BID | 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 | 16 Participants |
| DGAT2i/PF-06865571 75 mg BID | 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 | 25 Participants |
| DGAT2i/PF-06865571 150 mg BID | 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 | 21 Participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 23 Participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 14 Participants |
| DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID | 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 | 19 Participants |
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.04, 0.32]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.11, 0.27]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.07, 0.3]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.07, 0.43]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.12, 0.27]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.04, 0.42]
Comparison: Risk difference and 2-sided 50% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.50% CI: [0.08, 0.23]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.03, 0.31]
Comparison: Risk difference and 2-sided 50% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.50% CI: [0.09, 0.26]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.03, 0.35]
Secondary
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
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.
Time frame: Week 48
Population: Full analysis set included all randomized participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. This outcome measure was not planned to be analyzed in combination arms (DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID and DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | 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 | 0.33 Proportion of participants |
| DGAT2i/PF-06865571 25 mg BID | 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 | 0.28 Proportion of participants |
| DGAT2i/PF-06865571 75 mg BID | 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 | 0.25 Proportion of participants |
| DGAT2i/PF-06865571 150 mg BID | 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 | 0.24 Proportion of participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 0.22 Proportion of participants |
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [-0.16, 0.02]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [-0.2, 0.03]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [-0.23, 0.04]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [-0.26, 0.05]
Secondary
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
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.
Time frame: Week 48
Population: Full analysis set included all randomized participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. This outcome measure was not planned to be analyzed in combination arms (DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID and DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | 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 | 0.05 Proportion of participants |
| DGAT2i/PF-06865571 25 mg BID | 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 | 0.08 Proportion of participants |
| DGAT2i/PF-06865571 75 mg BID | 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 | 0.09 Proportion of participants |
| DGAT2i/PF-06865571 150 mg BID | 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 | 0.09 Proportion of participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 0.10 Proportion of participants |
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [-0.01, 0.08]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [-0.02, 0.09]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [-0.02, 0.11]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [-0.02, 0.12]
Secondary
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
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.
Time frame: Week 48
Population: Full analysis set included all randomized participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. This outcome measure was not planned to be analyzed in combination arms (DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID and DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | 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 | 0.24 Proportion of participants |
| DGAT2i/PF-06865571 25 mg BID | 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 | 0.42 Proportion of participants |
| DGAT2i/PF-06865571 75 mg BID | 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 | 0.47 Proportion of participants |
| DGAT2i/PF-06865571 150 mg BID | 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 | 0.49 Proportion of participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 0.51 Proportion of participants |
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [0.05, 0.31]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [0.09, 0.36]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [0.1, 0.38]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [0.11, 0.4]
Secondary
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
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.
Time frame: Week 48
Population: FAS included all randomized participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. This outcome measure was not planned to be analyzed in combination arms (DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID and DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | 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 | 0.11 Proportion of participants |
| DGAT2i/PF-06865571 25 mg BID | 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 | 0.32 Proportion of participants |
| DGAT2i/PF-06865571 75 mg BID | 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 | 0.37 Proportion of participants |
| DGAT2i/PF-06865571 150 mg BID | 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 | 0.40 Proportion of participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 0.41 Proportion of participants |
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [0.09, 0.32]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [0.15, 0.37]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [0.18, 0.39]
Comparison: The model was applied to the raw number of responders and non-responders utilizing a Bayesian methodology approach with non-informative priors as described in the SAP.90% CI: [0.19, 0.42]
Secondary
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
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.
Time frame: Week 48
Population: Full analysis set included all randomized participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 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 | 12 Participants |
| DGAT2i/PF-06865571 25 mg BID | 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 | 10 Participants |
| DGAT2i/PF-06865571 75 mg BID | 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 | 10 Participants |
| DGAT2i/PF-06865571 150 mg BID | 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 | 14 Participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 13 Participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 4 Participants |
| DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID | 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 | 12 Participants |
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.21, 0.13]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.25, 0.02]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.17, 0.17]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.15, 0.22]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.3, -0.05]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.13, 0.26]
Comparison: Risk difference and 2-sided 50% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.50% CI: [-0.03, 0.12]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.12, 0.23]
Comparison: Risk difference and 2-sided 50% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.50% CI: [0.17, 0.38]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.06, 0.53]
Secondary
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
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.
Time frame: Week 48
Population: Full analysis set included all randomized participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 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 | 1 Participants |
| DGAT2i/PF-06865571 25 mg BID | 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 | 4 Participants |
| DGAT2i/PF-06865571 75 mg BID | 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 | 3 Participants |
| DGAT2i/PF-06865571 150 mg BID | 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 | 5 Participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 7 Participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 2 Participants |
| DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID | 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 | 6 Participants |
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.01, 0.43]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.02, 0.29]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.01, 0.43]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.01, 0.57]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.02, 0.33]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.01, 0.58]
Comparison: Risk difference and 2-sided 50% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.50% CI: [0.02, 0.16]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.04, 0.3]
Comparison: Risk difference and 2-sided 50% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.50% CI: [0.06, 0.24]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.01, 0.44]
Secondary
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
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.
Time frame: Week 48
Population: Full analysis set included all randomized participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 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 | 8 Participants |
| DGAT2i/PF-06865571 25 mg BID | 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 | 13 Participants |
| DGAT2i/PF-06865571 75 mg BID | 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 | 28 Participants |
| DGAT2i/PF-06865571 150 mg BID | 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 | 21 Participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 25 Participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 12 Participants |
| DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID | 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 | 19 Participants |
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.04, 0.36]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.15, 0.53]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.06, 0.46]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.27, 0.63]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.03, 0.38]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.18, 0.58]
Comparison: Risk difference and 2-sided 50% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.50% CI: [0.15, 0.28]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.03, 0.35]
Comparison: Risk difference and 2-sided 50% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.50% CI: [0.16, 0.32]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.03, 0.42]
Secondary
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
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.
Time frame: Week 48
Population: Full analysis set included all randomized participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | 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 | 3 Participants |
| DGAT2i/PF-06865571 25 mg BID | 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 | 11 Participants |
| DGAT2i/PF-06865571 75 mg BID | 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 | 22 Participants |
| DGAT2i/PF-06865571 150 mg BID | 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 | 13 Participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 22 Participants |
| DGAT2i/PF-06865571 300 mg BID | 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 | 13 Participants |
| DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID | 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 | 17 Participants |
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.04, 0.51]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.13, 0.63]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.04, 0.49]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.26, 0.75]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.1, 0.61]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.2, 0.72]
Comparison: Risk difference and 2-sided 50% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.50% CI: [0.24, 0.39]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [0.12, 0.48]
Comparison: Risk difference and 2-sided 50% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.50% CI: [0.06, 0.23]
Comparison: Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo/corresponding BID rate and estimated odds ratio from the logistic regression model.90% CI: [-0.06, 0.33]
Secondary
Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters
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.
Time frame: From first dose of study drug (Day 1) upto Week 48 (maximum up to approximately 50 weeks)
Population: Safety population included all participants who took at least 1 dose of investigational product. Here, ''Number of Participants Analyzed'' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters | 0 Participants |
| DGAT2i/PF-06865571 25 mg BID | Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters | 0 Participants |
| DGAT2i/PF-06865571 75 mg BID | Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters | 0 Participants |
| DGAT2i/PF-06865571 150 mg BID | Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters | 0 Participants |
| DGAT2i/PF-06865571 300 mg BID | Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters | 0 Participants |
| DGAT2i/PF-06865571 300 mg BID | Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters | 0 Participants |
| DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID | Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters | 0 Participants |
Secondary
Number of Participants With Clinically Significant Abnormalities in Vital Signs
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.
Time frame: From first dose of study drug (Day 1) upto Week 48 (maximum up to approximately 50 weeks)
Population: Safety population included all participants who took at least 1 dose of investigational product. Here, ''Number of Participants Analyzed'' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| DGAT2i/PF-06865571 25 mg BID | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| DGAT2i/PF-06865571 75 mg BID | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| DGAT2i/PF-06865571 150 mg BID | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| DGAT2i/PF-06865571 300 mg BID | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| DGAT2i/PF-06865571 300 mg BID | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
| DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID | Number of Participants With Clinically Significant Abnormalities in Vital Signs | 0 Participants |
Secondary
Number of Participants With Laboratory Test Abnormalities
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).
Time frame: From first dose of study drug (Day 1) up to 4 weeks after last dose of study drug (maximum up to approximately 52 weeks)
Population: Safety population included all participants who took at least 1 dose of investigational product. Here, ''Number of Participants Analyzed'' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Laboratory Test Abnormalities | 31 Participants |
| DGAT2i/PF-06865571 25 mg BID | Number of Participants With Laboratory Test Abnormalities | 32 Participants |
| DGAT2i/PF-06865571 75 mg BID | Number of Participants With Laboratory Test Abnormalities | 46 Participants |
| DGAT2i/PF-06865571 150 mg BID | Number of Participants With Laboratory Test Abnormalities | 39 Participants |
| DGAT2i/PF-06865571 300 mg BID | Number of Participants With Laboratory Test Abnormalities | 34 Participants |
| DGAT2i/PF-06865571 300 mg BID | Number of Participants With Laboratory Test Abnormalities | 27 Participants |
| DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID | Number of Participants With Laboratory Test Abnormalities | 30 Participants |
Secondary
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
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.
Time frame: From first dose of study drug (Day 1) up to 4 weeks after last dose of study drug (maximum up to approximately 52 weeks)
Population: Safety population included all participants who took at least 1 dose of investigational product.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 26 Participants |
| DGAT2i/PF-06865571 25 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 25 Participants |
| DGAT2i/PF-06865571 75 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 38 Participants |
| DGAT2i/PF-06865571 150 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 30 Participants |
| DGAT2i/PF-06865571 300 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 25 Participants |
| DGAT2i/PF-06865571 300 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 26 Participants |
| DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID | Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | 23 Participants |
Secondary
Percent Change From Baseline in Liver Fat at Week 48: Bayesian Dose Response Model
Magnetic resonance imaging proton density fat fraction (MRI-PDFF) is an established method that enables quantification of fat content in the liver.
Time frame: Baseline, Week 48
Population: Full analysis set: all randomized participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. This outcome measure was not planned to be analyzed in combination arms (DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID and DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID). Here, ''Number of Participants Analyzed'' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Placebo | Percent Change From Baseline in Liver Fat at Week 48: Bayesian Dose Response Model | -10.79 Percent change |
| DGAT2i/PF-06865571 25 mg BID | Percent Change From Baseline in Liver Fat at Week 48: Bayesian Dose Response Model | -36.76 Percent change |
| DGAT2i/PF-06865571 75 mg BID | Percent Change From Baseline in Liver Fat at Week 48: Bayesian Dose Response Model | -46.20 Percent change |
| DGAT2i/PF-06865571 150 mg BID | Percent Change From Baseline in Liver Fat at Week 48: Bayesian Dose Response Model | -51.33 Percent change |
| DGAT2i/PF-06865571 300 mg BID | Percent Change From Baseline in Liver Fat at Week 48: Bayesian Dose Response Model | -55.53 Percent change |
90% CI: [-58.42, -2.57]
90% CI: [-69.41, -5.42]
90% CI: [-75.55, -7.32]
90% CI: [-81.72, -8.42]
Secondary
Percent Change From Baseline in Liver Fat at Week 48: Pairwise Comparisons With Analysis of Covariance (ANCOVA)
MRI-PDFF is an established method that enables quantification of fat content in the liver.
Time frame: Baseline, Week 48
Population: Full analysis set: all randomized participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. Here, ''Number of Participants Analyzed'' signifies participants evaluable for this outcome measure.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Percent Change From Baseline in Liver Fat at Week 48: Pairwise Comparisons With Analysis of Covariance (ANCOVA) | 1.41 Percent change | Standard Error 22.11 |
| DGAT2i/PF-06865571 25 mg BID | Percent Change From Baseline in Liver Fat at Week 48: Pairwise Comparisons With Analysis of Covariance (ANCOVA) | -41.00 Percent change | Standard Error 18.89 |
| DGAT2i/PF-06865571 75 mg BID | Percent Change From Baseline in Liver Fat at Week 48: Pairwise Comparisons With Analysis of Covariance (ANCOVA) | -42.53 Percent change | Standard Error 15.66 |
| DGAT2i/PF-06865571 150 mg BID | Percent Change From Baseline in Liver Fat at Week 48: Pairwise Comparisons With Analysis of Covariance (ANCOVA) | -58.77 Percent change | Standard Error 19.44 |
| DGAT2i/PF-06865571 300 mg BID | Percent Change From Baseline in Liver Fat at Week 48: Pairwise Comparisons With Analysis of Covariance (ANCOVA) | -67.76 Percent change | Standard Error 19.93 |
| DGAT2i/PF-06865571 300 mg BID | Percent Change From Baseline in Liver Fat at Week 48: Pairwise Comparisons With Analysis of Covariance (ANCOVA) | -49.76 Percent change | Standard Error 23.7 |
| DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID | Percent Change From Baseline in Liver Fat at Week 48: Pairwise Comparisons With Analysis of Covariance (ANCOVA) | -68.83 Percent change | Standard Error 23.72 |
Comparison: Log-transformed relative changes from baseline are modelled using an ANCOVA model with treatment and baseline fibrosis stage (F2/F3) as factors, and log-transformed baseline liver fat as a covariate.90% CI: [-79.72, -50.15]
Comparison: Log-transformed relative changes from baseline are modelled using an ANCOVA model with treatment and baseline fibrosis stage (F2/F3) as factors, and log-transformed baseline liver fat as a covariate.90% CI: [-62.57, -9.57]
Comparison: Log-transformed relative changes from baseline are modelled using an ANCOVA model with treatment and baseline fibrosis stage (F2/F3) as factors, and log-transformed baseline liver fat as a covariate.90% CI: [-62.37, -14.64]
Comparison: Log-transformed relative changes from baseline are modelled using an ANCOVA model with treatment and baseline fibrosis stage (F2/F3) as factors, and log-transformed baseline liver fat as a covariate.90% CI: [-73.95, -36.55]
Comparison: Log-transformed relative changes from baseline are modelled using an ANCOVA model with treatment and baseline fibrosis stage (F2/F3) as factors, and log-transformed baseline liver fat as a covariate.90% CI: [-69.53, -19.44]
Comparison: Log-transformed relative changes from baseline are modelled using an ANCOVA model with treatment and baseline fibrosis stage (F2/F3) as factors, and log-transformed baseline liver fat as a covariate.90% CI: [-81.08, -50.07]
Comparison: Log-transformed relative changes from baseline are modelled using an ANCOVA model with treatment and baseline fibrosis stage (F2/F3) as factors, and log-transformed baseline liver fat as a covariate.50% CI: [-34.02, -7.32]
Comparison: Log-transformed relative changes from baseline are modelled using an ANCOVA model with treatment and baseline fibrosis stage (F2/F3) as factors, and log-transformed baseline liver fat as a covariate.90% CI: [-48.51, 18.76]
Comparison: Log-transformed relative changes from baseline are modelled using an ANCOVA model with treatment and baseline fibrosis stage (F2/F3) as factors, and log-transformed baseline liver fat as a covariate.50% CI: [-49.4, -23.95]
Comparison: Log-transformed relative changes from baseline are modelled using an ANCOVA model with treatment and baseline fibrosis stage (F2/F3) as factors, and log-transformed baseline liver fat as a covariate.90% CI: [-62.41, 2.37]