Study of Pharmacodynamics and Safety of DGAT2i and ACCi Coadministered in Participants With Sponsor-defined Presumed Non Alcoholic Steatohepatitis

Study Overview
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Brief Summary
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The study will evaluate the effect of coadministration of a range of doses of DGAT2i with 1 dose of ACCi, on hepatic steatosis and the ability of DGAT2i to mitigate ACCi-induced elevations in serum triglycerides. The study has a 2-part design with sequential conduct of Part 1 and Part 2 with each part conducted in distinct/separate cohorts of participants. The overall study design, objectives/endpoints, eligibility criteria for both parts is envisioned to be identical, however, data from Part 1 will be used to determine whether to conduct Part 2.

Official Title
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A PHASE 2A, 2-PART, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY PLACEBO-CONTROLLED, PARALLEL-GROUP (SPONSOR OPEN) STUDY TO ASSESS PHARMACODYNAMICS AND SAFETY OF PF-06865571 (DGAT2I) COADMINISTERED WITH PF-05221304 (ACCI) IN ADULT PARTICIPANTS WITH PRESUMED NONALCOHOLIC STEATOHEPATITIS (NASH)

Conditions
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Nonalcoholic Steatohepatitis, Nonalcoholic Fatty Liver Disease

Intervention / Treatment
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* Drug: PF-06865571
* Drug: PF-05221304
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: BMI ≥25 and ≤ 40 kg/m2 concomitant medical conditions associated with NAFLD 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 liver function tests Recent cardiovascular event(s), Malignancies

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Dose-ranging of combination doses
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Participants will receive medication for 6 weeks | Drug: Placebo<br>* Tablet<br>|
| Experimental: DGAT2i (25 mg BID) + ACCi (10 mg BID)<br>Participants will receive medication for 6 weeks | Drug: PF-06865571<br>* Tablet<br>* Other names: DGAT2i;Drug: PF-05221304<br>* Tablet<br>* Other names: ACCi;|
| Experimental: DGAT2i (100 mg BID) + ACCi (10 mg BID)<br>Participants will receive medication for 6 weeks | Drug: PF-06865571<br>* Tablet<br>* Other names: DGAT2i;Drug: PF-05221304<br>* Tablet<br>* Other names: ACCi;|
| Experimental: DGAT2i (300 mg QD) + ACCi (20 mg QD)<br>Participants will receive medication for 6 weeks | Drug: PF-06865571<br>* Tablet<br>* Other names: DGAT2i;Drug: PF-05221304<br>* Tablet<br>* Other names: ACCi;|
| Experimental: DGAT2i (300 mg BID) + ACCi (10 mg BID)<br>Participants will receive medication for 6 weeks | Drug: PF-06865571<br>* Tablet<br>* Other names: DGAT2i;Drug: PF-05221304<br>* Tablet<br>* Other names: ACCi;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline (CFB) in Percent (%) Liver Fat as Assessed Via Magnetic Resonance Imaging Using Proton Density Fat Fraction Acquisition (MRI-PDFF) at Week 6 | MRI-PDFF technique is an established method that enables quantification of fat content in the liver. It measures the fraction of mobile protons in the liver attributable to fat content and provides whole liver coverage so that fat content can be assessed across 8 Couinaud liver segments. Whole liver PDFF = the sum of PDFFs for (Segment I + Segment II + Segment III + Segment IVa + Segment IVb + Segment V + Segment VI + Segment VII + Segment VIII) divided by (number of segments assessed and no missing/mapping at Baseline, and on Week 6). If some segments did not have results reported at Baseline and/or Week 6, liver PDFF was to be calculated using data in segments that had data available at both Baseline visit and Week 6 visit. For this outcome measure (OM), baseline is defined as the assessment undertaken between Visit 3/Week -2 and Visit 4/Day 1. | Baseline, Week 6 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent CFB in Fasting Serum Triglycerides at Week 6 | Blood samples were collected before morning dose for the measurement of fasting serum triglycerides. Natural log transformed relative changes from baseline in fasting serum triglycerides were analyzed using mixed model repeated measures (MMRM) analysis with treatment, week and treatment by-week interaction as fixed effects, participant as random effect and log transformed baseline as a covariate using unstructured covariance structure. Values were back-transformed from the log scale. Relative change was converted to percent change as follows: Percent change = 100*(RC-1). For this OM, baseline is defined as the result closest prior to dosing on Day 1 (either predose on Day 1/Visit 4 or Week -2/Visit 3). | Baseline, Week 6 | 
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=all AEs included in the AE Case Report Form (CRF) page during the study. A serious adverse event (SAE) was any untoward medical occurrence at any dose that resulted in death; was life threatening; required inpatient hospitalization or prolongation of existing hospitalization; resulted in persistent or significant disability/incapacity; or resulted in congenital anomaly/birth defect. Severe TEAEs were defined as AEs that prevent normal everyday activities. Treatment-related TEAEs were determined by the investigator. | Baseline up to at least 28 days after the last administration of the study intervention or until study completion or withdrawal, whichever was longer (maximum of approximately 24 weeks). | 
| Number of Participants With TEAEs of Special Interest by Preferred Term (PT) | An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship with study treatment. TEAEs=all AEs included in the AE CRF page during the study. A 3-tier approach was used to summarize and classify TEAEs into 1 of 3 tiers by the investigator based on their incidence rate and clinical importance to the trial. Tier-1 events = pre-specified events of clinical importance that are maintained in a program level list. Tier-2 events = events that are not tier-1 but are common. A Medical Dictionary for Regulatory Activities Terminology (MedDRA) PT is defined as a tier-2 event if there are at least 4 participants with at least one occurrence in any treatment group, to distinguish Tier-2 events from Tier-3 events. Tier-3 events = events that do not meet criteria for either tier-1 or tier-2 event. TEAE(s) of special interest reported in at least 1 participant are presented in this OM. | Baseline up to at least 28 days after the last administration of the study intervention or until study completion or withdrawal, whichever was longer (maximum of approximately 24 weeks). | 
| Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality | Participants with laboratory test abnormalities (hematology, chemistry and urinalysis) meeting pre-specified criteria are reported without regard to baseline abnormality. LLN is lower limit of normal. ULN is upper limit of normal. Baseline was defined as the result closest prior to Day 1 dosing. | From baseline to end of follow-up or until study discontinuation/withdrawal, whichever was longer (maximum of approximately 19 weeks) | 
| Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria | Laboratory parameters of special interest included fasting serum triglycerides, platelet count, alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, total bilirubin, direct bilirubin, and fasting plasma glucose. Pre-specified criteria for laboratory parameters of special interest included flag level threshold (reflecting either the threshold for study entry or clinical significance) and alert level threshold (requiring rapid notification to site and study team when values exceeding the threshold were noted during the study). All flag level changes and alert level changes were cumulative from baseline (defined as result closest prior to dosing at Day 1). LLN is lower limit of normal. ULN is upper limit of normal. | From baseline to end of follow-up or until study discontinuation/withdrawal, whichever was longer (maximum of approximately 19 weeks) | 
| Number of Participants With Post-Baseline Vital Signs Data Meeting Pre-Defined Criteria | Pre-defined categorical criteria for vital signs data of special clinical concern included: seated systolic blood pressure (BP) absolute value <90 mmHg or change from baseline >=30 mmHg, seated diastolic BP absolute value <50 mmHg or change from baseline >=20 mmHg, seated pulse rate absolute value <40 beats per minute (bpm) or >120 bpm. Baseline was defined as the result closest prior to Day 1 dosing. | Baseline, Week 6, the first follow-up visit (Week 8), and the date of discontinuation/withdrawal from study (maximum of approximately 12 weeks after Day 1) if applicable | 
| Number of Participants With Post-Baseline Electrocardiogram (ECG) Data Meeting Pre-Defined Criteria | Pre-defined categorical criteria for ECG data of special clinical concern included: (1) QTc interval absolute value >450 and <=480 msec (mild prolongation), >480 and <=500 msec (moderate prolongation), >500 msec (severe prolongation); (2) QTc interval increase from baseline >=30 and <=60 msec (moderate prolongation), or >60 msec (severe prolongation); (3) uncorrected QT interval >500 msec. ECG abnormalities meeting prespecified criteria and reported in at least 1 participant are presented in this OM. Baseline was defined as the result closest prior to Day 1 dosing. | Baseline, Week 6, the first follow-up visit (Week 8), and the date of discontinuation/withdrawal from study (maximum of approximately 12 weeks after Day 1) if applicable |