Trial Outcomes & Findings for Study of Pharmacodynamics and Safety of DGAT2i and ACCi Coadministered in Participants With Sponsor-defined Presumed Non Alcoholic Steatohepatitis (NCT NCT04399538)

Last Updated: 2023-04-13

Results Overview

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.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

75 participants

Primary outcome timeframe

Baseline, Week 6

Results posted on

2023-04-13

Participant Flow

In Part 1, 76 participants were enrolled and 75 were randomized (including 1 participant who was randomized 2 times at the same site), and 74 unique participants received at least 1 dose of study intervention. A decision was made that Part 2 would not proceed based on Part 1 interim analysis, therefore enrollment for Part 2 was not conducted.

Participant milestones

Participant milestones
Measure	Placebo Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (placebo tablets matching the diacylglycerol acyltransferase 2 inhibitor \[DGAT2i\] PF-06865571) plus 1 small tablet (placebo tablet matching the acetyl-CoA carboxylase inhibitor \[ACCi\] PF-05221304). Two follow-up visits were scheduled after end of treatment.	PF-06865571 25 mg Twice Daily (BID) + PF-05221304 10 mg BID Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (1 DGAT2i-matching placebo tablet, 1 DGAT2i 25 mg tablet) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 100 mg BID + PF-05221304 10 mg BID Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 50 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment. Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg Once Daily (QD) + PF-05221304 20 mg QD Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. The morning dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 20 mg tablet). The evening dose contained 2 large tablets (2 DGAT2i-matching placebo tablets) plus 1 small tablet (ACCi-matching placebo tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg BID + PF-05221304 10 mg BID Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.
Double-Blind Treatment STARTED	15	15	13	18	14
Double-Blind Treatment COMPLETED	15	15	13	17	12
Double-Blind Treatment NOT COMPLETED	0	0	0	1	2
Follow-Up STARTED	15	15	13	17	13
Follow-Up COMPLETED	15	15	13	15	12
Follow-Up NOT COMPLETED	0	0	0	2	1

Reasons for withdrawal

Reasons for withdrawal
Measure	PF-06865571 300 mg Once Daily (QD) + PF-05221304 20 mg QD Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. The morning dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 20 mg tablet). The evening dose contained 2 large tablets (2 DGAT2i-matching placebo tablets) plus 1 small tablet (ACCi-matching placebo tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg BID + PF-05221304 10 mg BID Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.
Double-Blind Treatment Work schedule conflicts	1	1
Double-Blind Treatment Adverse Event	0	1
Follow-Up Adverse Event	0	1
Follow-Up Withdrawal by Subject	2	0

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Placebo n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (placebo tablets matching the diacylglycerol acyltransferase 2 inhibitor \[DGAT2i\] PF-06865571) plus 1 small tablet (placebo tablet matching the acetyl-CoA carboxylase inhibitor \[ACCi\] PF-05221304). Two follow-up visits were scheduled after end of treatment.	PF-06865571 25 mg BID + PF-05221304 10 mg BID n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (1 DGAT2i-matching placebo tablet, 1 DGAT2i 25 mg tablet) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 100 mg BID + PF-05221304 10 mg BID n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 50 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg QD + PF-05221304 20 mg QD n=18 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. The morning dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 20 mg tablet). The evening dose contained 2 large tablets (2 DGAT2i-matching placebo tablets) plus 1 small tablet (ACCi-matching placebo tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg BID + PF-05221304 10 mg BID n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	Total n=74 Participants Total of all reporting groups
Age, Continuous	57.00 Years n=5 Participants	54.00 Years n=7 Participants	56.00 Years n=5 Participants	50.00 Years n=4 Participants	56.00 Years n=21 Participants	54.50 Years n=10 Participants
Age, Customized 18-44 years	3 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	3 Participants n=4 Participants	4 Participants n=21 Participants	13 Participants n=10 Participants
Age, Customized 45-64 years	10 Participants n=5 Participants	11 Participants n=7 Participants	9 Participants n=5 Participants	12 Participants n=4 Participants	7 Participants n=21 Participants	49 Participants n=10 Participants
Age, Customized >=65 years	2 Participants n=5 Participants	2 Participants n=7 Participants	3 Participants n=5 Participants	3 Participants n=4 Participants	2 Participants n=21 Participants	12 Participants n=10 Participants
Sex: Female, Male Female	8 Participants n=5 Participants	8 Participants n=7 Participants	7 Participants n=5 Participants	7 Participants n=4 Participants	4 Participants n=21 Participants	34 Participants n=10 Participants
Sex: Female, Male Male	7 Participants n=5 Participants	7 Participants n=7 Participants	6 Participants n=5 Participants	11 Participants n=4 Participants	9 Participants n=21 Participants	40 Participants n=10 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	8 Participants n=5 Participants	9 Participants n=7 Participants	8 Participants n=5 Participants	9 Participants n=4 Participants	4 Participants n=21 Participants	38 Participants n=10 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	7 Participants n=5 Participants	6 Participants n=7 Participants	5 Participants n=5 Participants	9 Participants n=4 Participants	9 Participants n=21 Participants	36 Participants n=10 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants	4 Participants n=7 Participants	1 Participants n=5 Participants	4 Participants n=4 Participants	1 Participants n=21 Participants	13 Participants n=10 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants	2 Participants n=10 Participants
Race (NIH/OMB) White	12 Participants n=5 Participants	11 Participants n=7 Participants	11 Participants n=5 Participants	14 Participants n=4 Participants	11 Participants n=21 Participants	59 Participants n=10 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	0 Participants n=21 Participants	0 Participants n=10 Participants

PRIMARY outcome

Timeframe: Baseline, Week 6

Population: The analysis population included all participants randomized who received at least 1 dose of study intervention (Placebo/DGAT2i + ACCi), and had at least 1 observation in the model used for this OM.

Outcome measures

Outcome measures
Measure	Placebo n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (placebo tablets matching the diacylglycerol acyltransferase 2 inhibitor \[DGAT2i\] PF-06865571) plus 1 small tablet (placebo tablet matching the acetyl-CoA carboxylase inhibitor \[ACCi\] PF-05221304). Two follow-up visits were scheduled after end of treatment.	PF-06865571 25 mg BID + PF-05221304 10 mg BID n=14 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (1 DGAT2i-matching placebo tablet, 1 DGAT2i 25 mg tablet) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 100 mg BID + PF-05221304 10 mg BID n=12 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 50 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg QD + PF-05221304 20 mg QD n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. The morning dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 20 mg tablet). The evening dose contained 2 large tablets (2 DGAT2i-matching placebo tablets) plus 1 small tablet (ACCi-matching placebo tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg BID + PF-05221304 10 mg BID n=9 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.
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	-3.58 Percent change Interval -14.71 to 8.99	-54.07 Percent change Interval -59.54 to -47.85	-58.14 Percent change Interval -63.51 to -51.98	-60.28 Percent change Interval -65.27 to -54.57	-47.75 Percent change Interval -55.71 to -38.35

SECONDARY outcome

Timeframe: Baseline, 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).

Outcome measures

Outcome measures
Measure	Placebo n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (placebo tablets matching the diacylglycerol acyltransferase 2 inhibitor \[DGAT2i\] PF-06865571) plus 1 small tablet (placebo tablet matching the acetyl-CoA carboxylase inhibitor \[ACCi\] PF-05221304). Two follow-up visits were scheduled after end of treatment.	PF-06865571 25 mg BID + PF-05221304 10 mg BID n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (1 DGAT2i-matching placebo tablet, 1 DGAT2i 25 mg tablet) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 100 mg BID + PF-05221304 10 mg BID n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 50 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg QD + PF-05221304 20 mg QD n=17 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. The morning dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 20 mg tablet). The evening dose contained 2 large tablets (2 DGAT2i-matching placebo tablets) plus 1 small tablet (ACCi-matching placebo tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg BID + PF-05221304 10 mg BID n=10 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.
Percent CFB in Fasting Serum Triglycerides at Week 6	3.72 Percent change Interval -6.9 to 15.55	27.89 Percent change Interval 14.75 to 42.53	18.00 Percent change Interval 5.1 to 32.49	24.88 Percent change Interval 12.85 to 38.2	14.69 Percent change Interval 0.59 to 30.78

SECONDARY outcome

Timeframe: 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).

Population: The analysis population included all participants who were randomized to study intervention.

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.

Outcome measures

Outcome measures
Measure	Placebo n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (placebo tablets matching the diacylglycerol acyltransferase 2 inhibitor \[DGAT2i\] PF-06865571) plus 1 small tablet (placebo tablet matching the acetyl-CoA carboxylase inhibitor \[ACCi\] PF-05221304). Two follow-up visits were scheduled after end of treatment.	PF-06865571 25 mg BID + PF-05221304 10 mg BID n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (1 DGAT2i-matching placebo tablet, 1 DGAT2i 25 mg tablet) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 100 mg BID + PF-05221304 10 mg BID n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 50 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg QD + PF-05221304 20 mg QD n=18 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. The morning dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 20 mg tablet). The evening dose contained 2 large tablets (2 DGAT2i-matching placebo tablets) plus 1 small tablet (ACCi-matching placebo tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg BID + PF-05221304 10 mg BID n=14 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Treatment-related severe TEAE	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Treatment-related TEAE leading to discontinuation from study	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) All-causality TEAE	2 Participants	4 Participants	5 Participants	6 Participants	7 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) Treatment-related TEAE	0 Participants	0 Participants	3 Participants	2 Participants	3 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) SAE	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) All-causality severe TEAE	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) All-causality TEAE leading to discontinuation from study	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants

SECONDARY outcome

Timeframe: 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).

Population: The analysis population included all participants who were randomized to study intervention.

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.

Outcome measures

Outcome measures
Measure	Placebo n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (placebo tablets matching the diacylglycerol acyltransferase 2 inhibitor \[DGAT2i\] PF-06865571) plus 1 small tablet (placebo tablet matching the acetyl-CoA carboxylase inhibitor \[ACCi\] PF-05221304). Two follow-up visits were scheduled after end of treatment.	PF-06865571 25 mg BID + PF-05221304 10 mg BID n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (1 DGAT2i-matching placebo tablet, 1 DGAT2i 25 mg tablet) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 100 mg BID + PF-05221304 10 mg BID n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 50 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg QD + PF-05221304 20 mg QD n=18 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. The morning dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 20 mg tablet). The evening dose contained 2 large tablets (2 DGAT2i-matching placebo tablets) plus 1 small tablet (ACCi-matching placebo tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg BID + PF-05221304 10 mg BID n=14 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.
Number of Participants With TEAEs of Special Interest by Preferred Term (PT) Tier-1: Thrombocytopenia	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants
Number of Participants With TEAEs of Special Interest by Preferred Term (PT) Tier-1: Hypertriglyceridaemia	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: From baseline to end of follow-up or until study discontinuation/withdrawal, whichever was longer (maximum of approximately 19 weeks)

Population: The analysis population included all participants who were randomized and received at least 1 dose of study intervention. Number of participants analyzed = number of participants evaluable for this OM. Number analyzed = number of participants evaluable for each category.

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.

Outcome measures

Outcome measures
Measure	Placebo n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (placebo tablets matching the diacylglycerol acyltransferase 2 inhibitor \[DGAT2i\] PF-06865571) plus 1 small tablet (placebo tablet matching the acetyl-CoA carboxylase inhibitor \[ACCi\] PF-05221304). Two follow-up visits were scheduled after end of treatment.	PF-06865571 25 mg BID + PF-05221304 10 mg BID n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (1 DGAT2i-matching placebo tablet, 1 DGAT2i 25 mg tablet) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 100 mg BID + PF-05221304 10 mg BID n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 50 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg QD + PF-05221304 20 mg QD n=18 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. The morning dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 20 mg tablet). The evening dose contained 2 large tablets (2 DGAT2i-matching placebo tablets) plus 1 small tablet (ACCi-matching placebo tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg BID + PF-05221304 10 mg BID n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Urinalysis: Ketones >=1	0 Participants	0 Participants	2 Participants	2 Participants	2 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Urinalysis: Nitrite >=1	2 Participants	1 Participants	0 Participants	1 Participants	1 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Urinalysis: Urine leukocytes (/high power field [HPF]) >=20	2 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Hematology: Erythrocytes <0.8 x LLN	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Hematology: Erythrocytes Mean Corpuscular Volume <0.9 x LLN	1 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Hematology: Erythrocytes Mean Corpuscular Hemoglobin <0.9 x LLN	0 Participants	2 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Hematology: Lymphocytes >1.2 x ULN	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Hematology: Basophils >1.2 x ULN	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Hematology: Eosinophils >1.2 x ULN	0 Participants	1 Participants	0 Participants	1 Participants	1 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Clinical chemistry: Bicarbonate >1.1 X ULN	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Clinical chemistry: Creatine kinase >2.0 X ULN	0 Participants	0 Participants	1 Participants	0 Participants	1 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Urinalysis: Urine glucose >=1	2 Participants	1 Participants	1 Participants	3 Participants	2 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Urinalysis: Urine protein >=1	0 Participants	0 Participants	0 Participants	0 Participants	1 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Urinalysis: Urine hemoglobin	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Urinalysis: Urobilinogen >=1	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Urinalysis: Leukocyte Esterase >=1	5 Participants	3 Participants	3 Participants	4 Participants	3 Participants
Number of Participants With Laboratory Test Abnormalities Without Regard to Baseline Abnormality Urinalysis: Hyaline Casts (/low power field [LPF]) >1	2 Participants	0 Participants	0 Participants	0 Participants	0 Participants

SECONDARY outcome

Timeframe: From baseline to end of follow-up or until study discontinuation/withdrawal, whichever was longer (maximum of approximately 19 weeks)

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.

Outcome measures

Outcome measures
Measure	Placebo n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (placebo tablets matching the diacylglycerol acyltransferase 2 inhibitor \[DGAT2i\] PF-06865571) plus 1 small tablet (placebo tablet matching the acetyl-CoA carboxylase inhibitor \[ACCi\] PF-05221304). Two follow-up visits were scheduled after end of treatment.	PF-06865571 25 mg BID + PF-05221304 10 mg BID n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (1 DGAT2i-matching placebo tablet, 1 DGAT2i 25 mg tablet) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 100 mg BID + PF-05221304 10 mg BID n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 50 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg QD + PF-05221304 20 mg QD n=18 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. The morning dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 20 mg tablet). The evening dose contained 2 large tablets (2 DGAT2i-matching placebo tablets) plus 1 small tablet (ACCi-matching placebo tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg BID + PF-05221304 10 mg BID n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Aspartate aminotransferase >= 2xULN (flag level)	0 Participants	4 Participants	4 Participants	5 Participants	3 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Gamma glutamyl transferase >ULN (flag level)	6 Participants	7 Participants	9 Participants	10 Participants	4 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Alkaline phosphatase >3xULN (flag level)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Fasting plasma glucose <70 mg/dL (flag level)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Fasting plasma glucose >=140 mg/dL (flag level)	4 Participants	4 Participants	4 Participants	9 Participants	2 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Fasting serum triglycerides >=800 mg/dL (alert level)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Platelet count <100x10^3/mm^3 (flag level)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Platelet count <75x10^3/mm^3 (alert level)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Bilirubin >1.5xULN (flag level)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Bilirubin >3xULN (alert level)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Direct bilirubin >ULN (flag level)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Aspartate aminotransferase >3xULN (flag level)	0 Participants	1 Participants	0 Participants	1 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Aspartate aminotransferase >5xULN (flag level)	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Aspartate aminotransferase >8xULN (alert level)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Alanine aminotransferase >=2xULN (flag level)	4 Participants	6 Participants	7 Participants	6 Participants	4 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Alanine aminotransferase >3xULN (flag level)	0 Participants	3 Participants	1 Participants	3 Participants	2 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Alanine aminotransferase >5xULN (flag level)	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Alanine aminotransferase >8xULN (alert level)	0 Participants	1 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Alkaline phosphatase >=2xULN (flag level)	0 Participants	0 Participants	1 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Alkaline phosphatase >5xULN (flag level)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Fasting plasma glucose <=49 mg/dL (alert level)	0 Participants	0 Participants	0 Participants	0 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Fasting plasma glucose >270 mg/dL (alert level)	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Fasting serum triglycerides >=400 mg/dL (flag level)	1 Participants	0 Participants	3 Participants	4 Participants	1 Participants
Number of Participants With Abnormalities in Laboratory Parameters of Special Interest Meeting Pre-Defined Criteria Fasting serum triglycerides >=600 mg/dL (alert level)	1 Participants	0 Participants	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: 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

Population: The analysis population included all participants randomized who received at least 1 dose of study intervention and were evaluable for vital signs.

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.

Outcome measures

Outcome measures
Measure	Placebo n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (placebo tablets matching the diacylglycerol acyltransferase 2 inhibitor \[DGAT2i\] PF-06865571) plus 1 small tablet (placebo tablet matching the acetyl-CoA carboxylase inhibitor \[ACCi\] PF-05221304). Two follow-up visits were scheduled after end of treatment.	PF-06865571 25 mg BID + PF-05221304 10 mg BID n=15 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (1 DGAT2i-matching placebo tablet, 1 DGAT2i 25 mg tablet) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 100 mg BID + PF-05221304 10 mg BID n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 50 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg QD + PF-05221304 20 mg QD n=18 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. The morning dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 20 mg tablet). The evening dose contained 2 large tablets (2 DGAT2i-matching placebo tablets) plus 1 small tablet (ACCi-matching placebo tablet). Two follow-up visits were scheduled after end of treatment.	PF-06865571 300 mg BID + PF-05221304 10 mg BID n=13 Participants Participants had 2 oral doses per day (1 dose with the morning meal and 1 dose with the evening meal) for up to 6 weeks. Each dose contained 2 large tablets (2 DGAT2i 150 mg tablets) plus 1 small tablet (ACCi 10 mg tablet). Two follow-up visits were scheduled after end of treatment.
Number of Participants With Post-Baseline Vital Signs Data Meeting Pre-Defined Criteria	0 Participants	0 Participants	0 Participants	1 Participants	0 Participants

SECONDARY outcome

Timeframe: 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

Population: The analysis population included all participants randomized who received at least 1 dose of study intervention and were evaluable for ECG.

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.