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Clinical Trial Results:
A Phase 2, Randomized, Double-Blind, Double-Dummy, Placebo-Controlled, Dose-Ranging, Dose-Finding, Parallel Group Study to Assess Efficacy and Safety of PF-06865571 (DGAT2I) Alone and When Coadministered With PF-05221304 (ACCI) in Adult Participants With Biopsy-Confirmed Nonalcoholic Steatohepatitis and Fibrosis Stage 2 or 3

Summary
EudraCT number	2019-004775-39
Trial protocol	PL SK BG
Global end of trial date	23 Feb 2024

Results information
Results version number	v1(current)
This version publication date	02 Mar 2025
First version publication date	02 Mar 2025
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

Top of page

Sponsor protocol code

C2541013

ISRCTN number

US NCT number

NCT04321031

WHO universal trial number (UTN)

Sponsor organisation name

Pfizer Inc.

Sponsor organisation address

66 Hudson Boulevard East, New York, United States, NY 10017

Public contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Scientific contact

Pfizer ClinicalTrials.gov Call Center, Pfizer Inc., 001 8007181021, ClinicalTrials.gov_Inquiries@pfizer.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

10 May 2024

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

23 Feb 2024

Was the trial ended prematurely?

Main objective of the trial

To evaluate the effect of a range of diacylglycerol acyltransferase 2 inhibitor (PF-06865571/DGAT2i) doses administered alone, and coadministration of DGAT2i + acetyl-CoA carboxylase inhibitor (PF-05221304/ACCi), compared to placebo, and the coadministration of DGAT2i + ACCi relative to DGAT2i alone, in participants with biopsy confirmed nonalcoholic steatohepatitis (NASH) and fibrosis, on resolution of NASH without worsening of fibrosis or improvement in fibrosis by greater than or equal to (>=) 1 stage without worsening of NASH, or both.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trials participants were followed.

Background therapy

Evidence for comparator

Actual start date of recruitment

15 Jun 2020

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 1

Country: Number of subjects enrolled

Canada: 10

Country: Number of subjects enrolled

China: 4

Country: Number of subjects enrolled

Hong Kong: 14

Country: Number of subjects enrolled

India: 1

Country: Number of subjects enrolled

Japan: 45

Country: Number of subjects enrolled

Korea, Republic of: 8

Country: Number of subjects enrolled

Poland: 3

Country: Number of subjects enrolled

Puerto Rico: 15

Country: Number of subjects enrolled

Slovakia: 4

Country: Number of subjects enrolled

Taiwan: 5

Country: Number of subjects enrolled

United States: 145

Worldwide total number of subjects

255

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

188

From 65 to 84 years

85 years and over

Subject disposition

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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.

Screening 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.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Carer, Assessor

Blinding implementation details

Double blind, double dummy, placebo controlled.

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants were randomised to receive 2 tablets of DGAT2i matching placebo and 1 tablet of ACCi matching placebo twice a day (BID) for 48 weeks by oral administration. Participants were followed up to 52 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 2 tablets of DGAT2i matching placebo and 1 tablet of ACCi matching placebo orally BID for 48 weeks.

DGAT2i/PF-06865571 25 mg BID

Arm description

Participants were randomised 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.

Arm type

Experimental

Investigational medicinal product name

DGAT2i

Investigational medicinal product code

PF-06865571

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 1 tablet of DGAT2i 25 mg along with 1 tablet of DGAT2i and ACCi matching placebos orally BID for 48 weeks.

DGAT2i/PF-06865571 75 mg BID

Arm description

Participants were randomised 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.

Arm type

Experimental

Investigational medicinal product name

DGAT2i

Investigational medicinal product code

PF-06865571

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 1 tablet of DGAT2i 25 mg, 1 tablet of DGAT2i 50 mg and 1 tablet of ACCi matching placebo orally BID for 48 weeks.

DGAT2i/PF-06865571 150 mg BID

Arm description

Participants were randomised 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.

Arm type

Experimental

Investigational medicinal product name

DGAT2i

Investigational medicinal product code

PF-06865571

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 1 tablet of DGAT2i matching placebo, 1 tablet of DGAT2i 150 mg and 1 tablet of ACCi matching placebo orally BID for 48 weeks.

DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Arm description

Participants were randomised 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.

Arm type

Experimental

Investigational medicinal product name

DGAT2i + ACCi

Investigational medicinal product code

PF-06865571 + PF-05221304

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 1 tablet of DGAT2i matching placebo, 1 tablet of DGAT2i 150 mg and 1 tablet of ACCi 5 mg orally BID for 48 weeks.

DGAT2i/PF-06865571 300 mg BID

Arm description

Participants were randomised 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.

Arm type

Experimental

Investigational medicinal product name

DGAT2i

Investigational medicinal product code

PF-06865571

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 2 tablets of DGAT2i 150 mg and 1 tablet of ACCi matching placebo orally BID for 48 weeks.

DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Arm description

Participants were randomised 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.

Arm type

Experimental

Investigational medicinal product name

DGAT2i + ACCi

Investigational medicinal product code

PF-06865571 + PF-05221304

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants received 2 tablets of DGAT2i 150 mg and 1 tablet of ACCi 10 mg orally BID for 48 weeks.

Number of subjects in period 1	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
Started	34	35	48	42	35	31	30
Completed	32	31	45	35	32	26	28
Not completed	2	4	3	7	3	5	2
Consent withdrawn by subject	2	2	1	3	1	-	1
Adverse event, non-fatal	-	2	2	2	2	2	-
Non-compliance with study drug	-	-	-	-	-	1	-
Unspecified	-	-	-	1	-	-	-
Lost to follow-up	-	-	-	1	-	2	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

DGAT2i/PF-06865571 25 mg BID

Reporting group description

Reporting group title

DGAT2i/PF-06865571 75 mg BID

Reporting group description

Reporting group title

DGAT2i/PF-06865571 150 mg BID

Reporting group description

Reporting group title

DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Reporting group description

Reporting group title

DGAT2i/PF-06865571 300 mg BID

Reporting group description

Participants were randomised 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.

Reporting group title

DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Reporting group description

Participants were randomised 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.

Reporting group values	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
Number of subjects	34	35	48	42	35	31	30	255
Age categorical
Units: Subjects
In Utero	0	0	0	0	0	0	0	0
Preterm newborn infants (gestional age < 37 wks)	0	0	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0	0	0
Infants and toddlers (28 days - 23 months)	0	0	0	0	0	0	0	0
Children (2 - 11 years)	0	0	0	0	0	0	0	0
12 - 17 years	0	0	0	0	0	0	0	0
Adults (18 - 64 years)	25	27	33	29	26	23	25	188
From 65 - 84 years	9	8	15	13	9	8	5	67
85 years and over	0	0	0	0	0	0	0	0
Age continuous
Units: years
arithmetic mean (standard deviation)	55.21 ( 12.00 )	56.54 ( 11.38 )	56.02 ( 12.67 )	55.95 ( 11.32 )	56.60 ( 10.23 )	59.65 ( 7.49 )	54.23 ( 11.32 )	-
Sex: Female, Male
Units: Subjects
Male	17	16	17	14	11	11	15	101
Female	17	19	31	28	24	20	15	154
Race
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0	0	0
Asian	12	10	16	14	13	11	11	87
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0	0
Black or African American	0	2	0	1	1	1	0	5
White	21	20	31	24	19	17	18	150
More than one race	0	0	0	0	0	0	0	0
Unknown or Not Reported	1	3	1	3	2	2	1	13
Ethnicity
Units: Subjects
Hispanic or Latino	8	15	13	10	6	11	8	71
Not Hispanic or Latino	24	20	35	29	29	18	20	175
Unknown or Not Reported	2	0	0	3	0	2	2	9

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

DGAT2i/PF-06865571 25 mg BID

Reporting group description

Reporting group title

DGAT2i/PF-06865571 75 mg BID

Reporting group description

Reporting group title

DGAT2i/PF-06865571 150 mg BID

Reporting group description

Reporting group title

DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Reporting group description

Reporting group title

DGAT2i/PF-06865571 300 mg BID

Reporting group description

Participants were randomised 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.

Reporting group title

DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Reporting group description

Participants were randomised 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.

Primary: Mean Proportion of Participants Achieving Resolution of NASH Without Worsening or Improvement of Fibrosis by >=1 Stage Without Worsening of NASH or Both Based on Assessment by Sponsor-Identified Central Pathologist at Week 48: Bayesian Dose Response Model

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End point title

Mean Proportion of Participants Achieving Resolution of NASH Without Worsening or Improvement of Fibrosis by >=1 Stage Without Worsening of NASH or Both Based on Assessment by Sponsor-Identified Central Pathologist at Week 48: Bayesian Dose Response Model ^[1]

End point description

NASH resolution: disappearance of ballooning (NAS ballooning score=0; 0=no ballooning, 1= few balloon cells, 2= many cells, prominent ballooning; HS= more DA), residual/no LI (NAS LI 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 or 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 1 stage in BKS CTB. Improvement in fibrosis by>=1 stage: decrease of 1 stage in BKS CTB. No worsening of NASH: no change/increase in NAS for ballooning, inflammation, steatosis CTB. CI indicated credible interval below. BKS: scaling for fibrosis (0= none, 1= perisinusoidal/ periportal, 2= perisinusoidal, portal/ periportal, 3=bridging, 4= cirrhosis; higher scores= more DA). FAS was analysed. Endpoint was not planned in combination arms.

End point type

Primary

End point timeframe

Week 48

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the arms specified

End point values	Placebo	DGAT2i/PF-06865571 25 mg BID	DGAT2i/PF-06865571 75 mg BID	DGAT2i/PF-06865571 150 mg BID	DGAT2i/PF-06865571 300 mg BID
Number of subjects analysed	34	35	48	42	31
Units: Proportion of participants
arithmetic mean (confidence interval 90%)	0.38 (0.26 to 0.50)	0.45 (0.38 to 0.53)	0.48 (0.42 to 0.55)	0.50 (0.43 to 0.57)	0.51 (0.43 to 0.59)

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the statistical analysis plan (SAP).

Comparison groups

DGAT2i/PF-06865571 25 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.08

Confidence interval

level

90%

sides

2-sided

lower limit

-0.02

upper limit

0.2

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.1

Confidence interval

level

90%

sides

2-sided

lower limit

-0.03

upper limit

0.24

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.12

Confidence interval

level

90%

sides

2-sided

lower limit

-0.03

upper limit

0.26

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.13

Confidence interval

level

90%

sides

2-sided

lower limit

-0.04

upper limit

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

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End point title

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

End point description

Resolution of NASH: disappearance of ballooning (NAS ballooning score = 0), residual or no lobular inflammation (NAS lobular inflammation score of 0 or 1) and NAS steatosis score of 0, 1, 2 or 3. No worsening of fibrosis: no change or a decrease of at least 1 stage in Brunt-Kleiner scale compared to baseline. Improvement of fibrosis by >= 1 stage: a decrease of at least 1 stage in Brunt-Kleiner scale compared to baseline. No worsening of NASH: no change or no increase in NAS for ballooning, inflammation, steatosis compared to baseline. Brunt-Kleiner scale indicated scaling for fibrosis. Full analysis set included all randomised participants who took at least 1 dose of investigational product who had provided baseline data for the primary endpoint. Participants were analysed according to the treatment group they were randomised to.

End point type

Primary

End point timeframe

Week 48

End point values	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
Number of subjects analysed	34	35	48	42	35	31	30
Units: Participants	13	16	25	21	23	14	19

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

Logistic Regression model is used with treatment and baseline fibrosis stage (F2/F3) as factors. Risk difference and 2-sided 90% confidence interval for risk difference were calculated by using the observed placebo rate and estimated odds ratio from the logistic regression model.

Comparison groups

Placebo v DGAT2i/PF-06865571 25 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.08

Confidence interval

level

90%

sides

2-sided

lower limit

-0.11

upper limit

0.27

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.14

Confidence interval

level

90%

sides

2-sided

lower limit

-0.04

upper limit

0.32

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.12

Confidence interval

level

90%

sides

2-sided

lower limit

-0.07

upper limit

0.3

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.07

Confidence interval

level

90%

sides

2-sided

lower limit

-0.12

upper limit

0.27

Secondary: Percent Change From Baseline in Liver fat at Week 48: Bayesian Dose Response Model

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End point title

Percent Change From Baseline in Liver fat at Week 48: Bayesian Dose Response Model ^[2]

End point description

Magnetic resonance imaging proton density fat fraction (MRI-PDFF) is an established method that enables quantification of fat content in the liver. Bayesian dose response model was utilised to characterise the dose response across all BID treatment groups, to estimate the posterior mean relative change from baseline (and 90% credible interval) for each BID dose studied, and to estimate the placebo adjusted posterior mean relative change from baseline for each dose (and 90% credible interval). Full analysis set: all randomised participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. Participants were analysed according to treatment group they were randomised to. This endpoint was not planned to be analysed in combination arms. Here, ''Number of Subjects Analysed'' signifies participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 48

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the arms specified

End point values	Placebo	DGAT2i/PF-06865571 25 mg BID	DGAT2i/PF-06865571 75 mg BID	DGAT2i/PF-06865571 150 mg BID	DGAT2i/PF-06865571 300 mg BID
Number of subjects analysed	15	14	21	18	11
Units: Percent change
arithmetic mean (confidence interval 90%)	-10.79 (-38.30 to 18.99)	-36.76 (-52.57 to -20.15)	-46.20 (-59.64 to -32.82)	-51.33 (-66.78 to -36.59)	-55.53 (-77.23 to -37.64)

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

The model utilised a Bayesian methodology approach with non-informative priors as described in the statistical analysis plan (SAP).

Comparison groups

Placebo v DGAT2i/PF-06865571 25 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Means

Point estimate

-25.98

Confidence interval

level

90%

sides

2-sided

lower limit

-58.42

upper limit

-2.57

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

The model utilised a Bayesian methodology approach with non-informative priors as described in the statistical analysis plan (SAP).

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Means

Point estimate

-35.41

Confidence interval

level

90%

sides

2-sided

lower limit

-69.41

upper limit

-5.42

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

The model utilised a Bayesian methodology approach with non-informative priors as described in the statistical analysis plan (SAP).

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Means

Point estimate

-40.54

Confidence interval

level

90%

sides

2-sided

lower limit

-75.55

upper limit

-7.32

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

The model utilised a Bayesian methodology approach with non-informative priors as described in the statistical analysis plan (SAP).

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Difference in Means

Point estimate

-44.74

Confidence interval

level

90%

sides

2-sided

lower limit

-81.72

upper limit

-8.42

Secondary: Percent Change From Baseline in Liver fat at Week 48: Pairwise Comparisons with Analysis of Covariance (ANCOVA)

Top of page

End point title

Percent Change From Baseline in Liver fat at Week 48: Pairwise Comparisons with Analysis of Covariance (ANCOVA)

End point description

MRI-PDFF is an established method that enables quantification of fat content in the liver. Full analysis set included all randomised participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. Participants were analysed according to treatment group they were randomised to. This endpoint was not planned to be analysed in combination arms. Here, ''Number of Subjects Analysed'' signifies participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

Baseline, Week 48

End point values	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
Number of subjects analysed	9	12	18	12	11	8	8
Units: Percent change
least squares mean (standard error)	1.41 ( 22.11 )	-41.00 ( 18.89 )	-42.53 ( 15.66 )	-58.77 ( 19.44 )	-67.76 ( 19.93 )	-49.76 ( 23.70 )	-68.83 ( 23.72 )

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

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.

Comparison groups

Placebo v DGAT2i/PF-06865571 25 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean

Point estimate

-41.82

Confidence interval

level

90%

sides

2-sided

lower limit

-62.57

upper limit

-9.57

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

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.

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean

Point estimate

-43.33

Confidence interval

level

90%

sides

2-sided

lower limit

-62.37

upper limit

-14.64

Placebo vs DGAT2i 150 mg BID + ACCi 5 mg BID

Statistical analysis description

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.

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean

Point estimate

-68.21

Confidence interval

level

90%

sides

2-sided

lower limit

-79.72

upper limit

-50.15

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

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.

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean

Point estimate

-59.35

Confidence interval

level

90%

sides

2-sided

lower limit

-73.95

upper limit

-36.55

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

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.

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean

Point estimate

-50.46

Confidence interval

level

90%

sides

2-sided

lower limit

-69.53

upper limit

-19.44

Placebo vs DGAT2i 300 mg BID + ACCi 10 mg BID

Statistical analysis description

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.

Comparison groups

DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean

Point estimate

-69.27

Confidence interval

level

90%

sides

2-sided

lower limit

-81.08

upper limit

-50.07

DGAT2i 300mg BID vs DGAT2i 300mg BID+ACCi 10mg BID

Statistical analysis description

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.

Comparison groups

DGAT2i/PF-06865571 300 mg BID v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean

Point estimate

-37.97

Confidence interval

level

90%

sides

2-sided

lower limit

-62.41

upper limit

2.37

DGAT2i 300mg BID vs DGAT2i 300mg BID+ACCi 10mg BID

Statistical analysis description

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.

Comparison groups

DGAT2i/PF-06865571 300 mg BID v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean

Point estimate

-37.97

Confidence interval

level

50%

sides

2-sided

lower limit

-49.4

upper limit

-23.95

DGAT2i 150mg BID vs DGAT2i 150mg BID+ACCi 5mg BID

Statistical analysis description

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.

Comparison groups

DGAT2i/PF-06865571 150 mg BID v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean

Point estimate

-21.8

Confidence interval

level

50%

sides

2-sided

lower limit

-34.02

upper limit

-7.32

DGAT2i 150mg BID vs DGAT2i 150mg BID+ACCi 5mg BID

Statistical analysis description

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.

Comparison groups

DGAT2i/PF-06865571 150 mg BID v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean

Point estimate

-21.8

Confidence interval

level

90%

sides

2-sided

lower limit

-48.51

upper limit

18.76

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

Top of page

End point title

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 ^[3]

End point description

Resolution of NASH: disappearance of ballooning (NAS ballooning score= 0), residual or no lobular inflammation (NAS lobular inflammation score of 0 or 1), NAS steatosis score of 0, 1, 2, 3. No worsening of fibrosis: no change/decrease of at least 1 stage in BKS compared to baseline. BKS: scaling for fibrosis. Bayesian dose response model was utilised to characterise dose response across all BID treatment groups, estimate posterior mean relative change from baseline (and 90% CI) for BID dose studied, estimate placebo adjusted posterior mean relative change from baseline for each dose (and 90% CI). c Full analysis set: all randomised participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. Participants were analysed according to treatment group they were randomised to. Endpoint was not planned to be analysed in combination arms.

End point type

Secondary

End point timeframe

Week 48

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the arms specified

End point values	Placebo	DGAT2i/PF-06865571 25 mg BID	DGAT2i/PF-06865571 75 mg BID	DGAT2i/PF-06865571 150 mg BID	DGAT2i/PF-06865571 300 mg BID
Number of subjects analysed	34	35	48	42	31
Units: Proportion of participants
arithmetic mean (confidence interval 90%)	0.11 (0.04 to 0.20)	0.32 (0.23 to 0.40)	0.37 (0.31 to 0.44)	0.40 (0.33 to 0.47)	0.41 (0.34 to 0.50)

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 25 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.21

Confidence interval

level

90%

sides

2-sided

lower limit

0.09

upper limit

0.32

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.31

Confidence interval

level

90%

sides

2-sided

lower limit

0.19

upper limit

0.42

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.29

Confidence interval

level

90%

sides

2-sided

lower limit

0.18

upper limit

0.39

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.27

Confidence interval

level

90%

sides

2-sided

lower limit

0.15

upper limit

0.37

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

Top of page

End point title

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

End point description

End point type

Secondary

End point timeframe

Week 48

End point values	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
Number of subjects analysed	34	35	48	42	35	31	30
Units: Participants	3	11	22	13	22	13	17

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

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.

Comparison groups

Placebo v DGAT2i/PF-06865571 25 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.23

Confidence interval

level

90%

sides

2-sided

lower limit

0.04

upper limit

0.51

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.37

Confidence interval

level

90%

sides

2-sided

lower limit

0.13

upper limit

0.63

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.22

Confidence interval

level

90%

sides

2-sided

lower limit

0.04

upper limit

0.49

Placebo vs DGAT2i 150 mg BID + ACCi 5 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.54

Confidence interval

level

90%

sides

2-sided

lower limit

0.26

upper limit

0.75

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.34

Confidence interval

level

90%

sides

2-sided

lower limit

0.1

upper limit

0.61

DGAT2i 150mg BID vs DGAT2i 150mg BID+ACCi 5mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 150 mg BID v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.32

Confidence interval

level

90%

sides

2-sided

lower limit

0.12

upper limit

0.48

Placebo vs DGAT2i 300 mg BID + ACCi 10 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.48

Confidence interval

level

90%

sides

2-sided

lower limit

0.2

upper limit

0.72

DGAT2i 150mg BID vs DGAT2i 150mg BID+ACCi 5mg BID

Statistical analysis description

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.

Comparison groups

DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.32

Confidence interval

level

50%

sides

2-sided

lower limit

0.24

upper limit

0.39

DGAT2i 300mg BID vs DGAT2i 300mg BID+ACCi 10mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 300 mg BID v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.14

Confidence interval

level

50%

sides

2-sided

lower limit

0.06

upper limit

0.23

DGAT2i 300mg BID vs DGAT2i 300mg BID+ACCi 10mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 300 mg BID v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.14

Confidence interval

level

90%

sides

2-sided

lower limit

-0.06

upper limit

0.33

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

Top of page

End point title

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 ^[4]

End point description

Improvement in fibrosis by >=1 stage: decrease of at least 1 stage in Brunt-Kleiner scale compared to baseline. No worsening of NASH: no change or no increase in NAS for ballooning, inflammation, or steatosis compared to baseline. Brunt-Kleiner scale included scaling for fibrosis. Bayesian dose response model was utilised to characterise the dose response across all BID treatment groups, to estimate the posterior mean relative change from baseline (and 90% credible interval) for each BID dose studied, and to estimate the placebo adjusted posterior mean relative change from baseline for each dose (and 90% credible interval). Full analysis set included all randomised participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. Participants were analysed according to treatment group they were randomised to. This endpoint was not planned to be analysed in combination arms.

End point type

Secondary

End point timeframe

Week 48

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the arms specified

End point values	Placebo	DGAT2i/PF-06865571 25 mg BID	DGAT2i/PF-06865571 75 mg BID	DGAT2i/PF-06865571 150 mg BID	DGAT2i/PF-06865571 300 mg BID
Number of subjects analysed	34	35	48	42	31
Units: Proportion of participants
arithmetic mean (confidence interval 90%)	0.33 (0.22 to 0.45)	0.28 (0.21 to 0.35)	0.25 (0.20 to 0.31)	0.24 (0.18 to 0.30)	0.22 (0.14 to 0.30)

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 25 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

-0.05

Confidence interval

level

90%

sides

2-sided

lower limit

-0.16

upper limit

0.02

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

-0.1

Confidence interval

level

90%

sides

2-sided

lower limit

-0.26

upper limit

0.05

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

-0.09

Confidence interval

level

90%

sides

2-sided

lower limit

-0.23

upper limit

0.04

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

-0.07

Confidence interval

level

90%

sides

2-sided

lower limit

-0.2

upper limit

0.03

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

Top of page

End point title

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

End point description

End point type

Secondary

End point timeframe

Week 48

End point values	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
Number of subjects analysed	34	35	48	42	35	31	30
Units: Participants	12	10	10	14	13	4	12

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 25 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

-0.07

Confidence interval

level

90%

sides

2-sided

lower limit

-0.21

upper limit

0.13

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

-0.14

Confidence interval

level

90%

sides

2-sided

lower limit

-0.25

upper limit

0.02

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

-0.02

Confidence interval

level

90%

sides

2-sided

lower limit

-0.17

upper limit

0.17

Placebo vs DGAT2i 150 mg BID + ACCi 5 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.02

Confidence interval

level

90%

sides

2-sided

lower limit

-0.15

upper limit

0.22

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

-0.22

Confidence interval

level

90%

sides

2-sided

lower limit

-0.3

upper limit

-0.05

DGAT2i 150mg BID vs DGAT2i 150mg BID+ACCi 5mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.04

Confidence interval

level

50%

sides

2-sided

lower limit

-0.03

upper limit

0.12

Placebo vs DGAT2i 300 mg BID + ACCi 10 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.05

Confidence interval

level

90%

sides

2-sided

lower limit

-0.13

upper limit

0.26

DGAT2i 300mg BID vs DGAT2i 300mg BID+ACCi 10mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 300 mg BID v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.27

Confidence interval

level

50%

sides

2-sided

lower limit

0.17

upper limit

0.38

DGAT2i 150mg BID vs DGAT2i 150mg BID+ACCi 5mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 150 mg BID v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.04

Confidence interval

level

90%

sides

2-sided

lower limit

-0.12

upper limit

0.23

DGAT2i 300mg BID vs DGAT2i 300mg BID+ACCi 10mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 300 mg BID v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.27

Confidence interval

level

90%

sides

2-sided

lower limit

0.06

upper limit

0.53

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

Top of page

End point title

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 ^[5]

End point description

Improvement in fibrosis by >=2 stage: decrease of at least 2 stages in the Brunt-Kleiner scale compared to baseline, without progression of fibrosis. No worsening of NASH: no change or no increase in NAS for ballooning, inflammation, or steatosis compared to baseline. Brunt-Kleiner scale included scaling for fibrosis. Bayesian dose response model was utilised to characterise the dose response across all BID treatment groups, to estimate the posterior mean proportion of responders (and 90% credible interval) for each BID dose studied. Full analysis set included all randomised participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. Participants were analysed according to treatment group they were randomised to. This endpoint was not planned to be analysed in combination arms.

End point type

Secondary

End point timeframe

Week 48

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the arms specified

End point values	Placebo	DGAT2i/PF-06865571 25 mg BID	DGAT2i/PF-06865571 75 mg BID	DGAT2i/PF-06865571 150 mg BID	DGAT2i/PF-06865571 300 mg BID
Number of subjects analysed	34	35	48	42	31
Units: Proportion of participants
arithmetic mean (confidence interval 90%)	0.05 (0.01 to 0.10)	0.08 (0.04 to 0.11)	0.09 (0.05 to 0.12)	0.09 (0.06 to 0.14)	0.10 (0.06 to 0.16)

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 25 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.03

Confidence interval

level

90%

sides

2-sided

lower limit

-0.01

upper limit

0.08

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.05

Confidence interval

level

90%

sides

2-sided

lower limit

-0.02

upper limit

0.12

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.05

Confidence interval

level

90%

sides

2-sided

lower limit

-0.02

upper limit

0.11

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.04

Confidence interval

level

90%

sides

2-sided

lower limit

-0.02

upper limit

0.09

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

Top of page

End point title

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

End point description

End point type

Secondary

End point timeframe

Week 48

End point values	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
Number of subjects analysed	34	35	48	42	35	31	30
Units: Participants	1	4	3	5	7	2	6

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 25 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.09

Confidence interval

level

90%

sides

2-sided

lower limit

-0.01

upper limit

0.43

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.03

Confidence interval

level

90%

sides

2-sided

lower limit

-0.02

upper limit

0.29

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.09

Confidence interval

level

90%

sides

2-sided

lower limit

-0.01

upper limit

0.43

Placebo vs DGAT2i 150 mg BID + ACCi 5 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.17

Confidence interval

level

90%

sides

2-sided

lower limit

0.01

upper limit

0.57

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.04

Confidence interval

level

90%

sides

2-sided

lower limit

-0.02

upper limit

0.33

DGAT2i 150mg BID vs DGAT2i 150mg BID+ACCi 5mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 150 mg BID v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.08

Confidence interval

level

90%

sides

2-sided

lower limit

-0.04

upper limit

0.3

Placebo vs DGAT2i 300 mg BID + ACCi 10 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.17

Confidence interval

level

90%

sides

2-sided

lower limit

0.01

upper limit

0.58

DGAT2i 150mg BID vs DGAT2i 150mg BID+ACCi 5mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 150 mg BID v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.08

Confidence interval

level

50%

sides

2-sided

lower limit

0.02

upper limit

0.16

DGAT2i 300mg BID vs DGAT2i 300mg BID+ACCi 10mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 300 mg BID v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.13

Confidence interval

level

50%

sides

2-sided

lower limit

0.06

upper limit

0.24

DGAT2i 300mg BID vs DGAT2i 300mg BID+ACCi 10mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 300 mg BID v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.13

Confidence interval

level

90%

sides

2-sided

lower limit

-0.01

upper limit

0.44

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

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End point title

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 ^[6]

End point description

Improvement of >=2 points in Total NAS: decrease of at least 2 points in Total NAS compared to baseline, without progression of fibrosis. No progression of fibrosis: no change/decrease of at least 1 stage in BKS CTB. Total NAS ranged from 0 to 8, was calculated as sum of scores of steatosis (0 to 3), lobular inflammation (0 to 3), ballooning (0 to 2). BKS included scaling for fibrosis. If any of sub-scale scores were non evaluable/missing, total score was derived as missing. BDRM was utilised to characterise dose response across all BID treatment groups, estimate posterior mean relative change from baseline (90% CI) for each BID dose studied, estimate placebo adjusted posterior mean relative change from baseline for each dose (90% CI). CI=credible interval and note that CI labelled as confidence intervals below. Full analysis set was analysed. Participants were analysed according to treatment group they were randomised to. Endpoint was not planned to be analysed in combination arms.

End point type

Secondary

End point timeframe

Week 48

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The end point is reporting statistics for the arms specified

End point values	Placebo	DGAT2i/PF-06865571 25 mg BID	DGAT2i/PF-06865571 75 mg BID	DGAT2i/PF-06865571 150 mg BID	DGAT2i/PF-06865571 300 mg BID
Number of subjects analysed	34	35	48	42	31
Units: Proportion of participants
arithmetic mean (confidence interval 90%)	0.24 (0.13 to 0.37)	0.42 (0.33 to 0.50)	0.47 (0.40 to 0.54)	0.49 (0.42 to 0.57)	0.51 (0.43 to 0.59)

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 25 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.18

Confidence interval

level

90%

sides

2-sided

lower limit

0.05

upper limit

0.31

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.25

Confidence interval

level

90%

sides

2-sided

lower limit

0.1

upper limit

0.38

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.27

Confidence interval

level

90%

sides

2-sided

lower limit

0.11

upper limit

0.4

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

The model was applied to the raw number of responders and non-responders utilising a Bayesian methodology approach with non-informative priors as described in the SAP.

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.23

Confidence interval

level

90%

sides

2-sided

lower limit

0.09

upper limit

0.36

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

Top of page

End point title

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

End point description

Improvement of >=2 points in Total NAS was defined as a decrease of at least 2 points in Total NAS compared to baseline, without progression of fibrosis. No progression of fibrosis: no change or a decrease of at least 1 stage in the Brunt-Kleiner scale compared to baseline. Total NAS ranged from 0 to 8 and was calculated as the sum of scores of steatosis (0 to 3), lobular inflammation (0 to 3) and ballooning (0 to 2). Brunt-Kleiner scale included scaling for fibrosis. If any of the sub-scale scores were non evaluable/missing, then the total score was derived as missing. Full analysis set included all randomised participants who took at least 1 dose of investigational product who had provided baseline data for primary endpoint. Participants were analysed according to treatment group they were randomised to.

End point type

Secondary

End point timeframe

Week 48

End point values	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
Number of subjects analysed	34	35	48	42	35	31	30
Units: Participants	8	13	28	21	25	12	19

Placebo vs DGAT2i/PF-06865571 75 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 75 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.35

Confidence interval

level

90%

sides

2-sided

lower limit

0.15

upper limit

0.53

Placebo vs DGAT2i 150 mg BID + ACCi 5 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.48

Confidence interval

level

90%

sides

2-sided

lower limit

0.27

upper limit

0.63

Placebo vs DGAT2i/PF-06865571 150 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 150 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.26

Confidence interval

level

90%

sides

2-sided

lower limit

0.06

upper limit

0.46

Placebo vs DGAT2i/PF-06865571 25 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 25 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.14

Confidence interval

level

90%

sides

2-sided

lower limit

-0.04

upper limit

0.36

DGAT2i 300mg BID vs DGAT2i 300mg BID+ACCi 10mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 300 mg BID v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.24

Confidence interval

level

50%

sides

2-sided

lower limit

0.16

upper limit

0.32

DGAT2i 150mg BID vs DGAT2i 150mg BID+ACCi 5mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 150 mg BID v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.22

Confidence interval

level

90%

sides

2-sided

lower limit

0.03

upper limit

0.35

DGAT2i 150mg BID vs DGAT2i 150mg BID+ACCi 5mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 150 mg BID v DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.22

Confidence interval

level

50%

sides

2-sided

lower limit

0.15

upper limit

0.28

Placebo vs DGAT2i/PF-06865571 300 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.16

Confidence interval

level

90%

sides

2-sided

lower limit

-0.03

upper limit

0.38

Placebo vs DGAT2i 300 mg BID + ACCi 10 mg BID

Statistical analysis description

Comparison groups

Placebo v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.4

Confidence interval

level

90%

sides

2-sided

lower limit

0.18

upper limit

0.58

DGAT2i 300mg BID vs DGAT2i 300mg BID+ACCi 10mg BID

Statistical analysis description

Comparison groups

DGAT2i/PF-06865571 300 mg BID v DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

0.24

Confidence interval

level

90%

sides

2-sided

lower limit

0.03

upper limit

0.42

Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

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End point title

Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

End point description

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 hospitalisation or prolongation of existing hospitalisation, 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. Safety population included all participants who took at least 1 dose of investigational product. Participants were analysed according to the treatment they actually received.

End point type

Secondary

End point timeframe

From first dose of study drug (Day 1) up to Week 48 (maximum up to approximately 52 weeks)

End point values	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
Number of subjects analysed	34	35	48	42	35	31	30
Units: Participants	26	25	38	30	25	26	23

No statistical analyses for this end point

Secondary: Number of Participants With Laboratory Test Abnormalities

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End point title

Number of Participants With Laboratory Test Abnormalities

End point description

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). Safety population was analysed. ''Number of Subjects Analysed''=participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From first dose of study drug (Day 1) up to Week 48 (maximum up to approximately 52 weeks)

End point values	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
Number of subjects analysed	34	34	48	42	35	31	30
Units: Participants	31	32	46	39	34	27	30

No statistical analyses for this end point

Secondary: Number of Participants With Clinically Significant Abnormalities in Vital Signs

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End point title

Number of Participants With Clinically Significant Abnormalities in Vital Signs

End point description

Number of participants with clinically significant laboratory abnormalities were reported in this endpoint. Vital signs included blood pressure, and heart rate. Clinical significance in vital signs abnormalities was judged by investigator. Safety population included all participants who took at least 1 dose of investigational product. Participants were analysed according to the treatment they actually received.

End point type

Secondary

End point timeframe

From first dose of study drug (Day 1) up to Week 48 (maximum up to approximately 50 weeks)

End point values	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
Number of subjects analysed	34	35	48	42	35	31	30
Units: Participants	0	0	0	0	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters

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End point title

Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters

End point description

Number of participants with clinically significant ECG abnormalities were reported in this outcome measure. ECG parameters included heart rate, PR, QRS and QTcF interval. Safety population included all participants who took at least 1 dose of investigational product. Participants were analysed according to the treatment they actually received. Here, ''Number of Subjects Analysed'' signifies participants evaluable for this endpoint.

End point type

Secondary

End point timeframe

From first dose of study drug (Day 1) up to Week 48 (maximum up to approximately 50 weeks)

End point values	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
Number of subjects analysed	34	32	47	39	35	28	28
Units: Participants	0	0	0	0	0	0	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose of study drug (Day 1) up to 4 weeks after last dose of study drug (maximum up to approximately 52 weeks)

Adverse event reporting additional description

Same event may appear as both non-SAE and SAE but what is presented are distinct events. Event may be categorized as serious in 1 participant and non-serious in other, or participant may have experienced both serious and non-serious event. Safety population included all participants who took at least 1 dose of investigational product.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

27.0

Reporting group title

Placebo

Reporting group description

Participants were randomized to receive 2 tablets of DGAT2i matching placebo and 1 tablet of ACCi matching placebo BID for 48 weeks by oral administration. Participants were followed up to 52 weeks.

Reporting group title

DGAT2i/PF-06865571 150 mg BID

Reporting group description

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.

Reporting group title

DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID

Reporting group description

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.

Reporting group title

DGAT2i/PF-06865571 25 mg BID

Reporting group description

Participants were randomized to receive 1 tablet of DGAT2i 25 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.

Reporting group title

DGAT2i/PF-06865571 75 mg BID

Reporting group description

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.

Reporting group title

DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID

Reporting group description

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.

Reporting group title

DGAT2i/PF-06865571 300 mg BID

Reporting group description

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.

Serious adverse events	Placebo	DGAT2i/PF-06865571 150 mg BID	DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID	DGAT2i/PF-06865571 25 mg BID	DGAT2i/PF-06865571 75 mg BID	DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID	DGAT2i/PF-06865571 300 mg BID
Total subjects affected by serious adverse events
subjects affected / exposed	1 / 34 (2.94%)	1 / 42 (2.38%)	5 / 35 (14.29%)	1 / 35 (2.86%)	5 / 48 (10.42%)	2 / 30 (6.67%)	4 / 31 (12.90%)
number of deaths (all causes)	0	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 48 (2.08%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Mucoepidermoid carcinoma
subjects affected / exposed	0 / 34 (0.00%)	1 / 42 (2.38%)	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Venous thrombosis
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 48 (2.08%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
Cardiac disorders
Coronary artery stenosis
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 48 (0.00%)	1 / 30 (3.33%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 48 (0.00%)	1 / 30 (3.33%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Pyrexia
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 48 (2.08%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Obstructive pancreatitis
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 48 (2.08%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 48 (2.08%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis acute
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 48 (2.08%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic haemorrhage
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subcapsular hepatic haematoma
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 48 (2.08%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	1 / 35 (2.86%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Appendicitis
subjects affected / exposed	1 / 34 (2.94%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	1 / 35 (2.86%)	0 / 48 (0.00%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Placebo	DGAT2i/PF-06865571 150 mg BID	DGAT2i/PF-06865571 150 mg BID + ACCi/PF-05221304 5 mg BID	DGAT2i/PF-06865571 25 mg BID	DGAT2i/PF-06865571 75 mg BID	DGAT2i/PF-06865571 300 mg BID + ACCi/PF-05221304 10 mg BID	DGAT2i/PF-06865571 300 mg BID
Total subjects affected by non serious adverse events
subjects affected / exposed	21 / 34 (61.76%)	22 / 42 (52.38%)	19 / 35 (54.29%)	21 / 35 (60.00%)	28 / 48 (58.33%)	15 / 30 (50.00%)	19 / 31 (61.29%)
Investigations
SARS-CoV-2 test positive
subjects affected / exposed	0 / 34 (0.00%)	2 / 42 (4.76%)	2 / 35 (5.71%)	1 / 35 (2.86%)	1 / 48 (2.08%)	0 / 30 (0.00%)	3 / 31 (9.68%)
occurrences all number	0	2	2	1	1	0	3
Alanine aminotransferase increased
subjects affected / exposed	2 / 34 (5.88%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences all number	2	0	0	0	0	0	0
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 34 (0.00%)	1 / 42 (2.38%)	2 / 35 (5.71%)	1 / 35 (2.86%)	0 / 48 (0.00%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	1	2	1	0	0	0
Procedural pain
subjects affected / exposed	0 / 34 (0.00%)	1 / 42 (2.38%)	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 48 (0.00%)	4 / 30 (13.33%)	0 / 31 (0.00%)
occurrences all number	0	1	0	0	0	4	0
Nervous system disorders
Dizziness
subjects affected / exposed	0 / 34 (0.00%)	1 / 42 (2.38%)	1 / 35 (2.86%)	0 / 35 (0.00%)	2 / 48 (4.17%)	0 / 30 (0.00%)	2 / 31 (6.45%)
occurrences all number	0	1	1	0	2	0	2
Headache
subjects affected / exposed	4 / 34 (11.76%)	1 / 42 (2.38%)	4 / 35 (11.43%)	2 / 35 (5.71%)	5 / 48 (10.42%)	1 / 30 (3.33%)	0 / 31 (0.00%)
occurrences all number	4	1	4	2	6	1	0
Hypoaesthesia
subjects affected / exposed	2 / 34 (5.88%)	0 / 42 (0.00%)	0 / 35 (0.00%)	1 / 35 (2.86%)	0 / 48 (0.00%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences all number	2	0	0	1	0	0	0
General disorders and administration site conditions
Fatigue
subjects affected / exposed	0 / 34 (0.00%)	1 / 42 (2.38%)	0 / 35 (0.00%)	0 / 35 (0.00%)	4 / 48 (8.33%)	1 / 30 (3.33%)	3 / 31 (9.68%)
occurrences all number	0	1	0	0	4	1	3
Puncture site pain
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	0 / 35 (0.00%)	2 / 35 (5.71%)	1 / 48 (2.08%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences all number	0	0	0	2	1	0	1
Pyrexia
subjects affected / exposed	2 / 34 (5.88%)	1 / 42 (2.38%)	1 / 35 (2.86%)	1 / 35 (2.86%)	3 / 48 (6.25%)	1 / 30 (3.33%)	1 / 31 (3.23%)
occurrences all number	4	1	1	2	4	2	3
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	3 / 34 (8.82%)	3 / 42 (7.14%)	2 / 35 (5.71%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences all number	4	3	2	0	0	0	1
Abdominal pain
subjects affected / exposed	1 / 34 (2.94%)	2 / 42 (4.76%)	1 / 35 (2.86%)	4 / 35 (11.43%)	3 / 48 (6.25%)	0 / 30 (0.00%)	2 / 31 (6.45%)
occurrences all number	1	2	1	4	3	0	2
Vomiting
subjects affected / exposed	0 / 34 (0.00%)	2 / 42 (4.76%)	0 / 35 (0.00%)	1 / 35 (2.86%)	4 / 48 (8.33%)	2 / 30 (6.67%)	0 / 31 (0.00%)
occurrences all number	0	2	0	2	5	2	0
Diarrhoea
subjects affected / exposed	2 / 34 (5.88%)	1 / 42 (2.38%)	2 / 35 (5.71%)	1 / 35 (2.86%)	5 / 48 (10.42%)	2 / 30 (6.67%)	0 / 31 (0.00%)
occurrences all number	2	1	2	2	7	2	0
Constipation
subjects affected / exposed	0 / 34 (0.00%)	3 / 42 (7.14%)	2 / 35 (5.71%)	2 / 35 (5.71%)	1 / 48 (2.08%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences all number	0	3	2	2	1	0	1
Reproductive system and breast disorders
Postmenopausal haemorrhage
subjects affected / exposed	1 / 34 (2.94%)	0 / 42 (0.00%)	0 / 35 (0.00%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	2 / 31 (6.45%)
occurrences all number	1	0	0	0	0	0	2
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 34 (5.88%)	1 / 42 (2.38%)	1 / 35 (2.86%)	1 / 35 (2.86%)	3 / 48 (6.25%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences all number	2	1	2	1	3	0	1
Nasal congestion
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	2 / 35 (5.71%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences all number	0	0	2	0	0	0	1
Oropharyngeal pain
subjects affected / exposed	0 / 34 (0.00%)	2 / 42 (4.76%)	1 / 35 (2.86%)	1 / 35 (2.86%)	0 / 48 (0.00%)	0 / 30 (0.00%)	2 / 31 (6.45%)
occurrences all number	0	2	1	1	0	0	2
Skin and subcutaneous tissue disorders
Asteatosis
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	2 / 35 (5.71%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences all number	0	0	2	0	0	0	0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 34 (0.00%)	2 / 42 (4.76%)	1 / 35 (2.86%)	0 / 35 (0.00%)	1 / 48 (2.08%)	0 / 30 (0.00%)	3 / 31 (9.68%)
occurrences all number	0	2	1	0	1	0	3
Arthralgia
subjects affected / exposed	2 / 34 (5.88%)	2 / 42 (4.76%)	3 / 35 (8.57%)	0 / 35 (0.00%)	2 / 48 (4.17%)	2 / 30 (6.67%)	3 / 31 (9.68%)
occurrences all number	2	3	3	0	2	3	3
Osteoarthritis
subjects affected / exposed	1 / 34 (2.94%)	0 / 42 (0.00%)	0 / 35 (0.00%)	2 / 35 (5.71%)	0 / 48 (0.00%)	1 / 30 (3.33%)	1 / 31 (3.23%)
occurrences all number	1	0	0	2	0	1	1
Pain in extremity
subjects affected / exposed	1 / 34 (2.94%)	3 / 42 (7.14%)	3 / 35 (8.57%)	0 / 35 (0.00%)	2 / 48 (4.17%)	0 / 30 (0.00%)	0 / 31 (0.00%)
occurrences all number	1	4	5	0	2	0	0
Muscle spasms
subjects affected / exposed	0 / 34 (0.00%)	1 / 42 (2.38%)	0 / 35 (0.00%)	0 / 35 (0.00%)	1 / 48 (2.08%)	2 / 30 (6.67%)	1 / 31 (3.23%)
occurrences all number	0	2	0	0	1	2	1
Infections and infestations
Gastroenteritis
subjects affected / exposed	1 / 34 (2.94%)	1 / 42 (2.38%)	2 / 35 (5.71%)	0 / 35 (0.00%)	0 / 48 (0.00%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences all number	1	1	2	0	0	0	1
COVID-19
subjects affected / exposed	2 / 34 (5.88%)	3 / 42 (7.14%)	1 / 35 (2.86%)	2 / 35 (5.71%)	4 / 48 (8.33%)	2 / 30 (6.67%)	3 / 31 (9.68%)
occurrences all number	2	3	1	2	4	2	3
Nasopharyngitis
subjects affected / exposed	4 / 34 (11.76%)	2 / 42 (4.76%)	2 / 35 (5.71%)	1 / 35 (2.86%)	4 / 48 (8.33%)	0 / 30 (0.00%)	3 / 31 (9.68%)
occurrences all number	5	3	2	11	5	0	3
Upper respiratory tract infection
subjects affected / exposed	1 / 34 (2.94%)	0 / 42 (0.00%)	4 / 35 (11.43%)	1 / 35 (2.86%)	2 / 48 (4.17%)	2 / 30 (6.67%)	0 / 31 (0.00%)
occurrences all number	1	0	5	1	2	2	0
Tooth abscess
subjects affected / exposed	0 / 34 (0.00%)	0 / 42 (0.00%)	2 / 35 (5.71%)	1 / 35 (2.86%)	0 / 48 (0.00%)	1 / 30 (3.33%)	0 / 31 (0.00%)
occurrences all number	0	0	2	1	0	1	0
Sinusitis
subjects affected / exposed	0 / 34 (0.00%)	4 / 42 (9.52%)	3 / 35 (8.57%)	2 / 35 (5.71%)	1 / 48 (2.08%)	0 / 30 (0.00%)	1 / 31 (3.23%)
occurrences all number	0	5	4	3	1	0	1
Urinary tract infection
subjects affected / exposed	1 / 34 (2.94%)	3 / 42 (7.14%)	2 / 35 (5.71%)	1 / 35 (2.86%)	0 / 48 (0.00%)	2 / 30 (6.67%)	1 / 31 (3.23%)
occurrences all number	1	3	2	1	0	2	2
Metabolism and nutrition disorders
Diabetes mellitus inadequate control
subjects affected / exposed	4 / 34 (11.76%)	3 / 42 (7.14%)	2 / 35 (5.71%)	6 / 35 (17.14%)	5 / 48 (10.42%)	2 / 30 (6.67%)	2 / 31 (6.45%)
occurrences all number	4	4	2	6	5	2	2

More information

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Were there any global substantial amendments to the protocol? Yes

30 Aug 2021

Evaluation of 2 arms with administration of DGAT2i alone (150 mg once a day [QD] and 300 mg QD) was no longer being pursued. Those previously randomised to these 2 arms were switched in a blinded manner to receive the corresponding BID regimen that maintained the same total daily dose. Number randomised to trigger 1st safety review by E-DMC retained but proportion updated.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Mean Proportion of Participants Achieving Resolution of NASH Without Worsening or Improvement of Fibrosis by >=1 Stage Without Worsening of NASH or Both Based on Assessment by Sponsor-Identified Central Pathologist at Week 48: Bayesian Dose Response Model

Primary: Mean Proportion of Participants Achieving Resolution of NASH Without Worsening or Improvement of Fibrosis by >=1 Stage Without Worsening of NASH or Both Based on Assessment by Sponsor-Identified Central Pathologist at Week 48: Bayesian Dose Response Model

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

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

Secondary: Percent Change From Baseline in Liver fat at Week 48: Bayesian Dose Response Model

Secondary: Percent Change From Baseline in Liver fat at Week 48: Bayesian Dose Response Model

Secondary: Percent Change From Baseline in Liver fat at Week 48: Pairwise Comparisons with Analysis of Covariance (ANCOVA)

Secondary: Percent Change From Baseline in Liver fat at Week 48: Pairwise Comparisons with Analysis of Covariance (ANCOVA)

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

Secondary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

Secondary: Number of Participants With Laboratory Test Abnormalities

Secondary: Number of Participants With Laboratory Test Abnormalities

Secondary: Number of Participants With Clinically Significant Abnormalities in Vital Signs

Secondary: Number of Participants With Clinically Significant Abnormalities in Vital Signs

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters

Secondary: Number of Participants With Clinically Significant Abnormalities in Electrocardiograms (ECG) Parameters

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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