Phase 2a, Dose-ranging Study With PF-05221304 in Nonalcoholic Fatty Liver Disease (NAFLD)

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03248882
• Collaborator: (none)
• Enrollment: 305
• Locations: 140
• Arms: 5
• Actual Duration (Months): 19.1
• Patients Per Site: 2.2
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

Phase 2a, dose-ranging Study with PF-05221304 in Nonalcoholic Fatty Liver Disease (NAFLD)

Condition or Disease	Intervention/Treatment	Phase
Nonalcoholic Fatty Liver Disease; Nonalcoholic Steatohepatitis	Drug: Placebo; Drug: PF-05221304	Phase 2

Detailed Description

A Phase 2a, Randomized, Double-blind, Placebo-controlled, Dose-ranging, Parallel Group Study To Evaluate Safety, Tolerability, And Pharmacodynamics Of PF-05221304 Administered Daily For 16-weeks To Adult Subjects With Nonalcoholic Fatty Liver Disease

Study Design

• Study Type: Interventional
• Actual Enrollment: 305 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: C1171002 is a randomized, double blind, placebo controlled, 5 arm (placebo, plus 4 active doses of PF 05221304), parallel group study.C1171002 is a randomized, double blind, placebo controlled, 5 arm (placebo, plus 4 active doses of PF 05221304), parallel group study.
• Masking: Double (Participant, Investigator)
• Masking Description: Double-Blind
• Primary Purpose: Treatment
• Official Title: A PHASE 2A, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, DOSE-RANGING, PARALLEL GROUP STUDY TO EVALUATE SAFETY, TOLERABILITY, AND PHARMACODYNAMICS OF PF-05221304 ADMINISTERED DAILY FOR 16-WEEKS TO ADULT SUBJECTS WITH NONALCOHOLIC FATTY LIVER DISEASE
• Actual Study Start Date: Aug 22, 2017
• Actual Primary Completion Date: Feb 26, 2019
• Actual Study Completion Date: Mar 27, 2019

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Double-Blind, PF-05221304-matching Placebo	Drug: Placebo; Placebo
Active Comparator: PF-05221304 - 2 mg PF-05221304 - 2 mg, once-daily	Drug: PF-05221304; PF-05221304, Experimental Drug
Active Comparator: PF-05221304 - 10 mg PF-05221304 - 10 mg, once-daily	Drug: PF-05221304; PF-05221304, Experimental Drug
Active Comparator: PF-05221304 - 25 mg PF-05221304 - 25 mg, once-daily	Drug: PF-05221304; PF-05221304, Experimental Drug
Active Comparator: PF-05221304 - 50 mg PF-05221304 - 50 mg, once-daily	Drug: PF-05221304; PF-05221304, Experimental Drug

Outcome Measures

Primary Outcome Measures

1. Percent Change From Baseline in Liver Fat by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI- PDFF) at Week 16 [Baseline (between Day -14 and Day 1), Week 16]

   MRI-PDFF utilized a gradient echo sequence with low flip angle (FA) to minimize T1 bias, corrected T2* decay (due to iron overload) via modeling of the fat signal as a superposition of multiple frequency components from 5 different lipid types, and was applied in each of the 9 Couinaud segments. This technique improved fat quantification accuracy for the entire liver permitting quantification of small differences/changes following pharmacological intervention.

Secondary Outcome Measures

1. Percent Change From Baseline in Alanine Aminotransferase at Week 16 [Baseline (Day 1 pre-dose), Week 16]

   Potential improvement in liver function was denoted by reduction in alanine transaminase (ALT)

2. Number of Participants With Treatment-Emergent Adverse Events [From first dose of study treatment (Day 1) up to Week 20]

   An AE was any untoward medical occurrence in a study subject administered a product or medical device. A serious AE (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Any such events with initial onset or increasing in severity after the first dose of study treatment were counted as treatment-emergent.

3. Number of Participants With Laboratory Abnormalities [From first dose of study treatment (Day 1) up to Week 20]

   Following laboratory parameters were assessed against pre-defined abnormality criteria: hematology (hemoglobin, hematocrit, erythrocytes, reticulocytes, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time, prothrombin time [PT], PT/international normalized ratio, reticulocytes); chemistry (indirect bilirubin, direct bilirubin, protein, albumin, blood urea nitrogen, creatinine, creatine kinase, urate, calcium, sodium, potassium, chloride, bicarbonate, urine urobilinogen); urinalysis (pH, urine glucose, urine ketones, urine protein, urine hemoglobin, nitrites, leukocyte esterase, urine erythrocytes, urine leukocytes, urine hyaline casts, urine bilirubin, granular casts).

4. Number of Participants With Vital Signs Data Meeting Predefined Criteria [From first dose of study treatment (Day 1) up to Week 18]

   Vital signs categorical summarization criteria: 1) sitting systolic blood pressure (SBP) <90 or >180 millimeters of mercury (mmHg); 2) sitting diastolic blood pressure (DBP) <50 mmHg or >110 mmHg; 3) sitting pulse rate <40 or >120 beats per minute (bpm); 4) change from baseline (increase or decrease) in sitting DBP greater than or equal to (>=) 20 mmHg; 5) change from baseline (increase or decrease) in sitting SBP >=30 mmHg.

5. Number of Participants With 12-Lead Electrocardiogram (ECG) Data Meeting Predefined Criteria [From first dose of study treatment (Day 1) up to Week 18]

   ECG categorical summarization criteria: 1) QRS interval (time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization) >=140 milliseconds (msec); 2) QRS interval >=50% change from baseline; 3) PR interval (the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization) >=300 msec; 4) PR interval >=25% change when baseline is >200 msec or >=50% change when baseline is <=200 msec; 5) QT interval (time from ECG Q wave to the end of the T wave corresponding to electrical systole): absolute value of >=500 msec; 6) QTcF interval (QT corrected for heart rate using Fridericia's formula) absolute value of 450 to <480 msec; 7) QTcF interval: absolute value of 480 to <500 msec; 8) QTcF interval: absolute value >=500 msec; 9) QTcF interval: a change from baseline of 30 to <60 msec; 10) QTcF interval: a change from baseline >=60 msec.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Body Mass Index >= 25 kg/m2

• Body Weight > 50 kg

• Liver fat (assessed via MRI-PDFF) >= 8%

• Biopsy-proven NASH - diagnosed in previous 24-months

• Presumed NASH - per Sponsor's definition

• NAFLD with minimal inflammation/fibrosis

• Features of Metabolic Syndrome

Exclusion Criteria:

• Alcohol-induced steatohepatitis or other forms of chronic liver disease

• Positive for Hepatitis B, Hepatitis C, or Human Deficiency Virus

• Severe Renal Impairment

• Contraindications for MRI

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Franco Felizarta MD	Bakersfield	California	United States	93301
2	eStudySite	Chula Vista	California	United States	91911
3	San Diego Imaging Chula Vista	Chula Vista	California	United States	91911
4	University of California, San Diego (Altman Clinical and Translational Research Institute)	La Jolla	California	United States	92037
5	University of California, San Diego	La Jolla	California	United States	92037
6	eStudySite	La Mesa	California	United States	91942
7	Clinical Trials Research	Lincoln	California	United States	95648
8	National Research Institute	Los Angeles	California	United States	90057
9	Stanford University Medical Center, Blake wilbur Building	Palo Alto	California	United States	04304
10	Stanford University Medical Center	Palo Alto	California	United States	94304
11	Huntington Medical Research Institute	Pasadena	California	United States	91105
12	Inland Empire Liver Foundation	Rialto	California	United States	92377
13	Precision Research Institute	San Diego	California	United States	92114
14	Quest Clinical Research	San Francisco	California	United States	94115
15	South Denver Gastroenterology, P.C.	Englewood	Colorado	United States	80113
16	Jacksonville Center for Clinical Research	Jacksonville	Florida	United States	32216
17	Borland-Groover Clinic	Jacksonville	Florida	United States	32256
18	Ocean Blue Medical Research Center, Inc	Miami Springs	Florida	United States	33166
19	Schiff Center for Liver Diseases/University of Miami	Miami	Florida	United States	33136
20	Stand Up MRI of Miami	Miami	Florida	United States	33145
21	Avail Clinical Research, LLC	Orange City	Florida	United States	32763
22	Bioclinica Research	Orlando	Florida	United States	32806
23	Advanced Gastroenterology Associates, LLC	Palm Harbor	Florida	United States	34684
24	Qps-Mra, Llc	South Miami	Florida	United States	33143
25	Tampa General Medical Group	Tampa	Florida	United States	33606
26	University of South Florida	Tampa	Florida	United States	33612
27	South Florida Center Of Gastroenterology, PA	Wellington	Florida	United States	33414
28	Independent Imaging	Wellington	Florida	United States	33449
29	East-West Medical Research Institute	Honolulu	Hawaii	United States	96814
30	Invision Imaging	Honolulu	Hawaii	United States	96814
31	Midwest Institute for Clinical Research	Indianapolis	Indiana	United States	46260
32	Heartland Research Associates, LLC	Wichita	Kansas	United States	67207
33	Ascension Via Christi Imaging at St. Francis	Wichita	Kansas	United States	67214
34	Tulane University Health Sciences Center	New Orleans	Louisiana	United States	70112
35	Ochsner Medical Center	New Orleans	Louisiana	United States	70121
36	Mercy Medical Center	Baltimore	Maryland	United States	21202
37	Digestive Disease Associates, PA	Catonsville	Maryland	United States	21228
38	University of Michigan	Ann Arbor	Michigan	United States	48109
39	Henry Ford Health System	Detroit	Michigan	United States	48202
40	Mayo Clinic- Main Campus	Rochester	Minnesota	United States	55905
41	Gastrointestinal Associates, PA	Flowood	Mississippi	United States	39232
42	Colonnades at Baptist	Jackson	Mississippi	United States	39202
43	BioTelemetry Research	Rochester	New York	United States	14623
44	Investigational Drug Service, University of North Carolina Hospitals	Chapel Hill	North Carolina	United States	27514
45	The University of NC at Chapel Hill, Clinical and Translational Research Center (CTRC)	Chapel Hill	North Carolina	United States	27599
46	The University of North Carolina at Chapel Hill, Biomedical Research Imaging Center (MRI Facility)	Chapel Hill	North Carolina	United States	27599
47	Wake Research Associates, LLC	Raleigh	North Carolina	United States	27612
48	PMG Research of Wilmington, LLC	Wilmington	North Carolina	United States	28401
49	PMG Research, Inc.	Winston-Salem	North Carolina	United States	27103
50	Sterling Research Group, Ltd.	Cincinnati	Ohio	United States	45219
51	Prime Imaging (Chattanooga Outpatient Center)	Chattanooga	Tennessee	United States	37404
52	ClinSearch	Chattanooga	Tennessee	United States	37421
53	Touchstone	Austin	Texas	United States	78705
54	Baylor College of Medicine - Advanced Liver Therapies	Houston	Texas	United States	77030
55	Pinnacle Clinical Research	Rollingwood	Texas	United States	78746
56	Clinical Trials of Texas, Inc.	San Antonio	Texas	United States	78229
57	Pinnacle Clinical Research, PLLC	San Antonio	Texas	United States	78229
58	Clinical Research Advantage, Inc./Wasatch Peak Family Practice	Layton	Utah	United States	84041
59	National Clinical Research - Richmond, Inc.	Richmond	Virginia	United States	23294
60	Harborview Medical Center	Seattle	Washington	United States	98104
61	Australian Clinical Research Network	Maroubra	New South Wales	Australia	2035
62	Spectrum Medical Imaging	Randwick	New South Wales	Australia	2013
63	Castlereagh Imaging	Westmead	New South Wales	Australia	2145
64	Storr Liver Centre, Westmead Hospital	Westmead	New South Wales	Australia	2145
65	Dr. Jones & Partners Medical Imaging	Adelaide	South Australia	Australia	5000
66	Royal Adelaide Hospital, Department of Gastroenterology and Hepatology	Adelaide	South Australia	Australia	5000
67	Flinders Medical Centre/Department of Gastroenterology & Hepatology	Adelaide	South Australia	Australia	5042
68	Radiology SA	Adelaide	South Australia	Australia	5067
69	Royal Melbourne Hospital	Parkville	Victoria	Australia	3050
70	Dr TG Elliott Inc - BC Diabetes	Vancouver	British Columbia	Canada	V5Y 3W2
71	False Creek Healthcare Centre	Vancouver	British Columbia	Canada	V5Z 1C6
72	False Creek Healthcare	Vancouver	British Columbia	Canada	V5Z 1C6
73	LAIR Centre	Vancouver	British Columbia	Canada	V5Z 1H2
74	Discovery Clinical Services Ltd.	Victoria	British Columbia	Canada	V8T 5G4
75	West Coast Medical Imaging	Victoria	British Columbia	Canada	V8Z 0B9
76	Nova Scotia Health Authority, QEII Health Sciences Centre	Halifax	Nova Scotia	Canada	B3H 1V7
77	Nova Scotia Health Authority, QEII Health Sciences Centre	Halifax	Nova Scotia	Canada	B3H 2Y9
78	Nova Scotia Health Authority - QEII Health Sciences Centre	Halifax	Nova Scotia	Canada	B3H 3A7
79	Aggarwal and Associates Limited	Brampton	Ontario	Canada	L6T 0G1
80	St. Joseph's Health Care London	London	Ontario	Canada	N6A 4V2
81	London Health Sciences Centre - University Hospital	London	Ontario	Canada	N6A 5A5
82	Oxford Medical Imaging	Mississauga	Ontario	Canada	L5R 3K7
83	LMC Clinical Research Inc. (Bayview)	Toronto	Ontario	Canada	M4G 3E8
84	St. Michael's Hospital - MRI Research Centre	Toronto	Ontario	Canada	M5B 1W8
85	St. Michael's Hospital	Toronto	Ontario	Canada	M5B 1W8
86	University Health Network (UHN) - Toronto General Hospital - Toronto Centre for Liver Disease (TCLD)	Toronto	Ontario	Canada	M5G 2C4
87	University of Toronto - Toronto General Hospital	Toronto	Ontario	Canada	M5G 2C4
88	University Health Network (UHN)	Toronto	Ontario	Canada	M5G 2M9
89	Toronto Liver Centre - Liver Care Centre Corporation	Toronto	Ontario	Canada	M6H 3M1
90	Resonance Magnetique du Saguenay-Lac-Saint-Jean	Chicoutimi	Quebec	Canada	G7H 4J1
91	Ecogene-21	Chicoutimi	Quebec	Canada	G7H 7K9
92	Medpharmgene Inc	Montreal	Quebec	Canada	H2K 1H2
93	Clinique de Medecine Urbaine du Quartier Latin	Montreal	Quebec	Canada	H2L 4E9
94	Centre de recherche du CHUM	Montreal	Quebec	Canada	H2X 0A9
95	Cedar Cancer Center - McGill University Health Centre	Montreal	Quebec	Canada	H4A 3J1
96	Chronic Viral Illness Service - Royal Victoria Hospital - McGill University Health Centre (MUHC)	Montreal	Quebec	Canada	H4A 3J1
97	McGill University Health Centre	Montreal	Quebec	Canada	H4A 3J1
98	Research Institute of the MUHC	Montreal	Quebec	Canada	H4A 3J1
99	Radiologie Varad	Montreal	Quebec	Canada	H5B 1B2
100	Centre Intégré Universitaire de Santé et de Services Sociaux (CIUSSS) de l'Estrie	Sherbrooke	Quebec	Canada	J1G 2E8
101	Recherche Medicale St-Jerome Inc	St-Jerome	Quebec	Canada	J7Z 5T3
102	IRM Quebec	Quebec		Canada	G1J0H4
103	IRM Quebec	Quebec		Canada	G1J5B9
104	CHU de Quebec - Universite Laval - site Centre Hospitalier de l'Universite Laval (CHUL)	Quebec		Canada	G1V 4G2
105	Centre de recherche de l'Institut Universitaire de Cardiologie et de pneumologie de Quebec	Quebec		Canada	G1V 4G5
106	Centre de recherche Saint-Louis	Quebec		Canada	G1W 4R4
107	IRM Québec - Clinique St-Louis	Quebec		Canada	G1W 4R4
108	Alpha Recherche Clinique	Quebec		Canada	G3K 2P8
109	Clinix	Quebec		Canada	G3K 2P8
110	Hillel Yaffe Medical Center	Hadera		Israel	3810101
111	Rambam Health Care Campus	Haifa		Israel	3109601
112	Lady Davis Carmel Medical Center	Haifa		Israel	3434104
113	Shaare Zedek Medical Center	Jerusalem		Israel	9103102
114	Hadassah Hebrew University Medical Center - Ein Kerem	Jerusalem		Israel	9112001
115	Galilee Medical Center	Nahariya		Israel	2210001
116	Holy Family Hospital	Nazareth		Israel	1610001
117	Rabin Medical Center	Petah Tikva		Israel	4941492
118	The Chaim Sheba Medical Center	Ramat-Gan		Israel	5265601
119	Tel-Aviv Sourasky Medical Center	Tel-Aviv		Israel	6423906
120	ClinicMed Badurski i wspolnicy Spolka Jawna	Bialystok		Poland	15-879
121	Synexus Polska Sp. z o.o. Oddzial w Gdansku	Gdansk		Poland	80-382
122	Centrum Badan Klinicznych PI-House Sp. z o.o.	Gdansk		Poland	80-546
123	Synexus Polska Sp. z o.o. Oddzial w Gdyni	Gdynia		Poland	81-537
124	Osrodek Badan Klinicznych	Jaworze		Poland	43-384
125	Synexus Polska Sp. z o.o. Oddzial w Katowicach	Katowice		Poland	40-040
126	Silmedic Sp. z o.o. Oddzial w Katowicach	Katowice		Poland	40-282
127	Centrum Medyczne A-Z Clinic	Krakow		Poland	31-315
128	Krakowskie Centrum Medyczne sp. z o.o.	Krakow		Poland	31-501
129	Gabinet Lekarski Malgorzata Saryusz-Wolska	Lodz		Poland	90-132
130	Synexus Polska Sp. z o.o Oddzial w Poznaniu	Poznan		Poland	60-702
131	Centrum Medyczne Medyk	Rzeszow		Poland	35-326
132	Synexus Polska Sp. z o. o. Oddzial w Warszawie	Warszawa		Poland	01-192
133	Niepubliczny Zaklad Opieki Zdrowotnej Centrum Badan Klinicznych	Wroclaw		Poland	50-349
134	Synexus Polska Sp. z o.o. Oddzial we Wroclawiu	Wroclaw		Poland	50-381
135	DOBROSTAN - Gabinety Lekarskie	Wroclaw		Poland	53-301
136	Changhua Christian Hospital	Changhua city	Changhua County	Taiwan	500
137	Chung-Ho Memorial Hospital, Kaohsiung Medical University	Kaohsiung		Taiwan	807
138	National Cheng-Kung University Hospital	Tainan		Taiwan	704
139	National Taiwan University Hospital	Taipei		Taiwan	100
140	Taipei Veterans General Hospital	Taipei		Taiwan	11217

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

• Study Protocol - Oct 3, 2017
• Statistical Analysis Plan - Mar 14, 2019

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT03248882
• Other Study ID Numbers: C1171002; 2017-001156-55
• First Posted: Aug 14, 2017
• Last Update Posted: Dec 9, 2020
• Last Verified: Feb 1, 2020

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Pfizer: PF-05221304; NAFLD; NASH; features of metabolic syndrome; Dose-Ranging Study
• Additional relevant MeSH terms: Liver Diseases; Fatty Liver; Non-alcoholic Fatty Liver Disease

Study Results

Participant Flow

Arm/Group Title	Placebo	PF-05221304 2 mg	PF-05221304 10 mg	PF-05221304 25 mg	PF-05221304 50 mg
Arm/Group Description	Placebo matched to PF-05221304 tablet was administered orally once daily (QD) for up to 16 weeks.	PF-05221304 tablet was administered orally at 2 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 10 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 25 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 50 mg QD for up to 16 weeks.
Period Title: Overall Study
STARTED	61	63	62	58	61
Received Treatment	61	63	62	58	61
COMPLETED	54	58	55	48	48
NOT COMPLETED	7	5	7	10	13

Baseline Characteristics

Arm/Group Title	Placebo	PF-05221304 2 mg	PF-05221304 10 mg	PF-05221304 25 mg	PF-05221304 50 mg	Total
Arm/Group Description	Placebo matched to PF-05221304 tablet was administered orally once daily (QD) for up to 16 weeks.	PF-05221304 tablet was administered orally at 2 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 10 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 25 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 50 mg QD for up to 16 weeks.	Total of all reporting groups
Overall Participants	61	63	62	58	61	305
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	53.3 (10.8)	54.1 (11.9)	52.7 (12.8)	54.0 (11.6)	52.8 (13.1)	53.38 (11.99)
Sex: Female, Male (Count of Participants)
Female	36 59%	37 58.7%	33 53.2%	35 60.3%	30 49.2%	171 56.1%
Male	25 41%	26 41.3%	29 46.8%	23 39.7%	31 50.8%	134 43.9%
Race/Ethnicity, Customized (Count of Participants)
White	53 86.9%	50 79.4%	52 83.9%	46 79.3%	51 83.6%	252 82.6%
Black or African American	1 1.6%	1 1.6%	1 1.6%	1 1.7%	0 0%	4 1.3%
Asian	5 8.2%	7 11.1%	7 11.3%	9 15.5%	10 16.4%	38 12.5%
American Indian or Alaska Native	0 0%	1 1.6%	0 0%	0 0%	0 0%	1 0.3%
Native Hawaiian or Other Pacific Islander	0 0%	1 1.6%	0 0%	0 0%	0 0%	1 0.3%
Not Reported	2 3.3%	3 4.8%	2 3.2%	2 3.4%	0 0%	9 3%

Outcome Measures

1. Primary Outcome

Title	Percent Change From Baseline in Liver Fat by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI- PDFF) at Week 16
Description	MRI-PDFF utilized a gradient echo sequence with low flip angle (FA) to minimize T1 bias, corrected T2* decay (due to iron overload) via modeling of the fat signal as a superposition of multiple frequency components from 5 different lipid types, and was applied in each of the 9 Couinaud segments. This technique improved fat quantification accuracy for the entire liver permitting quantification of small differences/changes following pharmacological intervention.
Time Frame	Baseline (between Day -14 and Day 1), Week 16

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of randomized study treatment and with non-missing baseline and post-baseline endpoint.

Arm/Group Title	Placebo	PF-05221304 2 mg	PF-05221304 10 mg	PF-05221304 25 mg	PF-05221304 50 mg
Arm/Group Description	Placebo matched to PF-05221304 tablet was administered orally once daily (QD) for up to 16 weeks.	PF-05221304 tablet was administered orally at 2 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 10 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 25 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 50 mg QD for up to 16 weeks.
Measure Participants	55	59	57	54	51
Least Squares Mean (80% Confidence Interval) [Percent change]	-7.2	-17.1	-49.9	-55.9	-64.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, PF-05221304 2 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-10.7
	Confidence Interval	(2-Sided) 80%; -19.4 to -1.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, PF-05221304 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-46.0
	Confidence Interval	(2-Sided) 80%; -51.3 to -40.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, PF-05221304 25 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-52.4
	Confidence Interval	(2-Sided) 80%; -57.2 to -47.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, PF-05221304 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-62.1
	Confidence Interval	(2-Sided) 80%; -66.0 to -57.8
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percent Change From Baseline in Alanine Aminotransferase at Week 16
Description	Potential improvement in liver function was denoted by reduction in alanine transaminase (ALT)
Time Frame	Baseline (Day 1 pre-dose), Week 16

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of randomized study treatment and diagnosed/presumed with nonalcoholic steatohepatitis.

Arm/Group Title	Placebo	PF-05221304 2 mg	PF-05221304 10 mg	PF-05221304 25 mg	PF-05221304 50 mg
Arm/Group Description	Placebo matched to PF-05221304 tablet was administered orally once daily (QD) for up to 16 weeks.	PF-05221304 tablet was administered orally at 2 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 10 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 25 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 50 mg QD for up to 16 weeks.
Measure Participants	40	42	42	39	40
Least Squares Mean (80% Confidence Interval) [Percent change]	-8.5	-12.5	-27.7	-31.3	-46.8

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, PF-05221304 2 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-4.4
	Confidence Interval	(2-Sided) 80%; -14.0 to 6.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Placebo, PF-05221304 10 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-21.0
	Confidence Interval	(2-Sided) 80%; -29.0 to -12.2
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Placebo, PF-05221304 25 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-25.0
	Confidence Interval	(2-Sided) 80%; -32.8 to -16.1
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Placebo, PF-05221304 50 mg
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value
	Comments
	Method
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-41.8
	Confidence Interval	(2-Sided) 80%; -47.9 to -35.0
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events
Description	An AE was any untoward medical occurrence in a study subject administered a product or medical device. A serious AE (SAE) is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; life-threatening; initial or prolonged inpatient hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect. Any such events with initial onset or increasing in severity after the first dose of study treatment were counted as treatment-emergent.
Time Frame	From first dose of study treatment (Day 1) up to Week 20

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of randomized study treatment.

Arm/Group Title	Placebo	PF-05221304 2 mg	PF-05221304 10 mg	PF-05221304 25 mg	PF-05221304 50 mg
Arm/Group Description	Placebo matched to PF-05221304 tablet was administered orally once daily (QD) for up to 16 weeks.	PF-05221304 tablet was administered orally at 2 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 10 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 25 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 50 mg QD for up to 16 weeks.
Measure Participants	61	63	62	58	61
All-causality AE	41 67.2%	40 63.5%	42 67.7%	45 77.6%	40 65.6%
All-causality SAE	0 0%	1 1.6%	1 1.6%	2 3.4%	2 3.3%
Treatment-related AE	16 26.2%	9 14.3%	12 19.4%	16 27.6%	23 37.7%
Treatment-related SAE	0 0%	0 0%	0 0%	0 0%	0 0%

4. Secondary Outcome

Title	Number of Participants With Laboratory Abnormalities
Description	Following laboratory parameters were assessed against pre-defined abnormality criteria: hematology (hemoglobin, hematocrit, erythrocytes, reticulocytes, platelets, leukocytes, lymphocytes, neutrophils, basophils, eosinophils, monocytes, activated partial thromboplastin time, prothrombin time [PT], PT/international normalized ratio, reticulocytes); chemistry (indirect bilirubin, direct bilirubin, protein, albumin, blood urea nitrogen, creatinine, creatine kinase, urate, calcium, sodium, potassium, chloride, bicarbonate, urine urobilinogen); urinalysis (pH, urine glucose, urine ketones, urine protein, urine hemoglobin, nitrites, leukocyte esterase, urine erythrocytes, urine leukocytes, urine hyaline casts, urine bilirubin, granular casts).
Time Frame	From first dose of study treatment (Day 1) up to Week 20

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of randomized study treatment and had laboratory data.

Arm/Group Title	Placebo	PF-05221304 2 mg	PF-05221304 10 mg	PF-05221304 25 mg	PF-05221304 50 mg
Arm/Group Description	Placebo matched to PF-05221304 tablet was administered orally once daily (QD) for up to 16 weeks.	PF-05221304 tablet was administered orally at 2 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 10 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 25 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 50 mg QD for up to 16 weeks.
Measure Participants	59	63	62	58	61
Count of Participants [Participants]	39 63.9%	44 69.8%	36 58.1%	33 56.9%	40 65.6%

5. Secondary Outcome

Title	Number of Participants With Vital Signs Data Meeting Predefined Criteria
Description	Vital signs categorical summarization criteria: 1) sitting systolic blood pressure (SBP) <90 or >180 millimeters of mercury (mmHg); 2) sitting diastolic blood pressure (DBP) <50 mmHg or >110 mmHg; 3) sitting pulse rate <40 or >120 beats per minute (bpm); 4) change from baseline (increase or decrease) in sitting DBP greater than or equal to (>=) 20 mmHg; 5) change from baseline (increase or decrease) in sitting SBP >=30 mmHg.
Time Frame	From first dose of study treatment (Day 1) up to Week 18

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of randomized study treatment and had vital signs data.

Arm/Group Title	Placebo	PF-05221304 2 mg	PF-05221304 10 mg	PF-05221304 25 mg	PF-05221304 50 mg
Arm/Group Description	Placebo matched to PF-05221304 tablet was administered orally once daily (QD) for up to 16 weeks.	PF-05221304 tablet was administered orally at 2 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 10 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 25 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 50 mg QD for up to 16 weeks.
Measure Participants	60	63	62	58	61
Sitting SBP <90 mmHg	0 0%	0 0%	0 0%	0 0%	2 3.3%
Sitting SBP >180 mmHg	0 0%	0 0%	0 0%	1 1.7%	0 0%
Sitting SBP increase >=30 mmHg	5 8.2%	6 9.5%	2 3.2%	2 3.4%	0 0%
Sitting SBP decrease >=30 mmHg	2 3.3%	1 1.6%	5 8.1%	7 12.1%	6 9.8%
Sitting DBP <50 mmHg	1 1.6%	0 0%	0 0%	0 0%	0 0%
Sitting DBP >110 mmHg	0 0%	0 0%	0 0%	0 0%	1 1.6%
Sitting DBP increase >=20 mmHg	1 1.6%	4 6.3%	2 3.2%	2 3.4%	3 4.9%
Sitting DBP decrease >=20 mmHg	0 0%	4 6.3%	3 4.8%	4 6.9%	4 6.6%
Sitting pulse rate <40 bpm	0 0%	0 0%	0 0%	0 0%	0 0%
Sitting pulse rate >120 bpm	0 0%	0 0%	0 0%	0 0%	0 0%

6. Secondary Outcome

Title	Number of Participants With 12-Lead Electrocardiogram (ECG) Data Meeting Predefined Criteria
Description	ECG categorical summarization criteria: 1) QRS interval (time from ECG Q wave to the end of the S wave corresponding to ventricle depolarization) >=140 milliseconds (msec); 2) QRS interval >=50% change from baseline; 3) PR interval (the interval between the start of the P wave and the start of the QRS complex, corresponding to the time between the onset of the atrial depolarization and onset of ventricular depolarization) >=300 msec; 4) PR interval >=25% change when baseline is >200 msec or >=50% change when baseline is <=200 msec; 5) QT interval (time from ECG Q wave to the end of the T wave corresponding to electrical systole): absolute value of >=500 msec; 6) QTcF interval (QT corrected for heart rate using Fridericia's formula) absolute value of 450 to <480 msec; 7) QTcF interval: absolute value of 480 to <500 msec; 8) QTcF interval: absolute value >=500 msec; 9) QTcF interval: a change from baseline of 30 to <60 msec; 10) QTcF interval: a change from baseline >=60 msec.
Time Frame	From first dose of study treatment (Day 1) up to Week 18

Outcome Measure Data

Analysis Population Description

All randomized participants who received at least 1 dose of randomized study treatment and had ECG data.

Arm/Group Title	Placebo	PF-05221304 2 mg	PF-05221304 10 mg	PF-05221304 25 mg	PF-05221304 50 mg
Arm/Group Description	Placebo matched to PF-05221304 tablet was administered orally once daily (QD) for up to 16 weeks.	PF-05221304 tablet was administered orally at 2 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 10 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 25 mg QD for up to 16 weeks.	PF-05221304 tablet was administered orally at 50 mg QD for up to 16 weeks.
Measure Participants	60	63	61	58	60
PR interval >=300 msec	0 0%	0 0%	0 0%	0 0%	0 0%
%Change in PR interval >=25/50%	0 0%	1 1.6%	0 0%	1 1.7%	1 1.6%
QRS interval >=140 msec	0 0%	0 0%	1 1.6%	0 0%	0 0%
%Change in QRS interval >=50%	0 0%	0 0%	0 0%	0 0%	0 0%
QT interval >=500 msec	0 0%	0 0%	0 0%	1 1.7%	0 0%
QTcF interval >=450 to <480 msec	6 9.8%	10 15.9%	7 11.3%	9 15.5%	3 4.9%
QTcF interval >=480 to <500 msec	0 0%	1 1.6%	0 0%	1 1.7%	1 1.6%
QTcF interval >=500 msec	0 0%	0 0%	0 0%	0 0%	0 0%
QTcF interval increase >=30 to 60 msec	5 8.2%	6 9.5%	8 12.9%	10 17.2%	4 6.6%
QTcF interval increase >=60 msec	2 3.3%	1 1.6%	0 0%	0 0%	0 0%

Adverse Events

Time Frame	From first dose of study treatment up to 20 weeks
Arm/Group Title	Placebo		PF-05221304 2 mg		PF-05221304 10 mg		PF-05221304 25 mg		PF-05221304 50 mg
Arm/Group Description	Placebo matched to PF-05221304 tablet was administered orally once daily (QD) for up to 16 weeks.		PF-05221304 tablet was administered orally at 2 mg QD for up to 16 weeks.		PF-05221304 tablet was administered orally at 10 mg QD for up to 16 weeks.		PF-05221304 tablet was administered orally at 25 mg QD for up to 16 weeks.		PF-05221304 tablet was administered orally at 50 mg QD for up to 16 weeks.
All Cause Mortality
	Placebo		PF-05221304 2 mg		PF-05221304 10 mg		PF-05221304 25 mg		PF-05221304 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/61 (0%)		0/63 (0%)		0/62 (0%)		0/58 (0%)		0/61 (0%)
Serious Adverse Events
	Placebo		PF-05221304 2 mg		PF-05221304 10 mg		PF-05221304 25 mg		PF-05221304 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/61 (0%)		1/63 (1.6%)		1/62 (1.6%)		2/58 (3.4%)		2/61 (3.3%)
Cardiac disorders
Angina unstable	0/61 (0%)		0/63 (0%)		0/62 (0%)		1/58 (1.7%)		0/61 (0%)
Myocardial infarction	0/61 (0%)		1/63 (1.6%)		0/62 (0%)		0/58 (0%)		0/61 (0%)
Myocardial ischaemia	0/61 (0%)		0/63 (0%)		0/62 (0%)		1/58 (1.7%)		0/61 (0%)
Infections and infestations
Pneumonia	0/61 (0%)		1/63 (1.6%)		0/62 (0%)		0/58 (0%)		0/61 (0%)
Upper respiratory tract infection	0/61 (0%)		0/63 (0%)		1/62 (1.6%)		0/58 (0%)		0/61 (0%)
Injury, poisoning and procedural complications
Rib fracture	0/61 (0%)		0/63 (0%)		1/62 (1.6%)		0/58 (0%)		0/61 (0%)
Renal and urinary disorders
Renal colic	0/61 (0%)		0/63 (0%)		0/62 (0%)		0/58 (0%)		1/61 (1.6%)
Respiratory, thoracic and mediastinal disorders
Asthma	0/61 (0%)		0/63 (0%)		0/62 (0%)		0/58 (0%)		1/61 (1.6%)
Other (Not Including Serious) Adverse Events
	Placebo		PF-05221304 2 mg		PF-05221304 10 mg		PF-05221304 25 mg		PF-05221304 50 mg
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	27/61 (44.3%)		21/63 (33.3%)		25/62 (40.3%)		31/58 (53.4%)		29/61 (47.5%)
Gastrointestinal disorders
Abdominal pain upper	1/61 (1.6%)		0/63 (0%)		1/62 (1.6%)		6/58 (10.3%)		1/61 (1.6%)
Diarrhoea	3/61 (4.9%)		3/63 (4.8%)		8/62 (12.9%)		2/58 (3.4%)		4/61 (6.6%)
Nausea	3/61 (4.9%)		0/63 (0%)		3/62 (4.8%)		5/58 (8.6%)		4/61 (6.6%)
General disorders
Fatigue	5/61 (8.2%)		3/63 (4.8%)		2/62 (3.2%)		2/58 (3.4%)		2/61 (3.3%)
Infections and infestations
Nasopharyngitis	2/61 (3.3%)		0/63 (0%)		3/62 (4.8%)		3/58 (5.2%)		2/61 (3.3%)
Upper respiratory tract infection	2/61 (3.3%)		6/63 (9.5%)		3/62 (4.8%)		3/58 (5.2%)		2/61 (3.3%)
Urinary tract infection	1/61 (1.6%)		1/63 (1.6%)		2/62 (3.2%)		5/58 (8.6%)		4/61 (6.6%)
Investigations
Blood triglycerides increased	0/61 (0%)		0/63 (0%)		1/62 (1.6%)		3/58 (5.2%)		2/61 (3.3%)
Metabolism and nutrition disorders
Hypertriglyceridaemia	2/61 (3.3%)		1/63 (1.6%)		6/62 (9.7%)		4/58 (6.9%)		10/61 (16.4%)
Musculoskeletal and connective tissue disorders
Arthralgia	1/61 (1.6%)		1/63 (1.6%)		3/62 (4.8%)		4/58 (6.9%)		0/61 (0%)
Muscle spasms	4/61 (6.6%)		0/63 (0%)		2/62 (3.2%)		1/58 (1.7%)		0/61 (0%)
Pain in extremity	2/61 (3.3%)		3/63 (4.8%)		4/62 (6.5%)		2/58 (3.4%)		1/61 (1.6%)
Nervous system disorders
Dizziness	4/61 (6.6%)		3/63 (4.8%)		1/62 (1.6%)		3/58 (5.2%)		3/61 (4.9%)
Headache	8/61 (13.1%)		3/63 (4.8%)		3/62 (4.8%)		7/58 (12.1%)		4/61 (6.6%)
Skin and subcutaneous tissue disorders
Pruritus	1/61 (1.6%)		2/63 (3.2%)		0/62 (0%)		3/58 (5.2%)		1/61 (1.6%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.