A Study To Assess Pharmacodynamics, Safety And Tolerabili... | NCT03776175

Status Module

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Placebo	Placebo Comparator	Placebo (PF 05221304) BID Placebo (PF 06865571) BID	Drug: Placebo
PF-05221304 Monotherapy	Experimental	15 mg PF-05221304 BID Placebo (PF-06865571) BID	Drug: PF-05221304 Monotherapy Drug: Placebo
PF-06865571 Monotherapy	Experimental	Placebo (PF-05221304) BID 300 mg PF-06865571 BID	Drug: PF-06865571 Monotherapy Drug: Placebo
PF-05221304 and PF-06865571 Combination	Experimental	15 mg PF-05221304 BID 300 mg PF-06865571 BID	Drug: PF-05221304 Monotherapy Drug: PF-06865571 Monotherapy Drug: PF-05221304 and PF-06865571 Combination

Interventions

Name	Type	Description	Arm Group Labels	Other Names
PF-05221304 Monotherapy	Drug	Participants enrolled in this Arm will receive 15 mg dose of PF-05221304 (3 tablets of 5 mg each) and 3 tablets of Placebo for PF-06865571, each to be taken twice daily for 41 days and once on Day 42.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
Percent Change From Baseline in Whole Liver Proton Density Fat Fraction (PDFF) at Day 42	Magnetic resonance imaging proton density fat fraction (MRI-PDFF) technique is an established method that enables quantification of fat content in the liver. It measures the fraction of mobile protons in the liver attributable to fat content and provides whole liver coverage so that fat content can be assessed across 8 Couinaud liver segments. Whole liver PDFF = PDFFs for (Segment I + Segment II + Segment III + Segment IVa + Segment IVb + Segment V + Segment VI + Segment VII + Segment VIII) divided by total number of segments assessed.	Baseline, Day 42

Secondary Outcomes

Measure	Description	Time Frame
Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)	An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included all serious and non-serious adverse events.

Eligibility Module

Eligibility Criteria

Inclusion Criteria:

Male subjects or female subjects of non childbearing potential
Total body weight of >50 kg (110 lbs) and a BMI greater than or equal to 25 kg/m2
Medical diagnosis of Type 2 Diabetes Mellitus (T2DM) being treated with no more than 1 acceptable oral antidiabetic drug OR Subjects without a diagnosis of T2DM that meet 2 or more of the following 5 criteria commonly associated with metabolic syndrome
- Fasting Plasma Glucose (FPG) greater than or equal to 100 mg/dL;
- Documentation of at least stage 1 hypertension or medical history of hypertension;
- Fasting serum HDL C <40 mg/dL for males and <50 mg/dL for females, or on pharmacological agents with explicit purpose to increase HDL-C;
- Fasting serum triglyceride (TG) greater than or equal to 150 mg/dL or on pharmacological agents with explicit purpose to decrease TG;
- Waist circumference greater than or equal to 40 inches (102 cm) for males and 35 inches (89 cm) for females.
Liver fat greater than or equal to 8% measured by MRI PDFF

Exclusion Criteria:

Subjects with acute or chronic medical or psychiatric condition.
Subjects with any of the following clinical laboratory abnormalities:
- Fasting TG >400 mg/dL;
- AST, ALT, or GGT >2.0x ULN;
- Hemoglobin A1c (HbA1c) >7.0%;
- Fasting plasma glucose >270 mg/dL;
- Total bilirubin >1.5x ULN;
- Albumin < lower limit of normal (LLN);
- Platelet count <0.95x LLN;
- International normalized ratio (INR) greater than or equal to 1.3.
A positive urine test for illicit drugs.
History of regular alcohol consumption.
Seated systolic BP>=160 mmHg and/or diastolic BP>=100 mmHg.
Supine 12 lead ECG demonstrating a corrected QT (QTcF) interval >450 msec or a QRS interval >120 msec.
Subjects with an estimated GFR <60 mL/min/1.73m2.
Evidence or diagnosis of other forms of chronic liver diseases.
Subjects with any of the following medical conditions:
- Any condition possibly affecting drug absorption (eg prior bariatric surgery, gastrectomy, ileal resection);
- Diagnosis of type 1 diabetes mellitus;
- History of congestive heart failure, unstable angina, myocardial infarction, stroke, or transient ischemic attack;
- Any malignancy not considered cured (except basal cell carcinoma and squamous cell carcinoma of the skin);
- Active placement of medical devices in/on thoracic or abdominal cavities such as pacemakers, defibrillators;
Subjects with any anatomical or pathological abnormality that would either preclude or tend to confound the analysis of study data.
Blood donation of approximately 1 pint or more within 60 days prior to dosing.
Subjects taking prohibited concomitant medication(s) or those unwilling/unable to switch to permitted concomitant medication(s)
Weight loss of greater than or equal to 5% within 1 month prior to Screening.
Unwilling or unable to comply with the Lifestyle Requirements criteria of the protocol.
Pregnant female subjects; breastfeeding female subjects; female subjects of childbearing potential; fertile male subjects who are unwilling or unable to use highly effective method(s) of contraception.
Investigator site staff members or Pfizer employees, including their family members, directly involved in the conduct of the study.
Subjects with known prior treatment with or participation in a clinical trial involving any of the IPs

Name	Affiliation	Role
Pfizer CT.gov Call Center	Pfizer	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
Franco Felizarta, Md		Bakersfield	California	93301	United States
Westside Medical Associates of Los Angeles

PubMed Identifier	Type	Citation	Retractions
34635855	Derived	Calle RA, Amin NB, Carvajal-Gonzalez S, Ross TT, Bergman A, Aggarwal S, Crowley C, Rinaldi A, Mancuso J, Aggarwal N, Somayaji V, Inglot M, Tuthill TA, Kou K, Boucher M, Tesz G, Dullea R, Bence KK, Kim AM, Pfefferkorn JA, Esler WP. ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease: two parallel, placebo-controlled, randomized phase 2a trials. Nat Med. 2021 Oct;27(10):1836-1848. doi: 10.1038/s41591-021-01489-1. Epub 2021 Oct 11.

Label	URL
To obtain contact information for a study center near you, click here.	View source

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	Placebo	Participants were randomized to receive placebo (3 tablets) matched to PF-05221304 and placebo (3 tablets) matched to PF-06865571 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
FG001	PF-05221304 15mg + Placebo

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot	Yes	No	No	Study Protocol	Oct 2, 2018	Sep 2, 2020

Arm/Group Information

ID	Title	Description
BG000	Placebo	Participants were randomized to receive placebo (3 tablets) matched to PF-05221304 and placebo (3 tablets) matched to PF-06865571 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
BG001	PF-05221304 15mg + Placebo	Participants were randomized to receive PF-05221304 15 mg tablets (3 tablets, each of 5 mg) and placebo (3 tablets) matched to PF-06865571, orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
BG002	PF-06865571 300 mg + Placebo	Participants were randomized to receive PF-06865571 300 mg (3 tablets, each of 100 mg) and placebo (3 tablets) matched to PF-05221304 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
BG003	PF-05221304 15 mg + PF-06865571 300 mg	Participants were randomized to receive PF-05221304 15 mg (3 tablets, each of 5 mg) and PF-06865571 300 mg (3 tablets, each of 100 mg) orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
BG004	Total	Total of all reporting groups

Type

Title

Description

Population Description

Reporting Status

Anticipated Posting Date

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Time Frame

Units Analyzed

Denominator Units Selected

Arm/Group Information

Denominators

Classes

Analyses

Primary

Percent Change From Baseline in Whole Liver Proton Density Fat Fraction (PDFF) at Day 42

Magnetic resonance imaging proton density fat fraction (MRI-PDFF) technique is an established method that enables quantification of fat content in the liver. It measures the fraction of mobile protons in the liver attributable to fat content and provides whole liver coverage so that fat content can be assessed across 8 Couinaud liver segments. Whole liver PDFF = PDFFs for (Segment I + Segment II + Segment III + Segment IVa + Segment IVb + Segment V + Segment VI + Segment VII + Segment VIII) divided by total number of segments assessed.

Full analysis set population included all randomized participants who received at least 1 dose of investigational product and participants were assigned to the randomized treatment regardless of what treatment was received. Here 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure.

Posted

Least Squares Mean

90% Confidence Interval

percent change

Baseline, Day 42

ID	Title	Description
OG000	Placebo	Participants were randomized to receive placebo (3 tablets) matched to PF-05221304 and placebo (3 tablets) matched to PF-06865571 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
OG001	PF-05221304 15mg + Placebo	Participants were randomized to receive PF-05221304 15 mg tablets (3 tablets, each of 5 mg) and placebo (3 tablets) matched to PF-06865571, orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
OG002	PF-06865571 300 mg + Placebo	Participants were randomized to receive PF-06865571 300 mg (3 tablets, each of 100 mg) and placebo (3 tablets) matched to PF-05221304 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
OG003	PF-05221304 15 mg + PF-06865571 300 mg	Participants were randomized to receive PF-05221304 15 mg (3 tablets, each of 5 mg) and PF-06865571 300 mg (3 tablets, each of 100 mg) orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.

Units	Counts
Participants	OG00012 OG00122 OG00224 OG003

Title

Denominators

Categories

Title	Measurements
	OG0008.14(-8.56 to 27.89) OG001-40.01(-47.00 to -32.09) OG002-30.14(-37.97 to -21.33) OG003

Group IDs	Group Description	Statistical Method	Statistical Comment	P-Value	P-Value Comment	Parameter Type	Parameter Value	Dispersion Type	Dispersion Value	Confidence Interval Sides	Confidence Interval %	CI Lower Limit	CI Upper Limit	CI Lower Limit Comment	CI Upper Limit Comment	Estimate Comment	Tested Non-Inferiority	Non-Inferiority Type	Non-Inferiority Comment	Other Analysis Description
OG000 OG001	Natural log-transformed of individual relative change from baseline to Day 42 was analyzed using the ANCOVA model with treatment as a fixed effect, natural log-transformed baseline whole liver fat by MRI-PDFF as covariate. Values were back-transformed from the log scale. 90% CI was calculated on difference in least square (LS) mean between groups	ANCOVA		0.0000		Difference in LS mean	-44.52			2-Sided	90	-54.97	-31.65			LS mean difference was not a simple subtraction between LS means of groups but through statistical model.		Superiority

Secondary

Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)

An AE was any untoward medical occurrence in a participant who received investigational product without regard to possibility of causal relationship. SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly; medically important events. A treatment emergent AE was defined as an event that emerged during the treatment period that was absent before treatment, or worsened during the treatment period relative to the pretreatment state. AEs included all serious and non-serious adverse events.

Safety analysis population included all participants who received at least 1 dose of investigational product post-randomization.

Posted

Count of Participants

Participants

Baseline up to 35 days from last dose of study drug or early termination: (maximum up to Day 77)

ID	Title	Description
OG000	Placebo	Participants were randomized to receive placebo (3 tablets) matched to PF-05221304 and placebo (3 tablets) matched to PF-06865571 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
OG001	PF-05221304 15mg + Placebo	Participants were randomized to receive PF-05221304 15 mg tablets (3 tablets, each of 5 mg) and placebo (3 tablets) matched to PF-06865571, orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.

Secondary

Number of Participants With Laboratory Abnormalities

Clinical chemistry: Bilirubin (milligram per deciliter [mg/dL]), direct bilirubin (mg/dL)>3.0*upper limit of normal (ULN), alanine aminotransferase international units per liter (U/L), aspartate aminotransferase (U/L), alkaline phosphatase (U/L), gamma glutamyl transferase (U/L)>5.0*ULN, urea nitrogen (mg/dL)>2.0*ULN, low density lipoprotein direct endpoint measure (mg/dL)>1.5*ULN, triglycerides (mg/dL)>2.0*ULN, creatinine based estimated glomerular filtration rate by modification of diet in renal disease equation and cystatin based eGFR by chronic kidney disease epidemiology collaboration equation (C <60 milliliter per minute per 1.73 square of meter), very low density lipoprotein (millimoles per liter), Cholesterol >2.0*ULN.

Safety analysis population included all participants who received at least 1 dose of investigational product. Here 'Overall Number of Participants Analyzed' signifies participants evaluable for laboratory abnormalities.

Posted

Count of Participants

Participants

Baseline up to 35 days last from dose of study drug or early termination (maximum up to Day 77)

ID	Title	Description
OG000	Placebo	Participants were randomized to receive placebo (3 tablets) matched to PF-05221304 and placebo (3 tablets) matched to PF-06865571 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
OG001	PF-05221304 15mg + Placebo

Secondary

Maximum Change (Increase or Decrease) From Baseline to Post-last Dose of Study Drug in Vital Signs: Blood Pressure

Vital signs included systolic blood pressure, diastolic blood pressure and pulse rate.

Safety analysis population included all participants who received at least 1 dose of investigational product post-randomization. Here 'Overall Number of Participants Analyzed' signifies participants evaluable for this outcome measure.

Posted

Mean

Standard Deviation

millimeter of mercury

Baseline, Post-last dose of study drug (up to Day 42)

ID	Title	Description
OG000	Placebo	Participants were randomized to receive placebo (3 tablets) matched to PF-05221304 and placebo (3 tablets) matched to PF-06865571 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
OG001	PF-05221304 15mg + Placebo	Participants were randomized to receive PF-05221304 15 mg tablets (3 tablets, each of 5 mg) and placebo (3 tablets) matched to PF-06865571, orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
OG002	PF-06865571 300 mg + Placebo

Secondary

Maximum Change (Increase or Decrease) From Baseline to Post-last Dose of Study Drug in Vital Signs: Pulse Rate

Vital signs included systolic blood pressure, diastolic blood pressure and pulse rate.

Posted

Mean

Standard Deviation

beats per minute

Baseline, Post- last dose of study drug (up to Day 42)

ID	Title	Description
OG000	Placebo	Participants were randomized to receive placebo (3 tablets) matched to PF-05221304 and placebo (3 tablets) matched to PF-06865571 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
OG001	PF-05221304 15mg + Placebo	Participants were randomized to receive PF-05221304 15 mg tablets (3 tablets, each of 5 mg) and placebo (3 tablets) matched to PF-06865571, orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
OG002	PF-06865571 300 mg + Placebo	Participants were randomized to receive PF-06865571 300 mg (3 tablets, each of 100 mg) and placebo (3 tablets) matched to PF-05221304 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.

Secondary

Number of Participants Meeting Pre-Specified Electrocardiogram (ECG) Criteria

ECG criteria included: 1) PR interval (milliseconds [msec]): baseline greater than (>) 200 msec and maximum increase from baseline greater than or equal to (>=) 25 percent (%) or baseline less than or equal to (<=) 200 msec and maximum increase from baseline >=50%; 2) QRS interval (msec): maximum increase from baseline >=50%; 3) QT interval corrected using Fridericia's formula (QTcF): a) change from baseline >30 msec and <=60 msec, b) change from baseline >60 msec.

Posted

Count of Participants

Participants

Baseline up to 35 days last dose of study drug or early termination (maximum up to Day 77)

ID	Title	Description
OG000	Placebo	Participants were randomized to receive placebo (3 tablets) matched to PF-05221304 and placebo (3 tablets) matched to PF-06865571 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.
OG001	PF-05221304 15mg + Placebo	Participants were randomized to receive PF-05221304 15 mg tablets (3 tablets, each of 5 mg) and placebo (3 tablets) matched to PF-06865571, orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.

Arm/Groups

ID	Title	Description	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Placebo	Participants were randomized to receive placebo (3 tablets) matched to PF-05221304 and placebo (3 tablets) matched to PF-06865571 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.	14	0	14	3	14
EG001	PF-05221304 15mg + Placebo	Participants were randomized to receive PF-05221304 15 mg tablets (3 tablets, each of 5 mg) and placebo (3 tablets) matched to PF-06865571, orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.	29	0	29	6	29
EG002	PF-06865571 300 mg + Placebo	Participants were randomized to receive PF-06865571 300 mg (3 tablets, each of 100 mg) and placebo (3 tablets) matched to PF-05221304 orally, twice daily for 41 days and once on Day 42. Participants were followed up to maximum of 35 days after last dose of study drug.	28	0	28	6	28
EG003	PF-05221304 \|15mg Q12H + \|PF-06865571 \|300mg Q12H	Participants were randomized to receive PF-05221304 15 mg tablets and PF-06865571 300 mg tablets, orally, twice daily for 42 days. Participants were followed up to maximum of 35 days after last dose of study drug.	28	1	28	1	28

Other Adverse Events

Term	Organ System	Source Vocabulary	Assessment Type	Statistical Information
Abdominal pain	Gastrointestinal disorders	MedDRA v22.1	Non-systematic Assessment	EG0001 affected14 at risk EG0010 affected29 at risk EG0021 affected28 at risk EG0030 affected28 at risk
Constipation	Gastrointestinal disorders	MedDRA v22.1	Non-systematic Assessment	EG0001 affected14 at risk EG0011 affected29 at risk EG0021 affected28 at risk EG003
Diarrhoea	Gastrointestinal disorders	MedDRA v22.1	Non-systematic Assessment	EG0000 affected14 at risk EG0011 affected29 at risk EG0022 affected28 at risk EG003
Pyrexia	General disorders	MedDRA v22.1	Non-systematic Assessment	EG0001 affected14 at risk EG0010 affected29 at risk EG0020 affected28 at risk EG003
Folliculitis	Infections and infestations	MedDRA v22.1	Non-systematic Assessment	EG0001 affected14 at risk EG0010 affected29 at risk EG0020 affected28 at risk EG003
Urinary tract infection	Infections and infestations	MedDRA v22.1	Non-systematic Assessment	EG0000 affected14 at risk EG0012 affected29 at risk EG0020 affected28 at risk EG003
Blood thyroid stimulating hormone increased	Investigations	MedDRA v22.1	Non-systematic Assessment	EG0001 affected14 at risk EG0010 affected29 at risk EG0020 affected28 at risk EG003
Hypertriglyceridaemia	Metabolism and nutrition disorders	MedDRA v22.1	Non-systematic Assessment	EG0001 affected14 at risk EG0010 affected29 at risk EG0020 affected28 at risk EG003
Type 2 diabetes mellitus	Metabolism and nutrition disorders	MedDRA v22.1	Non-systematic Assessment	EG0001 affected14 at risk EG0011 affected29 at risk EG0020 affected28 at risk EG003
Headache	Nervous system disorders	MedDRA v22.1	Non-systematic Assessment	EG0000 affected14 at risk EG0011 affected29 at risk EG0022 affected28 at risk EG003
Rash	Skin and subcutaneous tissue disorders	MedDRA v22.1	Non-systematic Assessment	EG0000 affected14 at risk EG0010 affected29 at risk EG0022 affected28 at risk EG003

ID	Term
D005234	Fatty Liver
D008107	Liver Diseases
D004066	Digestive System Diseases