A Study To Assess Pharmacodynamics, Safety And Tolerability Of PF-05221304 And PF-06865571 Co-Administered For 6 Weeks In Adults With Non-Alcoholic Fatty Liver Disease.

• ClinicalTrials.gov Identifier: NCT03776175
• Recruitment Status: Completed
• First Posted: December 14, 2018
• Results First Posted: September 23, 2020
• Last Update Posted: September 23, 2020
• Sponsor: Pfizer
• Information provided by (Responsible Party): Pfizer

Tracking Information

• First Submitted Date: December 12, 2018
• First Posted Date: December 14, 2018
• Results First Submitted Date: September 2, 2020
• Results First Posted Date: September 23, 2020
• Last Update Posted Date: September 23, 2020
• Actual Study Start Date: January 4, 2019
• Actual Primary Completion Date: September 9, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 2, 2020)

Percent Change From Baseline in Whole Liver Proton Density Fat Fraction (PDFF) at Day 42 [ Time Frame: Baseline, 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.

Original Primary Outcome Measures (submitted: December 12, 2018)

Relative change in whole liver fat as assessed by magnetic resonance imaging proton density fat fraction (MRI-PDFF). [ Time Frame: Baseline up to Day 42 ]

Mean relative changes between placebo and each active drug arm (PF-05221304 monotherapy, PF-06865571 monotherapy and PF-05221304 plus PF-06865571 combination) will be evaluated.

Current Secondary Outcome Measures (submitted: September 2, 2020)

• Number of Participants With Treatment Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 35 days from last dose of study drug or early termination: (maximum up to Day 77) ]
  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.
• Number of Participants With Laboratory Abnormalities [ Time Frame: Baseline up to 35 days last from dose of study drug or early termination (maximum up to Day 77) ]
  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.
• Maximum Change (Increase or Decrease) From Baseline to Post-last Dose of Study Drug in Vital Signs: Blood Pressure [ Time Frame: Baseline, Post-last dose of study drug (up to Day 42) ]
  Vital signs included systolic blood pressure, diastolic blood pressure and pulse rate.
• Maximum Change (Increase or Decrease) From Baseline to Post-last Dose of Study Drug in Vital Signs: Pulse Rate [ Time Frame: Baseline, Post- last dose of study drug (up to Day 42) ]
  Vital signs included systolic blood pressure, diastolic blood pressure and pulse rate.
• Number of Participants Meeting Pre-Specified Electrocardiogram (ECG) Criteria [ Time Frame: Baseline up to 35 days last dose of study drug or early termination (maximum up to Day 77) ]
  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.

Original Secondary Outcome Measures (submitted: December 12, 2018)

• Percentage of Participants With Treatment-Emergent Adverse Events (AEs) or Serious Adverse Events (SAEs) [ Time Frame: Baseline up to 14 Days after last dose ]
  An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship.
• Number of Participants With Change From Baseline in Electrocardiogram (ECG) Findings [ Time Frame: Baseline up to 14 Days after last dose ]
  Clinically significant ECG findings included: QT interval, heart rate, QTcF interval, PR interval, and QRS interval.
• Percentage of Participants With Clinically Significant Change From Baseline in Vital Signs [ Time Frame: Baseline up to 14 Days after last dose ]
  Changes from baseline in systolic blood pressure, diastolic blood pressure and pulse rate.
• Number of Participants With Clinically Significant Change From Baseline in Laboratory Abnormalities [ Time Frame: Baseline up to 14 Days after last dose ]
  Laboratory parameters included: hematology, chemistry, and urinalysis Clinical significance of laboratory parameters was determined at the investigator's discretion.

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study To Assess Pharmacodynamics, Safety And Tolerability Of PF-05221304 And PF-06865571 Co-Administered For 6 Weeks In Adults With Non-Alcoholic Fatty Liver Disease.
• Official Title: A PHASE 2A, RANDOMIZED, DOUBLE BLIND (SPONSOR-OPEN), PLACEBO CONTROLLED, PARALLEL GROUP STUDY TO ASSESS THE PHARMACODYNAMICS, SAFETY AND TOLERABILITY OF PF-05221304 AND PF-06865571 CO-ADMINISTERED FOR 6 WEEKS IN ADULTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
• Brief Summary: This study is to assess the effect of PF 05221304 alone, PF 06865571 alone, the co administration of PF 05221304 and PF 06865571, or placebo on whole liver fat in subjects with NAFLD. In addition, this study will evaluate the safety and tolerability of co administration of PF 05221304 and PF 06865571 along with the effects on selected pharmacodynamics (PD)/exploratory parameters, compared to administration of PF 05221304 alone, PF 06865571 alone, and placebo in adults with NAFLD.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
• Condition: Non-Alcoholic Fatty Liver Disease (NAFLD)

Intervention

• Drug: PF-05221304 Monotherapy
  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.
  Other Name: Arm B
• Drug: PF-06865571 Monotherapy
  Participants enrolled in this Arm will receive 300 mg dose of PF-06865571 (3 tablets of 100 mg each) and 3 tablets of Placebo for PF-05221304, all to be taken twice daily for 41 days and once on Day 42.
  Other Name: Arm C
• Drug: Placebo
  Participants enrolled in this Arm will receive 3 tablets for Placebo of PF-05221304 and 3 tablets of Placebo of PF-06865571, to be taken twice daily for 41 days and once on Day 42.
  Other Name: Arm A
• Drug: PF-05221304 and PF-06865571 Combination
  Participants enrolled in this Arm will receive 15 mg dose of PF-05221304 (3 tablets of 5 mg each) and 3 tablets of PF-06865571 (3 tablets of 100 mg each), each to be taken twice daily for 41 days and once on Day 42.
  Other Name: Arm D

Study Arms

• Placebo Comparator: Placebo
  Placebo (PF 05221304) BID Placebo (PF 06865571) BID
  Intervention: Drug: Placebo
• Experimental: PF-05221304 Monotherapy
  15 mg PF-05221304 BID Placebo (PF-06865571) BID
  Interventions:

  • Drug: PF-05221304 Monotherapy
  • Drug: Placebo
• Experimental: PF-06865571 Monotherapy
  Placebo (PF-05221304) BID 300 mg PF-06865571 BID
  Interventions:

  • Drug: PF-06865571 Monotherapy
  • Drug: Placebo
• Experimental: PF-05221304 and PF-06865571 Combination
  15 mg PF-05221304 BID 300 mg PF-06865571 BID
  Interventions:

  • Drug: PF-05221304 Monotherapy
  • Drug: PF-06865571 Monotherapy
  • Drug: PF-05221304 and PF-06865571 Combination

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: November 6, 2019): 99
• Original Estimated Enrollment (submitted: December 12, 2018): 98
• Actual Study Completion Date: October 11, 2019
• Actual Primary Completion Date: September 9, 2019 (Final data collection date for primary outcome measure)

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 70 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03776175
• Other Study ID Numbers: C3711001
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.
• URL: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

• Responsible Party: Pfizer
• Study Sponsor: Pfizer
• Collaborators: Not Provided

Investigators

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

• PRS Account: Pfizer
• Verification Date: September 2020