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

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

Detailed Description
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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

Official Title
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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

Conditions
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Nonalcoholic Fatty Liver Disease, Nonalcoholic Steatohepatitis

Intervention / Treatment
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* Drug: Placebo
* Drug: PF-05221304


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: C1171002 is a randomized, double blind, placebo controlled, 5 arm (placebo, plus 4 active doses of PF 05221304), parallel group study.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Double-Blind, PF-05221304-matching Placebo | Drug: Placebo<br>* Placebo<br>|
| Active Comparator: PF-05221304 - 2 mg<br>PF-05221304 - 2 mg, once-daily | Drug: PF-05221304<br>* PF-05221304, Experimental Drug<br>|
| Active Comparator: PF-05221304 - 10 mg<br>PF-05221304 - 10 mg, once-daily | Drug: PF-05221304<br>* PF-05221304, Experimental Drug<br>|
| Active Comparator: PF-05221304 - 25 mg<br>PF-05221304 - 25 mg, once-daily | Drug: PF-05221304<br>* PF-05221304, Experimental Drug<br>|
| Active Comparator: PF-05221304 - 50 mg<br>PF-05221304 - 50 mg, once-daily | Drug: PF-05221304<br>* PF-05221304, Experimental Drug<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Liver Fat by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI- PDFF) at 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. | Baseline (between Day -14 and Day 1), Week 16 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline in Alanine Aminotransferase at Week 16 | Potential improvement in liver function was denoted by reduction in alanine transaminase (ALT) | Baseline (Day 1 pre-dose), Week 16 | 
| Number of Participants With Treatment-Emergent Adverse Events | 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. | From first dose of study treatment (Day 1) up to Week 20 | 
| Number of Participants With Laboratory Abnormalities | 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). | From first dose of study treatment (Day 1) up to Week 20 | 
| Number of Participants With Vital Signs Data Meeting Predefined Criteria | 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. | From first dose of study treatment (Day 1) up to Week 18 | 
| Number of Participants With 12-Lead Electrocardiogram (ECG) Data Meeting Predefined Criteria | 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. | From first dose of study treatment (Day 1) up to Week 18 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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PF-05221304, NAFLD, NASH, features of metabolic syndrome, Dose-Ranging Study