| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Nonalcoholic Fatty Liver Disease (NAFLD) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Nonalcoholic Fatty Liver Disease (NAFLD) |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10053219 |
| E.1.2 | Term | Non-alcoholic steatohepatitis |
| E.1.2 | System Organ Class | 10019805 - Hepatobiliary disorders |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the dose-response for the effect on liver fat with a range of PF-05221304 doses administered daily in adults with nonalcoholic fatty liver disease (entire study population) |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate the dose-response for the effect on ALT with a range of PF-05221304 doses administered daily in the 1st tier stratification comprising of adults with diagnosed/presumed nonalcoholic steatohepatitis, only
• To evaluate the safety and tolerability of a range of PF-05221304 doses administered daily in adults with nonalcoholic fatty liver disease (entire study population) |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female subjects between the ages of 18 (or the minimum country-specific age of consent if > 18) and 70 years, inclusive, at Visit 1 (Screen 1):
• Male and female subjects of childbearing potential must agree to use highly effective method(s) of contraception.
• Female subjects of childbearing potential must not be pregnant, breastfeeding, or planning to become pregnant for the duration of their participation in this study and within 28-days following last dose of blinded investigational product.
• Female subjects of non-childbearing potential must meet at least 1 of the following criteria:
a. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state, with a single repeat assessment, via the sponsor-identified central laboratory, permitted to assess postmenopausal state, if needed;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c. Have medically confirmed ovarian failure;
All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential.
• At Pre-Qualification and Visit 1 (Screen 1), in all female subjects, serum beta human chorionic gonadotropin (β-hCG) level, with a single repeat assessment, via the sponsor-identified central laboratory, permitted to assess non-pregnant state, if needed.
2. At Pre-Qualification, pass the hula-hoop test with a single repeat assessment, permitted, if needed, to assess eligibility.
3. At Pre-Qualification, have an arm circumference compatible with the largest blood pressure cuff size available at individual sites with a single repeat assessment, permitted, if needed, to assess eligibility.
4. At Pre-Qualification and Visit 1 (Screen 1), total body weight of > 50 kg (110 lbs) with BMI ≥ 25 kg/m2 (for sites in Africa, Europe, North America) or BMI ≥ 22.5 kg/m2 (for sites in Asia), with a single repeat assessment of body weight and/or BMI permitted to assess eligibility, if needed, at each of these 2 visits.
5. At Pre-Qualification and Visit 1 (Screen 1), meet the following criteria for liver fat, based on assessment via FibroScan®, with a single repeat permitted to assess eligibility, if needed, at each of these 2 visits:
• CAPTM ≥ 280 dB/m;
6. At Pre-Qualification and Visit 1 (Screen 1), meet the following criteria, as assessed by sponsor-identified central laboratory; with a single repeat on any of these parameters permitted to assess eligibility, if needed, at each of these 2 visits:
• International Normalized Ratio (INR) ≤ 1.3;
• Albumin ≥ lower limit of normal (LLN);
• Platelet count ≥ 0.95x LLN;
• Fasting triglycerides ≤ 400 mg/dL (4.5 mmol/L);
• HbA1C ≤ 9.5%;
• Fasting plasma glucose ≤ 270 mg/dL (15.0 mmol/L);
• Total bilirubin < 1.5x upper limit of normal (ULN) and direct bilirubin ≤ ULN.
7. Documented liver biopsy ≤ 24-months prior to Visit 1 (Screen 1) with histological evidence of NASH in order to be classified in the sub-population with biopsy-proven NASH, only.
8. In those without biopsy-proven NASH, only, at Pre-Qualification and Visit 1 (Screen 1), meet the following criteria for liver stiffness, based on assessment via FibroScan®, with a single repeat permitted to assess eligibility, if needed, at each of these 2 visits:
• LSM ≥ 7.0 kPa – classified as presumed NASH;
• LSM < 7.0 kPa – classified as NAFLD with likely minimal inflammation and fibrosis;
9. In those without biopsy-proven NASH, only, at Pre-Qualification and Visit 1 (Screen 1), meet the following criteria, as assessed by the sponsor-identified central laboratory, with a single repeat permitted to assess eligibility, if needed, at each of these 2 visits:
• ALT > ULN and ≤ 5x ULN – classified as presumed NASH;
• ALT ≤ 1.25x ULN – classified as NAFLD with likely minimal inflammation and fibrosis;
10. In those without biopsy-proven NASH, only, at Pre-Qualification and Visit 1 (Screen 1), meet ≥ 2 of the following 5 criteria for metabolic syndrome:
• FPG ≥ 100 mg/dL (5.6 mmol/L), or on pharmacological agents with explicit purpose of improving glycemic control;
• Fasting serum HDL-C < 40 mg/dL (1 mmol/L) for males and < 50 mg/dL (1.3 mmol/L) for females, or on pharmacological agents with explicit purpose to increase HDL-C;
• Fasting serum triglyceride (TG) ≥ 150 mg/dL (1.7 mmol/L), or on pharmacological agents with explicit purpose to decrease TG;
• Seated blood pressure (BP) ≥ 130 / 85 mm Hg, or on pharmacological agents with explicit purpose for BP control;
• Waist circumference ≥ 40 inches (102 cm) for males and ≥ 35 inches (89 cm) for females.
Please refer to the protocol for inclusion criteria 11 to 13. |
|
| E.4 | Principal exclusion criteria |
1. Subjects with known prior participation (ie, randomized and received at least 1 dose of investigational product) in a trial involving PF-05221304.
2. Participation in other studies involving investigational drug(s) within 30-days prior to Visit 1 (Screen 1) and during study participation (ie, up to 2nd Follow-up).
3. At Pre-Qualification and Visit 1 (Screen 1), history of regular alcohol consumption exceeding 14 drinks/week for females or 21 drinks/week for males [1 drink = 5 ounces (150 mL) of wine or 12 ounces (360 mL) of beer or 1.5 ounces (45 mL) of hard liquor)] within the previous 6 months.
4. At Pre-Qualification and Visit 1 (Screen 1), a total score of ≥ 8 on the AUDIT questionnaire, indicating harmful or hazardous ethanol consumption.
5. At Pre-Qualification and Visit 1 (Screen 1), a positive urine drug test for illicit drugs.
6. At Pre-Qualification and Visit 1 (Screen 1), a persistent severe, uncontrolled
hypertension; for example: seated systolic blood pressure (SBP) ≥180 mm Hg and/or diastolic blood pressure (DBP) ≥ 105 mm Hg after ≥ 5-minute of rest, with a single repeat permitted to assess eligibility, if needed, at each of these 2 visits:
• For subjects with SBP ≥ 160 mm Hg or DBP ≥ 100 mm Hg, the Run-in Period must be used to refine the doses of the agents used for management of blood pressure with the aim to have SBP ≤ 159 mm Hg and DBP ≤ 99 mm Hg at the time of randomization;
7. At Pre-Qualification and Visit 1 (Screen 1), a supine 12-lead ECG demonstrating QTc interval >450 msec or a QRS interval >120 msec:
• If QTc interval exceeds 450 msec, or QRS interval exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTc intervals or QRS intervals should be used to determine the subject’s eligibility.
8. At Pre-Qualification and Visit 1 (Screen 1), clinical evidence of hepatic decompensation, including, but not limited to esophageal varices, ascites or hepatic encephalopathy.
9. At Pre-Qualification and Visit 1 (Screen 1), evidence of other forms of chronic liver disease including but not limited to the entities listed below; evidence may include laboratory tests, as assessed by the sponsor-identified central laboratory, with a single repeat permitted to assess eligibility, if needed, at each of those two visit:
• Hepatitis B virus (HBV), defined by presence of hepatitis B surface antigen (HBsAg);
• Hepatitis C virus (HCV), defined by presence of hepatitis C antibody (HCVAb) irrespective of HCV RNA result (when reflexed based on a positive result for HCVAb);
• Human Immunodeficiency Virus (HIV) infection, defined as presence of HIV antibody;
• Known diagnosis of primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, or overlap syndrome;
• Alcoholic liver disease, as evaluated via history along with laboratory tests including serum % carbohydrate deficient transferrin result ≥ 1.5x ULN deemed to be highly suggestive to alcohol abuse;
• History of genetic reason for fatty liver;
• Wilson's disease, defined as ceruloplasmin level < LLN;
• Known diagnosis of hemochromatosis;
• Alpha-1-antitrypsin (A1AT) deficiency, defined as alpha-1-antitrypsin level < LLN;
• Prior known drug-induced liver injury;
• Known or suspected Hepatocellular Carcinoma or other liver cancer;
• History of liver transplant, current placement on a liver transplant list, or current model of end-stage liver disease (MELD) score >12;
• Histological presence of cirrhosis on prior biopsy.
10. At Pre-Qualification and Visit 1 (Screen 1), subjects with an estimated glomerular filteration rate (eGFR) of < 30 mL/min using the Modification of Diet in Renal Disease (MDRD) equation, and serum creatinine (SCr), as assessed by the sponsor-identified central laboratory, with a single repeat permitted to assess eligibility, if needed, at each of these 2 visits.
Please refer to protocol for exclusion criteria 11 to 18. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Percent change from baseline in liver fat, as assessed using MRI-PDFF |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Percent change from baseline in ALT
- Assessment of TEAEs, safety-related clinical laboratory tests, vital signs, and 12-lead ECGs |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Percent change from baseline in ALT: at Week 16
- Assessment of TEAEs, safety-related clinical laboratory tests, vital signs, and 12-lead ECGs: at each visit
|
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 19 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 27 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Canada |
| Israel |
| Poland |
| Taiwan |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| End of trial in a Member State of the European Union is defined as the time at which it is deemed that a sufficient number of subjects have been recruited and completed the study as stated in the regulatory application and ethics application in the Member State. Poor recruitment (recruiting less than the anticipated number in the CTA) by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 14 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 14 |
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