A Randomized, Double-Blind, Controlled, Multi-Center Phase 2 Study to Evaluate the Effect of Roflumilast Plus Pioglitazone on Liver Enzymes and Liver Fat Content in Subjects with Nonalcoholic Steatohepatitis Study Number: ROF-NASH_205
The purpose of this study is to evaluate the effect of roflumilast and pioglitazone therapy
on serum transaminase (ALT) levels in adults with Nonalcoholic SteatoHepatitis.
1. In the opinion of the investigator, the patient is capable of understanding and complying with protocol requirements.
2. The patient or, when applicable, the patient's legally acceptable representative signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
3. Has a historical diagnosis of NASH, established no more than 6 months prior to study entry based on histology (liver biopsy).
4. Has a NAFLD Activity Score (NAS) of ≥3, with a score of at least 1 in steatosis and lobular inflammation - the subcomponents of NAS. It is acceptable if the score for hepatocyte ballooning is "zero".
5. The subject has a MRI determined liver fat fraction of equal or higher than 7 percent.
6. The subject is female or male and aged 18 to 80 years, inclusive.
7. A male who is nonsterilized and sexually active with a female partner of childbearing potential agrees to use adequate contraception from signing of informed consent throughout the duration of the study and for 12 weeks after last dose.
8. A female of childbearing potential who is sexually active with a nonsterilized male partner agrees to use routinely adequate contraception from signing of informed consent throughout the duration of the study.
9. If taking Vitamin E and/or pentoxifylline, the subject has been receiving a stable dose for 6 months prior to randomization, started Vitamin E and/or pentoxifylline therapy prior to the qualifying liver biopsy, and agrees to maintain a stable dose throughout the study when possible.
10. Subject has an ALT level at Screening between 55 and 250 IU/L, inclusive, and between 60 and 250 IU/L at one other occasion during the 6 months prior to Randomization.
11. If taking a statin, should be on stable dose for 6 months prior to screening.
12. If taking angiotensin receptor blockers, should be on a stable dose for at least 3 month prior to screening
13. If diabetic, the subject is on a stable dose of metformin, dipeptidyl peptidase-4 inhibitor, sulfonylurea or insulin or a combination thereof for at least 3 months prior to Screening.
1. The subject has a history of chronic liver disease other than NASH eg, chronic or acute hepatitis, Wilson's disease, alcoholic liver diseases or any other non-NASH active liver disease.
2. Subjects with liver cirrhosis (of any cause) or laboratory or clinical signs of functional liver failure
3. Clinically relevant abnormal laboratory values suggesting an undiagnosed disease other than NASH requiring further clinical evaluation (as assessed by the Investigator).
4. The subject has active cancer or a history of a malignant disease (except basal cell carcinoma) within 5 years prior to Screening or any history of bladder cancer.
5. Subject with a history of weight loss or weight gain of >10 pounds within 6 months prior to Screening.
6. Subject with a history of bariatric surgery within 5 years prior to Screening.
7. The subject has received any investigational compound within 30 days prior to Screening or is currently participating in another clinical study.
8. The subject has a history of hypersensitivity or allergies to roflumilast or pioglitazone including any associated excipients.
9. The subject is required to take excluded medications (see Section 7.3 Excluded Medications and Treatments) including thiazolidinediones to treat his/her diabetes.
10. The subject has taken oral or injectable glucocorticoids for longer than 7 days within 3 months prior to Screening.
11. The subject has poorly controlled Type 1 or Type 2 diabetes mellitus with an HbA1c ≥8.5 at Screening or per Investigator judgment.
12. The subject has hepatitis A, B or C.
13. The subject has severe immunological diseases (eg, known HIV infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy) assessed at Screening.
14. The subject had a history of diabetic gastroparesis or history of gastric bypass surgery.
15. The subject had a history of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within 6 months prior to Screening.
16. The subject had New York Heart Association heart failure of Class (II-IV) regardless of therapy.
17. The subject had a diastolic blood pressure greater than 100 mm Hg or a systolic blood pressure of greater than 160 mm Hg (The mean of the 3 serial BP measurements will be used to determine subject eligibility).
18. The subject has presence or history of psychotic disorder that may be associated with suicidal thinking, ideation or behavior. These disorders include, but are not limited to, depression, psychosis, psychotic disorder, and schizophrenia. Subjects will be monitored by Columbia-Suicide Severity Rating Scales throughout the duration of the study.
19. The subject has a history of drug abuse (defined as illicit drug use) or a history of alcohol abuse (defined as regular or daily consumption of more than 2 alcoholic drinks per day for women or 3 alcoholic drinks per day for men. One drink is equivalent to a 12-ounce beer, a 4-ounce glass of wine, or a 1-ounce shot of hard liquor.) within 1 year prior to the Screening visit.
20. The subject has a hemoglobin <120 g/L for men and <100 g/L for women.
21. The subject has received pioglitazone or roflumilast in a previous clinical study or as a therapeutic agent within 1 year prior to screening.
22. If female, the subject is pregnant or lactating or intending to become pregnant before, during, or within 1 month after participating in this study; or intending to donate ova during such time period.
23. The subject is an immediate family member, study site employee, or is in a dependent relationship with a study site employee who is involved in conduct of this study (eg, spouse, parent, child, sibling) or may consent under duress.
24. The subject has significant results from physical examinations or clinical laboratory results that, at the discretion of the investigator, would make it difficult to successfully manage and follow the subject according to the protocol.