Safety and Efficacy of Roflumilast and Pioglitazone in Treating Adults With Nonalcoholic SteatoHepatitis
Condition: Nonalcoholic Steatohapatitis
MeSH terms: Fatty Liver; Non-alcoholic Fatty Liver Disease
Intervention: Roflumilast; Pioglitazone; Placebo; Placebo
Intervention description: Roflumilast dose; Pioglitazone dose; Pioglitazone placebo-matching dose; Roflumilast placebo-matching dose
Intervention MeSH terms: Pioglitazone
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Maximum age: 80 Years
Healthy volunteers: No
Keywords: Drug therapy

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          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 12 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 30 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 and for 30 days after last dose.

          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 and fish oil, 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.

        Exclusion Criteria:

          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.

         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.