Safety and Efficacy of Roflumilast and Pioglitazone in Treating Adults With Nonalcoholic SteatoHepatitis

This proof of concept study will evaluate the effect of roflumilast and pioglitazone on
transaminase levels and liver fat content.

Takeda has chosen not to continue this Study, however, randomized subjects were allowed to
complete the study per protocol.

The decision to terminate the study is not related to any safety concerns with either of the
study medications.

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.