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

• ClinicalTrials.gov Identifier: NCT01703260
• Recruitment Status: Terminated
• First Posted: October 10, 2012
• Results First Posted: February 23, 2016
• Last Update Posted: February 1, 2017
• Sponsor: AstraZeneca
• Information provided by (Responsible Party): AstraZeneca

Study Description

Brief 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.

Condition or disease	Intervention/treatment	Phase
Nonalcoholic Steatohapatitis	Drug: Roflumilast; Drug: Pioglitazone; Drug: Placebo	Phase 2

Detailed Description:

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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 Start Date: June 2013
• Actual Primary Completion Date: September 2014
• Actual Study Completion Date: September 2014

Arms and Interventions

Arm	Intervention/treatment
Experimental: Roflumilast + pioglitazone; Roflumilast dose and pioglitazone dose, orally for up to 4 months	Drug: Roflumilast; Roflumilast dose; Other Name: Daxas, Daliresp; Drug: Pioglitazone; Pioglitazone dose; Other Name: Actos
Experimental: Roflumilast; Roflumilast dose and pioglitazone matching-placebo dose orally for up to 4 months.	Drug: Roflumilast; Roflumilast dose; Other Name: Daxas, Daliresp; Drug: Placebo; Pioglitazone placebo-matching dose
Experimental: Pioglitazone; Pioglitazone dose, orally and roflumilast matching-placebo dose, orally for up to 4 months	Drug: Pioglitazone; Pioglitazone dose; Other Name: Actos; Drug: Placebo; Roflumilast placebo-matching dose

Outcome Measures

Primary Outcome Measures :

1. Amount of Serum Alanine Transaminase (ALT) at Baseline [ Time Frame: Baseline ]
2. Percent Change From Baseline in Serum ALT at Month 4 [ Time Frame: Month 4 ]
   The percent change between the serum ALT value collected at Month 4 or final visit relative to baseline.

Secondary Outcome Measures :

1. Amount of Serum Aspartate Transaminase (AST) at Baseline [ Time Frame: Baseline ]
2. Percent Change From Baseline in Serum AST at Month 4 [ Time Frame: Month 4 ]
   The percent change between the serum AST value collected at Month 4 or final visit relative to baseline.
3. Liver Fat Content at Baseline [ Time Frame: Baseline ]
   Liver fat content was quantitatively measured by evaluating the percentage of proton density fat fraction (PDFF) from an abdominal magnetic resonance imaging (MRI). On the basis of Couinaud classification (a classification used to describe functional liver anatomy), the liver was divided into 8 segments: caudate, left superolateral, left inferolateral, left superomedial (4a), left inferomedial (4b), right anteroinferior, right posteroinferior, right posterosuperior and right anterosuperior.
4. Change From Baseline in Liver Fat Content at Month 4 [ Time Frame: Baseline and Month 4 ]
   Liver fat content was quantitatively measured by evaluating the percentage of PDFF from an abdominal MRI. On the basis of Couinaud classification (a classification used to describe functional liver anatomy), the liver was divided into 8 segments: caudate, left superolateral, left inferolateral, left superomedial (4a), left inferomedial (4b), right anteroinferior, right posteroinferior, right posterosuperior and right anterosuperior.

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 80 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

United States, California

Coronado, California, United States, 92118

Coronado, California, United States

United States, Maryland

Annapolis, Maryland, United States, 21401

Baltimore, Maryland, United States, 21202

Sponsors and Collaborators

AstraZeneca

Investigators

• Study Director: AstraZeneca AstraZeneca; AstraZeneca

More Information

• Responsible Party: AstraZeneca
• ClinicalTrials.gov Identifier: NCT01703260
• Other Study ID Numbers: ROF-NASH_205; U1111-1129-5051 ( Registry Identifier: WHO )
• First Posted: October 10, 2012
• Results First Posted: February 23, 2016
• Last Update Posted: February 1, 2017
• Last Verified: September 2016

Keywords provided by AstraZeneca:

Drug therapy

Additional relevant MeSH terms:

Fatty Liver; Non-alcoholic Fatty Liver Disease; Liver Diseases; Digestive System Diseases; Pioglitazone; Hypoglycemic Agents; Physiological Effects of Drugs