Nonalcoholic SteatohapatitisPhase 2NCT01703260

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

A Phase 2 study testing Roflumilast and Pioglitazone in people with Nonalcoholic Steatohapatitis, run by AstraZeneca at 4 sites in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record

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Trial 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. Read more about this study

Who is it for?: Ages 18 to 80 years
Conditions the study is for: Nonalcoholic Steatohapatitis
What is being tested?: Roflumilast and Pioglitazone
Type of treatment: Pill or oral medicine
Could I receive a placebo?: Yes, some participants may receive a placebo
How many people: 20 participants
Where: 4 sitesUnited States
Study dates: Jun 2013to Sep 2014
Phase: Phase 2
Are there results?: Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

Ages 18 to 80 years
All sexes
No healthy volunteers
Adult, Older adult

Who may be able to join

In the opinion of the investigator, the patient is capable of understanding and complying with protocol requirements.
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.
Has a historical diagnosis of NASH, established no more than 12 months prior to study entry based on histology (liver biopsy).
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".
The subject has a MRI determined liver fat fraction of equal or higher than 7 percent.
The subject is female or male and aged 18 to 80 years, inclusive.

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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.
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.
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.
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.
If taking a statin, should be on stable dose for 6 months prior to screening.
If taking angiotensin receptor blockers and fish oil, should be on a stable dose for at least 3 month prior to screening.
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.

Who cannot join

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.
Subjects with liver cirrhosis (of any cause) or laboratory or clinical signs of functional liver failure
Clinically relevant abnormal laboratory values suggesting an undiagnosed disease other than NASH requiring further clinical evaluation (as assessed by the Investigator).
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.
Subject with a history of weight loss or weight gain of >10 pounds within 6 months prior to Screening.
Subject with a history of bariatric surgery within 5 years prior to Screening.

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The subject has received any investigational compound within 30 days prior to Screening or is currently participating in another clinical study.
The subject has a history of hypersensitivity or allergies to roflumilast or pioglitazone including any associated excipients.
The subject is required to take excluded medications.
The subject has taken oral or injectable glucocorticoids for longer than 7 days within 3 months prior to Screening.
The subject has poorly controlled Type 1 or Type 2 diabetes mellitus with an HbA1c ≥8.5 at Screening or per Investigator judgment.
The subject has hepatitis A, B or C.
The subject has severe immunological diseases (eg, known HIV infection, multiple sclerosis, lupus erythematosus, progressive multifocal leukoencephalopathy) assessed at Screening.
The subject had a history of diabetic gastroparesis or history of gastric bypass surgery.
The subject had a history of coronary angioplasty, coronary stent placement, coronary bypass surgery, or myocardial infarction within 6 months prior to Screening.
The subject had New York Heart Association heart failure of Class (II-IV) regardless of therapy.
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).
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.
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.
The subject has a hemoglobin <120 g/L for men and <100 g/L for women.
The subject has received pioglitazone or roflumilast in a previous clinical study or as a therapeutic agent within 1 year prior to screening.
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.
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.
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.

Trial locations and contacts

4 sites in 1 country.

United States4 sites

Study site
Annapolis, Maryland, 21401
Study site
Baltimore, Maryland, 21202
Study site
Coronado, California, 92118
Study site
Coronado, California

Other trials in United States

About this study

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

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.

Read the 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.

Conditions: Nonalcoholic Steatohapatitis
Being tested: Roflumilast, Pioglitazone, Placebo
Keywords: Drug therapy

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

RoflumilastDrug
Also called Daxas, Daliresp
Roflumilast dose
PioglitazoneDrug
Also called Actos
Pioglitazone dose
PlaceboDrug
Pioglitazone placebo-matching dose
PlaceboDrug
Roflumilast placebo-matching dose

Study groups in NCT01703260
Study group	Role	What they receive
Roflumilast + pioglitazone	Experimental	Roflumilast dose and pioglitazone dose, orally for up to 4 months Receives: Drug: Roflumilast; Drug: Pioglitazone
Roflumilast	Experimental	Roflumilast dose and pioglitazone matching-placebo dose orally for up to 4 months. Receives: Drug: Roflumilast; Drug: Placebo
Pioglitazone	Experimental	Pioglitazone dose, orally and roflumilast matching-placebo dose, orally for up to 4 months Receives: Drug: Pioglitazone; Drug: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

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

Secondary outcomes (4)

Amount of Serum Aspartate Transaminase (AST) at Baseline
Measured: Baseline
Percent Change From Baseline in Serum AST at Month 4
The percent change between the serum AST value collected at Month 4 or final visit relative to baseline.
Measured: Month 4
Liver Fat Content at 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.
Measured: Baseline
Change From Baseline in Liver Fat Content at 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.
Measured: Baseline and Month 4

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

Jun 2013Sep 2014

First posted10 Oct 2012 (estimated)
Study startJun 2013
Primary completionSep 2014
Study completionSep 2014

Why it stopped: Company decision; No safety or efficacy concerns (see detailed description)

Resources

Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
Other trials for Nonalcoholic SteatohapatitisStudies of the same condition, open and under way.
More trials run by AstraZenecaThe sponsor's other registered studies.
What the trial phases meanHow a treatment moves from first tests in people to approval.

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design

Study type: Interventional
Phase: Phase 2
Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind
Who is masked: Participant, Care provider, Investigator, Outcomes assessor
Enrolment: 20 participants (actual)

IDs, dates and publications

ClinicalTrials.gov ID: NCT01703260
Sponsor's protocol ID: ROF-NASH_205
Other IDs: U1111-1129-5051
Status last verified: Sep 2016
First submitted: 2 Oct 2012
Last updated: 1 Feb 2017
Results posted: Yes, on ClinicalTrials.gov
Data monitoring committee: No

Study at a glance

From the registry record, last updated by the sponsor on 1 Feb 2017. Recruitment status is as the sponsor reported it: confirm with the study team.

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
ClinicalTrials.gov ID: NCT01703260
Acronym / sponsor ID: ROF-NASH_205
Conditions: Nonalcoholic Steatohapatitis
Keywords: Drug therapy
Phase: Phase 2
Study type: Interventional
Recruitment status: TerminatedReason stopped: Company decision; No safety or efficacy concerns (see detailed description)
Enrolment: 20 participants (actual)
Lead sponsor: AstraZenecaIndustry (pharma, biotech, devices)
Study start: Jun 2013
Primary completion: Sep 2014 (actual)
Study completion: Sep 2014 (actual)
First posted: 10 Oct 2012 (estimated)
Results: Posted 23 Feb 2016

Clinical summary

The research question as the sponsor registered it. This describes what the study plans to test, not what it found.

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.

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

Primary purpose: Treatment
Allocation: Randomised
Intervention model: Parallel groups
Masking: Quadruple blind (participant, care provider, investigator, outcomes assessor)
Number of arms: 3

Arm	Type	Receives
Roflumilast + pioglitazone	Experimental	Drug: Roflumilast, Drug: PioglitazoneRoflumilast dose and pioglitazone dose, orally for up to 4 months
Roflumilast	Experimental	Drug: Roflumilast, Drug: PlaceboRoflumilast dose and pioglitazone matching-placebo dose orally for up to 4 months.
Pioglitazone	Experimental	Drug: Pioglitazone, Drug: PlaceboPioglitazone dose, orally and roflumilast matching-placebo dose, orally for up to 4 months

Who may qualify

Ages: 18 to 80 years
Sex: All
Healthy volunteers: Not accepted
Age groups: Adult, Older adult

Key inclusion criteria (13 listed)

In the opinion of the investigator, the patient is capable of understanding and complying with protocol requirements.
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.
Has a historical diagnosis of NASH, established no more than 12 months prior to study entry based on histology (liver biopsy).
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".
The subject has a MRI determined liver fat fraction of equal or higher than 7 percent.

Key exclusion criteria (24 listed)

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.
Subjects with liver cirrhosis (of any cause) or laboratory or clinical signs of functional liver failure
Clinically relevant abnormal laboratory values suggesting an undiagnosed disease other than NASH requiring further clinical evaluation (as assessed by the Investigator).
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.
Subject with a history of weight loss or weight gain of >10 pounds within 6 months prior to Screening.

Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.

Interventions

Intervention	Type	Arms
RoflumilastAlso: Daxas, DalirespRoflumilast dose	Drug	Roflumilast, Roflumilast + pioglitazone
PioglitazoneAlso: ActosPioglitazone dose	Drug	Pioglitazone, Roflumilast + pioglitazone
PlaceboPioglitazone placebo-matching dose	Drug	Roflumilast
PlaceboRoflumilast placebo-matching dose	Drug	Pioglitazone

Primary outcome

Amount of Serum Alanine Transaminase (ALT) at Baseline
Time frame: Baseline
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.

4 secondary outcomes

Amount of Serum Aspartate Transaminase (AST) at Baseline
Time frame: Baseline
Percent Change From Baseline in Serum AST at Month 4
Time frame: Month 4
Liver Fat Content at Baseline
Time frame: Baseline
Change From Baseline in Liver Fat Content at Month 4
Time frame: Baseline and Month 4

Results and safety

Results posted to the registry on 23 Feb 2016, as reported by the sponsor. Figures are copied from the record, not re-analysed. Full results on ClinicalTrials.gov.

Participant flow

Group	Started	Completed
Roflumilast + Pioglitazone	7	4
Roflumilast Only	7	3
Pioglitazone Only	6	3

Primary outcome: Amount of Serum Alanine Transaminase (ALT) at Baseline

Time frame: Baseline. Mean (Standard Deviation). Unit: international units per liter (IU/L)

Measure	Roflumilast + Pioglitazone n = 7	Roflumilast Only n = 7	Pioglitazone Only n = 6
Value	101.7 (56.98)	83.4 (31.63)	118.8 (36.76)

Population analysed: Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline assessment available.

Primary outcome: Percent Change From Baseline in Serum ALT at Month 4

Time frame: Month 4. Mean (Standard Deviation). Unit: percent change

Measure	Roflumilast + Pioglitazone n = 3	Roflumilast Only n = 3	Pioglitazone Only n = 3
Value	-53.89 (23.362)	-56.22 (6.014)	-28.86 (53.298)

Population analysed: Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline and at least 1 post-baseline assessment available.

4 secondary outcomes are reported in the full results.

Adverse events

Time frame: Treatment-emergent AEs will be defined as any AEs, regardless of relationship to study drug, that occur or worsen after the first dose of double-blinded study drug and no more than 30 days after the last dose of study drug.. Other adverse events reported at 0% frequency or more

Group	Serious adverse events	Other adverse events	Deaths
Roflumilast + Pioglitazone	0 of 7 (0%)	5 of 7 (71.4%)	Not reported
Roflumilast Only	0 of 7 (0%)	4 of 7 (57.1%)	Not reported
Pioglitazone Only	0 of 6 (0%)	4 of 6 (66.7%)	Not reported

Loading the posted results from ClinicalTrials.gov…

Research links

Official record on ClinicalTrials.govLast updated by the sponsor 1 Feb 2017.
Posted resultsParticipant flow, baseline, all outcome measures and adverse events.

Referral and contact

AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.

AstraZeneca AstraZeneca study director

AstraZeneca

4 sites in 1 country: see every site and its status.

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Roflumilast and Pioglitazone in people with Nonalcoholic Steatohapatitis, run by AstraZeneca at 4 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 13 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 1 Feb 2017. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 23 Feb 2016). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Amount of Serum Alanine Transaminase (ALT) at Baseline (time frame: Baseline). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01703260.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 1 Feb 2017.