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

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ClinicalTrials.gov Identifier: NCT01703260
Recruitment Status : Terminated (Company decision; No safety or efficacy concerns (see detailed description))
First Posted : October 10, 2012
Results First Posted : February 23, 2016
Last Update Posted : February 1, 2017
Sponsor:
Information provided by (Responsible Party):
AstraZeneca

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Nonalcoholic Steatohapatitis
Interventions Drug: Roflumilast
Drug: Pioglitazone
Drug: Placebo
Enrollment 20
Recruitment Details Participants took part at 11 sites in the United States from 26 April 2013 to 30 September 2014.
Pre-assignment Details Participants with a historical diagnosis of nonalcoholic steatohepatitis (NASH) and nonalcoholic fatty liver disease (NAFLD) activity score (NAS) of greater than or equal to (>=) 3 were enrolled in 1 of 3 treatment groups as follows: roflumilast + pioglitazone; roflumilast only; pioglitazone only.
Arm/Group Title Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only
Hide Arm/Group Description Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months. Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months. Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.
Period Title: Overall Study
Started 7 7 6
Completed 4 3 3
Not Completed 3 4 3
Reason Not Completed
Adverse Event             1             2             2
Lost to Follow-up             1             0             0
Withdrawal by Subject             0             0             1
Study Termination             1             2             0
Arm/Group Title Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only Total
Hide Arm/Group Description Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months. Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months. Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months. Total of all reporting groups
Overall Number of Baseline Participants 7 7 6 20
Hide Baseline Analysis Population Description
The randomized set included all participants who were randomized.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 7 participants 7 participants 6 participants 20 participants
45.4  (9.64) 43.9  (14.77) 42.5  (8.67) 44.0  (10.93)
Age, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 6 participants 20 participants
18 - 39 years 3 2 3 8
40 - 59 years 4 4 3 11
60 - 80 years 0 1 0 1
Gender  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 6 participants 20 participants
Female
5
  71.4%
2
  28.6%
2
  33.3%
9
  45.0%
Male
2
  28.6%
5
  71.4%
4
  66.7%
11
  55.0%
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 6 participants 20 participants
Hispanic or Latino 0 3 1 4
Non-Hispanic or Latino 7 4 5 16
Race/Ethnicity, Customized  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 6 participants 20 participants
Asian 0 2 0 2
White 7 4 6 17
Multiracial 0 1 0 1
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 7 participants 7 participants 6 participants 20 participants
7 7 6 20
Height  
Mean (Standard Deviation)
Unit of measure:  Centimeter (cm)
Number Analyzed 7 participants 7 participants 6 participants 20 participants
165.6  (15.13) 168.7  (8.62) 174.3  (7.50) 169.3  (11.13)
Weight  
Mean (Standard Deviation)
Unit of measure:  Kilogram (kg)
Number Analyzed 7 participants 7 participants 6 participants 20 participants
102.19  (21.041) 92.06  (20.784) 110.15  (15.456) 101.03  (19.887)
Body Mass Index (BMI)  
Mean (Standard Deviation)
Unit of measure:  Kilogram per square meter(kg/m^2)
Number Analyzed 7 participants 7 participants 6 participants 20 participants
37.18  (5.192) 32.19  (6.189) 36.60  (7.475) 35.26  (6.381)
Smoking Classification  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 6 participants 20 participants
Had Never Smoked 3 6 5 14
Current Smoker 1 1 1 3
Ex-Smoker 3 0 0 3
Type 2 Diabetes Mellitus  
Measure Type: Number
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 6 participants 20 participants
Had Diabetes Mellitus 2 2 1 5
Did Not Have Diabetes Mellitus 5 5 5 15
1.Primary Outcome
Title Amount of Serum Alanine Transaminase (ALT) at Baseline
Hide Description [Not Specified]
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline assessment available.
Arm/Group Title Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only
Hide Arm/Group Description:
Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.
Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.
Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.
Overall Number of Participants Analyzed 7 7 6
Mean (Standard Deviation)
Unit of Measure: international units per liter (IU/L)
101.7  (56.98) 83.4  (31.63) 118.8  (36.76)
2.Primary Outcome
Title Percent Change From Baseline in Serum ALT at Month 4
Hide Description The percent change between the serum ALT value collected at Month 4 or final visit relative to baseline.
Time Frame Month 4
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only
Hide Arm/Group Description:
Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.
Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.
Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.
Overall Number of Participants Analyzed 3 3 3
Mean (Standard Deviation)
Unit of Measure: percent change
-53.89  (23.362) -56.22  (6.014) -28.86  (53.298)
3.Secondary Outcome
Title Amount of Serum Aspartate Transaminase (AST) at Baseline
Hide Description [Not Specified]
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline assessment available.
Arm/Group Title Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only
Hide Arm/Group Description:
Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.
Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.
Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.
Overall Number of Participants Analyzed 7 7 6
Mean (Standard Deviation)
Unit of Measure: IU/L
64.0  (43.49) 44.9  (15.25) 88.3  (73.06)
4.Secondary Outcome
Title Percent Change From Baseline in Serum AST at Month 4
Hide Description The percent change between the serum AST value collected at Month 4 or final visit relative to baseline.
Time Frame Month 4
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only
Hide Arm/Group Description:
Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.
Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.
Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.
Overall Number of Participants Analyzed 3 3 3
Mean (Standard Deviation)
Unit of Measure: percent change
-41.31  (36.087) -43.20  (7.339) -17.56  (45.458)
5.Secondary Outcome
Title Liver Fat Content at Baseline
Hide Description 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.
Time Frame Baseline
Hide Outcome Measure Data
Hide Analysis Population Description
Safety analysis set included all participants who were randomized, received at least 1 dose of double-blind study medication and had baseline assessment available.
Arm/Group Title Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only
Hide Arm/Group Description:
Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.
Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.
Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.
Overall Number of Participants Analyzed 7 7 6
Mean (Standard Deviation)
Unit of Measure: percentage of PDFF
Caudate; (n= 6, 7, 6) 22.233  (8.2750) 19.107  (7.7990) 20.117  (9.8492)
Left superolateral; (n= 6, 6, 6) 19.485  (8.8080) 17.813  (7.4410) 17.278  (7.2225)
Left inferolateral; (n= 6, 7, 6) 22.385  (8.9894) 19.747  (7.8306) 19.153  (10.5909)
Left superomedial: (n= 6, 7, 6) 22.115  (9.7126) 20.426  (7.9170) 20.100  (9.8688)
Left inferomedial: (n= 6, 6, 6) 21.553  (9.5912) 18.977  (8.6970) 21.530  (9.5193)
Right anteroinferior: (n= 6, 7, 6) 22.478  (9.0548) 19.994  (9.0103) 20.742  (8.7829)
Right posteroinferior: (n= 6, 7, 6) 23.710  (8.6478) 18.804  (6.6882) 20.070  (9.9727)
Right posterosuperior: (n= 6, 7, 6) 23.282  (9.5984) 18.870  (7.5764) 19.943  (8.9666)
Right anterosuperior: (n=6, 7, 6) 23.630  (8.7454) 19.786  (8.5929) 21.527  (9.6648)
6.Secondary Outcome
Title Change From Baseline in Liver Fat Content at Month 4
Hide Description 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.
Time Frame Baseline and Month 4
Hide Outcome Measure Data
Hide Analysis Population Description
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.
Arm/Group Title Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only
Hide Arm/Group Description:
Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months.
Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months.
Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.
Overall Number of Participants Analyzed 7 7 6
Mean (Standard Deviation)
Unit of Measure: percent change in PDFF
Caudate; (n= 3, 3, 3) -18.787  (11.5646) -11.590  (5.5674) -10.287  (8.8098)
Left superolateral; (n= 6, 6, 6) -15.170  (13.7442) -10.287  (1.9695) -8.067  (7.6318)
Left inferolateral; (n= 3, 3, 3) -14.290  (13.1654) -10.077  (2.9030) -8.773  (7.0821)
Left superomedial: (n= 3, 3, 3) -14.687  (13.6909) -11.177  (3.9429) -9.217  (8.7999)
Left inferomedial: (n= 3, 3, 3) -14.107  (15.2957) -10.977  (5.0052) -9.417  (8.9360)
Right anteroinferior: (n= 3, 3, 3) -13.990  (13.1266) -10.260  (6.9972) -7.693  (9.7985)
Right posteroinferior: (n=3, 3, 3) -18.073  (13.1470) -9.250  (1.6808) -8.790  (10.2188)
Right posterosuperior: (n=3, 3, 3) -17.717  (13.0691) -9.797  (4.4053) -8.113  (10.4166)
Right anterosuperior: (n=3, 3, 3) -16.127  (13.9820) -9.803  (3.3661) -8.647  (10.1658)
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.
Adverse Event Reporting Description At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.
 
Arm/Group Title Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only
Hide Arm/Group Description Roflumilast, 500 microgram (mcg), tablet, orally, once daily and pioglitazone, 30 milligram (mg), tablet, orally, once daily for up to 4 months. Roflumilast, 500 mcg, tablet, orally, once daily and pioglitazone placebo-matching tablet, orally, once daily for up to 4 months. Pioglitazone, 30 mg, tablet, orally, once daily and roflumilast placebo-matching tablet, orally, once daily for up to 4 months.
All-Cause Mortality
Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/7 (0.00%)   0/7 (0.00%)   0/6 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Roflumilast + Pioglitazone Roflumilast Only Pioglitazone Only
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   5/7 (71.43%)   4/7 (57.14%)   4/6 (66.67%) 
Gastrointestinal disorders       
Diarrhoea  1  2/7 (28.57%)  1/7 (14.29%)  1/6 (16.67%) 
Nausea  1  1/7 (14.29%)  2/7 (28.57%)  0/6 (0.00%) 
Vomiting  1  1/7 (14.29%)  1/7 (14.29%)  0/6 (0.00%) 
Dyspepsia  1  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%) 
Eructation  1  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%) 
General disorders       
Chills  1  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%) 
Fatigue  1  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%) 
Pyrexia  1  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%) 
Infections and infestations       
Influenza  1  1/7 (14.29%)  1/7 (14.29%)  1/6 (16.67%) 
Urinary tract infection  1  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%) 
Investigations       
Liver function test abnormal  1  0/7 (0.00%)  0/7 (0.00%)  2/6 (33.33%) 
Weight decreased  1  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%) 
Metabolism and nutrition disorders       
Decreased appetite  1  1/7 (14.29%)  1/7 (14.29%)  0/6 (0.00%) 
Cow's milk intolerance  1  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%) 
Increased appetite  1  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%) 
Musculoskeletal and connective tissue disorders       
Myalgia  1  0/7 (0.00%)  1/7 (14.29%)  1/6 (16.67%) 
Pain in extremity  1  2/7 (28.57%)  0/7 (0.00%)  0/6 (0.00%) 
Arthralgia  1  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%) 
Nervous system disorders       
Headache  1  1/7 (14.29%)  2/7 (28.57%)  2/6 (33.33%) 
Paraesthesia  1  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%) 
Sciatica  1  1/7 (14.29%)  0/7 (0.00%)  0/6 (0.00%) 
Psychiatric disorders       
Insomnia  1  0/7 (0.00%)  1/7 (14.29%)  0/6 (0.00%) 
Respiratory, thoracic and mediastinal disorders       
Cough  1  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%) 
Nasal congestion  1  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%) 
Rhinorrhoea  1  0/7 (0.00%)  0/7 (0.00%)  1/6 (16.67%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA (17.0)
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: AstraZeneca Clinical Study Information Center
Organization: AstraZeneca
Phone: 1-877-240-9479
EMail: information.center@astrazeneca.com
Layout table for additonal information
Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT01703260     History of Changes
Other Study ID Numbers: ROF-NASH_205
U1111-1129-5051 ( Registry Identifier: WHO )
First Submitted: October 2, 2012
First Posted: October 10, 2012
Results First Submitted: September 21, 2015
Results First Posted: February 23, 2016
Last Update Posted: February 1, 2017