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Effects of Roflumilast on Insulin and Blood Sugar Levels in Prediabetic Overweight and Obese Individuals

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01862029
Recruitment Status : Completed
First Posted : May 24, 2013
Results First Posted : September 4, 2018
Last Update Posted : September 4, 2018
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )

Tracking Information
First Submitted Date  ICMJE May 22, 2013
First Posted Date  ICMJE May 24, 2013
Results First Submitted Date  ICMJE July 26, 2018
Results First Posted Date  ICMJE September 4, 2018
Last Update Posted Date September 4, 2018
Study Start Date  ICMJE May 22, 2013
Actual Primary Completion Date July 25, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: August 28, 2018)
  • Change in Insulin Sensitivity- Pre-roflumilast [ Time Frame: Baseline ]
    Our primary outcome measure is the change in peripheral insulin sensitivity. The hyperinsulinemic euglycemic clamp procedure's M value, which was obtained before the subjects began roflumilast, was used to assess the primary outcome.
  • Change in Insulin Sensitivity - Post-roflumilast [ Time Frame: 6 weeks ]
    Our primary outcome measure is the change in peripheral insulin sensitivity. The hyperinsulinemic euglycemic clamp procedure's M value, which was obtained post-roflumilast, was used for this primary outcome assessment.
Original Primary Outcome Measures  ICMJE
 (submitted: May 22, 2013)
The primary outcome in this study is changes in insulin sensitivity as measured by the stable isotope0-labeled tracer technique and FSIVGTT. [ Time Frame: 3 years ]
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: May 22, 2013)
The secondary outcomes are changed in beta-cell function, postprandial plasma incretin concentrations, circulating levels of adipokines, cytokines, and inflammatory markers, and alterrations in total body fat and lean body mass. [ Time Frame: 3 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Effects of Roflumilast on Insulin and Blood Sugar Levels in Prediabetic Overweight and Obese Individuals
Official Title  ICMJE An Exploratory Study to Evaluate the Effects of Roflumilast on Insulin Sensitivity and Metabolic Parameters in Prediabetic Overweight and Obese Individuals
Brief Summary

Background:

- Roflumilast is a drug used to treat chronic obstructive pulmonary disease (COPD). It is designed to help reduce lung inflammation. However, during testing, roflumilast also appeared to reduce high blood sugar levels in people with COPD and type 2 diabetes. Other tests showed that roflumilast also improved blood sugar levels in people who only had type 2 diabetes. Researchers want to see how roflumilast affects insulin and blood sugar levels in overweight or obese people who are not diabetic, but who have high blood sugar levels.

Objectives:

- To see how well roflumilast improves blood sugar and insulin levels in prediabetic overweight or obese individuals.

Eligibility:

- Individuals between 30 to 65 years old who are overweight or obese (body mass index of 24.9 to 39.9 kg/m2) and have elevated blood sugar levels.

Design:

  • This study will last approximately 8 weeks. Participants will have approximately five study visits over about 7 weeks. Two of these visits will be overnight inpatient stays.
  • Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. They will also have a 3-day diet and exercise assessment with a dietitian.
  • In Week 1, participants will have a special diet for 2 days to keep their regular weight. They will then have a 2-day inpatient stay. During their stay, they will have multiple tests, including blood sugar tests and full body scans. They may provide a fat and muscle tissue biopsy sample. They will then receive the study drug to take during the study.
  • In Week 2, participants will repeat the diet study from the screening visit. They will receive a different dose of the study drug.
  • In Week 3, participants will review their diet results and have blood and urine tests.
  • In Week 5, participants will repeat the diet and exercise study from the screening visit.
  • In Week 6, participants will repeat the inpatient studies and tests from Week 1.

In the last week, participants will have a final follow-up visit.

Detailed Description Resveratrol, a polyphenol most notably found in red wine has anti-aging properties in mice fed a high-fat diet; resveratrol protects against obesity and type 2 diabetes. Several clinical trials have been conducted to study the metabolic effects of resveratrol. Although these trials have used different subject groups (e.g. obese healthy, type 2 diabetics or older adults with glucose intolerance), they suggest that resveratrol may improve insulin sensitivity. However, the therapeutic potential of resveratrol is diminished by the fact that it has a very promiscuous target profile. In order to translate resveratrol biology into clinical application, it is helpful to identify the cellular target(s) of resveratrol that mediate the desired effects and to develop therapies specific for that target(s). Recently, we discovered that the metabolic effects of resveratrol appear to result from competitive inhibition of cAMP-degrading phosphodiesterases (PDEs), which increases cAMP levels. The cAMP-dependent pathways activate AMP-activated protein kinase (AMPK), which is essential for the metabolic effects of resveratrol. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including protection against diet-induced obesity and an increase in mitochondrial content, fat oxidation, physical stamina and glucose tolerance in mice. Based on results from cellular and preclinical studies, we hypothesize that PDE4 inhibition will ameliorate insulin resistance in pre-diabetic individuals. To test these hypotheses, we will conduct an exploratory study on the potential beneficial effects of roflumilast (Daxas (Registered Trademark)), a PDE4 inhibitor, on insulin sensitivity in pre-diabetic individuals.Each study participant will receive oral roflumilast (250 (micro)g, once a day for 2 weeks, followed by 500 (micro)g once a day for 4 weeks). At baseline and after the 6-week treatment period, we will assess insulin sensitivity (hyperinsulinemiceuglycemic glucose clamp technique, glucose clamp ). In addition, Beta-cell function, skeletal muscle mitochondrial function, body composition, and circulating adipocytokine profile will be measured at baseline and after treatment to evaluate potential changes that may be related to improvements in metabolic function. Vascular function is not only an indicator of insulin sensitivity, but is also important for glucose delivery and metabolism. If possible, vascular function will be assessed along with the other parameters at baseline and after treatment with roflumilast. Regarding vascular function, we may measure basal and insulin-stimulated brachial artery blood flow (large conduit artery assessed by Doppler ultrasound) as well as capillary recruitment in forearm skeletal muscle (small nutritive arterioles assessed by ultrasound with microbubble contrast). This study will explore whether roflumilast is effective at improving insulin sensitivity in pre-diabetic individuals. Results from this study may have important implications for the potential use of roflumilast in treating type 2 diabetes.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Obesity
Intervention  ICMJE Drug: Roflumilast
Selective phosphodiesterase 4 (PDE4) inhibitor
Study Arms  ICMJE Experimental: Roflumilast
Intervention: Drug: Roflumilast
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 26, 2017)
24
Original Estimated Enrollment  ICMJE
 (submitted: May 22, 2013)
200
Actual Study Completion Date  ICMJE July 25, 2017
Actual Primary Completion Date July 25, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE
  • INCLUSION CRITERIA:
  • Adult, weight- and diet-stable men and women in good general health with no significant underlying illnesses and normal or clinically insignificant results (medical histories, laboratory profiles, physical examination, and electrocardiograms),
  • Women must be non-pregnant or post-menopausal, or women of childbearing potential must be non-lactating and using an effective form of birth control during and for 30 days after the study period (partner's use of condoms or partner's vasectomy is not an acceptable contraception method for this study),
  • Must be 30 - 65 years of age, inclusive
  • Body Mass Index (BMI) > 24.9 and < 39.5 kg/m(2) with a stable (plus-minus 2.5 kg) weight for the last 6 months by history,
  • Pre-diabetes, as defined by a fasting blood glucose of greater than 100 mg/dL and less than 126 mg/dL and/or A1C equal or greater than 5.7 and less than or equal to 6.5 %
  • Subjects must be able to understand the protocol and provide written informed consent.

EXCLUSION CRITERIA:

  • Women will be excluded from our study if they are pregnant, breastfeeding, or if they plan to become pregnant prior to the end of the study,
  • Cannot be on any medications including multivitamins or nutritional supplements that in the investigator s opinion will affect insulin sensitivity
  • Currently taking systemic corticosteroids, insulin, or anticoagulants, anxiolytics, ketoconazole, erythromycin, cimetidine, enoxacin, strong CYP 3A4/1A2 inducers (e.g., rifampicin, phenobarbital, carbamazepine, phenytoin), birth control pills containing gestodene and ethinyl estradiol, use food supplements that cannot be discontinued, or any other medication that the investigators deem a contraindication.
  • AST or ALT > 3 times the upper normal limit
  • Hepatitis B antigen, HIV or C positive antibody tests,
  • Liver disease, pulmonary disease, renal insufficiency, , (serum creatinine > 1.5mg/dl), coronary heart disease, heart failure (New York Heart Association heart failure Class III or IV), peripheral vascular disease, coagulopathy.
  • History of or current diagnosis of major depressive disorder, or history of or current diagnosis of other psychiatric disorders that in the opinion of the investigator would make participant unsafe for the participant.
  • Currently being treated for any form of cancer or have a history of cancer, that in the investigator s judgment would not make the participant a candidate for the study for safety or scientific reasons.
  • Claustrophobic,
  • On a weight loss program with ongoing weight loss, or a history of eating disorders. Actively using tobacco products or have used tobacco products within last year (>3 cigarettes/day), regular alcoholic beverage intake of more than two drinks per day. Subjects with any condition that would have made them, in the opinion of the principal investigator (PI), unsuitable for the study.
  • Subjects with a contraindication for the ultrasound contrast agent.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 30 Years to 65 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01862029
Other Study ID Numbers  ICMJE 130123
13-H-0123
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
Study Sponsor  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Jay H Chung, M.D. National Heart, Lung, and Blood Institute (NHLBI)
PRS Account National Institutes of Health Clinical Center (CC)
Verification Date February 26, 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP