Effects of Roflumilast on Insulin and Blood Sugar Levels in Prediabetic Overweight and Obese Individuals
- 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.
- To see how well roflumilast improves blood sugar and insulin levels in prediabetic overweight or obese individuals.
- 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.
- This study will last 4 to 5 months. Participants will have 10 study visits over about 14 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 either the study drug or a placebo to take during the study.
- In Week 3, participants will repeat the diet and exercise study from the screening visit.
- In Week 4, participants will review their diet and exercise results and have blood and urine tests. They will receive a different dose of the study drug or a placebo.
- In Week 11, participants will repeat the diet and exercise study from the screening visit.
- In Week 12, participants will repeat the inpatient studies and tests from Week 1.
- In the last week, participants will have a final follow-up visit.
|Study Design:||Allocation: Non-Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||An Exploratory Study to Evaluate the Effects of Roflumilast on Insulin Sensitivity and Metabolic Parameters in Prediabetic Overweight and Obese Individuals|
- 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 ] [ Designated as safety issue: No ]
- 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 ] [ Designated as safety issue: No ]
|Study Start Date:||April 2013|
|Estimated Study Completion Date:||March 2016|
|Estimated Primary Completion Date:||March 2015 (Final data collection date for primary outcome measure)|
Selective phosphodiesterase 4 (PDE4) inhibitor
|Placebo Comparator: Placebo||
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 and improve glucose tolerance in pre-diabetic individuals. To test these hypotheses, we will conduct a randomized, placebo-controlled, double-blind study on the potential beneficial effects of roflumilast (Daxas ), a PDE4 inhibitor, on insulin sensitivity and glucose tolerance in pre-diabetic individuals. Each study participant will receive either placebo or oral roflumilast (250 (micro)g, once a day for three weeks, followed by 500 (micro)g once a day for nine weeks). At baseline and after the 12-week treatment period, we will assess insulin sensitivity. 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. Regarding vascular function, we will 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT01862029
|Contact: Sandra D MacDonald, R.N.||(301) firstname.lastname@example.org|
|Contact: Jay H Chung, M.D.||(301) email@example.com|
|United States, Maryland|
|National Institutes of Health Clinical Center, 9000 Rockville Pike||Not yet recruiting|
|Bethesda, Maryland, United States, 20892|
|Contact: For more information at the NIH Clinical Center contact Patient Recruitment and Public Liaison Office (PRPL) 800-411-1222 ext TTY8664111010 firstname.lastname@example.org|
|Principal Investigator:||Jay H Chung, M.D.||National Heart, Lung, and Blood Institute (NHLBI)|