A Phase 1/2 interventional study of Roflumilast in Obesity, sponsored by National Heart, Lung, and Blood Institute (NHLBI). Completed at 1 site in United States. Open to participants aged 30 Years to 65 Years, including healthy volunteers. Per ClinicalTrials.gov, last updated 2018-09-04.
Sponsored by National Heart, Lung, and Blood Institute (NHLBI) · Phase 1/2, Interventional, and Treatment
Background:
Objectives:
Eligibility:
Design:
In the last week, participants will have a final follow-up visit.
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.
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Browse Overweight studies →National Heart, Lung, and Blood Institute (NHLBI) is the lead sponsor of 1,117 studies on the registry; 71 are open to participants now.
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EXCLUSION CRITERIA:
Drug: Roflumilast
Selective phosphodiesterase 4 (PDE4) inhibitor
Change in Insulin Sensitivity- Pre-roflumilast
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.
Time frame: Baseline
Change in Insulin Sensitivity - Post-roflumilast
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.
Time frame: 6 weeks
Subjects who passed the telephone screening were invited to undergo further screening in the clinic. A total of 24 subjects were subsequently screened. Among these subjects, 14 subjects met the study's inclusion criteria.
| Milestone | Subjects Who Took Roflumilast |
|---|---|
| Started | 9 |
| Completed | 8 |
| Not completed | 1 |
| Withdrew: Physician decision | 1 |
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.
| mg/grams Fat Free Mass/minute | Pre-roflumilast |
|---|---|
| Change in Insulin Sensitivity- Pre-roflumilast | 48.7 ± 10.4 |
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.
| mg/grams Fat Free Mass/minute | Post-roflumilast |
|---|---|
| Change in Insulin Sensitivity - Post-roflumilast | 70 ± 20.1 |
Collected over Adverse events data was collected in the seven weeks time period of the study calendar. Six of these weeks were while the subjects were on roflumilast and one week was after the subject discontinued roflumilast.. Non-serious events are listed at a 1% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Subjects Who Took Roflumilast | 0/9 (0%) | 0/9 (0%) | 6/9 (66.7%) |
| Event | Subjects Who Took Roflumilast |
|---|---|
| Changes in appetiteMetabolism and nutrition disorders | 4/9 |
| HeadacheNervous system disorders | 4/9 |
| InsomniaGeneral disorders | 4/9 |
| FatigueGeneral disorders | 2/9 |
| DiarrheaGastrointestinal disorders | 2/9 |
| IrritabilityGeneral disorders | 2/9 |
| NauseaGastrointestinal disorders | 1/9 |
| DizzinessGeneral disorders | 1/9 |
| Neck PainMusculoskeletal and connective tissue disorders | 1/9 |
| TremorNervous system disorders | 1/9 |
| Age, Continuous(years) | Roflumilast |
|---|---|
| Mean | 49.6 ± 6.4 |
| Sex: Female, Male(Participants) | Roflumilast |
|---|---|
| Female | 3 |
| Male | 6 |
| Race/Ethnicity, Customized(Participants) | Roflumilast |
|---|---|
| Black or African-American | 6 |
| White | 2 |
| Hispanic | 1 |
| Region of Enrollment(participants) | Roflumilast |
|---|---|
| United States | 9 |
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National Heart, Lung, and Blood Institute (NHLBI)