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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified August 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier:
NCT01862029
First received: May 22, 2013
Last updated: September 5, 2014
Last verified: August 2014
  Purpose

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 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.

Condition Intervention Phase
Obesity
Drug: Roflumilast
Drug: Placebo
Phase 1
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • 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 ]

Estimated Enrollment: 50
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)
Arms Assigned Interventions
Experimental: Roflumilast Drug: Roflumilast
Selective phosphodiesterase 4 (PDE4) inhibitor
Placebo Comparator: Placebo Drug: Placebo
N/A

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 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.

  Eligibility

Ages Eligible for Study:   30 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria
  • 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 a 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 greater than 5.7 and less than 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
  • Serum creatinine > 1.5 mg/dl,
  • Hepatitis B antigen, HIV or C positive antibody tests,
  • Liver disease, pulmonary disease, renal insufficiency, 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01862029

Contacts
Contact: Sandra D MacDonald, R.N. (301) 451-4899 macdonas@nhlbi.nih.gov
Contact: Jay H Chung, M.D. (301) 496-3075 chungj@nhlbi.nih.gov

Locations
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    prpl@mail.cc.nih.gov   
Sponsors and Collaborators
Investigators
Principal Investigator: Jay H Chung, M.D. National Heart, Lung, and Blood Institute (NHLBI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Heart, Lung, and Blood Institute (NHLBI) )
ClinicalTrials.gov Identifier: NCT01862029     History of Changes
Other Study ID Numbers: 130123, 13-H-0123
Study First Received: May 22, 2013
Last Updated: September 5, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Mitochondria in Diabetes
Obesity
Roflumilast
Phosphodiesterase-4
Pre-Diabetes

Additional relevant MeSH terms:
Obesity
Overweight
Body Weight
Nutrition Disorders
Overnutrition
Signs and Symptoms

ClinicalTrials.gov processed this record on October 20, 2014