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

NCT01862029 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 13012313-H-0123
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

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.

Conditions

Obesity

Keywords

Mitochondria in Diabetes; Obesity; Roflumilast; Phosphodiesterase-4; Pre-Diabetes

Outcome Measures

Primary Outcomes (2)

• 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.

  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.

  6 weeks

Study Arms (1)

Roflumilast

EXPERIMENTAL

Drug: Roflumilast

Interventions

Roflumilast DRUG

Selective phosphodiesterase 4 (PDE4) inhibitor

Roflumilast

Eligibility Criteria

• Age: 30 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• National Heart, Lung, and Blood Institute (NHLBI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Wouters EF, Bredenbroker D, Teichmann P, Brose M, Rabe KF, Fabbri LM, Goke B. Effect of the phosphodiesterase 4 inhibitor roflumilast on glucose metabolism in patients with treatment-naive, newly diagnosed type 2 diabetes mellitus. J Clin Endocrinol Metab. 2012 Sep;97(9):E1720-5. doi: 10.1210/jc.2011-2886. Epub 2012 Jun 20.

  PMID: 22723325 BACKGROUND

• Yajima H, Komatsu M, Schermerhorn T, Aizawa T, Kaneko T, Nagai M, Sharp GW, Hashizume K. cAMP enhances insulin secretion by an action on the ATP-sensitive K+ channel-independent pathway of glucose signaling in rat pancreatic islets. Diabetes. 1999 May;48(5):1006-12. doi: 10.2337/diabetes.48.5.1006.

  PMID: 10331404 BACKGROUND

• Millesi H. Peripheral nerve surgery today: turning point or continuous development? J Hand Surg Br. 1990 Aug;15(3):281-7. doi: 10.1016/0266-7681_90_90004-n. No abstract available.

  PMID: 2230491 BACKGROUND

• Muo IM, MacDonald SD, Madan R, Park SJ, Gharib AM, Martinez PE, Walter MF, Yang SB, Rodante JA, Courville AB, Walter PJ, Cai H, Glicksman M, Guerrieri GM, Ben-Dor RR, Ouwerkerk R, Mao S, Chung JH. Early effects of roflumilast on insulin sensitivity in adults with prediabetes and overweight/obesity involve age-associated fat mass loss - results of an exploratory study. Diabetes Metab Syndr Obes. 2019 May 27;12:743-759. doi: 10.2147/DMSO.S182953. eCollection 2019.

  PMID: 31213865 DERIVED

Related Links

• NIH Clinical Center Detailed Web Page

MeSH Terms

Conditions

Obesity; Glucose Intolerance

Interventions

Roflumilast

Condition Hierarchy (Ancestors)

Overweight; Overnutrition; Nutrition Disorders; Nutritional and Metabolic Diseases; Body Weight; Signs and Symptoms; Pathological Conditions, Signs and Symptoms; Hyperglycemia; Glucose Metabolism Disorders; Metabolic Diseases

Limitations and Caveats

The sample size for the assessment of the primary outcome was less than planned.

Results Point of Contact

• Title: Jay H. Chung, Ph.D, MD
• Organization: National Institute of Health, NHLBI, Laboratory of Obesity and Aging Research

chungj@nhlbi.nih.gov

301-496-3075

Study Officials

• Jay H Chung, M.D.

  National Heart, Lung, and Blood Institute (NHLBI)

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 22, 2013
• First Posted: May 24, 2013
• Study Start: May 22, 2013
• Primary Completion: July 25, 2017
• Study Completion: July 25, 2017
• Last Updated: September 4, 2018
• Results First Posted: September 4, 2018

Record last verified: 2018-02-26

Locations

US (1)