The Role of Phosphodiesterase Inhibitors in Incretin Secretion

NCT02363335 | Completed Phase 1 FDA Drug

• 2 other identifiers: 99991507415-AG-N074
• Study Type: interventional
• Target: 29
• Locations: 1 country
• Sites: 1

Brief Summary

Background: The drug Roflumilast (Daliresp) is used to treat Chronic Obstructive Pulmonary Disease (COPD). COPD is a lung disease that makes it difficult to breathe. Studies have shown that this drug decreased the blood sugar of people with type 2 diabetes. Sitagliptin (Januvia) is a medication presently used to treat diabetes. Researchers think that both of these drugs may decrease blood sugar by causing an increase in the hormone GLP-1.This hormone is secreted in the small intestines and stomach and is also known as an incretin. Researchers want to study how these drugs affect blood sugar, insulin, and other hormones in the blood. Objectives:

• To study the effects of Roflumilast (Daliresp) and Sitagliptin (Januvia) on blood sugar and insulin.
• To better understand GLP-1 and other gut hormones. This may lead to new treatments for type 2 diabetes. Eligibility:
• Healthy volunteers age 21 55.
• Body Mass Index (BMI) less than 30 Design:
• This study will require one screening visit and four study visits, scheduled about 3-weeks apart. Screening visit requires participants to arrive after fasting for 10 hours and have the following:
• Medical history, physical exam, height, weight, blood pressure measurements and blood and urine tests.
• A 2-hour oral glucose tolerance test (OGTT). Participants will drink an orange-flavored drink containing 75 grams of sugar (300 calories). A blood sample will be taken prior to drinking the beverage and 2-hours later.
• An electrocardiogram (EKG) to measure the electrical activity of the heart.
• Questionnaires about risk for depression or suicide. Study visits 1to 4:
• Participants will arrive the evening prior and blood work will be done to confirm eligibility. They will not eat or drink anything except water starting at 8:00 p.m.
• About 6:30 a.m. the following day, an I.V. (small plastic tube) will be placed in an arm vein and used to take 20 blood samples over a period of about 11 hours.
• Participants will receive one of the following study medication/placebo groupings in random order:
• Roflumilast (Daliresp) 500 mcg pill; and 1 placebo pill
• Sitaglipitin (Januvia) 100 mg pill; and 1 placebo pill
• Roflumilast (Daliresp) 500 mcg pill; and Sitagliptin (Januvia) 100 mg pill
• 2 placebo pills
• One hour later, they will have a 10-hour mixed meal test (MMT). They will be asked to drink a nutritional shake (Ensure Plus). Blood samples will be taken over the next 10 hours to measure blood sugar, insulin and other hormones. At the end of the test, they will be given a meal.
• Participants will answer questions about side effects and symptoms. They will receive a follow-up phone call within 10 days.

Conditions

Healthy Volunteers

Keywords

GLP-1; Phosphodiesterase Inhibitor; GIP

Outcome Measures

Primary Outcomes (1)

• PDE4 inhibitor roflumilast enhances GLP-1 secretion from L cells.

  GIP \& GLP-1 response to a mixed meal.

  1-10 hours after ingestion

Secondary Outcomes (5)

• 5.PDE4 inhibitor roflumilast and DPP4 inhibitor sitagliptin have synergistic effect on glucose metabolism involving plasma glucose, insulin, ghrelin, glucagon, pancreatic polypeptide, C-peptide and fibroblast growth factor (FGF) 19, 21, 23.

  1-10 hours after ingestion

• 4.PDE4 inhibitor roflumilast has an effect on glucose metabolism involving plasma glucose, insulin, ghrelin, glucagon, pancreatic polypeptide, C-peptide and fibroblast growth factor (FGF) 19, 21, 23.

  1-10 hours after ingestion

• 3.PDE4 inhibitor roflumilast and DPP4 inhibitor sitagliptin have synergistic effect on elevating circulating active GIP levels.

  1-10 hours after ingestion

• 2.PDE4 inhibitor roflumilast enhances GIP secretion from K cells.

  1-10 hours after ingestion

• 1.PDE4 inhibitor roflumilast and DPP4 inhibitor sitagliptin have synergistic effect on elevating circulating active GLP-1 levels.

  1-10 hours after ingestion

Study Arms (4)

Placebo

PLACEBO COMPARATOR

randomized, double-blind, placebo-controlled cross-over study

Other: Placebo

Roflumilast

EXPERIMENTAL

randomized, double-blind, placebo-controlled cross-over study

Other: Placebo; Other: Roflumilast

Roflumilast/Sitaglip

EXPERIMENTAL

randomized, double-blind, placebo-controlled cross-over study

Other: Placebo; Other: Roflumilast/Sitagliptin

Sitagliptin

EXPERIMENTAL

randomized, double-blind, placebo-controlled cross-over study

Other: Placebo; Other: Sitagliptin

Interventions

Placebo OTHER

mixed meal

Placebo; Roflumilast; Roflumilast/Sitaglip; Sitagliptin

Roflumilast/Sitagliptin OTHER

Both Roflumilast and Sitagliptin together

Roflumilast/Sitaglip

Sitagliptin OTHER

This is already known to increase GLP-1 \& GIP secretion.

Sitagliptin

Roflumilast OTHER

This is already known to increase GLP-1 \& GIP secretion

Roflumilast

Eligibility Criteria

• Age: 21 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age 21-55 (Age restriction is used to remove age as a confounding factor because (beta) cells function and insulin resistance tend to deteriorate with age and may affect GLP-1 and GIP levels.
• Screening laboratory evaluations with no clinically significant abnormal results (minor deviations from normal lab results will be at the discretion of the principal investigator):
• fasting comprehensive metabolic panel
• complete blood count with differential and platelet
• thyroid function test (TSH)
• urine drug screen
• Point of care urine pregnancy test (for women who are not surgically sterile)
• BMI \< 30 (participants with BMI greater than or equal to 30 are excluded because obesity has been associated with attenuation in GLP-1 secretion.
• Have had a history of stable weight (maintained weight within +/- 5%) over the past year
• Have NOT participated in another clinical trial involving any pharmacologic agents within the past 30 days
• Able to complete an inform consent
• Agree to not participate in other clinical trials within the study period (at the discretion of the study investigator)

You may not qualify if:

• FPG greater than or equal to 100 mg/dl or 2-hr OGTT greater than or equal to 140 mg/dL (evidence of glucose intolerance or diabetes)
• History of anemia, or Hemoglobin \< 12.5 mg/dL for men and \< 11.5 mg/dL for women during screening visit
• Weight \< 110 pounds (due to blood volume requirement)
• Evidence of illicit drug use
• History of substance abuse including marijuana within the past 6 months
• History of smoking any tobacco products within six months prior to screening
• Alcohol intake \> 30 grams (drink more than 2 beers per day OR equivalent amount of alcohol)
• History of Human Immunodeficiency Virus (HIV) infection
• History of active or chronic Hepatitis B and/or C infection
• History of psychiatric illnesses including major depressive disorder, schizophrenia, bipolar disorder
• Any lifetime history of suicide attempt
• History of any suicidal ideation of type 4 or 5 on the Columbia-Suicide Severity Rating Scale (C-SSRS) in the last year
• Any suicidal ideation of type 4 or 5 on the C-SSRS during any follow-up visits.
• Patient Health Questionnaire-9 (PHQ-9) score greater than or equal to 10 during screening visit or any follow-up study visits
• Generalized Anxiety Disorder-7 (GAD-7) score greater than or equal to 10 during screening visit or any follow-up visits

Sponsors & Collaborators

• National Institute on Aging (NIA): lead

Study Sites (1)

National Institute of Aging, Clinical Research Unit

Baltimore, Maryland, 21224, United States

Location

MeSH Terms

Interventions

Roflumilast; Sitagliptin Phosphate

Intervention Hierarchy (Ancestors)

Triazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrazines

Study Officials

• Chee W Chia, M.D.

  National Institute on Aging (NIA)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: BASIC SCIENCE
• Intervention Model: FACTORIAL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 13, 2015
• First Posted: February 16, 2015
• Study Start: February 13, 2015
• Primary Completion: September 19, 2016
• Study Completion: September 19, 2016
• Last Updated: March 13, 2026

Record last verified: 2026-03-11

Locations

US (1)