Differentiating the Effects of Substance P and Beta-endorphin

NCT ID: NCT01854177

Last Updated: 2018-10-30

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: NA
• Total Enrollment: 10 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2013-07-31
• Study Completion Date: 2013-11-30

Brief Summary

In previous studies we demonstrated that endogenous opioids (inhibitory neuropeptides) modulate the perception of breathing difficulty in patients with chronic obstructive pulmonary disease (COPD). Recently, we found that antagonism of substance P (an excitatory neuropeptide) with aprepitant did not affect the perception of breathing difficulty. However, after administration of aprepitant, blood levels of both substance P(+ 54 ± 39%) and beta-endorphin (+ 27 ± 17%) increased significantly. As these blood levels reflect cellular/tissue activity, we postulated that the concomitant release of excitatory (substance P) and inhibitory (beta-endorphin) neuropeptides had opposing effects (counterbalanced each other) on the perception of breathing difficulty.

The objective of the present study is to further examine the possible role of substance P on the perception of breathlessness. We propose to administer oral aprepitant and oral placebo in a randomized clinical trial in patients with COPD. However, four hours after patients take these medications, intravenous naloxone will be administered in order to block the effects of endogenous opioids (beta-endorphin) on opioid receptors. Five minutes later, patients will breathe thru a tube with fine wire mesh to provoke breathing difficulty, and then provide ratings of the intensity and unpleasantness of breathlessness every minute.

The two competing hypothesis of the study are:

1. if breathlessness ratings with aprepitant/naloxone = placebo/naloxone, then substance P has no effect on perception of breathing difficulty;

2. if breathlessness ratings with aprepitant/naloxone ≠ placebo/naloxone, then substance P has an effect on perception of breathing difficulty.

Detailed Description

This study is a randomized, controlled clinical trial comparing the acute effects of oral aprepitant (selective antagonist of substance P receptor) vs. placebo on ratings of breathlessness during resistive load breathing in patients with COPD. Four hours after randomization, all patients will receive intravenous naloxone (antagonist of opioid receptors) to block the effects of endogenous opioids on perception of breathlessness. The two competing hypothesis of the study are:

Breathing difficulty will be induced by the patient breathing thru a tube with fine wire mesh for approximately 10 - 20 minutes in the laboratory.

Approximately 20 patients with COPD will be recruited from the out-patient clinic at the Dartmouth-Hitchcock Medical Center. The population will consist of female or male adults at least 50 years of age, at least 10 pack-year history of smoking, and a diagnosis of COPD associated with chronic bronchitis based on standard criteria.

Conditions

Chronic Obstructive Pulmonary Disease

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: CROSSOVER
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: QUADRUPLE

Study Groups

Aprepitant

Aprepitant 125 mg

Group Type: ACTIVE_COMPARATOR

Aprepitant

Intervention Type: DRUG

Placebo

Inert capsule

Group Type: PLACEBO_COMPARATOR

Placebo

Intervention Type: DRUG

Interventions

Aprepitant

Intervention Type: DRUG

Placebo

Intervention Type: DRUG

Other Intervention Names

aprepitant 125 mg capsule; inert capsule

Eligibility Criteria

Inclusion Criteria

• male or female patient 50 years of age or older
• a diagnosis of COPD; former smoker with a history of greater than or equal to 10 pack-years
• a clinical diagnosis of chronic bronchitis (productive cough on most days for a minimum of three months per year for at least two successive years)
• a post-bronchodilator forced expiratory volume in one second (FEV1) greater than or equal to 30% predicted and less than or equal to 80% predicted
• a post-bronchodilator FEV1/forced vital capacity (FVC) ratio less than 70%; and clinically stable COPD.

Exclusion Criteria

• current smoker
• pregnant women
• current or previous (within the past two weeks) use or of a narcotic medication
• any patient who has a concomitant disease that might interfere with study procedures or evaluation including lactose intolerance
• use of a drug that may cause possible drug interaction with aprepitant [including cilostazol, dofetilide, ergot alkaloids, oral or non-oral contraceptives, progestins, ranolazine, reboxetine, warfarin, ziprasidone, anxiolytic medications, anti-depressive medications, cholesterol lowering drugs (e.g., atorvastatin, simvastatin), theophylline, antifungal antibiotics, and macrolide antibiotics]
• use of a contraindicated medication including astemizole, cisapride, pimozide, and terfenadine;
• use of angiotensin converting enzyme inhibitor

• Minimum Eligible Age: 50 Years
• Maximum Eligible Age: 90 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Dartmouth-Hitchcock Medical Center

OTHER

Sponsor Role: lead

Responsible Party

Donald A. Mahler

Professor of Medicine

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Donald A Mahler, M.D.

Role: PRINCIPAL_INVESTIGATOR

Dartmouth-Hitchcock Medical Center

Locations

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, United States

Countries

United States

Other Identifiers

CPHS#23992

Identifier Type: -

Identifier Source: org_study_id