Differentiating the Effects of Substance P and Beta-endorphin

NCT01854177 | Completed Results

• 1 other identifier: CPHS#23992
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 1

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

Conditions

Chronic Obstructive Pulmonary Disease

Keywords

breathlessness; substance P; beta-endorphin

Outcome Measures

Primary Outcomes (2)

• Unpleasantness of Breathlessness

  Unpleasantness of breathlessness was reported each minute by the patient on a visual analog scale. The scale range is 0-10 where 0 = No breathlessness and 10 = Severe breathlessness. The measures were collected up to 20 minutes per visit and combined for a final score. Total minimum score = 0, total maximum score 200. Data is collected during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) during which either Placebo or Aprepitant was administered. A high unpleasantness indicates that breathing difficulty feels very bad or terrifying regardless of whether the intensity is high or low

  Visit 2 (Approximately Day 3 where either Placebo or Aprepitant was administered).and Visit 3 (approximately Day 6 where either Placebo or Aprepitant was administered)

• Intensity of Breathlessness

  Intensity of Breathlessness was recorded on a visual analog scale. The scale range is 0-10 where 0 = minimum and 10 = maximal intensity. At each visit, participants were asked to report unpleasantness at 1 minute intervals. The measures were collected up to 20 minutes per visit and combined for a final score. Total minimum score = 0, total maximum score 200. Data is collected during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) during which either Placebo or Aprepitant was administered.

  Visit 2 (Approximately Day 3 where either Placebo or Aprepitant was administered).and Visit 3 (approximately Day 6 where either Placebo or Aprepitant was administered)

Study Arms (2)

Aprepitant

ACTIVE COMPARATOR

Aprepitant 125 mg

Drug: Aprepitant

Placebo

PLACEBO COMPARATOR

Inert capsule

Drug: Placebo

Interventions

Aprepitant DRUG

Also known as: aprepitant 125 mg capsule

Aprepitant

Placebo DRUG

Also known as: inert capsule

Placebo

Eligibility Criteria

• Age: 50 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Dartmouth-Hitchcock Medical Center: lead

Study Sites (1)

Dartmouth-Hitchcock Medical Center

Lebanon, New Hampshire, 03756-0001, United States

Location

MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive; Dyspnea

Interventions

Aprepitant

Condition Hierarchy (Ancestors)

Lung Diseases, Obstructive; Lung Diseases; Respiratory Tract Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Respiration Disorders; Signs and Symptoms, Respiratory; Signs and Symptoms

Intervention Hierarchy (Ancestors)

Morpholines; Oxazines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Study assessed acute effects of the intervention.

Results Point of Contact

• Title: Donald A. Mahler, M.D.
• Organization: Dartmouth-Hitchcock

Donald.a.mahler@hitchcock.org

603 650-5533

Study Officials

• Donald A Mahler, M.D.

  Dartmouth-Hitchcock Medical Center

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: BASIC SCIENCE
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor of Medicine

Study Record Dates

• First Submitted: May 13, 2013
• First Posted: May 15, 2013
• Study Start: July 1, 2013
• Primary Completion: November 1, 2013
• Study Completion: November 1, 2013
• Last Updated: October 30, 2018
• Results First Posted: October 30, 2018

Record last verified: 2018-08

Locations

US (1)