Efficacy of Morphine in Reducing the Rate of Early Non-Invasive Ventilation Failure in Acute Exacerbation of Chronic Obstructive Pulmonary Disease, Phase I/IIa

NCT04427826 | Recruiting Phase 1 DMC

• 1 other identifier: 2019-004274-25
• Study Type: interventional
• Target: 24
• Locations: 1 country
• Sites: 1

Brief Summary

Acute exacerbations of Chronic Obstructive Pulmonary Disease (COPD) are a major source of morbidity and mortality for patients and cost to the society. In case of acute respiratory failure with hypercapnia and acidosis, Non Invasive Ventilation (NIV) is preferred as a first line treatment. NIV failures are not uncommon, from 15% in intensive care to 25 - 30% in emergency departments. They most often occur at the start of the NIV or in the hours that follow. There are many reasons for these failure. Among these are; dyspnea, discomfort, the pain related to the exacerbation and also to the NIV are frequently noted. The use of certain drugs with anxiolytic, hypnotic and/or analgesic properties could also be useful. Some sedatives and opioids have already been studied in this indication but without a therapeutic trial and satisfactory methodology. Among the molecules of interest, Morphine seems interesting . It's administration could reduce the ventilatory rate, intensity of dyspnea, pain and anxiety as well as dynamic hyperinflation. The investigators believe that morphine administration will decrease the rate of early NIV failure by improving comfort (decreased dyspnea and pain) and ventilation (decreased respiratory rate and increase in tidal volume) in patients with exacerbations of COPD. However, before considering a randomized phase III efficacy study, it is necessary to determine the optimal dose of morphine in this indication, through a phase I/II dose-finding study taking into accounts both the efficacy and toxicity of morphine. The main objective of this study, is to determine the optimal dose of morphine administered at the initiation of NIV in patient with acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD), which is defined as the maximum gain function combining the probability of dose-limiting toxicity with PaCO2.Therefore, the impact of morphine administration on the physiological parameters of NIV- COPD exacerbation patients will be assessed.

Conditions

Chronic Obstructive Pulmonary Disease

Keywords

Acute exacerbation; COPD; NIV; Morphine; DLT

Outcome Measures

Primary Outcomes (2)

• The probability of dose - limiting toxicity (DTL), defined as the occurrence of one or more of the following criteria occurring within 4 hours of morphine administration

  Respiratory Rate ≤ 10/min; Richmond Agitation-Sedation Scale (RASS) \< -2;Vomiting and Naloxone administration

  4 hours

• Efficacy and toxicity

  PaCO2 1 hour after morphine injection, according to the hormetic dose-response model

  1 hour

Secondary Outcomes (1)

• Percentage of adverse events

  1, 4 and 24 hours

Study Arms (1)

Patient admitted for acute Exacerbation of Chronic Obstructive

EXPERIMENTAL

Patient admitted for acute Exacerbation of Chronic Obstructive Pulmonary Disease (COPD) and required NIV

Drug: Morphine hydrochloride

Interventions

Morphine hydrochloride DRUG

A single open-label injection of morphine (T0) at the dose closest to that defined by the model (estimation by Bayesian method) from among the following 4 doses: 0.02; 0.04; 0.07 and 0.1mg/kg will be adminestred to the patients.

Patient admitted for acute Exacerbation of Chronic Obstructive

Eligibility Criteria

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

You may qualify if:

• Patients Aged ≥ 18 years
• Current or former smoker at least 10 packs-years
• Patient with a history of COPD according to the Gold guidelines , after review of the medical record by the physician in charge
• Acute exacerbation of COPD (greater degradation of respiratory symptoms than the usual daily variations and requiring a modification of therapeutic management)
• Need to implement NIV treatment (respiratory acidosis with pH\<7.35)
• Ventilation frequency \> 20min
• Affiliation to the French security system (or equivalent)

You may not qualify if:

• Patient already treated by NIV during admission (e. g. introduction in pre-hospital by SMUR) or started more than one hour ago in the department.
• Chronic alcoholism
• Contra-indication to NIV: disturbances of consciousness (Glasgow \< 11) except moderate hypercapnic encephalopathy; indication of immediate intubation; risk of inhalation; sputum impossible; hemodynamic instability; inability to remove the mask; trauma, surgery or facial malformation; patients with pH \< 7.25 can only be included in intensive care unit or in the vital emergency room of the emergency department, under continuous monitoring
• Non-communicative patient or significant dementia making them unable to participate in the study
• Contra-indication to morphine without acute respiratory distress
• Pregnant or breastfeeding women
• Major mentioned in Articles L1121-6 and 1121-8 of French public health cod
• Subject cannot be contacted in case of emergency

Sponsors & Collaborators

• University Hospital, Grenoble: lead

Study Sites (1)

Emergency Department of Grenoble Alpes University Hospital

Grenoble, Isère, Auvergne-Rhône-Alpes, 38043, France

RECRUITING

Related Publications (14)

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  PMID: 25526796 RESULT

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  PMID: 28860265 RESULT

• Osadnik CR, Tee VS, Carson-Chahhoud KV, Picot J, Wedzicha JA, Smith BJ. Non-invasive ventilation for the management of acute hypercapnic respiratory failure due to exacerbation of chronic obstructive pulmonary disease. Cochrane Database Syst Rev. 2017 Jul 13;7(7):CD004104. doi: 10.1002/14651858.CD004104.pub4.

  PMID: 28702957 RESULT

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  PMID: 26341216 RESULT

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  PMID: 31125359 RESULT

• Yeung WY, Reigner B, Beyer U, Diack C, Sabanes Bove D, Palermo G, Jaki T. Bayesian adaptive dose-escalation designs for simultaneously estimating the optimal and maximum safe dose based on safety and efficacy. Pharm Stat. 2017 Nov;16(6):396-413. doi: 10.1002/pst.1818. Epub 2017 Jul 9.

  PMID: 28691311 RESULT

• Jolliet P, Ouanes-Besbes L, Abroug F, Ben Khelil J, Besbes M, Garnero A, Arnal JM, Daviaud F, Chiche JD, Lortat-Jacob B, Diehl JL, Lerolle N, Mercat A, Razazi K, Brun-Buisson C, Durand-Zaleski I, Texereau J, Brochard L; E.C.H.O. ICU Trial Investigators. A Multicenter Randomized Trial Assessing the Efficacy of Helium/Oxygen in Severe Exacerbations of Chronic Obstructive Pulmonary Disease. Am J Respir Crit Care Med. 2017 Apr 1;195(7):871-880. doi: 10.1164/rccm.201601-0083OC. Erratum In: Am J Respir Crit Care Med. 2018 Mar 15;197(6):839-840. doi: 10.1164/rccm.1976Erratum.

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• Lightowler JV, Wedzicha JA, Elliott MW, Ram FS. Non-invasive positive pressure ventilation to treat respiratory failure resulting from exacerbations of chronic obstructive pulmonary disease: Cochrane systematic review and meta-analysis. BMJ. 2003 Jan 25;326(7382):185. doi: 10.1136/bmj.326.7382.185.

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MeSH Terms

Conditions

Pulmonary Disease, Chronic Obstructive

Condition Hierarchy (Ancestors)

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

Study Officials

• Damien VIGLINO, MD, PhD

  Grenoble Alpes University Hospital, HP2 laboratory - INSERM U1042 and Grenoble Alpes University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Damien VIGLINO, MD, PhD

CONTACT

0033476766784; DViglino@chu-grenoble.fr

Prudence MABIALA MAKELE, PhD

CONTACT

0033476766784; PMabialamakele@chu-grenoble.fr

Study Design

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

Model Details: Phase I / IIa prospective, monocentric and open therapeutic study

Study Record Dates

• First Submitted: June 8, 2020
• First Posted: June 11, 2020
• Study Start: December 8, 2020
• Primary Completion (Estimated): June 8, 2027
• Study Completion (Estimated): January 1, 2028
• Last Updated: April 15, 2026

Record last verified: 2026-04

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP
• Time Frame: At the time of publication
• Access Criteria: The international writing and publication rules (The Uniform Requirements for Manuscripts of the ICMJE, April 2010) will be followed. And In accordance with the French law n ° 2002-303 of March 4th, 2002

Locations

FR (1)