Clinical trial NCT04234360: Eosinophil-driven Corticotherapy for Patients Hospitalized for COPD Exacerbation
Official title: Eosinophil-driven Corticotherapy for Patients Hospitalized for COPD Exacerbation: a Double-blind, Randomized, Controlled Trial
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: COPD Exacerbation
Lead sponsor: University Hospital, Montpellier
Sponsor class: OTHER
First posted: 2020-01-21
Enrollment: 600
Sex: ALL
Minimum age (years): 40
Maximum age (years): 85
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a randomised (1:1), 2-parallel arm, double-blind trial comparing outcomes for a group of eosinophilic COPD patients (n=150) treated via corticotherapy versus a 2nd, similar group (n=150) treated via placebo. Secondarily, the same comparison (2x n=150) will be made for non-eosinophilic patients (totally excluding non-eosinophilic patients would potentially affect biomarker knowledge and subsequent care decisions, leading to bias).
Primary purpose: TREATMENT

Brief summary: The primary objective of this study is to compare treatment failure rates between a group of eosinophilic (eosinophilia \> 2% on day 1 of hospitalization) patients hospitalised for a COPD exacerbation treated via corticotherapy versus a similar group treated via placebo.

Secondarily, treatment failure rates will also be compared between a group of non-eosinophilic patients hospitalised for a COPD exacerbation treated via corticotherapy versus a similar group treated via placebo. Study arms will also be compared for additional aspects of efficacy and safety:

* speed of recovery during the initial hospitalization;
* corticosteroid side effects / induced comorbidities;
* changes in symptoms and episodes of exacerbation;
* pulmonary function, oxygen use and ventilation;
* patient trajectories and resource use (e.g. survival, consults, episodes of hospitalization, medications);
* drug consumption (especially as relates to COPD management, exacerbations and induced comorbidities);
* health status, quality of life, activity/disability;
* patient safety / adverse events in general.

Eosinophilia thresholds optimizing the prediction of corticosteroid response and COPD outcomes will be re-evaluated. The relationships between corticosteroid response and key biomarkers (e.g. infectious groups) will be thoroughly explored, including within eosinophil strata. Potential gender subgroups differences will also be evaluated.

Finally, in prevision of further exploratory studies, a biological collection and an imaging library will be created in association with this protocol. The biological collection will be used to explore the genetic basis and physiology linked with treatment response, gender and patient trajectories. The image library will be used as a platform for the exploration of new imaging markers developed, for example, via machine learning and affiliated techniques.


Eligibility criteria: Inclusion Criteria:

* Adult patients admitted to a participating hospital (ward, ICU or emergency services) for an acute COPD exacerbation
* For patients with known COPD: COPD defined according to GOLD 2018 criteria: (1) Post-bronchodilator FEV1/FVC \< 70% of predicted values; (2) \> 10 pack years smoking history
* For incident COPD cases with no spirometric history: symptoms and exposure according to GOLD 2018 report will be considered for the diagnosis, but if the spirometric diagnosis is not confirmed during follow-up, then the patient will be excluded
* Signed consent has been obtained, or the appropriate emergency procedure (under French law) allows enrolment
* Subjects must be covered by public health insurance
* Patient available for 3 months of follow-up. Subjects must be able to attend all scheduled visits and to comply with all trial procedures.

Exclusion Criteria:

* Subject unable to read or write; language barrier
* Subject who is in a dependency or employment with the sponsor or investigator
* Pregnancy or lactation
* Patients who are prisoners or under other forms of judicial protection
* Patients under any kind of guardianship
* The patient has already participated in the present protocol
* The patient is participating in another interventional study or has done so in the past 3 months
* The patient is in an exclusion period determined by a previous study
* The patient has been taking long-term systemic corticosteroids for longer than 1 month prior to inclusion
* The patient has already received \> 1 mg/kg of systemic corticotherapy in the past 48h
* Intubated-ventilated patient
* Administration of oral experimental drug is impossible
* Cancer within the last 12 months
* Current diagnosis of Asthma
* T2-inflammation targeting biologics (Benralizumab, reslizumab, mepolizumab, dupilumab) treatment
* Admitted for any other reason including, but not limited to, pulmonary embolism, pneumothorax, heart failure
* Known allergy to corticosteroids
* Consideration of a potential negative drug interaction with corticosteroids (at the investigator's discretion)
* White blood cell formula already performed and distributed to implicated teams
* Directives for limitation-of-care ("LATA" in French) already established
* SARS-Cov2 positive test carry out during the COPD exacerbation

Primary outcomes:
measure: Treatment failure
timeFrame: 3 months
Secondary outcomes:
measure: The speed of initial recovery: Time elapsed before showing signs of improvement
timeFrame: During initial hospitalization (expected maximum of 28 days)
measure: The speed of initial recovery: Time elapsed in acidosis/hypercapnia
timeFrame: During initial hospitalization (expected maximum of 28 days)
measure: The speed of initial recovery: Time elapsed before meeting pre-defined discharge criteria
timeFrame: During initial hospitalization (expected maximum of 28 days)
measure: Presence /absence of comorbidities or steroid side effects: glycemia
timeFrame: During initial hospitalization (expected maximum of 28 days)
measure: Presence /absence of comorbidities or steroid side effects: glycemia
timeFrame: 1 month
measure: Presence /absence of comorbidities or steroid side effects: glycemia
timeFrame: 3 months
measure: The occurrence of new or worsened diabetes/hyperglycemia
timeFrame: Throughout the study (3 months)
measure: Body mass index
timeFrame: Baseline (day 0)
measure: Body mass index
timeFrame: At hospital discharge (expected maximum of 28 days)
measure: Body mass index
timeFrame: 1 month
measure: Body mass index
timeFrame: 3 month
measure: Hospital anxiety and depression scale (HAD)
timeFrame: baseline (day 0)
measure: Hospital anxiety and depression scale (HAD)
timeFrame: 3 months
measure: The occurrence of any other potentially corticosteroid-induced comorbidities throughout the study
timeFrame: Throughout the study; 3 months
measure: Episodes of pneumonia
timeFrame: Throughout the study; 3 months
measure: Episodes of infection
timeFrame: Throughout the study; 3 months
measure: Episodes of mild exacerbation.
timeFrame: Throughout the study; 3 months
measure: Episodes of moderate exacerbation.
timeFrame: Throughout the study; 3 months
measure: Episodes of severe exacerbation.
timeFrame: Throughout the study; 3 months
measure: Forced expiratory volume in 1 second (litres)
timeFrame: At hospital discharge (expected maximum of 28 days)
measure: Forced expiratory volume in 1 second (litres)
timeFrame: 3 months
measure: Forced expiratory volume in 1 second (% predicted)
timeFrame: At hospital discharge (expected maximum of 28 days)
measure: Forced expiratory volume in 1 second (% predicted)
timeFrame: 3 months
measure: Forced vital capacity (litres)
timeFrame: At hospital discharge (expected maximum of 28 days)
measure: Forced vital capacity (litres)
timeFrame: 3 months
measure: Forced vital capacity (% predicted)
timeFrame: At hospital discharge (expected maximum of 28 days)
measure: Forced vital capacity (% predicted)
timeFrame: 3 months
measure: Residual volume (litres)
timeFrame: At hospital discharge (expected maximum of 28 days)
measure: Residual volume (litres)
timeFrame: 3 months
measure: Residual volume (% predicted)
timeFrame: At hospital discharge (expected maximum of 28 days)
measure: Residual volume (% predicted)
timeFrame: 3 months
measure: Total lung capacity (litres)
timeFrame: At hospital discharge (expected maximum of 28 days)
measure: Total lung capacity (litres)
timeFrame: 3 months
measure: Total lung capacity (% predicted)
timeFrame: At hospital discharge (expected maximum of 28 days)
measure: Total lung capacity (% predicted)
timeFrame: 3 months
measure: Oxygen needs (litres/min) during initial hospitalisation
timeFrame: At hospital discharge (expected maximum of 28 days)
measure: Mode of pre-hospitalization living arrangements
timeFrame: Baseline (day 0)
measure: Hospital discharge modality
timeFrame: At hospital discharge (expected maximum of 28 days)
measure: Episodes of hospitalization
timeFrame: Throughout the study; 3 months
measure: Episodes of emergency department use
timeFrame: Throughout the study; 3 months
measure: Episodes of intensive care
timeFrame: Throughout the study; 3 months
measure: Consults
timeFrame: Throughout the study; 3 months
measure: The cumulative days alive and event-free
timeFrame: Throughout the study; 3 months
measure: Mortality/survival
timeFrame: Throughout the study; 3 months
measure: Medications
timeFrame: Throughout the study; 3 months
measure: VAS scale for coughing
timeFrame: Every morning during hospitalization (expected maximum of 28 days)
measure: VAS scale for coughing
timeFrame: 1 month
measure: VAS scale for coughing
timeFrame: 3 months
measure: VAS scale for dyspnoea
timeFrame: Every morning during hospitalization (expected maximum of 28 days)
measure: VAS scale for dyspnoea
timeFrame: 1 month
measure: VAS scale for dyspnoea
timeFrame: 3 months
measure: VAS scale for sputum production
timeFrame: Every morning during hospitalization (expected maximum of 28 days)
measure: VAS scale for sputum production
timeFrame: 1 month
measure: VAS scale for sputum production
timeFrame: 3 months
measure: VAS scale for sleep perturbation
timeFrame: Every morning during hospitalization (expected maximum of 28 days)
measure: VAS scale for sleep perturbation
timeFrame: 1 month
measure: VAS scale for sleep perturbation
timeFrame: 3 months
measure: VAS scale for anxiety
timeFrame: Every morning during hospitalization (expected maximum of 28 days)
measure: VAS scale for anxiety
timeFrame: 1 month
measure: VAS scale for anxiety
timeFrame: 3 months
measure: The Breathlessness, Cough and Sputum Scale
timeFrame: Baseline (day 0)
measure: The Breathlessness, Cough and Sputum Scale
timeFrame: On hospital discharge (expected maximum of 28 days)
measure: The Breathlessness, Cough and Sputum Scale
timeFrame: 1 month
measure: The Breathlessness, Cough and Sputum Scale
timeFrame: 3 months
measure: The modified medical research council (mMRC) dyspnoea scale
timeFrame: Baseline (day 0)
measure: The modified medical research council (mMRC) dyspnoea scale
timeFrame: 3 months
measure: The COPD assessment test
timeFrame: Baseline (day 0)
measure: The COPD assessment test
timeFrame: 1 month
measure: The COPD assessment test
timeFrame: 3 months
measure: The Euroqol (EQ-5D-5L) questionnaire
timeFrame: Baseline (day 0)
measure: The Euroqol (EQ-5D-5L) questionnaire
timeFrame: 1 month
measure: The Euroqol (EQ-5D-5L) questionnaire
timeFrame: 3 months
measure: The St George Respiratory Questionnaire
timeFrame: 3 months
measure: Six minute walking tests
timeFrame: 1 month (optional)
measure: Six minute walking tests
timeFrame: 3 months
measure: The DIRECT questionnaire
timeFrame: 3 months
Other outcomes:
measure: Blood differential
timeFrame: Baseline (day 0)
measure: Blood differential
timeFrame: day 2
measure: Blood differential
timeFrame: On hospital discharge (expected maximum of 28 days)
measure: Blood differential
timeFrame: 1 month
measure: Blood differential
timeFrame: 3 months
measure: C reactive protein
timeFrame: Baseline (day 0)
measure: C reactive protein
timeFrame: On hospital discharge (expected maximum of 28 days)
measure: Sputum bacteriological analysis (or nasal swab if no sputum)
timeFrame: Baseline (day 0)
measure: Nasal swab virology
timeFrame: Baseline (day 0)
measure: Computed tomography scan of lungs: presence/absence of consolidation
timeFrame: Baseline (day 0); optional
measure: Computed tomography scan of lungs: presence/absence of consolidation
timeFrame: 3 months; optional
measure: Computed tomography scan of lungs: % emphysema
timeFrame: Baseline (day 0); optional
measure: Computed tomography scan of lungs: % emphysema
timeFrame: 3 months; optional
Locations:
city: Amiens
country: France
facility: CHU Amiens
city: Brest
country: France
facility: CHU Brest - Hôpital Caval Blanche
city: Castelnau-le-Lez
country: France
facility: Clinique du Parc
city: Créteil
country: France
facility: Centre hospitalier intercommunal de Créteil
city: Libourne
country: France
facility: CH Libourne
city: Lille
country: France
facility: CHRU Lille
city: Lyon
country: France
facility: Hospice Civils de Lyon
city: Marseille
country: France
facility: APHM - Hôpital Nord
city: Montpellier
country: France
facility: CHU Montpellier
city: Nancy
country: France
facility: CHU Nancy
city: Nîmes
country: France
facility: CHU Nîmes
city: Paris
country: France
facility: APHP - Hopital Européen Georges Pompidou
city: Paris
country: France
facility: APHP - Hôpital BICHAT
city: Paris
country: France
facility: APHP - Hôpital Cochin
city: Paris
country: France
facility: APHP - Hôpital Universitaire Pitié-Salpétrière
city: Paris
country: France
facility: APHP - Hôpital Universitaire Pitié-Salpétrière
city: Pessac
country: France
facility: CHU Bordeaux - Hôpital Haut Lévêque
city: Reims
country: France
facility: CHU Reims
city: Roubaix
country: France
facility: CH Roubaix
city: Strasbourg
country: France
facility: CHRU Strasbourg
city: Toulouse
country: France
facility: Hôpital Larrey CHU Toulouse
city: Trévenans
country: France
facility: Hôpital Nord Franche-Comté
Study officials:
affiliation: a-bourdin@chu-montpellier.fr
name: Arnaud BOURDIN
role: PRINCIPAL_INVESTIGATOR
References:
citation: Suehs CM, Zysman M, Chenivesse C, Burgel PR, Couturaud F, Deslee G, Berger P, Raherison C, Devouassoux G, Brousse C, Roche N, Molimard M, Chinet T, Devillier P, Chanez P, Kessler R, Didier A, Martinat Y, Le Rouzic O, Bourdin A. Prioritising outcomes for evaluating eosinophil-guided corticosteroid therapy among patients with acute COPD exacerbations requiring hospitalisation: a Delphi consensus study. BMJ Open. 2020 Jul 1;10(7):e035811. doi: 10.1136/bmjopen-2019-035811.