Withdrawal of Dupilumab in Severe Asthma (WIDUSA)

WIthdrawal of DUpilumab in Severe Asthma: a Randomized Non-inferiority-controlled Trial

Asthma management has been revolutionised by the development of biological therapies. Dupilumab is an anti-interleukin4 receptor marketed in 2020 for severe asthmatic patients with 2 exacerbations or more within the last 12 months. Although data showed that safety and efficacy of dupilumab are sustained when treatment is extended up to 3 years, no study has emerged regarding dupilumab discontinuation. This study aims to demonstrate the non-inferiority regarding strategy failure at 24 months of stopping dupilumab (intervention group) compared with its continuation (control group) in controlled asthma patients receiving this drug for at least 3 years.

Study Overview

• Status: Not yet recruiting
• Conditions: Severe Asthma
• Intervention / Treatment: Drug: Stopping dupilumab

Detailed Description

Although dupilumab is a very effective drug in severe asthma, the optimal duration of this drug is unknown. However, this is a crucial question given the high cost of dupilumab and the lack of data regarding the long-term inhibition of type 2 pathway. Studies on biologic discontinuation are scarce in severe asthma. Studies with other biologics have shown that discontinuation of these drugs is feasible particularly for patients with low exacerbation rate before stopping treatment. In a study with pooled asthma biologics, 1247 (25.1%) stopped the biologic among the 4958 biologic users (including 19.8% of dupilumab users). Among all stoppers, 10.2% failed discontinuation of the asthma biologic in the 6 months after stopping, defined as an increase of 50% or more in exacerbations. Among patients who continued the biologic, 9.5% had an increase of 50% or more in exacerbations during a 6-month period, showing a similar failing rate. Such data for dupilumab discontinuation are lacking.

In this study, we plan to include patients with controlled asthma treated with dupilumab for at least 3 years who will be randomised to stopping dupilumab or dupilumab continuation with a follow-up of 24 months.

In total, 5 visits will occur for each patient: the inclusion/randomisation visit (baseline), 3 follow-up visits at month 6, month 12, month 24 as usually done in severe asthma, and a phone call visit at 18 months for exacerbations, treatments and adverse events collection. At each onsite visit, asthma medications, concomitant treatments, nasal polyp score (if applicable), number of exacerbations, Asthma Control Questionnaire, Severe Asthma Questionnaire, Treatment Burden Questionnaire and Sino-Nasal Outcome Test-22 scores, Forced expiratory volume in one second, Forced vital capacity, Fraction exhaled nitric oxide (if available), blood eosinophil, neutrophil and lymphocyte counts, adverse events, hospital admissions, and unscheduled medical visits will be recorded.

• Study Type: Interventional
• Enrollment (Estimated): 205
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Laurent GUILLEMINAULT, MD, PhD; Phone Number: +33 0567771850; Email: guilleminault.l@chu-toulouse.fr

Study Locations

• France
  • Amiens, France, 80480
    • CHU AMIENS-PICARDIE
    • Contact: Claire ANDREJAK, MD, PhD; Phone Number: +33 0322087893; Email: andrejak.claire@chu-amiens.fr
  • Angers, France, 49100
    • CHR d'Angers
    • Contact: Yasmina PASCAUD MANSOUR, MD; Phone Number: +33 0245353461; Email: yasmina.mansour@chu-angers.fr
  • Bayonne, France, 64100
    • CH de Bayonne
    • Contact: Cécilia NOCENT, MD; Phone Number: +33 0559443852; Email: cnocent@ch-cotebasque.fr
  • Besançon, France, 25000
    • CHU de Besançon
    • Contact: Cindy BARNIG, MD, PhD; Phone Number: +33 0647737530; Email: cbarnig@chu-besancon.fr
  • Brest, France, 29200
    • CHU de Brest
    • Contact: Françis COUTURAUD, MD, PhD; Phone Number: +33 0298347347; Email: francis.couturaud@chu-brest.fr
  • Caen, France, 14000
    • CHU de Caen
    • Contact: Helen FOUQUET, MD; Phone Number: +33 0231064677; Email: fouquet-h@chu-caen.fr
  • Cannes, France, 06400
    • CH de Cannes
    • Contact: Fabien ROLLAND, MD; Phone Number: +33 0493697860; Email: f.rolland@ch-cannes.fr
  • Clermont-Ferrand, France, 63000
    • CHU de Clermont-Ferrand
    • Contact: Camille ROLLAND-DEBORD, MD; Phone Number: +33 0473751653; Email: crollanddebord@chu-clermontferrand.fr
  • Créteil, France, 94000
    • Chi De Creteil
    • Contact: Amel BOUDJEMAA, MD; Phone Number: +33 0157022080; Email: amel.boudjemaa@chicreteil.fr
  • Dijon, France, 21000
    • CHU de Dijon
    • Contact: Philippe BONNIAUD, MD, PhD; Phone Number: +33 0380293772; Email: philippe.bonniaud@chu-dijon.fr
  • Epagny-Metz-Annecy, France, 74370
    • CH Annecy Genevois
    • Contact: Toufik DIDI, MD; Phone Number: +33 0450636603; Email: tdidi@ch-annecygenevois.fr
  • La Tronche, France, 38700
    • CHU Grenoble-Alpes
    • Contact: Christel SAINT-RAYMOND, MD; Phone Number: +33 0476765522; Email: csaint-raymond@chu-grenoble.fr
  • Le Kremlin-Bicêtre, France, 94270
    • Hôpital Kremlin Bicêtre
    • Contact: Antoine BEURNIER, MD; Phone Number: +33 0145217896; Email: antoine.beurnier@aphp.fr
  • Le Mans, France, 72037
    • CH Le Mans
    • Contact: François GOUPIL, MD; Phone Number: +33 0243434345; Email: fgoupil@ch-lemans.fr
  • Lille, France, 59000
    • Institut Cœur Poumon, CHU de Lille
    • Contact: Stéphanie FRY, MD; Phone Number: +33 0320445948; Email: stephanie.fry@chu-lille.fr
  • Lyon, France, 69004
    • Hopital croix rousse
    • Contact: Gille DEVOUASSOUX, MD, PhD; Phone Number: +33 0426732947; Email: gilles.devouassoux@chu-lyon.fr
  • Paris, France, 75015
    • Hôpital Européen Georges Pompidou
    • Contact: Thibaud SOUMAGNE, MD; Phone Number: +33 0156093462; Email: thibaud.soumagne@live.fr
  • Paris, France, 75018
    • Hôpital Bichat
    • Contact: Camille TAILLE, MD, PhD; Phone Number: +33 0140256802; Email: camille.taille@aphp.fr
  • Paris, France, 75012
    • Hopital Avicenne
    • Contact: Lucile SESE, MD; Phone Number: +33 06677289103; Email: Lucile.sese@aphp.fr
  • Pessac, France, 33600
    • CHU de Bordeaux
    • Contact: Pierre-Olivier GIRODET, MD, PhD; Phone Number: +33 0557623194; Email: pierre-olivier.girodet@chu-bordeaux.fr
  • Pierre-Bénite, France, 69495
    • Hôpital Lyon Sud
    • Contact: Nathalie FREYMOND, MD; Phone Number: +33 0478864401; Email: nathalie.freymond@chu-lyon.fr
  • Pointe-à-Pitre, France, 97159
    • CHU de Guadeloupe
    • Contact: Chantal RAHERISON SEMJEN, MD, PhD; Phone Number: +590 891360; Email: chantal.raherison@chu-guadeloupe.fr
  • Reims, France, 51092
    • CHU de Reims
    • Contact: Jeanne-Marie PEROTIN-COLLARD, MD, PhD; Phone Number: +33 0326787614; Email: jmperotin-collard@chu-reims.fr
  • Roubaix, France, 59100
    • CH de Roubaix
    • Contact: Nicolas JUST, MD; Phone Number: +33 0320993048; Email: nicolas.just@ch-roubaix.fr
  • Saint-Herblain, France, 44800
    • CHU de Nantes
    • Contact: François-Xavier BLANC, MD, PhD; Phone Number: +33 0240165710; Email: xavier.blanc@chu-nantes.fr
  • Strasbourg, France, 67000
    • Nouvel Hôpital Civil
    • Contact: Naji KHAYATH, MD; Phone Number: +33 0369550898; Email: naji.khayath@chru-strasbourg.fr
  • Suresnes, France, 92150
    • Hopital Foch
    • Contact: Colas TCHERAKIAN, MD, PhD; Phone Number: +33 0146252315; Email: c.tcherakian@hopital-foch.com
  • Tarbes, France, 65000
    • Hôpital Tarbes Lourdes
    • Contact: Joëlle COURDEAU, MD; Phone Number: +33 0562546060; Email: jcourdeau-labourie@ch-tarbes.vic.fr
  • CHU de Toulouse
    • Toulouse, CHU de Toulouse, France, 31059
      • CHU de Toulouse
      • Contact: Laurent GUILLEMINAULT, MD, PhD; Phone Number: +33 0567771850; Email: guilleminault.l@chu-toulouse.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Adult patients ≥ 18 years old
• Treated with dupilumab for at least 36 months for severe asthma
• Well controlled asthma defined by an Asthma Control Questionnaire score ≥ 18 and 0 or 1 exacerbation within the year prior to the inclusion visit

Exclusion Criteria:

• Patients who refuse to discontinue dupilumab, for any reason
• Patients with Forced expiratory volume in one second ≤ 30% of predicted values
• Patients treated by an oral corticosteroid dose ≥ 10 mg/day (in prednisone equivalent)
• Patients who have to discontinue dupilumab for a reason other than controlled asthma, such as an adverse drug reaction, a planned or current pregnancy, or a planned switch to another biologic indicated in severe asthma
• Patients who have to continue dupilumab for the treatment of comorbidities apart from nasal polyposis
• Active smoking
• Pregnancy or breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stopping dupilumab; The experimental strategy comprises stopping dupilumab with no dose-reducing or interval of time-increasing strategy from the day of inclusion/randomisation	Drug: Stopping dupilumab; Stopping dupilumab with no dose-reducing or interval of time-increasing strategy
No Intervention: Dupilumab continuation; Dupilumab continuation at the same dose and same interval as baseline

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Strategy failure	Proportion of patients with strategy failure defined as patients with an annualised number of asthma exacerbations ≥ 2 and/or dupilumab resume or switch to another biologic within 24 months following randomisation	24 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in asthma control test score	Comparing the interventional group with the control group regarding the change in asthma control test score at 6, 12 and 24 months compared to baseline. The asthma control test score is a self-administered questionnaire consisting of 5 questions related to the frequency of asthma symptoms and the use of rescue treatments over the past 4 weeks. The score ranges from 5 (poorest control) to 25 (perfect control)	6, 12 and 24 months
Resumption of dupilumab	Proportion of patients with resumption of dupilumab in the interventional group (stopping dupilumab) at 6, 12 and 24 months	6, 12 and 24 months
Adverse events or serious adverse events	Proportion of patients with adverse events or serious adverse events in both groups	24 months
Time to loss of control	Comparing the interventional group with the control group regarding the time between baseline to loss of control defined by a reduction of 5 points or more on asthma test control score	24 months
First exacerbation	Comparing the interventional group with the control group regarding the time to first exacerbation	24 months
Number of exacerbations	Comparing the interventional group with the control group regarding the number of exacerbations within 24 months	24 months
Proportion of patients with ≥ 1 exacerbation(s)	Comparing the interventional group with the control group regarding the proportion of patients with ≥ 1 exacerbation(s) or severe exacerbation(s) at 6, 12 and 24 months. A severe exacerbation is defined as an emergency room visit or hospital admission or death related to asthma exacerbation.	6, 12 and 24 months
Change in quality of life	Comparing the interventional group with the control group regarding the change in quality of life at 6, 12 and 24 months compared to baseline. The change in the severe asthma questionnary quality of life score and the Burden of Treatment Questionnaire score at 6, 12 and 24 months compared to baseline. The severe asthma questionnary is a health-related quality of life questionnaire validated for use in severe asthma. It is scored using the mean value of 16 items (severe asthma questionnary score) in addition to a single item global rating of health-related quality of life. The Burden of Treatment Questionnaire is a 15-item questionnaire that assesses the treatment burden of chronic diseases.	6, 12 and 24 months
Change in lung function	The lung function change is a qualitative clinical criteria of failure/success of the strategy. This failure is made up of 3 components : Forced Expiratory Volume in 1 second (in L and % predicted, pre- and post-bronchodilator), Forced Vital Capacity (in L and % predicted) and forced exhaled nitric oxide (in ppb) at 6, 12 and 24 months compared to baseline	6, 12 and 24 months
Change in the daily dose of oral corticosteroids	Comparing the interventional group with the control group regarding the change in the daily dose (mg/day) of oral corticosteroids (in prednisone equivalent) at 6, 12 and 24 months compared to baseline	6, 12 and 24 months
Change in the daily dose of inhaled corticosteroids	Comparing the interventional group with the control group regarding the change in the daily dose (μg/day) of inhaled corticosteroids (in beclomethasone equivalent) at 6, 12 and 24 months	6, 12 and 24 months
Effect on nasal polyposis	Comparing the interventional group with the control group regarding the change in nasal polyposis endoscopic score (if available) and Sino-Nasal Outcome Test-22 score at 6, 12 and 24 months compared to baseline. The french version of Sino-Nasal Outcome Test-22 is a further modification of the Sino-Nasal Outcome Test-20, a fully validated and easy-to-use outcome measure in rhinology. In addition to the normal 20-item version of the Sino-Nasal Outcome Test, 2 additional items were measured, nasal blockage, and loss of sense of taste and smell. The 22-question Sino-Nasal Outcome Test-22 is scored as 0 (no problem) to 5 (problem as bad as it can be) with a total range from 0 to 110 (higher scores indicate poorer outcomes).	6, 12 and 24 months

Collaborators and Investigators

• Sponsor: University Hospital, Toulouse
• Investigators: Principal Investigator: Laurent GUILLEMINAULT, MD, PhD, University Hospital, Toulouse

Study record dates

Study Major Dates

• Study Start (Estimated): April 2, 2025
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2029

Study Registration Dates

• First Submitted: November 19, 2024
• First Submitted That Met QC Criteria: February 7, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 7, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: exacerbation; dupilumab; severe asthma; discontinuation
• Additional Relevant MeSH Terms: Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Asthma; Physiological Effects of Drugs; Protective Agents; Cariostatic Agents; Tin Fluorides
• Other Study ID Numbers: RC31/24/0325; 2024-516789-13-00 (Ctis)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No