A Phase 4, Randomized, Double-blind, Placebo-controlled, Multicenter, Parallel-group Study of the Effect of Dupilumab on Sleep Disturbance in Patients With Uncontrolled Persistent Asthma (MORPHEO)

Primary Objective:

To assess the effect of dupilumab on sleep

Secondary Objectives:

• To evaluate the effect of dupilumab on additional participant reported sleep outcomes
• To evaluate the effect of dupilumab on objective sleep assessment
• To evaluate the effect of dupilumab on asthma symptoms
• To evaluate the effect of dupilumab on lung function
• To evaluate the safety of dupilumab

Study Overview

• Status: Completed
• Conditions: Asthma
• Intervention / Treatment: Drug: SAR231893; Drug: Placebo

Detailed Description

Study duration per participant was approximately 16 weeks and up to 29 weeks including up to 5 weeks screening period, a 12-week treatment period and up to 12 weeks post-treatment follow-up period or until the participant switched to commercialized dupilumab (or other biologic product), whichever came first.

• Study Type: Interventional
• Enrollment (Actual): 202
• Phase: Phase 4

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, C1121ABE
    • Investigational Site Number : 0320002
  • Buenos Aires
    • Caba, Buenos Aires, Argentina, C1414AIF
      • Investigational Site Number : 0320003
    • Caba, Buenos Aires, Argentina, C1425FVH
      • Investigational Site Number : 0320001
  • Santa Fe
    • Rosario, Santa Fe, Argentina, S2000DEJ
      • Investigational Site Number : 0320004
    • Rosario, Santa Fe, Argentina, S2002OJP
      • Investigational Site Number : 0320005
• Canada
  • Quebec, Canada, G1G 3Y8
    • Investigational Site Number : 1240009
  • Windsor, Canada, N8X 5A6
    • Investigational Site Number : 1240008
  • Ontario
    • Ajax, Ontario, Canada, L1S 2J5
      • Investigational Site Number : 1240012
    • Toronto, Ontario, Canada, M9V 4B4
      • Investigational Site Number : 1240005
• Germany
  • Berlin, Germany, 10787
    • Investigational Site Number : 2760002
  • Frankfurt am Main, Germany, 60596
    • Investigational Site Number : 2760005
  • Hannover, Germany, 30173
    • Investigational Site Number : 2760003
  • Koblenz, Germany, 56068
    • Investigational Site Number : 2760001
  • Leipzig, Germany, 04347
    • Investigational Site Number : 2760004
  • Lübeck, Germany, 23552
    • Investigational Site Number : 2760006
• Italy
  • Reggio Emilia, Italy, 42123
    • Investigational Site Number : 3800005
  • Cagliari
    • Monserrato, Cagliari, Italy, 09042
      • Investigational Site Number : 3800006
  • Torino
    • Orbassano, Torino, Italy, 10043
      • Investigational Site Number : 3800001
• Netherlands
  • Arnhem, Netherlands, 6815 AD
    • Investigational Site Number : 5280005
  • Breda, Netherlands, 4818 CK
    • Investigational Site Number : 5280001
  • Leeuwarden, Netherlands, 8934 AD
    • Investigational Site Number : 5280002
• Portugal
  • Aveiro, Portugal, 3810-501
    • Investigational Site Number : 6200001
  • Guimarães, Portugal, 4810-061
    • Investigational Site Number : 6200007
  • Lisboa, Portugal, 1769
    • Investigational Site Number : 6200006
  • Matosinhos, Portugal, 4464-513
    • Investigational Site Number : 6200003
  • Porto, Portugal, 4202-451
    • Investigational Site Number : 6200004
• Russian Federation
  • Moscow, Russian Federation, 115093
    • Investigational Site Number : 6430001
  • Moscow, Russian Federation, 115280
    • Investigational Site Number : 6430002
  • Moscow, Russian Federation, 115478
    • Investigational Site Number : 6430006
  • Moscow, Russian Federation, 117546
    • Investigational Site Number : 6430005
  • St-Petersburg, Russian Federation, 193231
    • Investigational Site Number : 6430007
  • St-Petersburg, Russian Federation, 194354
    • Investigational Site Number : 6430004
• Spain
  • Madrid, Spain, 28006
    • Investigational Site Number : 7240005
  • Galicia [Galicia]
    • Lugo / Lugo, Galicia [Galicia], Spain, 27003
      • Investigational Site Number : 7240001
  • Valenciana, Comunidad
    • Valencia, Valenciana, Comunidad, Spain, 46017
      • Investigational Site Number : 7240002
• Ukraine
  • Ivano-Frankivsk, Ukraine, 76018
    • Investigational Site Number : 8040002
  • Ivano-Frankivsk, Ukraine, 76018
    • Investigational Site Number : 8040006
  • Kharkiv, Ukraine, 61166
    • Investigational Site Number : 8040003
  • Kyiv, Ukraine, 01023
    • Investigational Site Number : 8040008
  • Kyiv, Ukraine, 01033
    • Investigational Site Number : 8040007
  • Vinnytsya, Ukraine, 21001
    • Investigational Site Number : 8040005
• United Kingdom
  • Cambridgeshire
    • Cambridge, Cambridgeshire, United Kingdom, CB2 2QQ
      • Investigational Site Number : 8260001
  • London, City Of
    • London, London, City Of, United Kingdom, EC1M 6BQ
      • Investigational Site Number : 8260002
• United States
  • California
    • Bakersfield, California, United States, 93301
      • Kern Allergy and Medical Research. Inc. Site Number : 8400003
    • Culver City, California, United States, 90230
      • Todd Astor MD Site Number : 8400016
    • Los Angeles, California, United States, 90048
      • Southern California Institute for Respiratory Diseases Site Number : 8400009
    • San Jose, California, United States, 95117
      • Allergy & Asthma Associates of Santa Clara Valley Site Number : 8400001
  • Colorado
    • Colorado Springs, Colorado, United States, 80907
      • Asthma and Allergy Associates, PC Site Number : 8400011
  • Florida
    • Sarasota, Florida, United States, 34239
      • Sarasota Clinical Research Site Number : 8400012
  • Kentucky
    • Owensboro, Kentucky, United States, 42301
      • Allergy & Asthma Specialists, PSC Site Number : 8400004
  • Nebraska
    • Bellevue, Nebraska, United States, 68123
      • The Asthma and Allergy Center Site Number : 8400010
  • Oklahoma
    • Edmond, Oklahoma, United States, 73034
      • OK Clinical Research LLC Site Number : 8400005
  • Oregon
    • Medford, Oregon, United States, 97504
      • Velocity Clinical Research, Medford Site Number : 8400007
  • South Carolina
    • Charleston, South Carolina, United States, 29407
      • National Allergy and Asthma Research, LLC Site Number : 8400008
  • Texas
    • Boerne, Texas, United States, 78006
      • TTS Research Site Number : 8400006

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 61 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Physician diagnosis of asthma based on the Global Initiative for Asthma (GINA) 2020 Guidelines for ≥12 months treated with medium to high dose inhaled corticosteroid (ICS) and a second controller (ie, long-acting beta agonist, leukotriene receptor antagonist). A third controller is allowed but not mandatory. The dose regimen should be stable for at least 1 month before the study and during the screening period
• History of at least one severe asthma exacerbation within 1 year prior to screening. Severe exacerbation is defined as deterioration of asthma that results in emergency treatment, hospitalization due to asthma, or treatment with systemic steroids (oral or injectable)

• Eosinophils ≥150 cells/μL and fractional exhaled nitric oxide (FeNO) ≥25 ppb during screening, prior to randomization

  • NOTES:
  • Historical values of blood eosinophil count meeting the eligibility criterion measured within 6 months prior to screening Visit 1 in the absence of oral corticosteroid (OCS) treatment are allowed
  • FeNO value to be checked for eligibility at Visit 2 as well
• Asthma control questionnaire (ACQ)-5 ≥2.5 at screening Visit 1 and Visit 2, prior to randomization
• Pre-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) ≤ 80% of predicted normal during screening and at Visit 2, prior to randomization
• Exhibit bronchodilator reversibility (≥12% and 200 mL improvement in FEV1 post short-acting beta agonist administration) during screening period, prior to randomization, unless reversibility test meeting the inclusion criteria was done within 6 months prior to screening Visit 1
• Weekly average nocturnal awakenings due to asthma symptoms in the week prior to screening Visit 1 is ≥1

Exclusion Criteria:

• Current smoker
• Former smoker for 10 years with a smoking history of >10 pack-years
• Severe asthma exacerbation during screening, prior to randomization
• History or clinical evidence of chronic obstructive pulmonary disease (COPD) including Asthma-COPD Overlap Syndrome (ACOS) or any other significant lung disease (eg, lung fibrosis, sarcoidosis, interstitial lung disease, pulmonary hypertension, bronchiectasis, Churg-Strauss Syndrome)
• History of or current evidence of clinically significant non-respiratory diseases that in the opinion of the investigator may interfere with the aims of the study or put the participant at undue risk
• Active tuberculosis (TB) or non-tuberculous mycobacterial infection, or a history of incompletely treated TB will be excluded unless it is well documented by a specialist that the participant has been adequately treated and can now start treatment with a biologic agent, in the medical judgment of the Investigator and/or infectious disease specialist. Tuberculosis testing would be performed on a country by country basis, according to local guidelines if required by Regulatory Authorities or ethics boards
• Diagnosed active endoparasitic infection; suspected or high risk of endoparasitic infection, unless clinical and (if necessary) laboratory assessment have ruled out active infection before randomization
• History of human immunodeficiency (HIV) infection or positive HIV test at screening Visit 1
• Active chronic or acute infection requiring treatment with systemic antibiotics, antivirals, antiprotozoals, or antifungals within 2 weeks before screening
• Known or suspected immunodeficiency including history of invasive opportunistic infections, despite infection resolution
• Current evidence of clinically significant oncological disease
• History of systemic hypersensitivity or anaphylaxis to any biologic therapy
• Severe uncontrolled depression
• Sleep disturbances not related to asthma, including sleep apnea, hypersomnia, or insomnia secondary to chronic pain, atopic dermatitis (AD), COPD or other conditions
• Participant who works night shift (ie, any work between 8 pm and 6 am)
• Erratic sleep habits, as determined by the Investigator
• Restless leg syndrome or periodic limb movement disorder
• Chronic treatment with oral corticosteroid (OCS) for more than 2 weeks before screening Visit 1
• Participant taking sedative, anxiolytic, or hypnotic treatments, including melatonin, within 3 months before randomization
• Participant taking systemic sedative antihistamines (excluding newer generations of antihistamines) or theophylline
• Current treatment with antidepressants, lipophilic beta blockers, clonidine, opioids, or other medications known to interfere with sleep and may confound the study assessments, as determined by the Investigator
• Participant who has taken biologic therapy (including dupilumab)/systemic immunosuppressant to treat inflammatory disease or autoimmune disease (eg, rheumatoid arthritis, inflammatory bowel disease, primary biliary cirrhosis, systemic lupus erythematosus, multiple sclerosis, etc) within 2 months or 5 half-lives before screening Visit 1, whichever is longer

• Treatment with live (attenuated) vaccine within 4 weeks before screening Visit 1

  • NOTE: For participants who have vaccination with live, attenuated vaccines planned during the course of the study (based on national vaccination schedule/local guidelines), it will be determined, after consultation with a physician, whether the administration of vaccine can be postponed until after the end of the study, (i.e. after the 12 week follow-up period off-treatment or until the participant switches to commercialized dupilumab or other biologic product, whichever comes first), or preponed to before the start of the study without compromising the health of the participant:
  • Participant for whom administration of live (attenuated) vaccine can be safely postponed would be eligible to enroll into the study
  • Participant who have their vaccination preponed can enroll in the study only after a gap of 4 weeks following administration of the vaccine

The above information is not intended to contain all considerations relevant to a patient's potential participation in a clinical trial.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dupilumab; Participants received a loading dose of 400 mg of dupilumab (2 injections × 200 mg) SC on Day 1, followed by 200 mg Q2W for 12 weeks.	Drug: SAR231893; Pharmaceutical form: Solution for injection; Route of administration: Subcutaneous; Other Names: Dupixent
Placebo Comparator: Placebo; Participants received an initial loading dose of matching placebo (2 injections of placebo) SC on Day 1, followed by 1 injection of placebo Q2W for 12 weeks.	Drug: Placebo; Pharmaceutical form: Solution for injection; Route of administration: Subcutaneous

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 12 in Sleep Disturbance Score Using the Asthma Sleep Disturbance Questionnaire (ASDQ)	The ASDQ is a participant-reported outcome (PRO) measure designed to assess the impact of asthma on participants' sleep. Participants were instructed to record the severity of the disturbance of their sleep due to asthma as: 0 = slept through the night, no asthma symptoms; 1 = slept well, no night time awakenings because of asthma, but some asthma symptoms in the morning; 2 = woke up once because of asthma (may or may not include early awakening); 3 = woke up several times because of asthma (may or may not include early awakening) and 4 = bad night, awake most of the night because of asthma. The participants recorded their sleep disturbance in an electronic diary, once a day upon awakening. Total scores ranges between 0 to 4 with 0 indicating no impact of asthma on sleep and 4 indicating higher impact of asthma on sleep. Higher scores indicated worse outcomes. Baseline was calculated by averaging the data collected/recorded from Day -6 to Day 1.	Baseline (Day -6 to Day 1) up to Week 12

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline to Week 12 on the Number of Nocturnal Awakenings (Sleep Diary)	Sleep diary is used to assess adult sleep disturbance due to asthma. Number of nocturnal awakenings was determined based on answer on question from sleep diary: "Approximately how many times did you wake up last night (not including when you woke up for the day today)?" Baseline was calculated by averaging the data collected/recorded from Day -6 to Day 1.	Baseline (Day -6 to Day 1) up to Week 12
Change From Baseline to Week 12 in Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep-Related Impairment 8a Scale	PROMIS sleep-related impairment eight-term 8a scale was administered to assess impact of sleep-related impairment during waking hours. The questionnaire focuses on self-reported perceptions of alertness, sleepiness, and tiredness during usual waking hours, and perceived functional impairments during wakefulness associated with sleep problems or impaired alertness. It assesses sleep-related impairment over the past 7 days. Each item is rated on a 5-point scale (1 = not at all; 2 = a little bit; 3 = somewhat; 4 = quite a bit; and 5 = very much) with a raw score from 8 to 40 with higher scores indicating greater sleep impairment. PROMIS T-score is presented which rescales the raw score into a standardized score with a mean of 50 and a standard deviation of 10. Possible range for T-score=30 to 80; higher scores=greater severity of sleep impairment. Baseline=last available valid (non-missing) value up to and including the day of first dose of investigational medicinal product (IMP).	Baseline (Day 1) up to Week 12
Change From Baseline to Week 12 in Sleep Quality (Sleep Diary)	Sleep diary is used to assess adult sleep disturbance due to asthma. Sleep quality was assessed on a 11-point scale which ranged from 0 (worst possible sleep) to 10 (best possible sleep); higher scores indicated better outcomes. Baseline was calculated by averaging the data collected/recorded from Day -6 to Day 1.	Baseline (Day -6 to Day 1) up to Week 12
Change From Baseline to Week 12 in Restorative Sleep (Sleep Diary)	Sleep Diary is used to assess adult sleep disturbance due to asthma. Question about restorative sleep asks participants to recall "when they got up for the day today". Restorative sleep was assessed on a 11-point scale which ranged from 0 (worst possible sleep) to 10 (best possible sleep); higher scores indicated better outcomes. Baseline was calculated by averaging the data collected/recorded from Day -6 to Day 1.	Baseline (Day -6 to Day 1) up to Week 12
Change From Baseline to Week 12 in Wake After Sleep Onset (WASO) (Sleep Diary)	Sleep Diary is used to assess adult sleep disturbance due to asthma. WASO was calculated as time awake after initial sleep onset but before the final awakening. Baseline was calculated by averaging the data collected/recorded from Day -6 to Day 1.	Baseline (Day -6 to Day 1) up to Week 12
Change From Baseline to Week 12 in WASO Based on Actigraphy Data	Wrist actigraphy is a procedure that records and integrates occurrence and degree of limb movement activity over an extended recording period. The signals generated by wrist movement are sensed by a tiny microcomputer contained within watch and translated into activity counts. Algorithms have been developed to translate these activity counts or "epochs" (or "periods") that correspond to times when a person is likely to be asleep or wake. Actigraph was worn on wrist of non-dominant hand to provide estimates of duration, timing and patterns of sleep in study participants. After the watch data were scored by a selected expert center, a number of summary measurements were generated for each participant, including WASO. Baseline was calculated by averaging the data collected/recorded from Day -6 to Day 1.	Baseline (Day -6 to Day 1) up to Week 12
Change From Baseline to Week 12 in Asthma Daytime Symptom Diary (ADSD)	The ADSD is a PRO measure designed to measure asthma symptoms in adult and adolescent (12 years of age and older) participants diagnosed with mild to severe asthma. ADSD assesses asthma severity based on participant self-report of asthma core symptoms, i.e., difficulty breathing, wheezing, shortness of breath, chest tightness, chest pain, and cough. Participants were asked to complete the ADSD every night before they go to bed, thinking about their asthma symptoms today, from when they got up this morning until now. ADSD is composed of 6 items rated using an 11-point NRS that ranges from 0 = None to 10 = as bad as you can imagine. The total score was calculated by averaging all 6 items and therefore the score ranged from 0 to 10. Higher scores indicated worse outcomes. Baseline value was average of the data from Day -7 to Day -1.	Baseline (Day -7 to Day -1) up to Week 12
Change From Baseline to Week 12 in Asthma Nighttime Symptom Diary (ANSD)	The ANSD is a PRO measure designed to measure asthma symptoms in adult and adolescent (12 years of age and older) participants diagnosed with mild to severe asthma. ANSD assesses asthma severity based on participant self-report of asthma core symptoms, i.e., difficulty breathing, wheezing, shortness of breath, chest tightness, chest pain, and cough. Participants were asked to complete the ANSD when getting up, thinking about their asthma symptoms last night from when they went to bed until now. ANSD is composed of 6 items rated using an 11-point NRS that ranges from 0 = None to 10 = as bad as you can imagine. The total score was calculated by averaging all 6 items and therefore the score ranged from 0 to 10. Higher scores indicated worse outcomes. Baseline value was average of the data from Day -6 to Day -1.	Baseline (Day -6 to Day -1) up to Week 12
Change From Baseline to Week 12 in Pre-Bronchodilator Forced Expiratory Volume (Pre-BD FEV1)	FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer. For pre-BD FEV1, spirometry was performed before IMP administration and after withholding the standard of care asthma treatment which was verified before performing the measurements. Baseline was defined as the last available valid (non-missing) value up to and including the day of first dose of IMP.	Baseline (Day 1) up to Week 12
Number of Participants With Treatment-Emergent Adverse Events (TEAEs), Treatment-Emergent Serious Adverse Events (TESAEs), and Treatment-Emergent Adverse Events Of Special Interest (TEAESIs)	AE: any untoward medical occurrence in participant or clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. TEAEs: AEs that developed or worsened or became serious during TEAE period, defined as time from first administration of IMP (on Day 1) to last administration of IMP + 98 days or until participant switches to commercialized dupilumab or other biologics. SAE: any untoward medical occurrence that, at any dose: resulted in death, was life-threatening, required inpatient hospitalization or prolongation of existing hospitalization, resulted in persistent or significant disability/incapacity, was a congenital anomaly/birth defect, was a medically important event. AESI: AE (serious or nonserious) of scientific and medical concern specific to Sponsor's product or program, for which ongoing monitoring and immediate notification by Investigator to Sponsor is required.	From first dose of study drug (Day 1) up to 12 weeks after last dose of study drug, approximately 30 weeks
Number of Participants With Potentially Clinically Significant Abnormalities (PCSA) in Vital Signs	Vital signs included systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and weight. Criteria for PCSA: SBP: ≤95 millimeters of mercury (mmHg) and decrease from baseline ≥20 mmHg, ≥160 mmHg and increase from baseline ≥20 mmHg; DBP: ≤45 mmHg and decrease from baseline ≥10 mmHg, ≥ 110 mmHg and increase from baseline ≥ 10 mmHg; HR: ≤ 50 beats per minute (bpm) and decrease from baseline ≥ 20 bpm, ≥120 bpm and increase from baseline ≥ 20 bpm; Weight: ≥ 5% increase from baseline, ≥5% decrease from baseline.	From first dose of study drug (Day 1) up to 12 weeks after last dose of study drug, approximately 30 weeks

Collaborators and Investigators

• Sponsor: Sanofi
• Collaborators: Regeneron Pharmaceuticals
• Investigators: Study Director: Clinical Sciences & Operations, Sanofi

Publications and helpful links

Helpful Links

• LPS16677 Plain language Results Summary

Study record dates

Study Major Dates

• Study Start (Actual): August 10, 2020
• Primary Completion (Actual): October 3, 2023
• Study Completion (Actual): November 10, 2023

Study Registration Dates

• First Submitted: August 4, 2020
• First Submitted That Met QC Criteria: August 4, 2020
• First Posted (Actual): August 6, 2020

Study Record Updates

• Last Update Posted (Actual): December 6, 2024
• Last Update Submitted That Met QC Criteria: December 4, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Mental Disorders; Immune System Diseases; Respiratory Tract Diseases; Lung Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Sleep Wake Disorders; Asthma; Dyssomnias; Parasomnias
• Other Study ID Numbers: LPS16677; 2020-001217-20 (EudraCT Number); U1111-1249-6054 (Registry Identifier: ICTRP)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Qualified researchers may request access to patient level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Patient level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://vivli.org

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No