Evaluation of Dupilumab in Patients With Severe Steroid Dependent Asthma

Asthma Clinical Trial

— VENTURE  

Official title:

A Randomized, Double-blind, Placebo-controlled Study to Evaluate the Efficacy and Safety of Dupilumab in Patients With Severe Steroid Dependent Asthma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02528214
• Other study ID #: EFC13691
• Secondary ID: 2015-001573-40U1
• Status: Completed
• Phase: Phase 3
• Start date: October 15, 2015
• Est. completion date: November 13, 2017

Study information

• Verified date: November 2017
• Source: Sanofi
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Primary Objective:

To evaluate the efficacy of dupilumab, compared with placebo, for reducing the use of maintenance oral corticosteroids (OCS) in participants with severe steroid-dependent asthma.

Secondary Objectives:

• To evaluate the safety and tolerability of dupilumab.

• To evaluate the effect of dupilumab in improving participants-reported outcomes.

• To evaluate dupilumab systemic exposure and the incidence of treatment-emergent antidrug antibodies.

Description:

The total study duration per participant was up to 46 weeks, consisting of a screening period of 3 to up to 8 weeks (up to 10 weeks for participants who experienced a clinically significant asthma exacerbation during the screening period), a randomized treatment period of up to 24 weeks, and a post-treatment period of 12 weeks.

Participants who completed treatment were considered for eligibility into the long term extension study LTS12551 (NCT02134028).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 210
• Est. completion date: November 13, 2017
• Est. primary completion date: September 20, 2017
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

Inclusion criteria :

Adult and adolescent (12 years of age or older) participants with a physician diagnosis of asthma for >=12 months, based on the Global Initiative for Asthma (GINA) 2014 guidelines and the following criteria:

• Participants with severe asthma and a well-documented, regular prescribed treatment of maintenance corticosteroids in the 6 months prior to Visit 1 and using a stable OCS dose (ie, no change of OCS dose) for 4 weeks prior to Visit 1. Participants must be taking 5 to 35 mg/day of prednisone/prednisolone, or the equivalent, at Visit 1 and at the randomization visit. In addition, the participants must agree to switch to study-required prednisone/prednisolone as their OCS and use it per protocol for the duration of the study.

• Existing treatment with high-dose inhaled corticosteroid (ICS; >500 mcg total daily dose of fluticasone propionate or equivalent) in combination with a second controller (ie, long-acting beta agonist [LABA], leukotriene receptor antagonist [LTRA]) for at least 3 months with a stable dose of ICS for >=1 month prior to Visit 1. In addition, participants requiring a third controller for their asthma are considered eligible for this study, and it should also be used for at least 3 months with a stable dose >= 1 month prior to Visit 1.

• A forced expiratory volume in 1 second (FEV1) <80% of predicted normal for adults and <=90% of predicted normal for adolescents at Visit 1.

• Evidence of asthma as documented by either: reversibility of at least 12% and 200 mL in FEV1 after the administration of 200 to 400 mcg (2 to 4 inhalations of albuterol/salbutamol or levalbuterol/levosalbutamol, or of a nebulized solution of albuterol/salbutamol or levalbuterol/levosalbutamol, if considered as a standard office practice) before randomization or documented in the 12 months prior to Visit 1 OR airway hyperresponsiveness (methacholine: provocative concentration that causes a positive reaction [PC20] of <8 mg/mL) documented in the 12 months prior to Visit 1.

Exclusion criteria:

• Participants <12 years of age or the minimum legal age for adolescents in the country of the investigative site, whichever is higher (for those countries where local regulations permit enrollment of adults only, participant recruitment will be restricted to those who were >=18 years of age).

• Participants who weighed <30.0 kg.

• Chronic obstructive pulmonary disease (COPD) or other lung diseases (eg, idiopathic pulmonary fibrosis, Churg-Strauss Syndrome, allergic bronchopulmonary aspergillosis, cystic fibrosis) which may impair lung function.

• Clinical evidence or imaging (eg, chest X-ray, computed tomography, magnetic resonance imaging) within 12 months of Visit 1 with clinically significant findings of lung disease(s) other than asthma, as per local standard of care.

• A participant who experiences a deterioration of asthma that results in emergency treatment or hospitalization within 4 weeks of Screening Visit 1.

• A participant who requires 12 puffs or more of rescue medication on any 1 day in the week prior to Visit 1.

• A participant who has experienced an upper or lower respiratory tract infection within the 4 weeks prior to screening.

• Current smoker or cessation of smoking within 6 months prior to Visit 1.

• Previous smoker with a smoking history >10 pack-years.

• Comorbid disease that might interfere with the evaluation of the investigational medicinal product.

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

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• Dupilumab
Solution for injection, Subcutaneous injection in the abdomen, upper thigh or upper arm.
• Placebo
Solution for injection, Subcutaneous injection in the abdomen, upper thigh or upper arm.
• Oral corticosteroid therapy (prednisone/prednisolone)
Oral administration.
• Inhaled corticosteroid (ICS) therapy
Oral inhalation, stable dose (high dose) of ICS in combination with up to 2 other controller medicines (second or third controller therapy).
• Albuterol/Salbutamol
Oral inhalation as needed.
• Levalbuterol/Levosalbutamol
Oral inhalation as needed.

Locations

Country	Name	City	State
Argentina	Investigational Site Number 032003	Buenos Aires
Argentina	Investigational Site Number 032001	Caba
Argentina	Investigational Site Number 032091	Caba
Belgium	Investigational Site Number 056002	Brussels
Belgium	Investigational Site Number 056003	Gent
Belgium	Investigational Site Number 056001	Leuven
Brazil	Investigational Site Number 076013	São Bernardo Do Campo
Brazil	Investigational Site Number 076011	Sao Paulo
Brazil	Investigational Site Number 076002	Sorocaba
Canada	Investigational Site Number 124009	Calgary
Canada	Investigational Site Number 124016	Hamilton
Canada	Investigational Site Number 124003	Mississauga
Canada	Investigational Site Number 124013	Ottawa
Canada	Investigational Site Number 124002	Toronto
Canada	Investigational Site Number 124017	Vancouver
Chile	Investigational Site Number 152007	Quillota
Chile	Investigational Site Number 152005	Santiago
Chile	Investigational Site Number 152008	Talca
Colombia	Investigational Site Number 170001	Bogota
Colombia	Investigational Site Number 170006	Bogota
Hungary	Investigational Site Number 348301	Balassagyarmat
Hungary	Investigational Site Number 348303	Edelény
Israel	Investigational Site Number 376003	Haifa
Israel	Investigational Site Number 376001	Kfar Saba
Israel	Investigational Site Number 376005	Petah-Tikva
Israel	Investigational Site Number 376002	Rehovot
Israel	Investigational Site Number 376004	Tel Hashomer
Italy	Investigational Site Number 380005	Catania
Italy	Investigational Site Number 380002	Genova
Italy	Investigational Site Number 380008	Napoli
Italy	Investigational Site Number 380009	Palermo
Italy	Investigational Site Number 380001	Pisa
Italy	Investigational Site Number 380003	Reggio Emilia
Mexico	Investigational Site Number 484016	Acapulco
Mexico	Investigational Site Number 484013	Chihuahua
Mexico	Investigational Site Number 484001	Guadalajara
Mexico	Investigational Site Number 484002	Mexico, Df
Mexico	Investigational Site Number 484003	Monterrey
Netherlands	Investigational Site Number 528001	Arnhem
Netherlands	Investigational Site Number 528002	Dordrecht
Poland	Investigational Site Number 616006	Bialystok
Poland	Investigational Site Number 616097	Krakow
Poland	Investigational Site Number 616001	Lodz
Poland	Investigational Site Number 616010	Warszawa
Poland	Investigational Site Number 616011	Znin
Romania	Investigational Site Number 642103	Bucharest
Romania	Investigational Site Number 642104	Bucharest
Romania	Investigational Site Number 642102	Cluj-Napoca
Romania	Investigational Site Number 642107	Cluj-Napoca
Romania	Investigational Site Number 642108	Cluj-Napoca
Romania	Investigational Site Number 642105	Timisoara
Romania	Investigational Site Number 642106	Timisoara
Russian Federation	Investigational Site Number 643006	Moscow
Russian Federation	Investigational Site Number 643007	Moscow
Russian Federation	Investigational Site Number 643011	Saint-Petersburg
Russian Federation	Investigational Site Number 643009	St-Petersburg
Russian Federation	Investigational Site Number 643099	St-Petersburg
Spain	Investigational Site Number 724002	Barcelona
Spain	Investigational Site Number 724014	Barcelona
Spain	Investigational Site Number 724013	Madrid
Spain	Investigational Site Number 724006	Pozuelo De Alarcón
Spain	Investigational Site Number 724007	Sant Boi De Llobregat
Spain	Investigational Site Number 724096	Santiago De Compostela
Ukraine	Investigational Site Number 804007	Chernivtsi
Ukraine	Investigational Site Number 804004	Ivano-Frankivsk
Ukraine	Investigational Site Number 804009	Ivano-Frankivsk
Ukraine	Investigational Site Number 804001	Kharkiv
Ukraine	Investigational Site Number 804003	Kyiv
Ukraine	Investigational Site Number 804011	Kyiv
Ukraine	Investigational Site Number 804006	Odessa
Ukraine	Investigational Site Number 804002	Poltava
Ukraine	Investigational Site Number 804019	Vinnytsya
United States	Investigational Site Number 840062	Amarillo	Texas
United States	Investigational Site Number 840022	Los Angeles	California
United States	Investigational Site Number 840070	McKinney	Texas
United States	Investigational Site Number 840128	McKinney	Texas
United States	Investigational Site Number 840010	Pittsburgh	Pennsylvania
United States	Investigational Site Number 840118	Plano	Texas
United States	Investigational Site Number 840014	Rolling Hills Estates	California
United States	Investigational Site Number 840002	Saint Louis	Missouri

Sponsors (2)

Lead Sponsor	Collaborator
Sanofi	Regeneron Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Canada,  Chile,  Colombia,  Hungary,  Israel,  Italy,  Mexico,  Netherlands,  Poland,  Romania,  Russian Federation,  Spain,  Ukraine, 

References & Publications (1)

Rabe KF, Nair P, Brusselle G, Maspero JF, Castro M, Sher L, Zhu H, Hamilton JD, Swanson BN, Khan A, Chao J, Staudinger H, Pirozzi G, Antoni C, Amin N, Ruddy M, Akinlade B, Graham NMH, Stahl N, Yancopoulos GD, Teper A. Efficacy and Safety of Dupilumab in G — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Annualized Rate of Severe Exacerbation Events During The 24-Week Treatment Period	A severe asthma exacerbation event was defined as a deterioration of asthma during the 24-week treatment period requiring: use of systemic corticosteroids for >=3 days (at least double the dose currently used); and/or hospitalization related to asthma symptoms or emergency room visit because of asthma requiring intervention with a systemic corticosteroid treatment. Annualized event rate was the total number of exacerbations that occurred during the treatment period divided by the total number of participant-years treated.	Baseline to Week 24
Other	Change From Baseline in Pre-Bronchodilator Forced Expiratory Volume in 1 Second (FEV1) at Weeks 12 and 24	FEV1 was the volume of air exhaled in the first second of a forced expiration as measured by spirometer.	Baseline, Week 12 and Week 24
Other	Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Score at Weeks 2, 4, 8, 12, 16, 20, and 24	The ACQ-5 has 5 questions, reflecting top-scoring 5 asthma symptoms: woken at night by symptoms, wake in mornings with symptoms, limitation of daily activities, shortness of breath and wheeze. Participants were asked to recall how their asthma had been during previous week and to respond to each of 5 symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total score was mean of scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control.	Baseline and at Weeks 2, 4, 8, 12, 16, 20, and 24
Other	Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Global Score at Week 12 and Week 24	AQLQ is a disease-specific, self-administered quality of life questionnaire designed to measure functional impairments that were most important to participants with asthma. AQLQ comprised of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), environmental stimuli (4 items). Each item was scored on a 7-point likert scale (1=maximal impairment, 7=no impairment). The 32 items of the questionnaire were averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired at all). Higher scores indicate better quality of life.	Baseline, Week 12 and Week 24
Other	Change From Baseline in European Quality of Life Working Group Health Status Measure 5 Dimensions, 5 Levels (EQ-5D-5L) Scores at Week 12 and Week 24	EQ-5D-5L is a standardized health-related quality of life questionnaire developed by EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal. EQ-5D consists of EQ-5D descriptive system and EQ visual analogue scale (VAS). EQ-5D descriptive system comprises of 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The 5D-5L systems are converted into a single index utility score between 0 to 1, where higher score indicates a better health state. EQ-5D-5L-VAS records participant's self-rated health on a vertical VAS that allows them to indicate their health state that can range from 0 (worst imaginable) to 100 (best imaginable).	Baseline, Week 12 and Week 24
Other	Change From Baseline in Hospital Anxiety and Depression Scale (HADS) Total Score at Week 12 and Week 24	The HADS is a general scale to detect states of anxiety and depression already used and validated in asthma, which includes HADS-A and HADS-D subscales. The instrument is comprised of 14 items: 7 related to anxiety (HADS-A) and 7 to depression (HADS-D). Each item on the questionnaire is scored from 0-3. And, the total score is the sum of the scores of the 14 items ranging from 0 (no symptoms) to 42 (severe symptoms), with higher scores indicating higher anxiety/depression complains.	Baseline, Week 12 and Week 24
Other	Change From Baseline in Sino Nasal Outcome Test-22 (SNOT-22) Global Score at Week 12 and Week 24	The SNOT-22 is a validated measure of health related quality of life in sino nasal disease. It is a 22 item questionnaire with each item assigned a score ranging from 0-5. The total score may range from 0 (no disease) -110 (worst disease), lower scores represent better health related quality of life.	Baseline, Week 12 and Week 24
Primary	Percentage Reduction From Baseline in Oral Corticosteroids (OCS) Dose at Week 24 While Maintaining Asthma Control	Percentage reduction of OCS dose was calculated as (optimized OCS dose [mg/day] at baseline - final OCS dose at Week 24)/optimized OCS dose at baseline x 100. Result is presented as Least Squares Mean (Standard Error) percentage reduction from baseline derived from ANCOVA model with missing data multiply imputed.	Baseline, Week 24
Primary	Supplementary Presentation of Primary Outcome Measure Data: Median Percentage Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	The Primary Outcome Measure (Percentage Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control) is summarized above, as LS Mean (SE). Table below provides a supplementary presentation of the Primary Outcome Measure data; result is presented as median (inter-quartile range). Percentage reduction of OCS dose was calculated as (optimized OCS dose [mg/day] at baseline - final OCS dose at Week 24)/optimized OCS dose at baseline x 100.	Baseline, Week 24
Secondary	Percentage of Participants Achieving >= 50% Reduction in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Participants were classified according to the binary status of whether or not the 50% OCS dose reduction criterion was achieved at week 24.	Week 24
Secondary	Percentage of Participants Achieving a Reduction in Oral Corticosteroids Dose to <5 mg/Day at Week 24 While Maintaining Asthma Control	Participants were classified according to the binary status of whether or not the reduction of OCS dose to <5 mg/day was achieved at Week 24.	Week 24
Secondary	Percentage of Participants Achieving Maximum Possible Reduction in Oral Corticosteroids Dose Per Protocol at Week 24 While Maintaining Asthma Control	For all participants except those with baseline OCS dose at 35 mg/day, the maximum possible reduction corresponds to reduction to 0 mg/day (no longer requiring OCS). For participants starting with 35 mg/day at baseline, the maximum possible reduction is 32.5 mg/day (i.e. minimum dose per protocol is 2.5 mg).	Week 24
Secondary	Percentage of Participants Who No Longer Required Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Participants were classified according to the binary status of whether or not the participant still required OCS at Week 24 while maintaining asthma control.	Week 24
Secondary	Absolute Reduction From Baseline in Oral Corticosteroids Dose at Week 24 While Maintaining Asthma Control	Absolute reduction was calculated by subtracting Week 24 value from baseline value.	Baseline and Week 24

External Links

•   Link