Efficacy, Safety, and Tolerability of Dupilumab in Patients With Persistent Moderate to Severe Eosinophilic Asthma

Randomized, Double-blind, Placebo-controlled, Parallel Group Study to Assess the Efficacy, Safety, and Tolerability of SAR231893/REGN668 Administered Subcutaneously Once Weekly for 12 Weeks in Patients With Persistent Moderate to Severe Eosinophilic Asthma Who Are Partially Controlled/Uncontrolled by Inhaled Corticosteroid Plus Long-acting beta2 Agonist Therapy

Status

Completed

Phases

Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01312961

Enrollment

104

Registered

2011-03-11

Start date

2011-03-31

Completion date

2012-10-31

Last updated

2017-06-08

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Asthma

Brief summary

Primary Objective: To investigate the effects of Dupilumab (SAR231893/REGN668) administered subcutaneously (SC) once weekly (qw) for 12 weeks as compared to placebo on reducing the incidence of asthma exacerbation in participants with persistent moderate to severe eosinophilic asthma. Secondary Objectives: * To assess the safety and tolerability of Dupilumab administered SC qw for 12 weeks in participants with persistent moderate to severe eosinophilic asthma. * To assess Dupilumab serum concentrations following qw SC dosing for 12 weeks in participants with persistent moderate to severe eosinophilic asthma.

Detailed description

The total duration of the study period per participant was 20-22 weeks broken down as follows: * Screening period: up to 14 days, * Treatment period: 12 weeks, * Follow-up period: 6-8 weeks.

Interventions

DRUGPlacebo (for Dupilumab)

Solution for injection, one subcutaneous injection.

DRUGDupilumab

Solution for injection, one subcutaneous injection.

DRUGFluticasone/Salmeterol combination therapy

Oral inhalation twice daily.

DRUGFluticasone monotherapy

Oral inhalation twice daily.

DRUGAlbuterol

Oral inhalation as needed.

DRUGLevalbuterol

Oral inhalation as needed.

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

TRIPLE (Subject, Caregiver, Investigator)

Eligibility

Sex/Gender

ALL

Age

18 Years to 65 Years

Healthy volunteers

Inclusion criteria

Medical diagnosis of persistent asthma for at least 12 months whose: * airway inflammation likely to be eosinophilic, * asthma partially controlled or uncontrolled on ICS plus LABA therapy. * On a stable dose of either Fluticasone/Salmeterol, Budesonide/Formoterol, Mometasone/Formoterol combination therapy for at least 1 month prior to screening. * Signed an Informed Consent Form and Health Insurance Portability and Accountability Act (HIPAA) Authorization Form.

Exclusion criteria

* Less than 18 years or greater than 65 years of age. * Clinically relevant abnormal laboratory values suggesting an unknown disease and requiring further evaluation. * Chronic obstructive pulmonary disease and/or other lung diseases impairing Pulmonary Function Tests. * Beta-adrenergic receptor blockers required for any reason. * Current smoker or cessation of smoking within the 6 months prior to screening. * Previous smoking with a smoking history \>10 cigarette pack/years. * Participation in another study within 6 months prior to screening if the study medication was an antibody or within 30 days prior to screening for all other study medications. * Known or suspected non-compliance, alcohol or drug abuse. * Inability to follow the procedures of the study (e.g, due to language problems, psychological disorders). * Concomitant severe diseases or diseases for which the use of ICS or LABA were contraindicated. * Known allergy to doxycycline or related compounds. * Pregnancy or intention to become pregnant during the course of the study, breast feeding, or unwillingness to use a highly effective method of contraception throughout the study in women of childbearing potential. * Recent history of a parasitic infection or travel to a parasitic endemic area within 6 months prior to screening. The above information is not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.

Design outcomes

Primary

Measure	Time frame	Description
Percentage of Participants With Asthma Exacerbation	Baseline up to Week 12	An asthma exacerbation was defined as the occurrence of any of the following: ≥30% reduction from baseline in morning PEF on 2 consecutive days; or ≥6 additional reliever puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; or deterioration of asthma, as determined by the investigator, requiring systemic steroid treatment, or an increase in inhaled corticosteroid (ICS) of ≥4 times the last dose received prior to discontinuation from the study, or hospitalization. The occurrence of asthma exacerbations by individual criteria are reported.

Secondary

Measure	Time frame	Description
Percentage of Participants With Composite Asthma Events	Baseline up to Week 12	Composite asthma event was defined as a 30% or greater reduction from baseline in morning PEF on 2 consecutive days together with 6 or more additional reliever puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days.
Change From Baseline in Forced Expiratory Flow in One Second (FEV1) to Week 12	Baseline, Week 12	FEV1 is the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation.
Change From Baseline in Peak Expiratory Flow (PEF) to Week 12	Baseline, Week 12	The PEF is a participant's maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PEF was performed at home (morning and evening) while sitting or standing prior to using any medication (if needed) for asthma.
Change From Baseline in Asthma Control Questionnaire (5-question Version [ACQ-5]) to Week 12	Baseline, Week 12	ACQ-5 questionnaire is a validated questionnaire comprising of 5 questions for asthma symptoms: woken at night by symptoms, wake in the mornings with symptoms, limitation of daily activities, shortness of breath, and wheeze. Participants were asked to rate their asthma symptoms during the previous week on a 7-point scale as 0=no impairment, 6=maximum impairment. ACQ-5 score is the mean of the 5 questions and range between 0 (disease totally controlled) and 6 (disease severely uncontrolled), a higher score indicated lower asthma control.
Time to First Asthma Exacerbation: Kaplan-Meier Estimates at Week 4, Week 8 and Week 12	Baseline up to Week 12	The time-to-asthma exacerbation was defined as the time from the date of randomization to the date of the first asthma exacerbation event; for participants without asthma exacerbation, it was censored at the end of treatment visit date. The median time to first asthma exacerbation was not estimated because the number of asthma exacerbations was too low in the Dupilumab arm. Therefore, alternative Kaplan-Meier statistics, the probability of asthma exacerbation at Week 4, 8 and 12, are presented as the descriptive measure statistics.
Change From Baseline in Morning Asthma Symptom Scores to Week 12	Baseline, Week 12	AM (ante meridiem) symptom scoring system rates were participant's overall asthma symptoms experienced during the night. It ranges from 0 to 4 as: 0 = No asthma symptoms, slept through the night, 1= Slept well, but some complaints in the morning. No nighttime awakenings,2= Woke up once because of asthma (including early awakening),3= Woke up several times because of asthma (including early awakening), 4= Bad night, awake most of the night because of asthma.
Change From Baseline in Evening Asthma Symptom Scores to Week 12	Baseline, Week 12	PM (post meridiem) symptom scoring system rates were participant's overall asthma symptoms experienced during the day. It ranges from 0 to 4 as: 0=very well, no asthma symptoms, 1=one episode of wheezing, cough, or breathlessness, 2=more than one episode of wheezing, cough, or breathlessness without interference of normal activities, 3=wheezing, cough, or breathlessness most of the day, which interfered to some extent with normal activities, 4=asthma very bad, unable to carry out daily activities as usual.
Change From Baseline in Number of Nocturnal Awakenings Per Day to Week 12	Baseline, Week 12	Participants recorded every morning on awakening the number of asthma-related nocturnal awakenings requiring use of rescue medication that occurred during the previous night.
Change From Baseline in Number of Inhalations Per Day of Albuterol or Levalbuterol to Week 12	Baseline, Week 12	Number of Albuterol or Levalbuterol inhalations were recorded daily by the participants in their electronic diary as Albuterol or Levalbuterol was to be used only as needed for symptoms, not on a regular basis or prophylactically.
Change From Baseline in 22-item Sinonasal Outcome Test (SNOT-22) Score to Week 12	Baseline, Week 12	The SNOT-22 is a validated measure of health related quality of life in sinonasal 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.

Countries

United States

Participant flow

Recruitment details

The study was conducted at 50 sites in the United States. A total of 491 participants were screened between March 2011 and June 2012, of whom 104 were randomized at 28 sites. A total of 387 participants were screen failures mainly due to inclusion criteria for eosinophilic asthma not met.

Pre-assignment details

Randomization was stratified according to prior inhaled corticosteroids/long-acting beta2-adrenergic agonist (ICS/LABA) combination therapy dose. Assignment to arms was done centrally using Interactive Voice Response System in 1:1 ratio to receive either Dupilumab 300 mg or Placebo.

Participants by arm

Arm	Count
Placebo (for Dupilumab) Placebo (for Dupilumab) SC injection qw for 12 weeks added to background therapy of ICS/LABA (Fluticasone/Salmeterol combination therapy at stable dose for 4 weeks followed by Fluticasone monotherapy, dose progressively decreased and discontinued at Week 9). Albuterol or Levalbuterol were given as rescue medication.	52
Dupilumab 300 mg qw Dupilumab 300 mg SC injection qw for 12 weeks added to background therapy of ICS/LABA (Fluticasone/Salmeterol combination therapy at stable dose for 4 weeks followed by Fluticasone monotherapy, dose progressively decreased and discontinued at Week 9). Albuterol or Levalbuterol was given as rescue medication.	52
Total	104

Withdrawals & dropouts

Period	Reason	FG000	FG001
Overall Study	Adverse Event	3	3
Overall Study	Lack of Efficacy	11	1
Overall Study	Other than specified above	2	3
Overall Study	Poor compliance to protocol	1	0

Baseline characteristics

Characteristic	Placebo (for Dupilumab)	Total	Dupilumab 300 mg qw
Age, Continuous	41.6 years STANDARD_DEVIATION 13.1	39.7 years STANDARD_DEVIATION 13.2	37.8 years STANDARD_DEVIATION 13.2
Ethnicity (NIH/OMB) Hispanic or Latino	4 Participants	16 Participants	12 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	48 Participants	88 Participants	40 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants
Morning Peak Expiratory Flow (PEF)	406.87 L/min STANDARD_DEVIATION 110.74	400.02 L/min STANDARD_DEVIATION 105.8	393.04 L/min STANDARD_DEVIATION 101.13
Number of Inhalations of Albuterol or Levalbuterol in a 24-hour Period	2.04 number of inhalations STANDARD_DEVIATION 1.78	2.10 number of inhalations STANDARD_DEVIATION 2.1	2.16 number of inhalations STANDARD_DEVIATION 2.4
Prior ICS/LABA Combination Therapy Dose High Dose	41 Participants	83 Participants	42 Participants
Prior ICS/LABA Combination Therapy Dose Medium Dose	11 Participants	21 Participants	10 Participants
Race Asian/Oriental	3 Participants	4 Participants	1 Participants
Race Black	9 Participants	14 Participants	5 Participants
Race Caucasian/White	38 Participants	83 Participants	45 Participants
Race Other than specified above	2 Participants	3 Participants	1 Participants
Sex: Female, Male Female	26 Participants	52 Participants	26 Participants
Sex: Female, Male Male	26 Participants	52 Participants	26 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	0 / 52	0 / 52
other Total, other adverse events	24 / 52	33 / 52
serious Total, serious adverse events	3 / 52	1 / 52

Outcome results

Primary

Percentage of Participants With Asthma Exacerbation

An asthma exacerbation was defined as the occurrence of any of the following: ≥30% reduction from baseline in morning PEF on 2 consecutive days; or ≥6 additional reliever puffs of albuterol or levalbuterol in a 24-hour period (compared to baseline) on 2 consecutive days; or deterioration of asthma, as determined by the investigator, requiring systemic steroid treatment, or an increase in inhaled corticosteroid (ICS) of ≥4 times the last dose received prior to discontinuation from the study, or hospitalization. The occurrence of asthma exacerbations by individual criteria are reported.

Time frame: Baseline up to Week 12

Population: Modified intent-to-treat (mITT) population that included all randomized participants who received at least one dose of study drug. Participants were analysed in the treatment group to which they were randomized.

Arm	Measure	Group	Value (NUMBER)
Placebo (for Dupilumab)	Percentage of Participants With Asthma Exacerbation	Systemic steroid treatment	9.6 percentage of participants
Placebo (for Dupilumab)	Percentage of Participants With Asthma Exacerbation	≥30% reduction from baseline in morning PEF	19.2 percentage of participants
Placebo (for Dupilumab)	Percentage of Participants With Asthma Exacerbation	Increase in ICS ≥4 times baseline dose of ICS	5.8 percentage of participants
Placebo (for Dupilumab)	Percentage of Participants With Asthma Exacerbation	Asthma exacerbation	44.2 percentage of participants
Placebo (for Dupilumab)	Percentage of Participants With Asthma Exacerbation	Hospitalization	0.0 percentage of participants
Placebo (for Dupilumab)	Percentage of Participants With Asthma Exacerbation	≥6additional albuterol/levalbuterol puffs	19.2 percentage of participants
Dupilumab 300 mg qw	Percentage of Participants With Asthma Exacerbation	Hospitalization	0.0 percentage of participants
Dupilumab 300 mg qw	Percentage of Participants With Asthma Exacerbation	Asthma exacerbation	5.8 percentage of participants
Dupilumab 300 mg qw	Percentage of Participants With Asthma Exacerbation	≥30% reduction from baseline in morning PEF	1.9 percentage of participants
Dupilumab 300 mg qw	Percentage of Participants With Asthma Exacerbation	Systemic steroid treatment	1.9 percentage of participants
Dupilumab 300 mg qw	Percentage of Participants With Asthma Exacerbation	Increase in ICS ≥4 times baseline dose of ICS	0.0 percentage of participants
Dupilumab 300 mg qw	Percentage of Participants With Asthma Exacerbation	≥6additional albuterol/levalbuterol puffs	1.9 percentage of participants

Comparison: Analysis was performed using a logistic regression model with treatment groups and stratification factor (prior ICS/LABA combination therapy dose) as covariates.p-value: <0.000195% CI: [0.021, 0.28]Regression, Logistic

Secondary

Change From Baseline in 22-item Sinonasal Outcome Test (SNOT-22) Score to Week 12

The SNOT-22 is a validated measure of health related quality of life in sinonasal 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.

Time frame: Baseline, Week 12