EXPEDITION: Evaluation of Dupilumab's Effects on Airway Inflammation in Patients With Asthma
Sponsor
Sanofi (Industry)
Overall Status
Completed
CT.gov ID
NCT02573233
Collaborator
Regeneron Pharmaceuticals (Industry)
42
16
2
23.2
2.6
0.1
Study Details
Study Description
Brief Summary
Primary Objective:
To evaluate the effect of dupilumab, compared to placebo, on airway inflammation in participants with persistent asthma.
Secondary Objective:
To assess the safety, tolerability, and immunogenicity of dupilumab compared to placebo.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Detailed Description
The total study duration for each participant was between approximately 29 and maximum of 30 weeks, consisting of a screening period of 5 weeks and optional up to 7 additional days, a treatment period of 12 weeks, and a post-treatment period of 12 weeks.
Participants who completed the treatment period could be eligible to participate in an open-label extension study.
Study Design
Study Type:
Interventional
Actual Enrollment
:
42 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Double
Primary Purpose:
Treatment
Official Title:
An Exploratory, Double-blind, Placebo-controlled Study of the Effects of Dupilumab on Airway Inflammation of Adults With Persistent Asthma
Actual Study Start Date
:
Jan 27, 2016
Actual Primary Completion Date
:
Jan 3, 2018
Actual Study Completion Date
:
Jan 3, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Placebo Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14, added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
Drug: Placebo
Pharmaceutical form:solution Route of administration: subcutaneous
Drug: fluticasone propionate and salmeterol
Pharmaceutical form:inhalation aerosol, inhalation powder Route of administration: inhaled
Other Names:
Drug: budesonide and formoterol
Pharmaceutical form:inhalation aerosol Route of administration: inhaled
Other Names:
Drug: mometasone furoate and formoterol
Pharmaceutical form:inhalation aerosol Route of administration: inhaled
Other Names:
|
| Experimental: Dupilumab Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14, added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
Drug: Dupilumab SAR231893/REGN668
Pharmaceutical form:solution Route of administration: subcutaneous
Drug: fluticasone propionate and salmeterol
Pharmaceutical form:inhalation aerosol, inhalation powder Route of administration: inhaled
Other Names:
Drug: budesonide and formoterol
Pharmaceutical form:inhalation aerosol Route of administration: inhaled
Other Names:
Drug: mometasone furoate and formoterol
Pharmaceutical form:inhalation aerosol Route of administration: inhaled
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change From Baseline in Eosinophils Cells Count in the Bronchial Submucosa at Week 12 [Baseline, Week 12]
Inflammatory cells i.e. eosinophils were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter.
- Change From Baseline in Mucin-Stained Area in the Bronchial Submucosa at Week 12 [Baseline, Week 12]
Mucin was identified by staining with Alcian-blue periodic acid-Schiff and/or immunostaining for MUC5AC and then the mucin-positive area was measured and expressed per square millimeter.
- Change From Baseline in Mast Cells Count (Chymase Positive) in the Bronchial Submucosa at Week 12 [Baseline, Week 12]
Inflammatory cells i.e. mast cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter.
- Change From Baseline in Mast Cells Count (Tryptase Positive) in the Bronchial Submucosa at Week 12 [Baseline, Week 12]
Inflammatory cells i.e. mast cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter.
- Change From Baseline in T-Lymphocytes Count in the Bronchial Submucosa at Week 12 [Baseline, Week 12]
T-Lymphocytes i.e. CD3 positive cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter.
- Change From Baseline in T-Helper Lymphocytes Count in the Bronchial Submucosa at Week 12 [Baseline, Week 12]
T-helper i.e. CD4 positive lymphocytes were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter.
Secondary Outcome Measures
- Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) at Week 12 [Baseline, Week 12]
FeNO is a surrogate marker for airway inflammation. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/second, and reported in ppb.
- Average Change in Fractional Exhaled Nitric Oxide (FeNO) From Baseline to Week 6 Through Week 12 [From Baseline to Week 6 through Week 12]
FeNO is a surrogate marker for airway inflammation. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/s, and reported in ppb. The average change in FeNO from baseline to Week 6 through Week 12 was calculated as follows: For each participant the change in FeNO from Baseline to Week 6, Week 8, Week 10 and Week 12 was calculated (value at Week X - value at baseline). Subsequently the weekly mean of these 4 "change from baseline" values was determined (Weeks 6, 8, 10 and 12). Using these weekly mean values the overall arithmetic mean and standard deviation of the average change in FeNO from baseline to Week 6 through Week 12 was calculated.
- Number of Participants With Antidrug Antibodies (ADA) [From Baseline up to 24 weeks]
Anti-drug antibodies were detected using a validated immunoassay. Incidence of ADA were classified as following: 1) Pre-existing immunoreactivity - an ADA positive response in the assay at baseline with all post treatment ADA results negative or an ADA positive response at baseline with all post treatment ADA responses less than 4-fold over baseline titer levels. 2) Treatment-emergent ADA: an ADA positive response in the assay post first dose, when baseline results were negative or missing. 3) Treatment-boosted ADA: an ADA positive response in the assay post first dose that was greater-than or equal to 4-fold over baseline titer levels, when baseline results were positive.
- Pharmacokinetics (PK) Assessment: Serum Functional Dupilumab Concentration [Week 0, Week 2, 6, 8, 12, 18, End of study (Week 24)]
Serum functional dupilumab concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) method.
- Number of Participants With Treatment Emergent Adverse Events (TEAEs) [Baseline up to Week 24]
Adverse event (AE) was defined as any untoward medical occurrence in a participant who received investigational medicinal product (IMP) without regard to possibility of causal relationship with this treatment. TEAEs: AEs that developed or worsened or became serious during between the first administration of study medication to the end of the 12 week Post-treatment Period. Serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included both serious and non-serious AEs.
Eligibility Criteria
Criteria
Ages Eligible for Study:
18 Years
to 65 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
Inclusion criteria:
-
Male and female adults with a physician diagnosis of persistent asthma for ≥12 months.
-
Existing treatment with medium to high dose inhaled corticosteroids in combination with a long-acting beta agonist for at least 3 months with a stable dose ≥1 month prior to Visit 1 (Screening Visit).
-
Treatment with a third asthma controller for at least 3 months with a stable dose >=1 month prior to Visit 1 was allowed.
-
Pre-bronchodilator forced expiratory volume (FEV1) 55 to 85% of predicted normal.
Exclusion criteria:
-
Participants <18 years or >65 years.
-
Fractional exhaled nitric oxide (FeNO) <26 parts per billion (ppb) at Visit 1 (Screening Visit).
-
Chronic obstructive pulmonary disease or other lung diseases (eg, idiopathic pulmonary fibrosis, eosinophilic granulomatosis with polyangiitis [Churg-Strauss Syndrome]) which could impair lung function.
-
A participant who experienced an asthma exacerbation that resulted in emergency treatment, hospitalization due to asthma, or treatment with systemic steroids at any time from 1 month prior to Visit 1.
-
A participant who had experienced an upper or lower respiratory tract infection within the 4 weeks prior to Visit 1.
-
Evidence of lung disease(s) other than asthma.
-
Previous smoker (smoking history >10 pack-years) or current smoker (within 6 months prior to Visit 1).
-
Comorbid disease that might interfere with the evaluation of investigational medicinal product or conduct of study procedures (e.g., bronchoscopy).
-
Anti-immunoglobulin E (IgE) therapy (omalizumab) or any other biologic therapy within 6 months of Visit 1.
-
Exposure to another investigative study medication within a time period prior to Visit 1 that is less than 5 half-lives of the study medication.
-
Treatment with systemic (oral or injectable) corticosteroids within 28 days of Visit
The above information was not intended to contain all considerations relevant to a participant's potential participation in a clinical trial.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Investigational Site Number 840402 | Tucson | Arizona | United States | 85724 |
| 2 | Investigational Site Number 840403 | Denver | Colorado | United States | 80206 |
| 3 | Investigational Site Number 840401 | Boston | Massachusetts | United States | 02115 |
| 4 | Investigational Site Number 840002 | Saint Louis | Missouri | United States | 63110 |
| 5 | Investigational Site Number 840404 | Winston-Salem | North Carolina | United States | 27157-1071 |
| 6 | Investigational Site Number 840028 | Pittsburgh | Pennsylvania | United States | 15213 |
| 7 | Investigational Site Number 124012 | Montreal | Canada | H2X 2P4 | |
| 8 | Investigational Site Number 124018 | Sainte Foy | Canada | G1V 4G5 | |
| 9 | Investigational Site Number 208002 | Hvidovre | Denmark | 2650 | |
| 10 | Investigational Site Number 208001 | København Nv | Denmark | 2400 | |
| 11 | Investigational Site Number 276013 | Frankfurt Am Main | Germany | 60596 | |
| 12 | Investigational Site Number 276011 | Großhansdorf | Germany | 22927 | |
| 13 | Investigational Site Number 276012 | Hannover | Germany | 30625 | |
| 14 | Investigational Site Number 752001 | Lund | Sweden | 221 85 | |
| 15 | Investigational Site Number 826010 | London | United Kingdom | W2 1NY | |
| 16 | Investigational Site Number 826009 | Oxford | United Kingdom | OX3 7LE |
Sponsors and Collaborators
- Sanofi
- Regeneron Pharmaceuticals
Investigators
- Study Director: Clinical Sciences & Operations, Sanofi
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Sanofi
ClinicalTrials.gov Identifier:
NCT02573233
Other Study ID Numbers:
- PDY14192
- 2015-001572-22
- U1111-1170-7168
First Posted:
Oct 9, 2015
Last Update Posted:
Apr 4, 2022
Last Verified:
Mar 1, 2022
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Studies a U.S. FDA-regulated Drug Product:
Yes
Studies a U.S. FDA-regulated Device Product:
No
Additional relevant MeSH terms:
Study Results
Participant Flow
| Recruitment Details | The study was conducted at 16 sites in 6 countries. A total of 133 participants were screened between January 2016 and January 2018. Of which, 42 participants were randomized. 91 participants were screen failures mainly due to exclusion criteria met and inclusion criteria not met. |
|---|---|
| Pre-assignment Detail | Participants were randomized in 1:1 ratio to receive dupilumab 300 mg every 2 weeks (q2w) and placebo q2w by using Interactive Voice/Web Response System (IVRS). Randomization was stratified by inhaled corticosteroids (ICS) dose (medium and high) and region (North America and Europe). |
| Arm/Group Title | Placebo | Dupilumab |
|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable inhaled corticosteroid/ long-acting beta-agonist (ICS/LABA) therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Period Title: Overall Study | ||
| STARTED | 22 | 20 |
| COMPLETED | 22 | 20 |
| NOT COMPLETED | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Placebo | Dupilumab | Total |
|---|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Total of all reporting groups |
| Overall Participants | 22 | 20 | 42 |
| Age (years) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [years] |
41.0
(10.3)
|
45.5
(10.6)
|
43.1
(10.6)
|
| Sex: Female, Male (Count of Participants) | |||
| Female |
8
36.4%
|
13
65%
|
21
50%
|
| Male |
14
63.6%
|
7
35%
|
21
50%
|
| Ethnicity (NIH/OMB) (Count of Participants) | |||
| Hispanic or Latino |
1
4.5%
|
1
5%
|
2
4.8%
|
| Not Hispanic or Latino |
21
95.5%
|
19
95%
|
40
95.2%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | |||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
1
5%
|
1
2.4%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
3
13.6%
|
3
15%
|
6
14.3%
|
| White |
19
86.4%
|
16
80%
|
35
83.3%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
| Baseline Eosinophils Count in Bronchial Tissue (cells/mm^2) [Median (Inter-Quartile Range) ] | |||
| Median (Inter-Quartile Range) [cells/mm^2] |
12.97
|
34.96
|
20.73
|
| Baseline Mucin-Stained Area in The Bronchial Tissue Specimen (cells/mm^2) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [cells/mm^2] |
561.12
(289.00)
|
520.57
(511.69)
|
542.33
(402.61)
|
| Baseline Mast Cells Count (Chymase Positive) in Bronchial Tissue (cells/mm^2) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [cells/mm^2] |
74.36
(58.63)
|
79.17
(68.07)
|
76.59
(62.42)
|
| Baseline Mast Cells Count (Tryptase Positive) in Bronchial Tissue (cells/mm^2) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [cells/mm^2] |
80.10
(64.92)
|
105.53
(104.68)
|
91.88
(85.49)
|
| Baseline Total T-Lymphocytes Count in Bronchial Tissue (cells/mm^2) [Median (Inter-Quartile Range) ] | |||
| Median (Inter-Quartile Range) [cells/mm^2] |
301.09
|
153.33
|
181.50
|
| Baseline T-Helper Lymphocytes Count in Bronchial Tissue (cells/mm^2) [Median (Inter-Quartile Range) ] | |||
| Median (Inter-Quartile Range) [cells/mm^2] |
237.10
|
200.85
|
215.05
|
| Baseline Fractional exhaled nitric oxide (FeNO) (parts per billion (ppb)) [Mean (Standard Deviation) ] | |||
| Mean (Standard Deviation) [parts per billion (ppb)] |
41.2
(31.5)
|
36.4
(22.8)
|
38.9
(27.5)
|
Outcome Measures
| Title | Change From Baseline in Eosinophils Cells Count in the Bronchial Submucosa at Week 12 |
|---|---|
| Description | Inflammatory cells i.e. eosinophils were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. |
| Time Frame | Baseline, Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on pharmacodynamic (PD) population which consisted of all randomized participants who underwent baseline and Week12/end of treatment (EOT) bronchoscopies and have adequate biopsies for analysis at both baseline and EOT. Here, overall number of participants analyzed = participants with available data for this outcome measure. |
| Arm/Group Title | Placebo | Dupilumab |
|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Measure Participants | 20 | 17 |
| Median (Inter-Quartile Range) [cells/mm^2] |
5.80
|
-6.04
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Dupilumab |
|---|---|---|
| Comments | Analysis was performed using a rank ANCOVA model stratified by ICS dose level and region. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.8400 |
| Comments | Threshold for significance at 0.05 level | |
| Method | Rank ANCOVA | |
| Comments | Rank ANCOVA model stratified by ICS dose level and region | |
| Title | Change From Baseline in Mucin-Stained Area in the Bronchial Submucosa at Week 12 |
|---|---|
| Description | Mucin was identified by staining with Alcian-blue periodic acid-Schiff and/or immunostaining for MUC5AC and then the mucin-positive area was measured and expressed per square millimeter. |
| Time Frame | Baseline, Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PD population. Here, overall number of participants analyzed = participants with available data for this outcome measure. |
| Arm/Group Title | Placebo | Dupilumab |
|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Measure Participants | 20 | 16 |
| Mean (Standard Deviation) [cells/mm^2] |
64.09
(391.96)
|
-142.74
(477.89)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Dupilumab |
|---|---|---|
| Comments | Analysis was performed using a linear fixed-effect model with treatment, region and ICS dose level as fixed effects, and the baseline value as continuous covariate. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0336 |
| Comments | Threshold for significance at 0.05 level | |
| Method | Linear fixed-effect model | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -235.02 | |
| Confidence Interval |
(2-Sided) 90% -414.19 to -55.84 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline in Mast Cells Count (Chymase Positive) in the Bronchial Submucosa at Week 12 |
|---|---|
| Description | Inflammatory cells i.e. mast cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. |
| Time Frame | Baseline, Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PD population. Here, overall number of participants analyzed = participants with available data for this outcome measure. |
| Arm/Group Title | Placebo | Dupilumab |
|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Measure Participants | 20 | 17 |
| Mean (Standard Deviation) [cells/mm^2] |
-14.80
(76.52)
|
1.76
(62.41)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Dupilumab |
|---|---|---|
| Comments | Analysis was performed using a linear fixed-effect model with treatment, region and ICS dose level as fixed effects, and the baseline value as continuous covariate. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4795 |
| Comments | Threshold for significance at 0.05 level. | |
| Method | Linear fixed-effect model | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean difference |
| Estimated Value | 13.89 | |
| Confidence Interval |
(2-Sided) 90% -19.00 to 46.78 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline in Mast Cells Count (Tryptase Positive) in the Bronchial Submucosa at Week 12 |
|---|---|
| Description | Inflammatory cells i.e. mast cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. |
| Time Frame | Baseline, Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PD population. Here, overall number of participants analyzed = participants with available data for this outcome measure. |
| Arm/Group Title | Placebo | Dupilumab |
|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Measure Participants | 21 | 17 |
| Mean (Standard Deviation) [cells/mm^2] |
2.37
(90.20)
|
-20.89
(59.09)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Dupilumab |
|---|---|---|
| Comments | Analysis was performed using a linear fixed-effect model with treatment, region and ICS dose level as fixed effects, and the baseline value as continuous covariate. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.4494 |
| Comments | Threshold for significance at 0.05 level. | |
| Method | Linear fixed-effect model | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS mean difference |
| Estimated Value | -18.98 | |
| Confidence Interval |
(2-Sided) 90% -60.92 to 22.97 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Change From Baseline in T-Lymphocytes Count in the Bronchial Submucosa at Week 12 |
|---|---|
| Description | T-Lymphocytes i.e. CD3 positive cells were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. |
| Time Frame | Baseline, Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PD population. Here, overall number of participants analyzed = participants with available data for this outcome measure. |
| Arm/Group Title | Placebo | Dupilumab |
|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Measure Participants | 20 | 16 |
| Median (Inter-Quartile Range) [cells/mm^2] |
-36.70
|
34.21
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Dupilumab |
|---|---|---|
| Comments | Analysis was performed using a rank ANCOVA model stratified by ICS dose level and region. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.6865 |
| Comments | Threshold for significance at 0.05 level. | |
| Method | Rank ANCOVA | |
| Comments | Rank ANCOVA model stratified by ICS dose level and region | |
| Title | Change From Baseline in T-Helper Lymphocytes Count in the Bronchial Submucosa at Week 12 |
|---|---|
| Description | T-helper i.e. CD4 positive lymphocytes were counted in the bronchial submucosa of biopsy thin sections using quantitative immunohistochemistry and reported as the number of cells per square millimeter. |
| Time Frame | Baseline, Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PD population. Here, overall number of participants analyzed = participants with available data for this outcome measure. |
| Arm/Group Title | Placebo | Dupilumab |
|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Measure Participants | 20 | 16 |
| Median (Inter-Quartile Range) [cells/mm^2] |
7.26
|
62.34
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Dupilumab |
|---|---|---|
| Comments | Analysis was performed using a rank ANCOVA model stratified by ICS dose level and region. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.7588 |
| Comments | Threshold for significance at 0.05 level | |
| Method | Rank ANCOVA | |
| Comments | Rank ANCOVA model stratified by ICS dose level and region | |
| Title | Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) at Week 12 |
|---|---|
| Description | FeNO is a surrogate marker for airway inflammation. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/second, and reported in ppb. |
| Time Frame | Baseline, Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on secondary PD population which consisted of all randomized and treated participants. Here, overall number of participants analyzed = participants with available data for this outcome measure. |
| Arm/Group Title | Placebo | Dupilumab |
|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Measure Participants | 21 | 18 |
| Mean (Standard Deviation) [ppb] |
3.9
(22.8)
|
-15.1
(18.3)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Dupilumab |
|---|---|---|
| Comments | Analysis was performed using a Mixed-effect Model with Repeated Measures (MRMM) with treatment, treatment-by-visit interaction, region, and ICS dose level as fixed effects, and baseline biomarker-by-visit interaction as fixed covariate, and assuming an unstructured covariance structure separately by treatment group. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0012 |
| Comments | Threshold for significance at 0.05 level | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -22.4 | |
| Confidence Interval |
(2-Sided) 90% -32.9 to -11.9 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Average Change in Fractional Exhaled Nitric Oxide (FeNO) From Baseline to Week 6 Through Week 12 |
|---|---|
| Description | FeNO is a surrogate marker for airway inflammation. FeNO was analyzed using a NIOX instrument or similar analyzer using a flow rate of 50 mL/s, and reported in ppb. The average change in FeNO from baseline to Week 6 through Week 12 was calculated as follows: For each participant the change in FeNO from Baseline to Week 6, Week 8, Week 10 and Week 12 was calculated (value at Week X - value at baseline). Subsequently the weekly mean of these 4 "change from baseline" values was determined (Weeks 6, 8, 10 and 12). Using these weekly mean values the overall arithmetic mean and standard deviation of the average change in FeNO from baseline to Week 6 through Week 12 was calculated. |
| Time Frame | From Baseline to Week 6 through Week 12 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on secondary PD population. |
| Arm/Group Title | Placebo | Dupilumab |
|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Measure Participants | 22 | 20 |
| Mean (Standard Deviation) [ppb] |
3.5
(18.0)
|
-16.0
(21.0)
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Placebo, Dupilumab |
|---|---|---|
| Comments | Analysis was performed using a Mixed-effect model with Repeated Measures (MMRM) with treatment, treatment-by-visit interaction, region, and ICS dose level as fixed effects, and baseline biomarker-by-visit interaction as fixed covariate, and assuming an unstructured covariance structure separately by treatment group. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.0005 |
| Comments | Threshold for significance at 0.05 level | |
| Method | MMRM | |
| Comments | ||
| Method of Estimation | Estimation Parameter | LS Mean Difference |
| Estimated Value | -22.0 | |
| Confidence Interval |
(2-Sided) 90% -31.3 to -12.8 |
|
| Parameter Dispersion |
Type: Value: |
|
| Estimation Comments | ||
| Title | Number of Participants With Antidrug Antibodies (ADA) |
|---|---|
| Description | Anti-drug antibodies were detected using a validated immunoassay. Incidence of ADA were classified as following: 1) Pre-existing immunoreactivity - an ADA positive response in the assay at baseline with all post treatment ADA results negative or an ADA positive response at baseline with all post treatment ADA responses less than 4-fold over baseline titer levels. 2) Treatment-emergent ADA: an ADA positive response in the assay post first dose, when baseline results were negative or missing. 3) Treatment-boosted ADA: an ADA positive response in the assay post first dose that was greater-than or equal to 4-fold over baseline titer levels, when baseline results were positive. |
| Time Frame | From Baseline up to 24 weeks |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on ADA population which consisted of all participants with at least one qualified ADA result in the ADA assay following the first dose of the study medication. |
| Arm/Group Title | Placebo | Dupilumab |
|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Measure Participants | 21 | 19 |
| With pre-existing immunoreactivity |
1
4.5%
|
0
0%
|
| With treatment-emergent ADA |
0
0%
|
1
5%
|
| With treatment-boosted ADA |
0
0%
|
0
0%
|
| Title | Pharmacokinetics (PK) Assessment: Serum Functional Dupilumab Concentration |
|---|---|
| Description | Serum functional dupilumab concentrations were determined using an enzyme-linked immunosorbent assay (ELISA) method. |
| Time Frame | Week 0, Week 2, 6, 8, 12, 18, End of study (Week 24) |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on PK population which consisted of all participants with at least one non-missing and eligible post-baseline dupilumab serum concentration data. Data for this outcome measure was not planned to be analyzed for placebo arm. Here, "number analyzed" represents number of subjects with available data for specified time points. |
| Arm/Group Title | Dupilumab |
|---|---|
| Arm/Group Description | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Measure Participants | 20 |
| Week 0 |
0.00
(0.00)
|
| Week 2 |
52675.00
(23107.55)
|
| Week 6 |
59969.00
(27422.27)
|
| Week 8 |
61097.95
(29775.23)
|
| Week 12 |
67387.00
(32800.44)
|
| Week 18 |
20728.17
(17718.93)
|
| Week 24 |
1851.20
(2796.78)
|
| Title | Number of Participants With Treatment Emergent Adverse Events (TEAEs) |
|---|---|
| Description | Adverse event (AE) was defined as any untoward medical occurrence in a participant who received investigational medicinal product (IMP) without regard to possibility of causal relationship with this treatment. TEAEs: AEs that developed or worsened or became serious during between the first administration of study medication to the end of the 12 week Post-treatment Period. Serious adverse event (SAE) was defined as any untoward medical occurrence that resulted in any of the following outcomes: death, life-threatening, required initial or prolonged in-patient hospitalization, persistent or significant disability/incapacity, congenital anomaly/birth defect, or considered as medically important event. Any TEAE included both serious and non-serious AEs. |
| Time Frame | Baseline up to Week 24 |
Outcome Measure Data
| Analysis Population Description |
|---|
| Analysis was performed on safety population which consisted of all participants randomized and exposed to study medication, regardless of the amount of treatment administered. |
| Arm/Group Title | Placebo | Dupilumab |
|---|---|---|
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. |
| Measure Participants | 22 | 20 |
| Any TEAE |
17
77.3%
|
15
75%
|
| Any treatment emergent SAE |
0
0%
|
1
5%
|
| Any TEAE leading to death |
0
0%
|
0
0%
|
| Any TEAE leading to permanent discontinuation |
0
0%
|
0
0%
|
Adverse Events
| Time Frame | All AEs were collected from signature of the informed consent form up to the end of study (i.e. up to the end of Post-treatment period [Week 24]) regardless of seriousness or relationship to investigational medicinal product (IMP). | |||
|---|---|---|---|---|
| Adverse Event Reporting Description | Reported AEs and deaths are treatment emergent AEs that developed/worsened and deaths that occurred during 'treatment-emergent period' (from first dose of investigational product injection up to the end of Post-treatment period [Week 24]). Analysis was performed on safety population. | |||
| Arm/Group Title | Placebo | Dupilumab | ||
| Arm/Group Description | Placebo (for dupilumab), 2 subcutaneous injections on Day 1 (Week 1) as a loading dose followed by a single injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | Dupilumab, 2 subcutaneous injections on Day 1 as a loading dose for a total of 600 mg, followed by a single 300 mg injection q2w from Week 2 to Week 14 added to stable ICS/LABA therapy. Salbutamol/albuterol or Levosalbutamol/levalbuterol was given as reliever medication. | ||
All Cause Mortality |
||||
| Placebo | Dupilumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/22 (0%) | 0/20 (0%) | ||
Serious Adverse Events |
||||
| Placebo | Dupilumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/22 (0%) | 1/20 (5%) | ||
| Blood and lymphatic system disorders | ||||
| Neutropenia | 0/22 (0%) | 0 | 1/20 (5%) | 1 |
Other (Not Including Serious) Adverse Events |
||||
| Placebo | Dupilumab | |||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 11/22 (50%) | 14/20 (70%) | ||
| Gastrointestinal disorders | ||||
| Nausea | 1/22 (4.5%) | 1 | 3/20 (15%) | 3 |
| Vomiting | 0/22 (0%) | 0 | 2/20 (10%) | 2 |
| General disorders | ||||
| Injection Site Erythema | 2/22 (9.1%) | 8 | 3/20 (15%) | 8 |
| Injection Site Inflammation | 2/22 (9.1%) | 3 | 1/20 (5%) | 3 |
| Injection Site Pruritus | 1/22 (4.5%) | 1 | 2/20 (10%) | 3 |
| Infections and infestations | ||||
| Nasopharyngitis | 4/22 (18.2%) | 6 | 2/20 (10%) | 2 |
| Upper Respiratory Tract Infection | 1/22 (4.5%) | 1 | 3/20 (15%) | 3 |
| Injury, poisoning and procedural complications | ||||
| Accidental Overdose | 1/22 (4.5%) | 1 | 2/20 (10%) | 3 |
| Road Traffic Accident | 0/22 (0%) | 0 | 2/20 (10%) | 2 |
| Musculoskeletal and connective tissue disorders | ||||
| Back Pain | 0/22 (0%) | 0 | 3/20 (15%) | 3 |
| Nervous system disorders | ||||
| Headache | 3/22 (13.6%) | 9 | 5/20 (25%) | 11 |
| Respiratory, thoracic and mediastinal disorders | ||||
| Asthma | 1/22 (4.5%) | 1 | 2/20 (10%) | 2 |
| Cough | 2/22 (9.1%) | 2 | 1/20 (5%) | 1 |
| Wheezing | 2/22 (9.1%) | 2 | 0/20 (0%) | 0 |
| Vascular disorders | ||||
| Hypertension | 2/22 (9.1%) | 3 | 1/20 (5%) | 1 |
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
If no publication has occurred within 12 months of the completion of the study, the Investigator shall have the right to publish/present independently the results of the study. The Investigator shall provide the Sponsor with a copy of any such presentation/publication for comment at least 30 days before any presentation/submission for publication. If requested by the Sponsor, any presentation/submission shall be delayed up to 90 days, to allow the Sponsor to preserve its proprietary rights.
Results Point of Contact
| Name/Title | Trial Transparency Team |
|---|---|
| Organization | Sanofi |
| Phone | 800-633-1610 ext 1# |
| Contact-US@sanofi.com |
Responsible Party:
Sanofi
ClinicalTrials.gov Identifier:
NCT02573233
Other Study ID Numbers:
- PDY14192
- 2015-001572-22
- U1111-1170-7168
First Posted:
Oct 9, 2015
Last Update Posted:
Apr 4, 2022
Last Verified:
Mar 1, 2022