Long-Term Safety Evaluation of Dupilumab in Patients With Asthma (LIBERTY ASTHMA TRAVERSE)

Study Overview
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Brief Summary
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Primary Objective: To evaluate the long-term safety and tolerability of dupilumab in participants with asthma who participated in a previous dupilumab asthma study (DRI12544, PDY14192, EFC13579, EFC13691). Secondary Objectives: To evaluate the long-term efficacy of dupilumab in participants with asthma who participated in a previous dupilumab asthma clinical study. To evaluate dupilumab in participants with asthma who participated in a previous dupilumab asthma clinical study, with regards to: Systemic exposure Anti-drug antibodies Biomarkers

Detailed Description
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A screening period, up to 3 weeks, applied only for participants who came from DRI12544 study. The total study duration, per participant, was a maximum of 108 weeks (or 111 weeks considering a maximum screening period of 3 weeks for study DRI12544) for the participants enrolled prior to Amendment 04 approval and a maximum of 60 weeks for the participants enrolled after Amendment 04 approval. Following amendment 04 (dated 31 Oct 2016) the open-label treatment duration was amended to 48 weeks (1 year); and the 16-week post-treatment period was shortened to 12 weeks.

Official Title
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Open-label Extension Study to Evaluate the Long-term Safety and Tolerability of Dupilumab in Patients With Asthma Who Participated in a Previous Dupilumab Asthma Clinical Study

Conditions
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Asthma

Intervention / Treatment
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* Drug: Dupilumab


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: - Participants with asthma who completed the treatment period in a previous dupilumab asthma clinical study (i.e., PDY14192, EFC13579 or EFC13691) or participants with asthma who completed the treatment and follow-up periods in previous dupilumab asthma Study DRI12544. Exclusion criteria: - Participants who experienced any hypersensitivity reactions to Investigational Medicinal Product (IMP) in the previous dupilumab asthma study, which, in the opinion of the Investigator, could indicate that continued treatment with dupilumab, may present an unreasonable risk for the participant. The above information was not intended to contain all considerations relevant to a Participant's potential participation in a clinical trial.

Ages Eligible for Study
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Minimum Age: 12 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: dupilumab treatment<br>For participants coming from the DRI12544 study: dupilumab loading dose subcutaneous (SC) on Day 1, followed by 1* Dose every 2 weeks added to current controller medications. For participants coming from other studies: dupilumab 1 * Dose SC every 2 weeks added to current controller medications. | Drug: Dupilumab<br>* Pharmaceutical form: Solution for injection Routes of administration: Subcutaneous<br>* Other names: REGN668;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | An Adverse Event (AE) was any untoward medical occurrence in a participant or clinical investigation participant administered a pharmaceutical product and which did not necessarily had to have causal relationship with treatment. TEAEs were defined as AEs that developed, worsened, or became serious during the treatment emergent AE period (time from first dose of investigational medicinal product [IMP] in LTS12551 up to the last dose of dupilumab plus 14 weeks). A Serious AE (SAE) was 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. | From the first IMP injection in LTS12551 to the last IMP injection plus 14 weeks (up to 108 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities During the TEAE Period | Criteria for potentially clinically significant vital sign abnormalities: Systolic blood pressure (SBP): Less than or equal to (≤) 95 Adults (≤90 Adolescents) millimeters of mercury (mmHg) and decrease from baseline (DFB) greater than or equal to (≥) 20 mmHg; ≥ 160 Adults (≥ 119 Adolescents) mmHg and increase from baseline (IFB) ≥ 20 mmHg. Diastolic blood pressure (DBP): ≤ 45 Adults (≤54 Adolescents) mmHg and DFB ≥ 10 mmHg; ≥ 110 Adults (≥78 Adolescents) mmHg and IFB ≥ 10 mmHg. Heart rate (HR): ≤ 50 beats per minute (bpm) and DFB ≥ 20 bpm; ≥ 120 bpm and IFB ≥ 20 bpm. Respiratory rate: less than (<) 12 breaths/min(b/m); greater than (>) 20 b/m. Weight (kg): ≥ 5 percent (%) DFB; ≥ 5% IFB. Temperature: ≥ 38.0 degree Celsius (°C) rectal/ear/temporal; ≥ 37.5°C oral; ≥ 37.2°C axillary. TEAE period was defined as the time from first dose of IMP in LTS12551 up to the last dose of dupilumab plus 14 weeks. | From the first IMP injection in LTS12551 to the last IMP injection plus 14 weeks (up to 108 weeks) | 
| Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Hematological Parameters (Red Blood Cells [RBCs], Platelets and Coagulation) During the TEAE Period | Criteria for potentially clinically significant abnormalities: Hemoglobin (Hb): ≤ 115 grams per liter (g/L)(Male [M]), ≤ 95 g/L (Female[ F]) (< 100 g/L Adolescents); ≥ 185 g/L (M), ≥ 165 g/L (F) (≥ 200 g/L Adolescents); DFB ≥ 20 g/L. Hematocrit: ≤ 0.37 volume/volume (v/v) (M); ≤ 0.32 v/v (F) (<0.32 v/v Adolescents); ≥ 0.55 v/v (M); 0.5 v/v (F) (>0.47 v/v Adolescents). RBCs: ≥ 6 Tera/L. Platelets: < 100 Giga(G)/L; ≥ 700 G/L. TEAE period was defined as the time from first dose of IMP in LTS12551 up to the last dose of dupilumab plus 14 weeks. | From the first IMP injection in LTS12551 to the last IMP injection plus 14 weeks (up to 108 weeks) | 
| Number of Severe Exacerbation Events | Severe asthma exacerbation events were defined as a deterioration of asthma which required: use of systemic corticosteroids for ≥ 3 days, (participants from study EFC13691 (NCT02528214), and who were taking systemic corticosteroids: the use of systemic corticosteroids at least double the current dose and for ≥3 days.) or, hospitalization or emergency room visit because of asthma, required systemic corticosteroids. | From the first IMP injection in LTS12551 to the last IMP injection plus 2 weeks (up to 96 weeks) | 
| Annualized Event Rate Per Participant-Years for Severe Exacerbation | The annualized event rate per participant-years was defined as the total number of events that occurred during the treatment period divided by the total number of participant-years during the treatment period. | From the first IMP injection in LTS12551 to the last IMP injection plus 2 weeks (up to 96 weeks) | 
| Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Weeks 48 and 96 | FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. For this analysis, baseline was defined as respective parent study baseline. | Baseline of parent study, Week 48 and Week 96 of this extension study | 
| Change From Baseline in Percent Predicted FEV1 at Weeks 48 and 96 | FEV1 was the volume of air exhaled from the lungs in the first second of a forced expiration as measured by spirometer. For this analysis, baseline was defined as respective parent study baseline. | Baseline of parent study, Week 48 and Week 96 of this extension study | 
| Change From Baseline in Forced Vital Capacity (FVC) at Weeks 48 and 96 | FVC was a standard pulmonary function test used to quantify respiratory muscle weakness. FVC was the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. For this analysis, baseline was defined as respective parent study baseline. | Baseline of parent study, Week 48, and Week 96 of this extension study | 
| Change From Baseline in Forced Expiratory Flow (FEF) 25-75% at Weeks 48 and 96 | FEF was the amount of air which can be forcibly exhaled from the lungs in the first second of a forced exhalation. FEF 25-75% was defined as the mean FEF between 25% and 75% of the FVC, where FVC was defined as the volume of air that can forcibly be blown out after full inspiration in the upright position, measured in liters. For this analysis, baseline was defined as respective parent study baseline. | Baseline of parent study, Week 48, and Week 96 of this extension study | 
| Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Mean Scores at Weeks 24 and 48 | The ACQ-5 had 5 questions, reflecting the top-scoring five 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 recall how their asthma had been during the previous week and to respond to each of the five symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 total mean score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled), higher scores indicated lower asthma control. For this analysis, baseline was defined as respective parent study baseline. | Baseline of parent study, Weeks 24, and 48 of this extension study | 
| Percentage of Participants Achieving ACQ-5 Score Response (ACQ-5 Responders) at Weeks 24 and 48 | ACQ-5 response was defined as change from baseline in ACQ-5 scores ≥ 0.5. The ACQ-5 had 5 questions, reflecting the top-scoring five 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 recall how their asthma had been during the previous week and to respond to each of the five symptom questions on a 7-point scale ranged from 0 (no impairment) to 6 (maximum impairment). ACQ-5 mean total score was mean of the scores of all 5 questions and, therefore, ranged from 0 (totally controlled) to 6 (severely uncontrolled). Higher score indicated lower asthma control. | At Weeks 24, and 48 of this extension study | 
| Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Global Scores at Weeks 24 and 48 | The AQLQ was designed to measure the functional impairments that are most troublesome to adults as a result of their asthma. The AQLQ comprised of 32 items in 4 domains: symptoms (12 items), activity limitation (11 items), emotional function (5 items), and environmental stimuli (4 items). Each item was scored on a 7-point likert scale ranged from 1=severely impaired to 7=not impaired. 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); higher scores indicated better quality of life. For this analysis, baseline was defined as respective parent study baseline. | Baseline of parent study, Weeks 24, and 48 of this extension study | 
| Percentage of Participants Achieving AQLQ Global Score Response (AQLQ Responders) at Weeks 24 and 48 | AQLQ global response was defined as participants with change from baseline in AQLQ global score ≥ 0.5. The AQLQ was designed to measure the functional impairments that are most troublesome to adults as a result of their asthma. The 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=severely impaired, 7=not impaired). The 32 items of the questionnaire are averaged to produce one overall quality of life score ranging from 1 (severely impaired) to 7 (not impaired). Higher scores indicated better quality of life. | At Weeks 24, and 48 of this extension study | 
| Serum Concentrations of Dupilumab Over Time Till Week 96 | For this analysis, baseline was defined as respective parent study baseline. Here, 'number analyzed'=number of participants with available data for each specified category. | Baseline of parent study, Weeks 0, 4, 12, 24, 48, 72, and 96 of this extension study | 
| Percentage of Participants With Antidrug Antibodies (ADA) Response | ADA response were categorized as: treatment emergent and treatment boosted response. 1) Treatment emergent was defined as an ADA positive response in the assay post first dose in LTS12551, when baseline results were negative or missing. 2) Treatment boosted was defined as: 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. The criteria for positive was defined as 30 to > 10,000, where low titer (< 1,000); moderate (1,000 ≤ titer ≤ 10,000) and high titer (> 10,000). | From the first IMP injection in LTS12551 to the last IMP injection plus 2 weeks (up to 96 weeks) | 
| Change From Baseline in Blood Eosinophils Cells Count at Weeks 48 and 96 | For this analysis, baseline was defined as respective parent study baseline. | Baseline of parent study, Week 48 and Week 96 of this extension study | 
| Change From Baseline in Morning Peak Expiratory Flow (PEF) at Weeks 48 and 96: Participants From Study DRI12544 | The PEF was a participant's maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PEF was performed at morning and evening. Morning PEF was performed within 15 minutes after arising (between 5:30 AM and 10 AM) prior to taking any salbutamol/albuterol or levosalbutamol/levalbuterol. For this analysis, baseline was defined as parent study DRI12544 baseline. | Baseline of parent study, Week 48 and Week 96 of this extension study | 
| Change From Baseline in Evening Peak Expiratory Flow (PEF) at Weeks 48 and 96: Participants From Study DRI12544 | The PEF was a participant's maximum speed of expiration, as measured with a peak flow meter. Peak flow testing for PEF was performed at morning and evening. Evening PEF was performed in the evening (between 5:30 PM and 10 PM) prior to taking any salbutamol/albuterol or levosalbutamol/levalbuterol. For this analysis, baseline was defined as parent DRI12544 study baseline. | Baseline of parent study, Week 48 and Week 96 of this extension study | 
| Change From Baseline in Morning Asthma Symptom Scores at Weeks 48 and 96: Participants From Study DRI12544 | Morning asthma symptom score was determined using AM (ante meridiem) symptom scoring system which evaluated 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; higher scores indicated more severe symptoms. For this analysis, baseline was defined as parent DRI12544 study baseline. | Baseline of parent study, Week 48 and Week 96 of this extension study | 
| Change From Baseline in Evening Asthma Symptom Scores at Weeks 48 and 96: Participants From Study DRI12544 | Evening asthma symptom score was determined using PM (post meridiem) symptom scoring system which evaluated participant's overall asthma symptoms experienced during the day. It ranged 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; higher scores indicated more severe symptoms. For this analysis, baseline was defined as parent DRI12544 study baseline. | Baseline of parent study, Week 48, and Week 96 of this extension study | 
| Change From Baseline in Number of Inhalations Per Day of Salbutamol/Albuterol or Levosalbutamol/Levalbuterol for Symptom Relief at Weeks 48 and 96: Participants From Study DRI12544 | The number of salbutamol/albuterol or levosalbutamol/levalbuterol inhalations was recorded daily by the participants in an electronic diary/PEF meter. Mean number of inhalations in last 7 days prior to each visit was calculated and was used in computation of data reported. For this analysis, baseline was defined as parent DRI12544 study baseline. | Baseline of parent study, Week 48, and Week 96 of this extension study | 
| Change From Baseline in Number of Nocturnal Awakenings at Weeks 48 and 96: Participants From Study DRI12544 | The number of nocturnal awakening because of asthma symptoms were recorded every morning by the participants in an electronic diary. Mean number of awakenings in last 7 days prior to each visit was calculated and was used in computation of data reported. For this analysis, baseline was defined as parent DRI12544 study baseline. | Baseline of parent study, Week 48 and Week 96 of this extension study | 
| Percent Change From Baseline in Oral Corticosteroid (OCS) Dose at Weeks 48, and 96: Participants From Study EFC13691 | OCS was allowed as background controller medication for the participants from study EFC13691 only. For this analysis, baseline was defined as parent study EFC13691 baseline. | Baseline of parent study, Weeks 48 and 96 of this extension study | 
| Percentage of Participants Achieving a Reduction of 50% or Greater (≥ 50% ) in OCS Dose Over Time at Weeks 48 and 96: Participants From Study EFC13691 | OCS was allowed as background controller medication for the participants from study EFC13691 only. Percentage of participants who achieved a reduction of ≥ 50% in OCS dose were reported. | Weeks 48 and 96 of this extension study | 
| Percentage of Participants With Background OCS Completely Tapered Off Over Time at Weeks 48 and 96: Participants From Study EFC13691 | OCS was allowed as background controller medication for the participants from study EFC13691 only. Number of participants who gradually discontinued or reduced therapeutic dose were reported in this outcome measure. | Weeks 48, and 96 of this extension study | 
| Change From Baseline in European-Quality of Life-5 Dimension Instrument-3 Levels (EQ-5D-3L) Index Scores at Weeks 48 and 96: Participants From Study DRI12544 | EQ-5D-3L: validated and reliable self-report health status questionnaire consisted of EQ-5D descriptive system and visual analogue scale (VAS). EQ-5D descriptive system comprises 5 dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension measured on 3 levels: no problem, some problems, and severe problems. The 5 dimensional 3-level systems was converted into single index utility score, and the score was 0 - 100, where 100=best health state; and 0=worst health state; where higher scores indicated better outcome. For this analysis, baseline was defined as parent DRI12544 study baseline. | Baseline of parent study, Week 48 and Week 96 of this extension study | 
| Change From Baseline in EQ-5D-3L VAS Scores at Weeks 48 and 96: Participants From Study DRI12544 | EQ-5D VAS was used to record a participant's rating for his/her current health-related quality of life state and captured on a vertical VAS (0-100), where 0=worst imaginable health state and 100=best imaginable health state, where higher states indicated better outcomes. For this analysis, baseline was defined as parent DRI12544 study baseline. | Baseline of parent study, Week 48 and Week 96 of this extension study |