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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02134028
Recruitment Status : Completed
First Posted : May 8, 2014
Results First Posted : November 2, 2020
Last Update Posted : November 2, 2020
Sponsor:
Collaborator:
Regeneron Pharmaceuticals
Information provided by (Responsible Party):
Sanofi

Tracking Information
First Submitted Date  ICMJE April 30, 2014
First Posted Date  ICMJE May 8, 2014
Results First Submitted Date  ICMJE October 5, 2020
Results First Posted Date  ICMJE November 2, 2020
Last Update Posted Date November 2, 2020
Actual Study Start Date  ICMJE August 5, 2014
Actual Primary Completion Date October 11, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 28, 2020)
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From the first IMP injection in LTS12551 to the last IMP injection plus 14 weeks (up to 108 weeks) ]
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.
Original Primary Outcome Measures  ICMJE
 (submitted: May 6, 2014)
Number of participants with adverse events [ Time Frame: Week 112 ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: October 28, 2020)
  • Number of Participants With Potentially Clinically Significant Vital Signs Abnormalities During the TEAE Period [ Time Frame: From the first IMP injection in LTS12551 to the last IMP injection plus 14 weeks (up to 108 weeks) ]
    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.
  • Number of Participants With Potentially Clinically Significant Laboratory Abnormalities: Hematological Parameters (Red Blood Cells [RBCs], Platelets and Coagulation) During the TEAE Period [ Time Frame: From the first IMP injection in LTS12551 to the last IMP injection plus 14 weeks (up to 108 weeks) ]
    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.
  • Number of Severe Exacerbation Events [ Time Frame: From the first IMP injection in LTS12551 to the last IMP injection plus 2 weeks (up to 96 weeks) ]
    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.
  • Annualized Event Rate Per Participant-Years for Severe Exacerbation [ Time Frame: From the first IMP injection in LTS12551 to the last IMP injection plus 2 weeks (up to 96 weeks) ]
    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.
  • Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) at Weeks 48 and 96 [ Time Frame: Baseline of parent study, Week 48 and Week 96 of this extension study ]
    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.
  • Change From Baseline in Percent Predicted FEV1 at Weeks 48 and 96 [ Time Frame: Baseline of parent study, Week 48 and Week 96 of this extension study ]
    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.
  • Change From Baseline in Forced Vital Capacity (FVC) at Weeks 48 and 96 [ Time Frame: Baseline of parent study, Week 48, and Week 96 of this extension study ]
    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.
  • Change From Baseline in Forced Expiratory Flow (FEF) 25-75% at Weeks 48 and 96 [ Time Frame: Baseline of parent study, Week 48, and Week 96 of this extension study ]
    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.
  • Change From Baseline in Asthma Control Questionnaire 5-Question Version (ACQ-5) Mean Scores at Weeks 24 and 48 [ Time Frame: Baseline of parent study, Weeks 24, and 48 of this extension study ]
    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.
  • Percentage of Participants Achieving ACQ-5 Score Response (ACQ-5 Responders) at Weeks 24 and 48 [ Time Frame: At Weeks 24, and 48 of this extension study ]
    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.
  • Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) Global Scores at Weeks 24 and 48 [ Time Frame: Baseline of parent study, Weeks 24, and 48 of this extension study ]
    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.
  • Percentage of Participants Achieving AQLQ Global Score Response (AQLQ Responders) at Weeks 24 and 48 [ Time Frame: At Weeks 24, and 48 of this extension study ]
    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.
  • Serum Concentrations of Dupilumab Over Time Till Week 96 [ Time Frame: Baseline of parent study, Weeks 0, 4, 12, 24, 48, 72, and 96 of this extension study ]
    For this analysis, baseline was defined as respective parent study baseline. Here, 'number analyzed'=number of participants with available data for each specified category.
  • Percentage of Participants With Antidrug Antibodies (ADA) Response [ Time Frame: From the first IMP injection in LTS12551 to the last IMP injection plus 2 weeks (up to 96 weeks) ]
    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).
  • Change From Baseline in Blood Eosinophils Cells Count at Weeks 48 and 96 [ Time Frame: Baseline of parent study, Week 48 and Week 96 of this extension study ]
    For this analysis, baseline was defined as respective parent study baseline.
  • Change From Baseline in Morning Peak Expiratory Flow (PEF) at Weeks 48 and 96: Participants From Study DRI12544 [ Time Frame: Baseline of parent study, Week 48 and Week 96 of this extension study ]
    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.
  • Change From Baseline in Evening Peak Expiratory Flow (PEF) at Weeks 48 and 96: Participants From Study DRI12544 [ Time Frame: Baseline of parent study, Week 48 and Week 96 of this extension study ]
    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.
  • Change From Baseline in Morning Asthma Symptom Scores at Weeks 48 and 96: Participants From Study DRI12544 [ Time Frame: Baseline of parent study, Week 48 and Week 96 of this extension study ]
    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.
  • Change From Baseline in Evening Asthma Symptom Scores at Weeks 48 and 96: Participants From Study DRI12544 [ Time Frame: Baseline of parent study, Week 48, and Week 96 of this extension study ]
    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.
  • 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 [ Time Frame: Baseline of parent study, Week 48, and Week 96 of this extension study ]
    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.
  • Change From Baseline in Number of Nocturnal Awakenings at Weeks 48 and 96: Participants From Study DRI12544 [ Time Frame: Baseline of parent study, Week 48 and Week 96 of this extension study ]
    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.
  • Percent Change From Baseline in Oral Corticosteroid (OCS) Dose at Weeks 48, and 96: Participants From Study EFC13691 [ Time Frame: Baseline of parent study, Weeks 48 and 96 of this extension study ]
    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.
  • 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 [ Time Frame: Weeks 48 and 96 of this extension study ]
    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.
  • Percentage of Participants With Background OCS Completely Tapered Off Over Time at Weeks 48 and 96: Participants From Study EFC13691 [ Time Frame: Weeks 48, and 96 of this extension study ]
    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.
  • 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 [ Time Frame: Baseline of parent study, Week 48 and Week 96 of this extension study ]
    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.
  • Change From Baseline in EQ-5D-3L VAS Scores at Weeks 48 and 96: Participants From Study DRI12544 [ Time Frame: Baseline of parent study, Week 48 and Week 96 of this extension study ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: May 6, 2014)
  • Assessment of safety parameters (laboratory data, electrocardiogram and vital signs) - clinically significant changes from baseline [ Time Frame: Week 112 ]
  • Forced expiratory volume in one second - clinically significant changes from baseline [ Time Frame: Week 112 ]
  • Asthma control questionnaire - clinically significant changes from baseline [ Time Frame: Week 112 ]
  • Asthma symptom scores - clinically significant changes from baseline [ Time Frame: Week 112 ]
  • Asthma Quality of Life Questionnaire (AQLQS) - clinically significant changes from baseline [ Time Frame: Week 112 ]
  • Anti-drug antibodies - changes from baseline [ Time Frame: Week 112 ]
  • Biomarkers - changes from baseline [ Time Frame: Week 96 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Long-Term Safety Evaluation of Dupilumab in Patients With Asthma (LIBERTY ASTHMA TRAVERSE)
Official Title  ICMJE 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
Brief Summary

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

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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 3
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Asthma
Intervention  ICMJE Drug: Dupilumab
Pharmaceutical form: Solution for injection Routes of administration: Subcutaneous
Other Names:
  • SAR231893
  • REGN668
Study Arms  ICMJE Experimental: dupilumab treatment

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.

Intervention: Drug: Dupilumab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: October 28, 2020)
2282
Original Estimated Enrollment  ICMJE
 (submitted: May 6, 2014)
560
Actual Study Completion Date  ICMJE October 11, 2019
Actual Primary Completion Date October 11, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.

Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 12 Years and older   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Canada,   Mexico,   Argentina,   Australia,   Belgium,   Brazil,   Chile,   Colombia,   Denmark,   France,   Germany,   Hungary,   Israel,   Italy,   Japan,   Korea, Republic of,   Netherlands,   Poland,   Romania,   Russian Federation,   South Africa,   Spain,   Taiwan,   Turkey,   Ukraine,   United Kingdom,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02134028
Other Study ID Numbers  ICMJE LTS12551
2013-003856-19 ( EudraCT Number )
U1111-1117-6745 ( Other Identifier: UTN )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: Qualified researchers may request access to participant level data and related study documents including the clinical study report, study protocol with any amendments, blank case report form, statistical analysis plan, and dataset specifications. Participant level data will be anonymized and study documents will be redacted to protect the privacy of trial participants. Further details on Sanofi's data sharing criteria, eligible studies, and process for requesting access can be found at: https://www.clinicalstudydatarequest.com/
Responsible Party Sanofi
Study Sponsor  ICMJE Sanofi
Collaborators  ICMJE Regeneron Pharmaceuticals
Investigators  ICMJE
Study Director: Clinical Sciences & Operations Sanofi
PRS Account Sanofi
Verification Date October 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP