Clinical Trial Results:
A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Proof-of-Concept Study to Evaluate the Efficacy and Safety of TEV-48574 in Adults with T2-Low/Non-T2 Severe Uncontrolled Asthma
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Summary
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EudraCT number |
2020-001927-15 |
Trial protocol |
DE BG CZ |
Global end of trial date |
17 Jan 2022
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Results information
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Results version number |
v1(current) |
This version publication date |
20 Jan 2023
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First version publication date |
20 Jan 2023
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
TV48574-AS-20031
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT04545385 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Teva Branded Pharmaceutical Products R&D, Inc.
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Sponsor organisation address |
145 Brandywine Parkway, West Chester, United States, 19380
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Public contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc., MedInfo@tevaeu.com
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Scientific contact |
Director, Clinical Research, Teva Branded Pharmaceutical Products R&D, Inc., MedInfo@tevaeu.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
17 Jan 2022
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
17 Jan 2022
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Global end of trial reached? |
Yes
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Global end of trial date |
17 Jan 2022
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
The primary objective of the study was to evaluate the effect of TEV-48574 compared with placebo
on loss of asthma control (LoAC) in adult participants with T2-low and non-T2 severe asthma uncontrolled on inhaled corticosteroids plus long-acting beta-agonists (ICS+LABA).
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Protection of trial subjects |
This study was conducted in full accordance with the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP) Consolidated Guideline (E6) and any applicable national and local laws and regulations (for example, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56, 312, and 314 and European Union (EU) Directive 2001/20/EC on the approximation of the laws,
regulations, and administrative provisions of the Member States relating to the implementation
of GCP in the conduct of clinical studies on medicinal products for human use).
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
07 Oct 2020
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Bulgaria: 6
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Country: Number of subjects enrolled |
Czechia: 17
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Country: Number of subjects enrolled |
Germany: 4
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Country: Number of subjects enrolled |
Poland: 10
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Country: Number of subjects enrolled |
United States: 28
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Worldwide total number of subjects |
65
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EEA total number of subjects |
37
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
40
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From 65 to 84 years |
25
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85 years and over |
0
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Recruitment
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Recruitment details |
- | ||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
A total of 65 participants were randomly assigned to treatment (33 participants in the TEV-48574 group and 32 participants in the placebo group). Of these, 64 participants received at least 1 dose of study drug. | ||||||||||||||||||||||||||||||
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Period 1
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Period 1 title |
Overall Study (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Carer, Assessor | ||||||||||||||||||||||||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||
Arm description |
Participants received placebo matched to TEV-48574 subcutaneously (SC) every 2 weeks for a total of 8 doses. | ||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
Placebo matched to TEV-48574 was administered per schedule specified in the arm.
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Arm title
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TEV-48574 | ||||||||||||||||||||||||||||||
Arm description |
Participants received TEV-48574 loading dose SC on the day of randomization and the subsequent corresponding TEV-48574 maintenance doses SC every 2 weeks for a total of 8 doses (1 loading dose and 7 maintenance doses). | ||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||
Investigational medicinal product name |
TEV-48574
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Solution for infusion
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Routes of administration |
Subcutaneous use
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Dosage and administration details |
TEV-48574 was administered per schedule specified in the arm.
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Baseline characteristics reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received placebo matched to TEV-48574 subcutaneously (SC) every 2 weeks for a total of 8 doses. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
TEV-48574
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Reporting group description |
Participants received TEV-48574 loading dose SC on the day of randomization and the subsequent corresponding TEV-48574 maintenance doses SC every 2 weeks for a total of 8 doses (1 loading dose and 7 maintenance doses). | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Participants received placebo matched to TEV-48574 subcutaneously (SC) every 2 weeks for a total of 8 doses. | ||
Reporting group title |
TEV-48574
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Reporting group description |
Participants received TEV-48574 loading dose SC on the day of randomization and the subsequent corresponding TEV-48574 maintenance doses SC every 2 weeks for a total of 8 doses (1 loading dose and 7 maintenance doses). | ||
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End point title |
Number of Participants who Experienced LoAC during the Treatment Period | |||||||||
End point description |
The LoAC was defined as any 1 of the following during the treatment period: - morning peak expiratory flow (PEF) decrease ≥30% from baseline on 2 consecutive days or morning handheld forced expiratory volume in the first second of exhalation (FEV1) decrease ≥20% from baseline on 2 consecutive days; - increase in short-acting beta-agonist (SABA)/quick-relief medication ≥6 puffs over baseline use in 24 hours on 2 consecutive days; increase in inhaled corticosteroids (ICS) dose ≥4 × most recent dose; - systemic corticosteroid use; - asthma emergency room (ER) visit or hospitalization. The intent-to-treat (ITT) analysis set included all randomized participants.
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End point type |
Primary
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End point timeframe |
From randomization (Week 0) until Week 16
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Statistical analysis title |
Statistical Analysis 1 | |||||||||
Statistical analysis description |
Analysis was performed using logistic regression with fixed effects for treatment, baseline FEV1, weight, age group, and gender.
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Comparison groups |
Placebo v TEV-48574
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Number of subjects included in analysis |
65
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Analysis specification |
Pre-specified
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Analysis type |
other | |||||||||
P-value |
= 0.7817 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.49
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0.545 | |||||||||
upper limit |
4.071 | |||||||||
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End point title |
Time From Randomization to LoAC During the Treatment Period | ||||||||||||
End point description |
Time (in days) from randomization to LoAC during the treatment period is the interval from randomization to the occurrence of the LoAC. The LoAC was defined as any 1 of the following during the treatment period: - morning PEF decrease ≥30% from baseline on 2 consecutive days or morning handheld FEV1 decrease ≥20% from baseline on 2 consecutive days; - increase in SABA/quick-relief medication ≥6 puffs over baseline use in 24 hours on 2 consecutive days; increase in ICS dose ≥4 × most recent dose; - systemic corticosteroid use; - asthma ER visit or hospitalization. The ITT analysis set included all randomized participants. '99999' signifies 'median and upper limit of 95% confidence interval (CI) could not be calculated due to smaller number of participants with an event'.
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End point type |
Secondary
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End point timeframe |
From randomization (Week 0) until Week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Asthma Control Questionnaire 6-Question Version (ACQ-6) Score at Week 16 | ||||||||||||
End point description |
The ACQ-6 is a 6-item validated asthma assessment tool that has been widely used. Six questions are self-assessments (completed by the participant), 5 questions assessing asthma symptoms: night-time waking, symptoms on waking, activity limitation, shortness of breath, wheezing, and 1 question for short-acting bronchodilator use. Each item on the ACQ-6 has a possible score ranges from 0 to 6, and the total score is the mean of all responses. The total score ranging from 0-6 (0=totally controlled and 6=severely uncontrolled). A higher score indicated poorer asthma control. The ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Forced Expiratory Volume in the First Second (FEV1) at Week 16 | ||||||||||||
End point description |
FEV1 (measured by handheld spirometer) is the volume of air that can be forcibly exhaled from the lungs in the first second. The ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Daily Average Use of Short-acting Beta-agonist (SABA) Quick Relief Medication at Week 16 | ||||||||||||
End point description |
Number of inhalations/puffs of SABA/quick relief inhaler used was recorded in the e-diary daily. The ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Time From Randomization to First CAE During the Treatment Period for Participants With CAE | ||||||||||||
End point description |
The CAEs during the study were defined as a worsening of asthma symptoms resulting in any 1 of the following: - the use of systemic corticosteroids (oral or injectable); - an emergency department visit due to asthma treated with systemic corticosteroids; - an inpatient hospitalization due to asthma.
Worsening asthma included new or increased symptoms or signs that either worried the participant or were related to an asthma-specific alert (if available through the e-diary/handheld spirometer). The ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
From randomization (Week 0) until Week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Participants who had a Clinical Asthma Exacerbation (CAE) During the Treatment Period | |||||||||
End point description |
The CAEs during the study were defined as a worsening of asthma symptoms resulting in any 1 of the following: - the use of systemic corticosteroids (oral or injectable); - an emergency department visit due to asthma treated with systemic corticosteroids; - an inpatient hospitalization due to asthma.
Worsening asthma included new or increased symptoms or signs that either worried the participant or were related to an asthma-specific alert (if available through the e-diary/handheld spirometer). The ITT analysis set included all randomized participants.
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End point type |
Secondary
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End point timeframe |
From randomization (Week 0) until Week 16
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| No statistical analyses for this end point | ||||||||||
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End point title |
Change From Baseline in Number of Nighttime Awakenings Due to Asthma at Week 16 | ||||||||||||
End point description |
Participants recorded the number of nighttime awakenings due to asthma in the e-diary daily, in the morning. The ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Percent Change in ICS Dose During the Treatment Period | ||||||||||||
End point description |
The ICS use were recorded as one of asthma medications in the prior and concomitant medication data on the case record form. Due to change in planned analysis, this outcome measure was not evaluated.
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End point type |
Secondary
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End point timeframe |
From randomization (Week 0) until Week 16
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| Notes [1] - Due to change in planned analysis, this outcome measure was not evaluated. [2] - Due to change in planned analysis, this outcome measure was not evaluated. |
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Forced Vital Capacity (FVC) at Week 16 | ||||||||||||
End point description |
FVC (measured by handheld spirometer) is the volume of air that can be forcibly and completely blown out after full inspiration, measured in liters. The ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Forced Expiratory Flow at 25-75% of Pulmonary Volume (FEF25%-75%) at Week 16 | ||||||||||||
End point description |
The FEF25%-75% (measured by handheld spirometer) is the forced expiratory flow from 25% to 75% of FVC. The ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Change From Baseline in Fractional Exhaled Nitric Oxide (FeNO) at Week 16 | ||||||||||||
End point description |
FeNO was performed prior to the on-site spirometry. The ITT analysis set included all randomized participants. Here, 'Overall number of participants analyzed' = participants evaluable for this endpoint.
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End point type |
Secondary
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End point timeframe |
Baseline, Week 16
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Number of Participants With Treatment-Emergent Adverse Events (TEAEs) | |||||||||
End point description |
An AE was defined as any untoward medical occurrence that develops or worsens in severity during the conduct of a clinical study and does not necessarily have a causal relationship to the study drug. Serious adverse events (SAEs) included death, a life-threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, persistent or significant disability or incapacity, a congenital anomaly or birth defect, or an important medical event that jeopardized the participant and required medical intervention to prevent 1 of the outcomes listed in this definition. AEs were considered treatment emergent (TEAEs) if onset occurred on or after the first dose date. A summary of serious and non-serious AEs regardless of causality is located in 'Reported Adverse Events module'. Safety analysis set included all randomized participants who received at least 1 dose of study drug.
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End point type |
Secondary
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End point timeframe |
From randomization (Week 0) until Week 24
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| No statistical analyses for this end point | ||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
From randomization (Week 0) until Week 24
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Adverse event reporting additional description |
Safety analysis set included all randomized participants who received at least 1 dose of study drug.
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
24.0
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Reporting groups
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Reporting group title |
TEV-48574
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Reporting group description |
Participants received TEV-48574 loading dose SC on the day of randomization and the subsequent corresponding TEV-48574 maintenance doses SC every 2 weeks for a total of 8 doses (1 loading dose and 7 maintenance doses). | |||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
Participants received placebo matched to TEV-48574 SC every 2 weeks for a total of 8 doses. | |||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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09 Nov 2020 |
The following major procedural changes (not all-inclusive) were made to the protocol:
- addition of a Joint Data Monitoring Committee to monitor safety of the participants; addition of a futility analysis at the interim analysis; - clarification that the window for the screening and run-in period could also be 4 weeks; - clarification regarding timing of FeNO assessment; additional procedures to confirm TB diagnosis; - clarification that handheld spirometers should not be used for FEV1 testing at screening; - addition of reslizumab to the list of examples of systemic immunosuppressive or immunomodulatory agents. |
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28 Apr 2021 |
The following major procedural changes (not all-inclusive) were made to the protocol:
- changes to the inclusion and exclusion criteria to increase enrollment to the study related to participants with prior COVID-19 infection, COVID-19 vaccination, and positive urine test for tetrahydrocannabinol (THC); - addition of malignancies to immunosuppression risk and immunosuppression risk to align with the informed consent form (ICF); - removal of sputum collection; - addition of defining criteria of a participant having T2-low/non-T2 asthma (possessing eosinophil count of <250 cells/microliter [μL] of blood); - addition of text ensuring participants who tested positive for COVID-19 infection were
discontinued from investigational medicinal product (IMP); - additional details for primary and secondary efficacy analysis and interim futility analysis; - clarification of specific examples of the types of respiratory conditions that would meet exclusion criterion “a” to provide further context for the investigators. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
