Clinical Trial Results:
A Multicentre, Randomized, Double-blind, Parallel Group, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Reducing Oral Corticosteroid Use in Adults and Adolescents with Oral Corticosteroid dependent Asthma (TROPOS)
Summary
|
|
EudraCT number |
2014-001391-54 |
Trial protocol |
DE NL BE FR PL |
Global end of trial date |
07 Sep 2017
|
Results information
|
|
Results version number |
v1(current) |
This version publication date |
15 Mar 2018
|
First version publication date |
15 Mar 2018
|
Other versions |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
|
|||
Trial identification
|
|||
Sponsor protocol code |
D2210C00013
|
||
Additional study identifiers
|
|||
ISRCTN number |
- | ||
US NCT number |
NCT02281357 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
|
|||
Sponsor organisation name |
AstraZeneca
|
||
Sponsor organisation address |
200 Orchard Ridge Drive, Gaithersburg, United States, MD 20878
|
||
Public contact |
Global Clinical Lead, AstraZeneca, 1 3013980582, ClinicalTrialTransparency@astrazeneca.com
|
||
Scientific contact |
Global Clinical Lead, AstraZeneca, 1 3013980582, ClinicalTrialTransparency@astrazeneca.com
|
||
Paediatric regulatory details
|
|||
Is trial part of an agreed paediatric investigation plan (PIP) |
Yes
|
||
EMA paediatric investigation plan number(s) |
EMEA-000782-PIP01-09 | ||
Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
|
||
Results analysis stage
|
|||
Analysis stage |
Final
|
||
Date of interim/final analysis |
07 Sep 2017
|
||
Is this the analysis of the primary completion data? |
Yes
|
||
Primary completion date |
07 Sep 2017
|
||
Global end of trial reached? |
Yes
|
||
Global end of trial date |
07 Sep 2017
|
||
Was the trial ended prematurely? |
No
|
||
General information about the trial
|
|||
Main objective of the trial |
To evaluate the effect of tralokinumab compared to placebo in reducing the prescribed oral corticosteroid (OCS) maintenance dose in adult and adolescent patients in the primary population with asthma requiring chronic treatment with maintenance OCS in addition to inhaled corticosteroid (ICS) plus long-acting β2-agonists (LABA).
|
||
Protection of trial subjects |
This study was performed in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with International Council on Harmonisation / Good Clinical Practice, applicable regulatory requirements and the AstraZeneca policy on Bioethics.
|
||
Background therapy |
Patients were maintained on their currently prescribed ICS-LABA therapy and any additional maintenance asthma controller medications throughout the study period. | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
19 Feb 2015
|
||
Long term follow-up planned |
No
|
||
Independent data monitoring committee (IDMC) involvement? |
Yes
|
||
Population of trial subjects
|
|||
Number of subjects enrolled per country |
|||
Country: Number of subjects enrolled |
Poland: 42
|
||
Country: Number of subjects enrolled |
Ukraine: 24
|
||
Country: Number of subjects enrolled |
Germany: 21
|
||
Country: Number of subjects enrolled |
France: 21
|
||
Country: Number of subjects enrolled |
United States: 19
|
||
Country: Number of subjects enrolled |
Netherlands: 9
|
||
Country: Number of subjects enrolled |
Belgium: 4
|
||
Worldwide total number of subjects |
140
|
||
EEA total number of subjects |
97
|
||
Number of subjects enrolled per age group |
|||
In utero |
0
|
||
Preterm newborn - gestational age < 37 wk |
0
|
||
Newborns (0-27 days) |
0
|
||
Infants and toddlers (28 days-23 months) |
0
|
||
Children (2-11 years) |
0
|
||
Adolescents (12-17 years) |
1
|
||
Adults (18-64 years) |
113
|
||
From 65 to 84 years |
26
|
||
85 years and over |
0
|
|
||||||||||||||||||||||
Recruitment
|
||||||||||||||||||||||
Recruitment details |
First patient enrolled: 19 February 2015; Last patient last visit: 07 September 2017. Study performed at 56 sites in 7 countries. | |||||||||||||||||||||
Pre-assignment
|
||||||||||||||||||||||
Screening details |
218 patients signed informed consent. 140 patients were randomised and all those randomised received study treatment. Prior to randomisation, patients completed a run-in period or run-in/OCS optimisation period (reached minimum effective dose of OCS and remained stable on that dose for 2 weeks). Primary population was the full analysis set (FAS). | |||||||||||||||||||||
Period 1
|
||||||||||||||||||||||
Period 1 title |
Overall Study (overall period)
|
|||||||||||||||||||||
Is this the baseline period? |
Yes | |||||||||||||||||||||
Allocation method |
Randomised - controlled
|
|||||||||||||||||||||
Blinding used |
Double blind | |||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst, Assessor | |||||||||||||||||||||
Arms
|
||||||||||||||||||||||
Are arms mutually exclusive |
Yes
|
|||||||||||||||||||||
Arm title
|
Tralokinumab | |||||||||||||||||||||
Arm description |
Tralokinumab 300 milligrams (mg) administered by subcutaneous (SC) injection every two weeks (Q2W) over a 40-week treatment period. | |||||||||||||||||||||
Arm type |
Experimental | |||||||||||||||||||||
Investigational medicinal product name |
Tralokinumab
|
|||||||||||||||||||||
Investigational medicinal product code |
CAT-354
|
|||||||||||||||||||||
Other name |
Tralo
|
|||||||||||||||||||||
Pharmaceutical forms |
Solution for injection in pre-filled syringe
|
|||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
|||||||||||||||||||||
Dosage and administration details |
150 milligrams/millilitre (mg/mL) solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 SC injections of 150 mg tralokinumab at each dosing interval to receive a total dose of 300 mg.
|
|||||||||||||||||||||
Arm title
|
Placebo | |||||||||||||||||||||
Arm description |
Placebo was administered by SC injection over a 40-week treatment period. | |||||||||||||||||||||
Arm type |
Placebo | |||||||||||||||||||||
Investigational medicinal product name |
Placebo
|
|||||||||||||||||||||
Investigational medicinal product code |
||||||||||||||||||||||
Other name |
||||||||||||||||||||||
Pharmaceutical forms |
Solution for injection in pre-filled syringe
|
|||||||||||||||||||||
Routes of administration |
Subcutaneous use
|
|||||||||||||||||||||
Dosage and administration details |
Placebo solution for injection in an accessorised pre-filled syringe, 1.0 mL fill volume. Each patient received 2 SC injections of placebo at each dosing interval.
|
|||||||||||||||||||||
|
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Baseline characteristics reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tralokinumab
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Tralokinumab 300 milligrams (mg) administered by subcutaneous (SC) injection every two weeks (Q2W) over a 40-week treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Placebo was administered by SC injection over a 40-week treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
End points reporting groups
|
|||
Reporting group title |
Tralokinumab
|
||
Reporting group description |
Tralokinumab 300 milligrams (mg) administered by subcutaneous (SC) injection every two weeks (Q2W) over a 40-week treatment period. | ||
Reporting group title |
Placebo
|
||
Reporting group description |
Placebo was administered by SC injection over a 40-week treatment period. |
|
|||||||||||||
End point title |
Percent change from baseline in the final daily, average, OCS dose at Week 40 while not losing asthma control. | ||||||||||||
End point description |
The 40-week treatment period consisted of 3 phases: an induction phase (Week 0 to Week 12) where patients remained on their optimised OCS dose; an OCS reduction phase (Week 12 to Week 32) where OCS dose reduction could have started at Week 12 with the possibility of dose titration every 4 weeks to reach the lowest possible OCS dose; and a maintenance phase (Week 32 to Week 40) where patients remained on the OCS dose reached at Week 32 to demonstrate asthma control was maintained after achieving the lowest OCS dose. The least squares (LS) mean percent change from baseline in average daily OCS dose is presented for the FAS, comprising all randomised patients who received at least one dose of study treatment. The average OCS dose was defined as {(Final daily average dose - baseline daily average dose)/baseline daily average dose}*100%.
|
||||||||||||
End point type |
Primary
|
||||||||||||
End point timeframe |
Baseline (Week 0) and Week 40
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Percent change from baseline in OCS dose | ||||||||||||
Statistical analysis description |
Tralokinumab vs placebo.
|
||||||||||||
Comparison groups |
Tralokinumab v Placebo
|
||||||||||||
Number of subjects included in analysis |
140
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
[1] | ||||||||||||
P-value |
= 0.271 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
LS Mean difference | ||||||||||||
Point estimate |
-7.78
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-21.7 | ||||||||||||
upper limit |
6.15 | ||||||||||||
Notes [1] - The null hypothesis was that the average percentage change in OCS dose on tralokinumab was equal to the average percentage change in OCS dose on placebo. The analysis of covariance (ANCOVA) model utilised a sandwich estimator for the variance. The model included treatment group as a fixed effect and baseline OCS dose as a continuous covariate. No interaction terms were included in the model. All group comparisons from the ANCOVA model were based on Type III sums of squares. |
|
||||||||||
End point title |
The number of patients with final daily average OCS dose ≤5 mg at Week 40. | |||||||||
End point description |
The 40-week treatment period consisted of 3 phases: an induction phase (Week 0 to Week 12) where patients remained on their optimised OCS dose; an OCS reduction phase (Week 12 to Week 32) where OCS dose reduction could have started at Week 12 with the possibility of dose titration every 4 weeks to reach the lowest possible OCS dose; and a maintenance phase (Week 32 to Week 40) where patients remained on the OCS dose reached at Week 32 to demonstrate asthma control was maintained after achieving the lowest OCS dose. The number of patients with a final daily average OCS dose ≤5.0 mg is presented for the FAS, comprising all randomised patients who received at least one dose of study treatment. The average OCS dose was defined as {(Final daily average dose - baseline daily average dose)/baseline daily average dose}*100%.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
At Week 40
|
|||||||||
|
||||||||||
Statistical analysis title |
Number of patients with OCS dose ≤5 mg | |||||||||
Statistical analysis description |
Tralokinumab vs placebo.
|
|||||||||
Comparison groups |
Tralokinumab v Placebo
|
|||||||||
Number of subjects included in analysis |
140
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
[2] | |||||||||
P-value |
= 0.442 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.33
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.65 | |||||||||
upper limit |
2.73 | |||||||||
Notes [2] - The model included treatment group as a fixed effect and baseline OCS dose as a continuous covariate. |
|
||||||||||
End point title |
The number of patients with ≥50% reduction in final average daily OCS dose at Week 40. | |||||||||
End point description |
The 40-week treatment period consisted of 3 phases: an induction phase (Week 0 to Week 12) where patients remained on their optimised OCS dose; an OCS reduction phase (Week 12 to Week 32) where OCS dose reduction could have started at Week 12 with the possibility of dose titration every 4 weeks to reach the lowest possible OCS dose; and a maintenance phase (Week 32 to Week 40) where patients remained on the OCS dose reached at Week 32 to demonstrate asthma control was maintained after achieving the lowest OCS dose. The number of patients with ≥50% reduction in average daily OCS dose is presented for the FAS, comprising all randomised patients who received at least one dose of study treatment. The average OCS dose was defined as {(Final daily average dose - baseline daily average dose)/baseline daily average dose}*100%. If this resulted in a value of -50% or less (more negative), that patient was classified as having at least a 50% reduction in final daily average OCS dose.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
At Week 40
|
|||||||||
|
||||||||||
Statistical analysis title |
Number of patients with ≥50% reduction in OCS dose | |||||||||
Statistical analysis description |
Tralokinumab vs placebo.
|
|||||||||
Comparison groups |
Tralokinumab v Placebo
|
|||||||||
Number of subjects included in analysis |
140
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
[3] | |||||||||
P-value |
= 0.356 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
1.38
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.7 | |||||||||
upper limit |
2.74 | |||||||||
Notes [3] - The model included treatment group as a fixed effect and baseline OCS dose as a continuous covariate. |
|
|||||||||||||
End point title |
Annual asthma exacerbation rate (AAER) up to Week 40. | ||||||||||||
End point description |
Asthma exacerbation was defined as a worsening of asthma that led to any of the following: • Use of systemic corticosteroids for at least 3 days; a single depo-injectable dose of corticosteroids was considered equivalent to a 3-day course of systemic corticosteroids. • An emergency room (ER) or urgent care (UC) visit (defined as evaluation and treatment for <24 hours in an ER or UC centre) due to asthma that required systemic corticosteroids (see above). • An inpatient hospitalisation (defined as admission to an inpatient facility and/or evaluation and treatment in a healthcare facility for ≥24 hours) due to asthma. AAER = number of exacerbations*365.25 / (follow-up date - date of randomisation + 1) (where maximum follow-up for a patient was 40 weeks). AAER in tralokinumab group was compared with AAER in placebo group up to Week 40 using a negative binomial model. AAER is presented for the FAS, comprising all randomised patients who received at least one dose of study treatment.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Baseline (Week 0) up to Week 40
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
AAER | ||||||||||||
Statistical analysis description |
Tralokinumab vs placebo.
|
||||||||||||
Comparison groups |
Tralokinumab v Placebo
|
||||||||||||
Number of subjects included in analysis |
140
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
[4] | ||||||||||||
P-value |
= 0.186 | ||||||||||||
Method |
Negative binomial | ||||||||||||
Parameter type |
Rate Ratio | ||||||||||||
Point estimate |
0.8
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
0.57 | ||||||||||||
upper limit |
1.12 | ||||||||||||
Notes [4] - Treatment group, OCS dose at baseline, and number of exacerbations in the previous year are included in the model as covariates. |
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
40 weeks.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Data is reported for adverse events with an onset date ≥ the first day of study treatment and ≤ (the last day of study treatment + 2 weeks). Patient population was the safety analysis set which included all patients who received at least one dose of study treatment.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
20.0
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Placebo was administered by SC injection over a 40-week treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Tralo 300 mg Q2W
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group description |
Tralokinumab 300 mg administered by SC injection Q2W over a 40-week treatment period. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||
Substantial protocol amendments (globally) |
|||
Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
||
11 May 2015 |
- Text clarified to state that only adult patients (and not adolescent) were to be stratified by the baseline OCS dose.
- The OCS dose reduction categories were revised to increase the granularity of the categories. The timing of the OCS dose reduction was also clarified.
- The adjudication committee responsibilities were updated to include review of cardiovascular, cerebrovascular and malignancy adverse events occurring after randomisation since patients with severe asthma have been described to suffer from an increased risk of co- morbid illnesses.
- Inclusion criteria were revised to clarify that every other day dosing of OCS was allowed and to provide clarification on the administration of theophylline relative to lung function measurements.
- Procedures for discontinuation of a patient from study treatment were clarified to allow a patient with an asthma-related event requiring non-invasive ventilation to continue receiving treatment.
- The run-in reversibility procedure was clarified. |
||
07 Aug 2015 |
- The OCS dose titration details were revised to clarify that for patients entering the OCS dose optimisation period, dose titration had to begin at Visit 2, and to clarify that the minimum maintenance OCS dose required applied to patients on a dose between 15 to 30 mg/day. |
||
22 Feb 2016 |
- Inclusion criteria were revised to allow patients with a pre-bronchodilator (BD) forced expiratory volume in 1 second (FEV1) <80% (<90% for patients 12 to 17 years of age) of their predicted normal value to be included into the study, and to remove the requirement of a post-BD reversibility in FEV1 being ≥200 mL.
- Exclusion criteria were revised to clarify the time restrictions for receipt of any marketed or investigational biologic agents by study patients, and to clarify the time restrictions for receipt of live attenuated vaccines by study patients. |
||
02 Aug 2017 |
- The possible primary populations for this study were clarified, based on the biomarker fractional exhaled nitric oxide concentrations, in light of the results from the pivotal study D2210C00007.
- The primary objective was modified to clarify that this objective applies to the primary population.
- The secondary objectives regarding the proportion of patients with prescribed OCS maintenance dose ≤5 mg at Week 40 and reduction of at least 50% of prescribed OCS dose at Week 40 were modified to clarify that each objective applies to the primary population.
- The reduction of exacerbation rate was elevated from an exploratory objective to a secondary objective.
- Removal of the term “at steady-state” regarding the serum trough concentration exploratory outcome variable for clarification purposes.
- The Biomarker objective was modified to allow the implementation of the biomarker strategy that is being decided from the pivotal study D2210C00007. Consequently, the sample size rationale was also modified.
- The PK analysis set description was updated.
- Testing strategy for primary and key secondary variables was revised. |
||
Interruptions (globally) |
|||
Were there any global interruptions to the trial? No | |||
Limitations and caveats |
|||
Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
None reported |