Asthma
Conditions
Keywords
Asthma, Reactive Airways, Repiratory Tract Disease, Obstructive Lung Disease, Lung Diseases
Brief summary
A Multicentre, Randomized, Double-blind, Parallel Group, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Reducing Oral Corticosteroid dependent Asthma.
Detailed description
This is a randomized, double-blind, parallel group, placebo-controlled study designed to evaluate the efficacy and safety of a fixed 300 mg dose of tralokinumab administered subcutaneously every 2 weeks in adult and adolescent subjects with oral corticosteroid dependent asthma. Approximately120 subjects will be randomized globally. Subjects will receive tralokinumab or placebo, administered via subcutaneous injection at the study site, over a 40-week treatment period.
Interventions
BIOLOGICALTralokinumab
Tralokinumab dose
OTHERPlacebo
Placebo dose
Sponsors
AstraZeneca
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1\) Age 12-75 2) Documented physician-diagnosed asthma. 3) Documented treatment with ICS at a total daily dose corresponding to ≥500µg fluticasone propionate dry powder formulation and a LABA. 4) Subjects must have received OCS for the treatment of asthma for 6 months prior to Visit 1 and on a stable OCS dose between ≥7.5 to ≤30mg daily or daily equivalent for at least one month prior to enrolment (Visit 1) . 5) Pre-BD FEV1 value \<80% (\<90% for patients 12-17 yrs of age) of their PNV. 6) Post-BD reversibility of ≥12% in FEV1.
Exclusion criteria
1\) Clinically important pulmonary disease other than asthma. 2) History of anaphylaxis following any biologic therapy. 3) Hepatitis B, C or HIV. 4) Pregnant or breastfeeding. 5) History of cancer. 6) Current tobacco smoking or a history of tobacco smoking for ≥10 pack-years. 7) Previous receipt of tralokinumab.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in the Final Daily, Average, OCS Dose at Week 40 While Not Losing Asthma Control. | Baseline (Week 0) and Week 40 | 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. Criteria used to assess asthma control included lung function assessments (forced expiratory volume in 1 second and morning peak expiratory flow), night awakenings, and the use of rescue medication and systemic corticosteroids. The least squares (LS) mean percent change from baseline in average daily OCS dose is presented. The final daily percent change from baseline was defined as {(Final daily average dose - baseline daily average dose)/baseline daily average dose}\*100%. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Number of Patients With Final Daily Average OCS Dose ≤5 mg at Week 40. | At Week 40 | 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 patients prescribed a fixed daily dose, then the average OCS dose was defined as the prescribed dose. For patients on a regimen where a different amount of OCS was to be taken each day, then the average OCS dose was defined as the average amount prescribed to be taken each day. |
| The Number of Patients With ≥50% Reduction in Final Average Daily OCS Dose at Week 40. | At Week 40 | 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. The final daily percent change from baseline 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. |
| Annual Asthma Exacerbation Rate (AAER) up to Week 40. | Baseline (Week 0) up to Week 40 | AAER up to Week 40 in the tralokinumab group was compared to that seen in the placebo group. The response variable was the number of exacerbations the patient experienced up to Week 40, with the logarithm of the time at risk in years of experiencing an exacerbation included as offset in the model. AAER = number of exacerbations\*365.25/(follow-up date - date of randomisation + 1). 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. * 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. |
Countries
Belgium, France, Germany, Netherlands, Poland, Ukraine, United States
Participant flow
Recruitment details
First patient enrolled: 19 February 2015; Last patient last visit: 07 September 2017. Study performed at 56 sites in 7 countries. Patients were maintained on their currently prescribed inhaled corticosteroid long-acting β2-agonist therapy and any additional asthma controller medications throughout the study period.
Pre-assignment details
218 patients were screened. Prior to randomisation, patients completed a run-in period or run-in/oral corticosteroid (OCS) optimisation period (reached their minimum effective dose of OCS and remained stable on that dose for 2 weeks). 140 patients were randomised to study treatment. All randomised patients received study treatment.
Participants by arm
| Arm | Count |
|---|---|
| Tralokinumab Tralokinumab 300 mg administered by SC injection Q2W over a 40-week treatment period. | 70 |
| Placebo Placebo was administered by SC injection over a 40-week treatment period. | 70 |
| Total | 140 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 2 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | Withdrawal by Subject | 4 | 3 |
Baseline characteristics
| Characteristic | Tralokinumab | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1 Participants | 0 Participants | 1 Participants |
| Age, Categorical >=65 years | 11 Participants | 15 Participants | 26 Participants |
| Age, Categorical Between 18 and 65 years | 58 Participants | 55 Participants | 113 Participants |
| Age, Continuous | 54.0 years STANDARD_DEVIATION 11.05 | 55.4 years STANDARD_DEVIATION 10.26 | 54.7 years STANDARD_DEVIATION 10.65 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 5 Participants | 7 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) White | 66 Participants | 63 Participants | 129 Participants |
| Sex: Female, Male Female | 48 Participants | 39 Participants | 87 Participants |
| Sex: Female, Male Male | 22 Participants | 31 Participants | 53 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 70 | 0 / 70 |
| other Total, other adverse events | 55 / 70 | 44 / 70 |
| serious Total, serious adverse events | 9 / 70 | 16 / 70 |
Outcome results
Primary
Percent Change From Baseline in the Final Daily, Average, OCS Dose at Week 40 While Not Losing Asthma Control.
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. Criteria used to assess asthma control included lung function assessments (forced expiratory volume in 1 second and morning peak expiratory flow), night awakenings, and the use of rescue medication and systemic corticosteroids. The least squares (LS) mean percent change from baseline in average daily OCS dose is presented. The final daily percent change from baseline was defined as {(Final daily average dose - baseline daily average dose)/baseline daily average dose}\*100%.
Time frame: Baseline (Week 0) and Week 40
Population: The FAS included all randomised patients who received at least one dose of study treatment, irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Tralokinumab | Percent Change From Baseline in the Final Daily, Average, OCS Dose at Week 40 While Not Losing Asthma Control. | -37.62 Percent change from baseline | Standard Error 4.98 |
| Placebo | Percent Change From Baseline in the Final Daily, Average, OCS Dose at Week 40 While Not Losing Asthma Control. | -29.85 Percent change from baseline | Standard Error 4.98 |
Comparison: Comparison of percent change from baseline in OCS dose: tralokinumab vs placebo.p-value: 0.27195% CI: [-21.7, 6.15]ANCOVA
Secondary
Annual Asthma Exacerbation Rate (AAER) up to Week 40.
AAER up to Week 40 in the tralokinumab group was compared to that seen in the placebo group. The response variable was the number of exacerbations the patient experienced up to Week 40, with the logarithm of the time at risk in years of experiencing an exacerbation included as offset in the model. AAER = number of exacerbations\*365.25/(follow-up date - date of randomisation + 1). 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. * 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.
Time frame: Baseline (Week 0) up to Week 40
Population: The FAS included all randomised patients who received at least one dose of study treatment, irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tralokinumab | Annual Asthma Exacerbation Rate (AAER) up to Week 40. | 1.84 Adjusted rate (events/year) |
| Placebo | Annual Asthma Exacerbation Rate (AAER) up to Week 40. | 2.31 Adjusted rate (events/year) |
Comparison: Comparison of AAER: tralokinumab vs placebo.p-value: 0.18695% CI: [0.57, 1.12]Negative binomial
Secondary
The Number of Patients With ≥50% Reduction in Final Average Daily OCS Dose at Week 40.
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. The final daily percent change from baseline 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.
Time frame: At Week 40
Population: The FAS included all randomised patients who received at least one dose of study treatment, irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tralokinumab | The Number of Patients With ≥50% Reduction in Final Average Daily OCS Dose at Week 40. | 31 Participants |
| Placebo | The Number of Patients With ≥50% Reduction in Final Average Daily OCS Dose at Week 40. | 26 Participants |
Comparison: Comparison of ≥50% reduction in OCS dose: tralokinumab vs placebo.p-value: 0.35695% CI: [0.7, 2.74]Regression, Logistic
Secondary
The Number of Patients With Final Daily Average OCS Dose ≤5 mg at Week 40.
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 patients prescribed a fixed daily dose, then the average OCS dose was defined as the prescribed dose. For patients on a regimen where a different amount of OCS was to be taken each day, then the average OCS dose was defined as the average amount prescribed to be taken each day.
Time frame: At Week 40
Population: The FAS included all randomised patients who received at least one dose of study treatment, irrespective of their protocol adherence and continued participation in the study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Tralokinumab | The Number of Patients With Final Daily Average OCS Dose ≤5 mg at Week 40. | 32 Participants |
| Placebo | The Number of Patients With Final Daily Average OCS Dose ≤5 mg at Week 40. | 28 Participants |
Comparison: Comparison of OCS dose ≤5.0 mg: tralokinumab vs placebo.p-value: 0.44295% CI: [0.65, 2.73]Regression, Logistic