A Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Adults and Adolescents With Uncontrolled Asthma

Study Overview
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Brief Summary
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A 52-Week, Multicentre, Randomized, Double-Blind, Parallel Group, Placebo Controlled, Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Adults and Adolescents with Asthma Inadequately Controlled on Inhaled Corticosteroid Plus Long-Acting β2-Agonist

Detailed Description
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This is a randomized, double-blind, parallel group, placebo-controlled study designed to evaluate efficacy and safety of tralokinumab administered subcutaneously in subjects with uncontrolled asthma on inhaled corticosteroid plus long-acting β2-agonist and having a history of asthma exacerbations. Approximately 1140 subjects will be randomized globally. Subjects will receive tralokinumab, or placebo, administered via subcutaneous injection at the study site, over a 52-week treatment period.

Official Title
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A Phase 3 Study to Evaluate the Efficacy and Safety of Tralokinumab in Adults and Adolescents With Asthma Inadequately Controlled on Inhaled Corticosteroid Plus Long-Acting β2-Agonist.

Conditions
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Uncontrolled Asthma

Intervention / Treatment
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* Biological: Tralokinumab
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 12 -75 Documented physician-diagnosed asthma. Documented treatment with ICS at a total daily dose corresponding to ≥500μg fluticasone propionate dry powder formulation equivalents) and a LABA Morning pre-BD FEV1 value of ≥40 and <80% value (<90% for patients 12 to 17 years of age) of their PNV. Post-BD reversibility of ≥12% and ≥200 mL in FEV1 ACQ-6 score ≥1.5 Exclusion Criteria: Pulmonary disease other than asthma History of anaphylaxis following any biologic therapy Hepatitis B, C or HIV Pregnant or breastfeeding History of cancer Current tobacco smoking or a history of tobacco smoking for ≥ 10 pack-years Previous receipt of tralokinumab

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Tralokinumab Dose Regimen 1<br>Tralokinumab subcutaneous injection | Biological: Tralokinumab<br>* Subcutaneous injection<br>|
| Placebo Comparator: Placebo Dose Regimen 1<br>Placebo subcutaneous injection | Other: Placebo<br>* Subcutaneous injection<br>|
| Experimental: Tralokinumab Dose Regimen 2<br>Tralokinumab subcutaneous injection | Biological: Tralokinumab<br>* Subcutaneous injection<br>|
| Placebo Comparator: Placebo Dose Regimen 2<br>Placebo subcutaneous injection | Other: Placebo<br>* Subcutaneous injection<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Annualised Asthma Exacerbation Rate (AAER) up to Week 52 | 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 time for a patient was approximately 52 weeks). AAER in the tralokinumab group was compared to that seen in the placebo group up to Week 52 using a negative binomial model; rate ratios and rate reductions are both presented for comparative statistical analyses. | Baseline (Week 0) up to Week 52 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percent Change From Baseline to Week 52 in Pre-dose/Pre-bronchodilator (BD) Forced Expiratory Volume in 1 Second (FEV1) | Lung function was assessed by FEV1 which was measured by spirometry. Spirometry was performed by the Investigator or authorised delegate according to American Thoracic Society/European Respiratory Society guidelines. The mean percent change from baseline in pre-BD FEV1 at Week 52 is presented. | Baseline (Week 0) and Week 52 | 
| Change From Baseline to Week 52 in Total Asthma Symptom Score (Bi-weekly Means) | Asthma symptoms during night-time and daytime were recorded by the patient each morning and evening in the Asthma Daily Diary. Symptoms were recorded using a 4-point response scale, which ranged from 0 to 3, where 0 indicated no asthma symptoms. Asthma symptom daytime score (recorded in the evening), night-time score (recorded in the morning), and total score were calculated separately. The daily asthma symptom total score was calculated by taking the sum of the night-time and daytime asthma symptom scores recorded each day, ranging from 0 to 6. A lower symptom score indicated a better outcome. The change from baseline in bi-weekly mean daily asthma symptom total score is presented. | Baseline (Week 0) and Week 52 | 
| Change From Baseline to Week 52 in Asthma Quality of Life Questionnaire for 12 Years and Older (AQLQ(S)+12) Total Score | The AQLQ(S)+12 is a questionnaire that measures health-related quality of life for patients with asthma aged 12 and older. The questionnaire comprises 32 questions and has 4 separate domains (asthma symptoms, activity limitations, emotional function and environmental stimuli). Patients were asked to recall their experiences during the previous 2 weeks and to score each of the questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The total score was calculated as the mean response to all questions, ranging from 1 (severe impairment) to 7 (no impairment). Individual AQLQ(S)+12 total score changes of ≥0.5 were considered to be clinically meaningful. The mean change from baseline in AQLQ(S)+12 score at Week 52 is presented. | Baseline (Week 0) and Week 52 | 
| Change From Baseline to Week 52 in Asthma Control Questionnaire-6 (ACQ-6) Score | The ACQ-6 questionnaire is a shortened version of the ACQ (omitting FEV1 measurement) that assesses asthma symptoms (night-time awakenings, symptoms on waking, activity limitation, dyspnoea, wheezing) and rescue short-acting β2-agonists medication use during the past week. Questions were weighted equally and scored on a 7-point scale from 0 (totally controlled) to 6 (severely uncontrolled). The mean ACQ-6 score was the mean of the responses, ranging from 0 (totally controlled) to 6 (severely uncontrolled). Mean scores of ≤0.75 indicate well-controlled asthma, scores between 0.75 and ≤1.5 indicate partly controlled asthma and a score >1.5 indicates not well-controlled asthma. Individual changes of at least 0.5 were considered to be clinically meaningful. The mean change from baseline in ACQ-6 score at Week 52 is presented. | Baseline (Week 0) and Week 52 | 
| AAER Associated With an ER/UC Visit, or a Hospitalisation up to Week 52 | The annual rate of exacerbations associated with an ER/UC visit or hospitalisation up to Week 52 are presented for non-adjudicated data (i.e. events assessed by the Investigator and recorded in the electronic case report form). AAER = Number of Exacerbations*365.25 / (Follow-up date - Date of randomisation + 1) (where maximum follow-up time for a patient was approximately 52 weeks). | Baseline (Week 0) up to Week 52 | 
| Change From Baseline in European Quality of Life - 5 Dimension 5 Levels (EQ-5D-5L) Visual Analogue Scale (VAS) Scores at Week 52 | The EQ-5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The patient was asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also included a VAS, where the patient was asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state. The mean change from baseline in EQ-5D-5L VAS scores at Week 52 is presented. | Baseline (Week 0) and Week 52 | 
| Change From Baseline in Total Asthma Rescue Medication Use at Week 52 (Bi-weekly Means) | Salbutamol, albuterol or levalbuterol were used as rescue medication during the study in the event of a worsening of asthma symptoms. Rescue medication use was measured by the bi-weekly mean number of inhalations (puffs) per day, calculated as: total morning puffs + total evening puffs + 2*(total morning nebuliser use + total evening nebuliser use)/ total number of days with data in bi-weekly period. The change from baseline in bi-weekly mean total asthma rescue medication use at Week 52 is presented. | Baseline (Week 0) and Week 52 | 
| Change From Baseline in Home Peak Expiratory Flow (PEF) (Morning and Evening) at Week 52 | Home PEF testing was performed by the patient using an electronic, hand-held spirometer (peak flow meter) and was performed in the morning upon awakening (prior to taking their morning asthma controller) and in the evening at bedtime (prior to taking their evening asthma controller). The mean change from baseline in home PEF values at Week 52 are presented separately for morning and evening. | Baseline (Week 0) and Week 52 | 
| Change From Baseline in Night-time Awakenings Due to Asthma Requiring Rescue Medication Use at Week 52 (Bi-weekly Means [Percentage]) | The patient captured night-time awakenings (yes/no) and the use of rescue medication during these awakenings (yes/no) each morning in the Asthma Daily Diary. Night-time awakenings (percentage) was defined as the number of nights with awakenings due to asthma and requiring rescue medication divided by number of nights with data. The change from baseline in bi-weekly means (percentage) night-time awakenings due to asthma requiring rescue medication use at Week 52 is presented. | Baseline (Week 0) and Week 52 | 
| Number of Patients With ≥1 Asthma Exacerbation up to Week 52 | The number of patients with ≥1 asthma exacerbation up to Week 52 is presented. | Baseline (Week 0) up to Week 52 | 
| Work Productivity and Activity Impairment Questionnaire and Classroom Impairment Questions (WPAI+CIQ): Productivity Loss at Week 52 | The WPAI+CIQ consists of questions about how asthma and asthma-related issues impact a patient's ability to work, attend classes and perform regular daily activities. The questionnaire contains 10 questions relating to the patient's experience over the previous 7 days. The WPAI+CIQ outcomes for productivity loss are presented separately for those currently employed and for those currently in school and are expressed as mean productivity loss (percentage) at Week 52, with higher numbers indicating less productivity. Work Productivity Loss = {Q2/(Q2+Q4)+[(1-Q2/(Q2+Q4))x(Q5/10)]}*100 (Absenteeism = Q2/(Q2+Q4)*100; Presenteeism = (Q5/10)*100). Class Productivity Loss = {Q7/(Q7+Q8) + [(1-Q7/(Q7+Q8))x(Q9/10)]}*100 (Absenteeism = Q7/ (Q7+Q8)*100; Presenteeism = (Q9/10)*100). Note: QX refers to response to question number X on WPAI+CIQ questionnaire. | At Week 52 | 
| WPAI+CIQ: Activity Impairment at Week 52 | The WPAI+CIQ consists of questions about how asthma and asthma-related issues impact a patient's ability to work, attend classes and perform regular daily activities. The questionnaire contains 10 questions relating to the patient's experience over the previous 7 days. The WPAI+CIQ outcomes for activity impairment are presented separately for those currently employed and for those currently in school and are expressed as mean impairment percentages at Week 52, with higher numbers indicating greater impairment. Activity impairment = (Q10/10)*100. Note: QX refers to response to question number X on WPAI+CIQ questionnaire. | At Week 52 | 
| Asthma-related Healthcare Encounters by Type up to Week 52 | Broad-based healthcare utilisation asthma-related event information was collected by the Investigator/authorised delegate at each visit. At Visit 1, healthcare resource utilisation information was collected with a 1-year recall period; subsequent visits collected information with a recall period of 'since the last scheduled visit'. Total number of times the healthcare encounter occurred was calculated across all patients for each of the following categories: Ambulance transport, Emergency room visits, Unscheduled outpatient visits (visit to specialist and/or visit to primary healthcare physician and/or other healthcare visit), Home visits (home visit, physician and/or other healthcare professional), Telephone calls (telephone calls to physician and/or nurse), and Advanced pulmonary function test. | Baseline (Week 0) up to Week 52 | 
| Asthma-related Healthcare Encounters by Type up to Week 52: Hospitalisations | Broad-based healthcare utilisation asthma-related event information was collected by the Investigator/authorised delegate at each visit. At Visit 1, healthcare resource utilisation information was collected with a 1-year recall period; subsequent visits collected information with a recall period of 'since the last scheduled visit'. Total number of days spent in hospital was calculated across all patients for the following healthcare encounter category: • Hospitalisations (hospitalisations, intensive care and/or general care). | Baseline (Week 0) up to Week 52 | 
| Asthma-related Healthcare Encounters by Type up to Week 52: Spirometry | Broad-based healthcare utilisation asthma-related event information was collected by the Investigator/authorised delegate at each visit. At Visit 1, healthcare resource utilisation information was collected with a 1-year recall period; subsequent visits collected information with a recall period of 'since the last scheduled visit'. Total number of assessments was calculated across all patients for the following healthcare encounter category: • Spirometry. | Baseline (Week 0) up to Week 52 | 
| Serum Trough Concentration (Ctrough) of Tralokinumab During the Study Period up to Week 72 | To evaluate the pharmacokinetics (PK), pre-dose blood samples were collected at each visit and tralokinumab concentrations in serum were determined. Mean Ctrough concentrations are presented at each indicated visit up to Week 72. | Blood samples were collected pre-dose at Baseline (Week 0), and at Week 4, Week 8, Week 26, Week 52 and Week 72 (follow-up) | 
| Number of Patients Positive for Anti-drug Antibodies (ADAs) | ADA assessments performed using a tiered approach (screening, confirmatory and titering assays). Confirmed ADA positive samples were also tested for neutralising antibodies (nAb). ADA prevalence defined as proportion of study population with drug-reactive antibodies at any point in time. ADA incidence (treatment-emergent ADA) defined as sum of treatment-induced (post-baseline ADA positive only) and treatment-boosted ADA. Persistently positive defined as positive at ≥2 post-baseline assessments (with ≥16 weeks between first and last positive) or positive at last post-baseline assessment. Transiently positive defined as having ≥1 post-baseline ADA positive assessment and not fulfilling conditions of persistently positive. Treatment-boosted ADA defined as baseline positive ADA titer boosted to a 4-fold or higher level following drug administration. In some category titles 'positive' is denoted by 'pos'. | Baseline (Week 0), Week 26, Week 56 (follow-up) and Week 72 (follow-up) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, Reactive Airways, Respiratory Tract Disease, Obstructive Lung Disease, Lung Diseases