A Study to Assess the Efficacy, Safety, and Tolerability of CAT-354 in Subjects With Asthma

Study Overview
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Brief Summary
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To investigate the effects of CAT-354 on airway hyper-responsiveness (AHR) in uncontrolled asthma.

Detailed Description
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This is a randomized, stratified, double-blind, placebo-controlled, multicenter, multinational study in subjects with uncontrolled asthma despite optimal treatment. Following confirmation of eligibility, subjects will be randomly assigned on Day 0, to 1 of 4 dose groups 1 mg/kg CAT-354, 5 mg/kg CAT-354, 10 mg/kg CAT or Placebo to match all doses of CAT-354. Doses of the assigned treatment will be administered on three occasions 28 days apart. Subjects will be assessed for efficacy, including airway hyper-responsiveness (AHR), safety, pharmacokinetic, pharmacodynamics and immunogenicity until Day 84 post-first dose.

Official Title
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A Double-Blind, Placebo-Controlled, Parallel-Group Study to Assess the Efficacy, Safety, and Tolerability of CAT-354

Conditions
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Asthma

Intervention / Treatment
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* Other: Placebo
* Biological: CAT-354 1 mg/kg
* Biological: CAT-354 5 mg/kg
* Other: CAT-354 10 mg/kg


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed and dated written informed consent is obtained prior to any study related procedure taking place Women either infertile (example [e.g.], hysterectomized, sterile or post-menopausal with amenorrhea of least 1 year duration) or who are practicing an acceptable form of birth control Uncontrolled (refractory) asthma despite treatment with a minimum dose of 800 microgram (mcg) beclomethasonedipropionate or equivalent inhaled corticosteroid per day plus 1 or more additional controller, that is, long-acting beta-agonist, leukotriene antagonist or theophylline. Oral corticosteroids (not parenteral) as additional treatment at any dose are acceptable A forced expiratory volume in 1 second (FEV1) acceptable for airway hyper-responsiveness (AHR) challenge tests (greater than 60 percent of predicted normal) on the challenge days A provocative concentration of methacholine causing a 20 percent fall in FEV1 (PC20) less than 4 milligram per milliliter (mg/mL) Aged 18-80 years A 12-lead electrocardiogram (ECG) with no-clinically significant abnormalities Clinical chemistry, hematology and urinalysis results within the laboratory reference ranges or deemed not clinically significant by the Investigator Body weight of less than 130 kilogram (kg) No other clinically significant abnormality on history and clinical examination Able to comply with the requirements of the protocol. Exclusion Criteria: Experienced a severe exacerbation within 28 days preceding Day -28/-14 to Day 0 Onset of uncontrolled seasonal allergy symptoms within 28 days preceding Day -28/-14 to Day 0 Subjects with a history of allergic rhinitis, seasonal allergy or esophagitis must be optimally controlled and remain on a stable treatment regimen during the study Participation in another study within 5 half-lives or 3 months of the start of this study, whichever is the longer Lower respiratory tract infection within 6 weeks of Day -28/-14 to Day 0 Current smokers or ex-smokers with greater than 10 pack-years Blood donation (more than 550 mL) in the previous 2 months Excessive intake of alcohol (as judged by the Investigator) or evidence of drug or solvent abuse Subjects with a physician-diagnosis of any other significant lung disease, including a primary diagnosis of chronic obstructive pulmonary disease or bronchiectasis, or lung cancer, sarcoidosis, tuberculosis, pulmonary fibrosis and cystic fibrosis Concurrent medication from Day -28/-14 to Day 0 (Screening visit) and for the duration of the study with any of the prohibited medications Significant, uncontrolled disease including serious psychological disorders, chronic renal failure, uncontrolled hypertension systolic blood pressure greater than 200 millimeters of mercury (mmHg), or diastolic blood pressure greater than 100 mmHg, heart disease, psoriasis requiring treatment and subjects who have had a heart attack or stroke within the 3 months preceding Day -28/-14 to Day 0, or who have a known aneurysm Onset of uncontrolled seasonal allergy symptoms within 28 days preceding Day -28/-14 to Day 0 Subjects with a history of allergic rhinitis, seasonal allergy or esophagitis must be optimally controlled and remain on a stable treatment regimen during the study Any factor which, in the opinion of the Investigator, would jeopardize the evaluation or safety or be associated with poor adherence to the protocol (that is, inability to complete study diary, perform peak expiratory flow (PEF) measurements) The subject's primary care physician recommends the subject should not take part in the study Known hypersensitivity to CAT-354 or its components, to the challenge agents used in the study or to related drugs.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo matched to CAT-354 intravenous infusion over 60 minutes on Day 0, 28 and 56. | Other: Placebo<br>* Placebo matched to CAT-354 intravenous infusion over 60 minutes on Day 0, 28 and 56.<br>* Other names: Tralokinumab;|
| Experimental: CAT-354 1 mg/kg<br>CAT-354 1 milligram per kilogram (mg/kg) of body weight intravenous infusion over 60 minutes on Day 0, 28 and 56. | Biological: CAT-354 1 mg/kg<br>* CAT-354 1 milligram/kilogram (mg/kg) of body weight intravenous infusion over 60 minutes on Day 0, 28 and 56.<br>* Other names: Tralokinumab;|
| Experimental: CAT-354 5 mg/kg<br>CAT-354 5 mg/kg of body weight intravenous infusion over 60 minutes on Day 0, 28 and 56. | Biological: CAT-354 5 mg/kg<br>* CAT-354 5 mg/kg of body weight intravenous infusion over 60 minutes on Day 0, 28 and 56.<br>* Other names: Tralokinumab;|
| Experimental: CAT-354 10 mg/kg<br>CAT-354 5 mg/kg of body weight intravenous infusion over 60 minutes on Day 0, 28 and 56 | Other: CAT-354 10 mg/kg<br>* CAT-354 10 mg/kg of body weight intravenous infusion over 60 minutes on Day 0, 28 and 56.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Doubling Concentration of Methacholine at Day 28 | Change in doubling concentrations of methacholine was calculated as Log2 PC20 (Visit x) - Log2 PC20 (Baseline), where x was the post-baseline assessment (Day 28) and PC20 was provocative concentration of methacholine causing 20 percent fall in forced expiratory volume in 1 second (FEV1). FEV1 was the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. Change in doubling concentration was summarized for sub-therapeutic dose (placebo and CAT-354 1 milligram/kilogram [mg/kg]) and therapeutic dose (CAT-354 5 mg/kg and CAT-354 10 mg/kg), as per planned analysis. | Baseline and Day 28 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change From Baseline in Doubling Concentration of Methacholine at Day 56, 84 or Early Termination | Change in doubling concentrations of methacholine was calculated as Log2 PC20 (Visit x) - Log2 PC20 (Baseline), where x was the post-baseline assessment (Day 28) and PC20 was provocative concentration of methacholine causing 20 percent fall in forced expiratory volume in 1 second (FEV1). FEV1 was the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. Change in doubling concentration was summarized for sub-therapeutic dose (placebo and CAT-354 1 mg/kg) and therapeutic dose (CAT-354 5 mg/kg and CAT-354 10 mg/kg), as per planned analysis. | Baseline, Day 56, 84 or early termination (any time before Day 84) | 
| Forced Expiratory Volume in 1 Second (FEV1) | The FEV1 was maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. FEV1 was summarized for sub-therapeutic dose (placebo and CAT-354 1 mg/kg) and therapeutic dose (CAT-354 5 mg/kg and CAT-354 10 mg/kg), as per planned analysis. | Predose, 30 minutes and 6 hours post-end of infusion on Day 0, 28 and 56; Day 4, 14, 35, 63, 84 or early termination (any time before Day 84) | 
| Forced Vital Capacity (FVC) | The FVC was volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. FVC was summarized for sub-therapeutic dose (placebo and CAT-354 1 mg/kg) and therapeutic dose (CAT-354 5 mg/kg and CAT-354 10 mg/kg), as per planned analysis. | Predose, 30 minutes and 6 hours post-end of infusion on Day 0, 28 and 56; Day 4, 14, 35, 63, 84 or early termination (any time before Day 84) | 
| Forced Expiratory Volume in 1 Second (FEV1) as Percentage of Forced Vital Capacity (FVC) | Percentage of FEV1 was calculated as (FEV1/FVC)*100. It signified the percentage of the total amount of air exhaled from the lungs during the first second of forced exhalation. FEV1 was the maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. FVC was the volume of air which can be forcibly exhaled from the lungs after taking the deepest breath possible. Result was summarized for sub-therapeutic dose (placebo and CAT-354 1 mg/kg) and therapeutic dose (CAT-354 5 mg/kg and CAT-354 10 mg/kg), as per planned analysis. | Predose, 30 minutes and 6 hours post-end of infusion on Day 0, 28 and 56; Day 4, 14, 35, Day 63, 84 or early termination (any time before Day 84) | 
| Asthma Control Questionnaire (ACQ) Total Score | The ACQ is questionnaire that comprises of 7-questions evaluating participant's asthma control. Six self-administered questions assess asthma control over the past week covering nocturnal waking, morning symptoms, activity limitations, shortness of breath, wheezing, and short-acting bronchodilator use; using 7-point ordinal rating scale from 0 (good control) to 6 (poor control). Seventh question is completed by a health professional on forced expiratory volume in 1 second (FEV1) percentage (%) predicted; scale: 0 (greater than [>] 95% predicted) to 6 (less than [<] 50% predicted. Final score is the average score of the 7 questions, with a score range of 0 (well controlled) to 6 (extremely poor controlled). Result was summarized for sub-therapeutic dose (placebo and CAT-354 1 mg/kg) and therapeutic dose (CAT-354 5 mg/kg and CAT-354 10 mg/kg), as per planned analysis. | Baseline, Day 28, 56, 84 or early termination (any time before Day 84) | 
| Post-bronchodilator Forced Expiratory Volume in 1 Second (FEV1) | The FEV1 was maximal volume of air exhaled in the first second of a forced expiration from a position of full inspiration. | Day 0 to 84 | 
| Number of Participants With Diary Data | Participants recorded asthma symptoms, use of reliever inhalers (beta-agonist use for symptom relief and as prophylaxis), and morning and evening peak expiratory flow (PEF) measurements in a diary. | Day 0, 4, 14, 28, 35, 56, 63 to Day and 84 | 
| Number of Participants With Exacerbations | Exacerbation was defined as: Mild (determined from diary data) - 2 consecutive days satisfying the same or 1 of the following criteria: any night with awakening(s) due to asthma or morning PEF 20 % or more below baseline where baseline = average of the 10 days before randomization or as-needed medication use of 2 inhalations or more in 24 hours above baseline where baseline = average of the 10 days before randomization. Severe (determined by taking an exacerbation update and history): deterioration of asthma resulting in emergency treatment or hospitalization or need for oral steroids for 3 days or more (as judged by the Investigator). | Day 0 to Day 84 | 
| Morning Peak Flow and Peak Flow Variability | Peak flow is a participant's maximum speed of expiration. | Day 0 to Day 84 | 
| Adult Asthma Quality of Life (QoL) Questionnaire Final Score | The AQLQ: a 32-item questionnaire evaluating quality of life of participants with asthma including 4 domains (symptoms, activity limitations, emotional function, and environmental stimuli). Participants are asked to recall their experiences during the previous 2 weeks and to score each of the 32 questions on a 7-point scale ranging from 7 (no impairment) to 1 (severe impairment). The overall score is calculated as the mean response to all questions. The 4 domain scores are the means of the responses to the questions in each of the domains. Overall AQLQ score and 4 domain scores ranged from 7 (no impairment) to 1 (severe impairment). | Day 0, 28, 84 or early termination (any time before Day 84) | 
| Maximum Observed Serum Concentration (Cmax) for CAT-354 |  | Predose, 10 minutes and 6 hours post-end of infusion on Day 0, 28 and 56 | 
| Minimum Observed Serum Concentration (Cmin) for CAT-354 |  | Predose, 10 minutes and 6 hours post-end of infusion on Day 0, 28 and 56 | 
| Area Under the Serum Concentration Time Curve From Time Zero to Last Measurable Concentration (AUC [0 - t]) for CAT-354 |  | Predose, 10 minutes and 6 hours post-end of infusion on Day 0, 28 and 56 | 
| Accumulation Ratio for CAT-354 (RA) | Accumulation ratio (RA) is calculated for Cmax, Cmin and AUC as RA for Cmax = Cmax (56 - 84)/Cmax (0 - 28); Similarily, RA for Cmin = Cmin (56 - 84)/Cmin (0 - 28) and RA for AUC= AUC (56 - 84)/AUC (0 - 28) where Cmax (0 - 28) and Cmax (56 - 84) are the maximum observed serum concentration after first dose (Day 0 to Day 28) and after third dose (Day 56 to Day 84), respectively; Cmin (0 - 28) and Cmin (56 - 84) are the minimum observed serum concentration after first and third dose, respectively; AUC (0 - 28) and AUC (56 - 84) are the area under the serum concentration time curve over a dosage interval determined after first and third dose, respectively. | Predose, 10 minutes and 6 hours post-end of infusion on Day 0, 28 and 56 | 
| Number of Participants Reporting Treatment-Emergent Adverse Events (TEAEs) and Treatment-Emergent Serious Adverse Events (TESAEs) | An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent are events between first dose of study drug and up to Day 84 that were absent before treatment or that worsened relative to pre-treatment state. | Day 0 to 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Asthma, CAT-354, Tralokinumab