C38072/3083

Teva Branded Pharmaceutical Products, R&D Inc.

41 Moores Road, Frazer, Pennsylvania, United States, 19355

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.com

Director, Clinical Research, Teva Branded Pharmaceutical Products, R&D Inc., 001 215-591-3000, ustevatrials@tevapharm.com

No

No

No

Final

24 Mar 2015

No

Yes

03 Apr 2014

No

The primary objective of this study is to determine whether reslizumab, at a dose of 3 mg/kg administered intravenously (iv) every 4 weeks over 12 months, is more effective than placebo in reducing the number of clinical asthma exacerbations (CAEs) in patients with eosinophilic asthma as assessed by the frequency of CAEs. A CAE is defined by 1 of the following: 1) a hospitalization because of asthma, 2) emergency treatment because of asthma, 3) a decrease in forced expiratory volume in 1 second (FEV1) by 20% or more from baseline, or 4) If the peak expiratory flow rate (PEFR) drops below 30% from baseline on 2 consecutive days worsening of asthma will be assessed. If there is a prescribed increase in baseline oral corticosteroid (OCS) or inhaled corticosteroid (ICS) or if the symptoms warrant additional asthma treatment (OCS) this would be considered a CAE.

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 (eg, Code of Federal Regulations [CFR] Title 21, Parts 50, 54, 56, 312, and 314; 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 good clinical practice in the conduct of clinical trials on medicinal products for human use). Information regarding any investigational study centers participating in this study that could not comply with these standards was documented. Written and/or oral information about the study was provided to all patients in a language understandable by the patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. For patients aged 12 through 17, a signed and dated informed consent form (ICF) was obtained from each parent/guardian and a signed and dated assent form was obtained from each patient before any study specific procedures or assessments are done and after the aims, methods, anticipated benefits, and potential hazards were explained, according to local IEC/IRB requirements. The patient’s willingness to participate in the study was documented in the assent form, which was signed by the patient with the date of that signature indicated. Each investigator kept the original consent/assent forms and copies were given to the patients. It was also explained to the patients that they were free to refuse entry into the study and free to withdraw from the study at any time without prejudice to future treatment.

22 Feb 2011

No

Yes

Romania: 18

Slovakia: 30

France: 11

Germany: 64

Greece: 7

Argentina: 14

Brazil: 21

Canada: 4

Korea, Republic of: 34

Mexico: 12

Peru: 68

Russian Federation: 40

Taiwan: 3

Ukraine: 107

United States: 31

464

130

0

0

0

0

0

12

415

37

0

Overall Trial (overall period)

Randomised - controlled

Patients were randomly assigned to treatment through an Interactive Response Technology (IRT). Using this system ensured a balance across treatment groups; no effort was made to maintain a balance among treatment groups, within a study center. To maintain the blinding to study drug in this 2 treatment group study, the volume of study drug (including active or placebo treatment) to be taken from each vial was assigned by IRT on the basis of the patient’s body weight and assigned treatment group.

Yes

Placebo

Solution for infusion

Intravenous use

Matching placebo (acetate sucrose buffer), administered intravenously (iv) once every 4 weeks for a total of 13 doses.

Reslizumab

Cinquil, humanized monoclonal antibody, CEP-38072

Solution for infusion

Intravenous use

Patients were administered intravenously over 15 to 30 minutes reslizumab at a dosage of 3.0 mg/kg at baseline and once every 4 weeks relative to baseline over 48 weeks for a total of 13 doses.

Placebo

Reslizumab 3.0 mg/kg

Placebo

Reslizumab 3.0 mg/kg

An exacerbation event was considered a CAE if the patient met either or both of the criteria listed below and this was corroborated with at least 1 other measurement to indicate the worsening of clinical signs and symptoms of asthma: • use of systemic, or an increase in the use of inhaled, corticosteroid treatment for 3 or more days; or an increased 2 or more fold for at least 3 or more days for patient's already on corticosteroids. • asthma-related emergency treatment, such as an unscheduled visit to the physician's office or emergency room for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms, or an asthma-related hospitalization. CAEs were adjudicated by committee to assure consistency. Adjusted CAE rate and confidence intervals were based on Negative Binomial regression model adjusted for stratification factors. Results are offered as adjusted means.

Primary

Day 1 to Month 12

The frequency of CAEs was analyzed using the generalized linear model (GLM) for data from the negative binomial distributions that is commonly referred to as the negative binomial (NB) regression model. The primary NB model included the treatment group and randomization stratification factors as model factors and the logarithm of follow up time excluding the summed duration of exacerbations in the treatment period as an offset variable.

Reslizumab 3.0 mg/kg v Placebo

464

Pre-specified

0.4063

2-sided

An exacerbation event was considered a CAE if the patient met either or both of the criteria listed below and this was corroborated with at least 1 other measurement to indicate the worsening of clinical signs and symptoms of asthma: • use of systemic, or an increase in the use of inhaled, corticosteroid treatment for 3 or more days; or an increased 2 or more fold for at least 3 or more days for patient's already on corticosteroids. • asthma-related emergency treatment, such as an unscheduled visit to the physician's office or emergency room for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms, or an asthma-related hospitalization CAEs were adjudicated by committee to assure consistency. Adjusted CAE rate and confidence intervals for the two criteria were based on Negative Binomial regression model adjusted for stratification factors. Results are offered as adjusted means.

Primary

Day 1 to Month 12

The frequency of CAEs was analyzed using the generalized linear model (GLM) for data from the negative binomial distributions that is commonly referred to as the negative binomial (NB) regression model. The primary NB model included the treatment group and randomization stratification factors as model factors and the logarithm of follow up time excluding the summed duration of exacerbations in the treatment period as an offset variable.

Reslizumab 3.0 mg/kg v Placebo

464

Pre-specified

0.3893

2-sided

The frequency of CAEs was analyzed using the generalized linear model (GLM) for data from the negative binomial distributions that is commonly referred to as the negative binomial (NB) regression model. The primary NB model included the treatment group and randomization stratification factors as model factors and the logarithm of follow up time excluding the summed duration of exacerbations in the treatment period as an offset variable.

Reslizumab 3.0 mg/kg v Placebo

464

Pre-specified

0.6686

2-sided

FEV1 is a standard measurement of air movement in the lungs of patients with asthma obtained from pulmonary function tests. It is the volume of air expired in the first second of a forced expiration using a spirometer. Positive change from baseline scores indicate improvement in asthma control.

Secondary

Day 1 (baseline, pre-dose), Week 16

A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially

Reslizumab 3.0 mg/kg v Placebo

428

Pre-specified

0.101

2-sided

Standard error of the mean

0.0397

FEV1 is a standard measurement of air movement in the lungs of patients with asthma obtained from pulmonary function tests. It is the volume of air expired in the first second of a forced expiration using a spirometer. During study values used a mixed effect model for repeated measures (MMRM) with treatment group, visit, treatment and visit interaction, and stratification factors as fixed effects and participant as a random effect. Covariates for baseline values were also included in the model; for pulmonary function test analyses, covariates for height and sex were included as well. Positive change from baseline scores indicate improvement in asthma control.

Secondary

Day 1 (baseline, pre-dose), Weeks 4, 8, 12 and 16

A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.

Reslizumab 3.0 mg/kg v Placebo

457

Pre-specified

0.093

2-sided

Standard error of the mean

0.0317

The AQLQ is a 32-item instrument administered as a self-assessment (Juniper et al 1992). The questionnaire is divided into 4 domains: activity limitation, symptoms, emotional function, and environmental stimuli. Patients were asked to recall their experiences during the last 2 weeks and to respond to each question on a 7-point scale (1=severe impairment, 7=no impairment). The overall AQLQ score is the mean of all 32 responses. Five of the activity questions were "patient-specific," which means that each patient identified and scored 5 activities in which the patient was limited by asthma; these 5 activities were identified at the first visit and retained for all subsequent follow-up visits. Positive change from baseline scores indicate improvement in quality of life.

Secondary

Day 1 (baseline, pre-dose), Week 16

A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.

Reslizumab 3.0 mg/kg v Placebo

429

Pre-specified

0.209

2-sided

Standard error of the mean

0.937

The ACQ is a 7-item instrument that measures asthma control (Juniper et al 1999). Six questions are self-assessments; the seventh item, completed by a member of the study staff, is the result of the patient's FEV1 measurement. Each item has 7 possible answers on a scale of 0 to 6, and the total score is the mean of all responses (the total scale is therefore 0-6). A higher score is an indication of poorer asthma control. The during treatment average ACQ was estimated using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements. Negative change from baseline scores indicate improvement in asthma control.

Secondary

Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16

A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.

Reslizumab 3.0 mg/kg v Placebo

458

Pre-specified

-0.196

2-sided

Standard error of the mean

0.0664

An exacerbation event was considered a CAE if the patient met either or both of the criteria listed below and this was corroborated with at least 1 other measurement to indicate the worsening of clinical signs and symptoms of asthma: • use of systemic, or an increase in the use of inhaled, corticosteroid treatment for 3 or more days; or an increased 2 or more fold for at least 3 or more days for patient's already on corticosteroids. • asthma-related emergency treatment, such as an unscheduled visit to the physician's office or emergency room for nebulizer treatment or other urgent treatment to prevent worsening of asthma symptoms, or an asthma-related hospitalization. CAEs were adjudicated by committee to assure consistency. The distributions were compared by a log rank test stratified by baseline usage of oral corticosteroid (yes or no) and geographical region (U.S. or other). Values of 9999 = Insufficient data to estimate time.

Secondary

Day 1 to Day 526 (longest treatment time plus 2 weeks)

Kaplan-Meier estimate of probability (%) of not experiencing a CAE by week 52. The first CAEs for each patient occurring after randomization and up to 2 weeks after the end of treatment period were analyzed. Patients without a CAE within this time frame were censored at two weeks after the treatment completion date or study discontinuation, whichever came first.

Reslizumab 3.0 mg/kg v Placebo

464

Pre-specified

0.486

2-sided

The ASUI is an 11-item instrument designed to assess the frequency and severity of asthma symptoms and side effects, weighted by patient preferences (Revicki et al 1998). ASUI is a utility score that ranges from 0 to 1, with higher values indicating better asthma control; info obtained from questionnaire about asthma symptoms. The during treatment average ASUI was estimated using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements. Positive change from baseline values indicate improvement in asthma symptoms. Information was obtained from questionnaire about asthma symptoms.

Secondary

Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16

A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.

Reslizumab 3.0 mg/kg v Placebo

451

Pre-specified

0.035

2-sided

Standard error of the mean

0.012

SABA are used for quick relief of asthma symptoms. To measure SABA use, at each clinical visit patients were asked to recall their usage of SABA therapy within the last 3 days of the scheduled visit. If usage was confirmed, the number of puffs used was recorded. For the purpose of summaries, an average daily usage was evaluated by dividing the total number of puffs recorded over 3 days by 3. The during treatment SABA use was estimated using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements. Negative change from baseline scores indicate improvement in asthma control.

Secondary

Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16

A pre-specified fixed sequence multiple testing procedure was implemented to test the secondary endpoints while controlling the overall Type I error rate at 0.05. At the point where p>0.05, no further comparisons were interpreted inferentially.

Reslizumab 3.0 mg/kg v Placebo

368

Pre-specified

-0.062

2-sided

Standard error of the mean

0.1775

The blood eosinophil counts were measured using a standard complete blood count (CBC) with differential blood test. Results of all differential blood tests conducted after randomization were blinded. The during-treatment average eosinophil count was estimated using a mixed-effect model for repeated measures (MMRM) with fixed effects (treatment, stratification factors, sex, visit, interaction of treatment and visit), covariates (height, baseline value), and patient as the random effect for the repeated measurements. Negative change from baseline values correlate to reduced asthma severity.

Secondary

Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 or early withdrawal

An adverse event (AE) was defined in the protocol 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. Severity was rated by the investigator on a scale of mild, moderate and severe, with severe= an inability to carry out usual activities. Relation of AE to treatment was determined by the investigator. Serious AEs include 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 patient and required medical intervention to prevent the previously listed serious outcomes.

Secondary

Day 1 (post-dose) to Week 65. The endpoint for adverse events was the last postbaseline observation, which included the 90 day follow-up visit.

Data represents participants with potentially clinically significant (PCS) abnormal serum chemistry, hematology (except for eosinophil values), and urinalysis values. Significance criteria: • Blood urea nitrogen: >=10.71 mmol/L • Creatinine: >=177 μmol/L • Urate: M>=625, F>=506 μmol/L • Aspartate aminotransferase (AST): >=3*upper limit of normal (ULN) • Alanine aminotransferase (ALT): >=3*ULN • GGT = gamma-glutamyl transpeptidase: >= 3*ULN • Total bilirubin: >=34.2 μmol/L • White blood cells (low): <=3.0*10^9/L • White blood cells (high): >=20*10^9/L • Hemoglobin (age >=18 years): M<=115, F<=95 g/dL • Hematocrit (age >=18 years): M<0.37, F<0.32 L/L • Eosinophils/leukocytes: >=10.0% • Platelets: <=75*10^9/L • Neutrophils: <=1.0*10^9/L • Urinalysis: blood, ketones, glucose, and protein: >=2 unit increase from baseline

Secondary

Week 4 to Week 52

Data represents participants with potentially clinically significant (PCS) vital sign values. Significance criteria • Sitting pulse (high): >100 and increase of >= 30 beats/minute • Sitting systolic blood pressure (low): <90 and decrease of >= 30 mmHg • Sitting systolic blood pressure (high): >160 and increase of >= 30 mmHg • Sitting diastolic blood pressure (low): <50 and decrease of >=12 mmHg (if 12-17 years old: <55 and decrease of >=12 mmHg 0 • Sitting diastolic blood pressure (high): >100 and increase of >=12 mmHg • Respiratory rate (low): <6 breaths/minute • Respiratory rate (high): >24 and increase of >=10 breaths/minute • Body temperature (low): <35.8° Celsius • Body temperature (high): >=38.1 and increase of >=1.1° Celsius

Secondary

Week 4 to Week 52

Counts of participants with a positive anti-drug antibody (ADA) response during treatment is offered for the experimental treatment arm. Blood samples were collected for determination of ADAs before study drug infusion.

Secondary

Baseline visit (prior to reslizumab exposure), Weeks 16, 32, 48 and 52

Day 1 (post-dose) to Week 65. The endpoint for adverse events was the last postbaseline observation, which included the 90 day follow-up visit.

15.0

Placebo

Reslizumab 3.0 mg/kg