C38072/3081

Teva Global Branded Pharmaceutical Products R&D, Inc.

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

Director, Clinical Research, Teva Global Branded Pharmaceutical Products R&D, Inc., 1 215-591-3000, ustevatrials@tevapharm.com

Director, Clinical Research, Teva Global Branded Pharmaceutical Products R&D, Inc., 1 215-591-3000, ustevatrials@tevapharm.com

No

No

No

Final

29 Jan 2015

No

Yes

12 Sep 2013

No

The primary objective of this study is to determine whether reslizumab, at a dosage of 0.3 or 3.0 mg/kg administered once every 4 weeks for a total of 4 doses, is more effective than placebo in improving lung function in patients with eosinophilic asthma as assessed by the overall change from baseline in forced expiratory volume in 1 second (FEV1).

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; 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 studies of medicinal products for human use). Each investigator was responsible for performing the study in accordance with the protocol, ICH guidelines, and GCP, and for collecting, recording, and reporting the data accurately and properly. Agreement of each investigator to conduct and administer this study in accordance with the protocol was documented in separate study agreements with the sponsor and other forms as required by national authorities in the country where the study center is located. Written and/or oral information about the study in a language understandable by the patient was provided to all patients. The information included an adequate explanation of the aims, methods, anticipated benefits, potential hazards, and insurance arrangements in force. Written informed consent was obtained from each patient before any study-specific procedures or assessments were done. For patients aged 12 to 17 years, a signed and dated informed consent form was obtained from a parent/guardian. It was explained to all 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. Each investigator kept the original consent/assent forms, and copies were given to the patients.

07 Feb 2011

Yes

Yes

Netherlands: 3

Poland: 28

Sweden: 3

Belgium: 13

Hungary: 28

Argentina: 43

Brazil: 19

Canada: 13

Colombia: 6

Israel: 18

Mexico: 26

United States: 115

315

75

0

0

0

0

0

15

283

17

0

Overall Trial (overall period)

Randomised - controlled

To maintain the blinding in this 3-group study, each patient was to receive a specific volume of study drug (including active or placebo) on the basis of the patient’s body weight and assigned treatment group. Interactive response technology (IRT) was used to randomly assign a patient to 1 of 3 treatment groups. To maintain blinding to eosinophil counts during the study, eosinophil count data were redacted from hematology results during the treatment period.

Yes

Placebo

Solution for infusion

Intravenous use

Placebo administered by iv infusion by qualified study personnel every 4 weeks for a total of 4 doses.

Reslizumab

Cinquil, humanized monoclonal antibody, CEP-38072

Solution for infusion

Intravenous use

3.0 mg/kg or 0.3 mg/kg doses administered intravenously (iv) by qualified site personnel once every 4 weeks, for a total of 4 doses.

Reslizumab

Cinquil, humanized monoclonal antibody, CEP-38072

Solution for infusion

Intravenous use

3.0 mg/kg or 0.3 mg/kg doses administered intravenously (iv) by qualified site personnel once every 4 weeks, for a total of 4 doses.

Placebo

Reslizumab - 0.3 mg/kg

Reslizumab - 3.0 mg/kg

Placebo

Reslizumab - 0.3 mg/kg

Reslizumab - 3.0 mg/kg

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.

Primary

Day 0 (baseline, pre-dose), Weeks 4, 8, 12 and 16

The primary variable was analyzed 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.

Placebo v Reslizumab - 3.0 mg/kg

205

Pre-specified

0.16

2-sided

Standard error of the mean

0.0507

The primary variable was analyzed 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.

Placebo v Reslizumab - 0.3 mg/kg

204

Pre-specified

0.115

2-sided

Standard error of the mean

0.0508

The FVC is the volume of air that can be forcibly blown out after full inspiration, measured in liters.

Secondary

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

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 3.0 mg/kg

205

Pre-specified

0.13

2-sided

Standard error of the mean

0.0543

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 0.3 mg/kg

204

Pre-specified

0.048

2-sided

Standard error of the mean

0.0543

The FEF 25%-75% is the force expiratory flow at 25% to 75% of the Forced Vital Capacity (FVC).

Secondary

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

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 3.0 mg/kg

205

Pre-specified

0.233

2-sided

Standard error of the mean

0.1212

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 0.3 mg/kg

204

Pre-specified

0.03

2-sided

Standard error of the mean

0.1215

The % predicted FEV1 is the ratio of the volume of air expired in the first second of a forced expiration to the FVC.

Secondary

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

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. A higher score is an indication of poorer asthma control. Negative change from baseline scores indicate improvement.

Secondary

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

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 3.0 mg/kg

204

Pre-specified

-0.359

2-sided

Standard error of the mean

0.111

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 0.3 mg/kg

204

Pre-specified

-0.238

2-sided

Standard error of the mean

0.1108

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) for a total scale of 32-224. 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. The AQLQ score was only assessed once during the study at week 16 or at early withdrawal if it met endpoint criteria for efficacy assessments: ie, last postbaseline assessment if within 3 to 5 weeks of the last dose of study drug.

Secondary

Day 1 (baseline, pre-dose), Week 16 or last observed value

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 3.0 mg/kg

200

Pre-specified

0.359

2-sided

Standard error of the mean

0.1582

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 0.3 mg/kg

197

Pre-specified

0.278

2-sided

Standard error of the mean

0.1591

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.

Secondary

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

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 3.0 mg/kg

204

Pre-specified

0.047

2-sided

Standard error of the mean

0.0193

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 0.3 mg/kg

204

Pre-specified

0.051

2-sided

Standard error of the mean

0.0193

At each clinic visit, to measure SABA use, 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.

Secondary

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

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 3.0 mg/kg

204

Pre-specified

-0.624

2-sided

Standard error of the mean

0.2551

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 0.3 mg/kg

203

Pre-specified

-0.648

2-sided

Standard error of the mean

0.2559

Blood eosinophil counts were measured using a standard CBC with differential blood test at each scheduled visit, and from all patients experiencing a serious adverse event, an adverse event leading to withdrawal, or an exacerbation of asthma symptoms.

Secondary

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

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 3.0 mg/kg

205

Pre-specified

-0.494

2-sided

Standard error of the mean

0.0242

As with the primary outcome, this respiratory test outcome was analyzed 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.

Placebo v Reslizumab - 3.0 mg/kg v Reslizumab - 0.3 mg/kg

306

Pre-specified

-0.323

2-sided

Standard error of the mean

0.0243

An adverse event 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 29. The last postbaseline value for approximately 10 patients in each treatment group is the 90-day follow-up visit post end-of-treatment (approx. Week 29).

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 Uric acid: M>=625, F>=506 μmol/L GGT = gamma-glutamyl transpeptidase: >= 3*upper limit of normal. Normal range is 5-49 U/L. Total bilirubin: >=34.2 μmol/L White blood cells: <=3.0 10^9/L Hemoglobin: M<=115, F<=95 g/dL Hematocrit: M<0.37, F<0.32 % Platelets: >=700 10^9/L Absolute neutrophil count: <=1.0 10^9/L Urinalysis: blood, glucose, ketones and total protein: >=2 unit increase from baseline Actual number of participants evaluated varies between 100-104 for each test and treatment arm.

Secondary

Day 2 to Week 29. The last postbaseline hematology value for approximately 10 patients in each treatment group is the 90-day follow-up visit post end-of-treatment (approx. Week 29).

Data represents participants with potentially clinically significant (PCS) vital sign values. Significance criteria Sitting pulse - high: >100 and increase of >= 30 beats/minute Sitting pulse - low: <50 and decrease of >=30 beats/minute Sitting diastolic blood pressure: >100 and increase of >=12 mmHg Respiration rate: >24 and increase of >=10 breaths/minute Body temperature: <96.5° Fahrenheit or <35.8° Celsius

Secondary

Day 2 to Week 29. The last postbaseline value for approximately 10 patients in each treatment group is the 90-day follow-up visit post end-of-treatment (approx. Week 29).

Participant counts in each category of shift from baseline to endpoint of ECG finding. Findings summarized as normal or abnormal.

Secondary

Weeks -4 to -2 (Screening Visit), Week 16

Counts of participants with a positive anti-drug antibody (ADA) response during treatment is offered for the two experimental treatment arms. Blood samples were collected for determination of ADAs before study drug infusion at baseline, visit 4 (week 8), and at visit 6 (week 16: EOT or early withdrawal) from patients in all 3 treatment groups (ie, placebo, 0.3 mg/kg reslizumab, and 3.0 mg/kg reslizumab); however, only the blood samples drawn from patients treated with either 0.3 mg/kg reslizumab or 3.0 mg/kg reslizumab were analyzed. Serum samples from patients who were treated with reslizumab were analyzed for ADA by Teva (Teva Biopharmaceuticals USA, Rockville, MD) using a validated homogeneous solution-based bridging enzyme-linked immunosorbent assay (ELISA).

Secondary

Day 1 (pre-dose), week 8, 16 and endpoint

Day 1 to Week 29. The last postbaseline value for approximately 10 patients in each treatment group is the 90-day follow-up visit post end-of-treatment (approx. Week 29). Events reported during the follow-up were treated as treatment-emergent.

Total subjects affected with non-serious AEs by treatment arm is consistent with the 5% threshold.

15.0

Placebo

Reslizumab - 0.3 mg/kg

Reslizumab - 3.0 mg/kg