A Study to Evaluate the Efficacy and Safety of Reslizumab (0.3 or 3.0 mg/kg) as Treatment for Patients (12-75 Years of Age) With Eosinophilic Asthma

A 16-Week, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Reslizumab (0.3 or 3.0 mg/kg) as Treatment for Patients (12-75 Years of Age) With Eosinophilic Asthma

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).

Study Overview

• Status: Completed
• Conditions: Eosinophilic Asthma
• Intervention / Treatment: Drug: Placebo; Drug: Reslizumab

• Study Type: Interventional
• Enrollment (Actual): 315
• Phase: Phase 3

Contacts and Locations

Study Locations

• Argentina
  • Ciudad Autonoma de Buenos Aire, Argentina
    • Teva Investigational Site 121
  • Ciudad Autonoma de Buenos Aire, Argentina
    • Teva Investigational Site 126
  • Ciudad Autonoma de Buenos Aire, Argentina
    • Teva Investigational Site 127
  • Quilmes-Buenos Aires, Argentina
    • Teva Investigational Site 128
  • Rosario, Argentina
    • Teva Investigational Site 125
  • Rosario-Santa Fe, Argentina
    • Teva Investigational Site 123
  • San Miguel de Tucuman - Tucuma, Argentina
    • Teva Investigational Site 120
  • San Miguel de Tucuman - Tucuma, Argentina
    • Teva Investigational Site 122
  • San Miguel de Tucuman - Tucuma, Argentina
    • Teva Investigational Site 124
• Belgium
  • Bruxelles, Belgium
    • Teva Investigational Site 261
  • Bruxelles, Belgium
    • Teva Investigational Site 264
  • Gent, Belgium
    • Teva Investigational Site 260
  • Liège, Belgium
    • Teva Investigational Site 263
• Brazil
  • Belo Horizonte, Brazil
    • Teva Investigational Site 146
  • Florianopolis, Brazil
    • Teva Investigational Site 150
  • Porto Alegre, Brazil
    • Teva Investigational Site 140
  • Porto Alegre, Brazil
    • Teva Investigational Site 143
  • Porto Alegre, Brazil
    • Teva Investigational Site 144
  • Porto Alegre, Brazil
    • Teva Investigational Site 145
  • Porto Alegre - RS, Brazil
    • Teva Investigational Site 147
  • Santo André, São Paulo, Brazil
    • Teva Investigational Site 142
  • Sao Paulo, Brazil
    • Teva Investigational Site 141
• Canada
  • Calgary, Canada
    • Teva Investigational Site 103
  • Montreal, Canada
    • Teva Investigational Site 101
  • Newmarket, Canada
    • Teva Investigational Site 104
  • Windsor, Canada
    • Teva Investigational Site 105
• Colombia
  • Bogota, Colombia
    • Teva Investigational Site 185
  • Bogota, Colombia
    • Teva Investigational Site 184
  • Bogotá, Colombia
    • Teva Investigational Site 181
  • Cali, Colombia
    • Teva Investigational Site 182
  • Floridablanca, Colombia
    • Teva Investigational Site 180
  • Medellin, Colombia
    • Teva Investigational Site 183
• France
  • Grenoble, France
    • Teva Investigational Site 343
  • Marseille, France
    • Teva Investigational Site 342
  • Montpellier, France
    • Teva Investigational Site 341
  • Nantes, France
    • Teva Investigational Site 340
  • Pessac, France
    • Teva Investigational Site 344
• Hungary
  • Balassagyarmat, Hungary
    • Teva Investigational Site 401
  • Edelény, Hungary
    • Teva Investigational Site 406
  • Miskolc, Hungary
    • Teva Investigational Site 400
  • Mosonmagyaróvár, Hungary
    • Teva Investigational Site 404
  • Sopron, Hungary
    • Teva Investigational Site 403
  • Százhalombatta, Hungary
    • Teva Investigational Site 407
  • Tatabánya, Hungary
    • Teva Investigational Site 402
• Israel
  • Petach Tikva, Israel
    • Teva Investigational Site 422
  • Rehovot, Israel
    • Teva Investigational Site 421
  • Tel-Aviv, Israel
    • Teva Investigational Site 420
• Mexico
  • Distrito Federal, Mexico
    • Teva Investigational Site 203
  • Distrito Federal, Mexico
    • Teva Investigational Site 205
  • Guadalajara, JAL, Mexico
    • Teva Investigational Site 204
  • Hermosillo, Sonora, Mexico
    • Teva Investigational Site 200
  • Tijuana, B.C., Mexico
    • Teva Investigational Site 202
• Netherlands
  • Heerlen, Netherlands
    • Teva Investigational Site 460
• Poland
  • Bialystok, Poland
    • Teva Investigational Site 507
  • Gdansk, Poland
    • Teva Investigational Site 513
  • Lodz, Poland
    • Teva Investigational Site 512
  • Lublin, Poland
    • Teva Investigational Site 505
  • Ostrow Wielkopolski, Poland
    • Teva Investigational Site 500
  • Sopot, Poland
    • Teva Investigational Site 502
  • Tarnow, Poland
    • Teva Investigational Site 504
• Sweden
  • Göteborg, Sweden
    • Teva Investigational Site 602
  • Lund, Sweden
    • Teva Investigational Site 600
  • Malmö, Sweden
    • Teva Investigational Site 601
• United States
  • California
    • Anaheim, California, United States
      • Teva Investigational Site 12
    • Fountain Valley, California, United States
      • Teva Investigational Site 11
    • Los Angeles, California, United States
      • Teva Investigational Site 43
    • Orange, California, United States
      • Teva Investigational Site 4
    • Walnut Creek, California, United States
      • Teva Investigational Site 15
  • Colorado
    • Colorado Springs, Colorado, United States
      • Teva Investigational Site 2
  • Florida
    • Largo, Florida, United States
      • Teva Investigational Site 24
    • Miami, Florida, United States
      • Teva Investigational Site 27
    • Miami, Florida, United States
      • Teva Investigational Site 5
    • Tallahassee, Florida, United States
      • Teva Investigational Site 19
    • Trinity, Florida, United States
      • Teva Investigational Site 17
    • Valrico, Florida, United States
      • Teva Investigational Site 18
  • Georgia
    • Lilburn, Georgia, United States
      • Teva Investigational Site 6
    • Savannah, Georgia, United States
      • Teva Investigational Site 3
  • Iowa
    • Iowa City, Iowa, United States
      • Teva Investigational Site 7
  • Nebraska
    • Omaha, Nebraska, United States
      • Teva Investigational Site 8
  • New Jersey
    • Summit, New Jersey, United States
      • Teva Investigational Site 26
  • Ohio
    • Cincinnati, Ohio, United States
      • Teva Investigational Site 20
  • Oregon
    • Medford, Oregon, United States
      • Teva Investigational Site 1
  • Rhode Island
    • Lincoln, Rhode Island, United States
      • Teva Investigational Site 73
    • Providence, Rhode Island, United States
      • Teva Investigational Site 9
  • South Carolina
    • Charleston, South Carolina, United States
      • Teva Investigational Site 21
  • Texas
    • Fort Worth, Texas, United States
      • Teva Investigational Site 16
    • Houston, Texas, United States
      • Teva Investigational Site 10
    • San Antonio, Texas, United States
      • Teva Investigational Site 14
    • San Antonio, Texas, United States
      • Teva Investigational Site 45

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 12 years to 75 years (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• The patient is male or female, 12 through 75 years of age, with a previous diagnosis of asthma. Patients 12 through 17 years of age are excluded from participating in Argentina.
• The patient has an ACQ score of at least 1.5.
• The patient has airway reversibility of at least 12% to beta-agonist administration at screening.
• The patient is currently taking fluticasone at a dosage of at least 440 μg daily (or equivalent). Patients' baseline asthma therapy regimens (including but not limited to inhaled corticosteroids, leukotriene antagonists, 5-lipoxygenase inhibitors, cromolyn) must be stable for 30 days before screening, and continue without dosage changes throughout study.
• The patient has a blood eosinophil count of at least 400/μL.
• Female patients must be surgically sterile, 2 years postmenopausal, or must have a negative pregnancy test ßHCG at screening (serum) and baseline (urine).
• Female patients of childbearing potential (not surgically sterile or 2 years postmenopausal), must use a medically accepted method of contraception and must agree to continue use of this method for the duration of the study and for 30 days after the end-of-treatment visit. Acceptable methods of contraception include barrier method with spermicide, abstinence, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected).
• Written informed consent is obtained. Patients 12 through 17 years old, where participating, need to provide assent in accordance with local standards.
• Other inclusion criteria apply.

Exclusion Criteria:

• The patient has a clinically meaningful comorbidity that would interfere with the study schedule or procedures, or compromise the patient's safety.
• The patient has known hypereosinophilic syndrome (HES).
• The patient has another confounding underlying lung disorder (eg, chronic obstructive pulmonary disease, pulmonary fibrosis, or lung cancer). The patient has other pulmonary conditions with symptoms of asthma and blood eosinophilia (eg, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis).
• The patient is a current smoker (ie, has smoked within the last 6 months prior to screening).
• The patient has a history of use of systemic immunosuppressive or immunomodulating agents (anti-IgE mAb, methotrexate, cyclosporin, interferon-α, or anti-tumor necrosis factor mAb) within 6 months prior to study entry (screening).
• The patient is currently using systemic corticosteroids (includes use of oral corticosteroids).
• The patient has a current infection or disease that may preclude assessment of asthma.
• The patient is expected to be poorly compliant with study drug administration, study procedures, or visits.
• The patient has any aggravating factors that are inadequately controlled (eg, gastroesophageal reflux disease).
• The patient has participated in any investigative drug or device study within 30 days prior to screening.
• The patient has participated in any investigative biologics study within 90 days prior to screening.
• The patient has previously received anti-hIL-5 monoclonal antibody (eg, mepolizumab).
• Female patients who are pregnant, or nursing, or, if of childbearing potential and not using a medically accepted, effective method of birth control (e.g. spermicide, abstinence, IUD, or steroidal contraceptive [oral, transdermal, implanted, and injected]) are excluded from this study.
• The patient has a current infection or disease that may preclude assessment of asthma.
• The patient has a history of concurrent immunodeficiency (human immunodeficiency, acquired immunodeficiency syndrome, or congenital immunodeficiency). Patients in Argentina must have documented serology testing for HIV performed during screening.
• Other exclusion criteria apply.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo administered intravenously (iv) once every 4 weeks, for a total of 4 doses.	Drug: Placebo; Placebo administered by iv infusion by qualified study personnel every 4 weeks for a total of 4 doses.
Experimental: Reslizumab - 0.3 mg/kg; 0.3 mg/kg, administered intravenously (iv) once every 4 weeks, for a total of 4 doses	Drug: Reslizumab; 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.; Other Names: Cinquil; humanized monoclonal antibody; CEP-38072
Experimental: Reslizumab - 3.0 mg/kg; 3.0 mg/kg, administered intravenously (iv) once every 4 weeks, for a total of 4 doses.	Drug: Reslizumab; 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.; Other Names: Cinquil; humanized monoclonal antibody; CEP-38072

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline In Forced Expiratory Volume In 1 Second (FEV1) Over 16 Weeks Using Mixed Model for Repeated Measures	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. The during treatment (weeks 4, 8, 12 and 16) average FEV1 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 scores indicate improvement in asthma control.	Day 0 (baseline, pre-dose), Weeks 4, 8, 12 and 16

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change From Baseline in Forced Vital Capacity (FVC) Over 16 Weeks Using Mixed Model for Repeated Measures	The FVC is the volume of air that can be forcibly blown out after full inspiration, measured in liters. The during treatment (weeks 4, 8, 12 and 16) average FVC 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.	Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
Change From Baseline in Forced Expiratory Flow at 25% to 75% Forced Vital Capacity (FEF 25%-75%) Over 16 Weeks Using Mixed Model for Repeated Measures	The FEF 25%-75% is the force expiratory flow at 25% to 75% of the Forced Vital Capacity (FVC). The during treatment (weeks 4, 8, 12 and 16) average FEF 25%-75% 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.	Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
Change From Baseline in % Predicted Expiratory Volume In 1 Second (FEV1) at Week 16 and at Endpoint	The percent predicted FEV1 is the ratio of the volume of air expired in the first second of a forced expiration to the patient's predicted FEV based on a similar population without asthma. Endpoint =week 16 or early withdrawal.	Day 1 (baseline, pre-dose), Week 16, endpoint
Change From Baseline in Asthma Control Questionnaire (ACQ) Over 16 Weeks Using Mixed Model for Repeated Measures	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 (weeks 4, 8, 12 and 16) 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.	Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) at Week 16 or at Last Observed Value	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. The AQLQ score was only assessed once during the study at week 16 or at early withdrawal, i.e. last postbaseline assessment if within 3 to 5 weeks of the last dose of study drug.	Day 1 (baseline, pre-dose), Week 16 or last observed value
Change From Baseline in Asthma Symptom Utility Index (ASUI) Over 16 Weeks Using Mixed Model for Repeated Measures	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. The during treatment (weeks 4, 8, 12 and 16) 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.	Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
Change From Baseline in Short-Acting Beta-Agonist (SABA) Use Over 16 Weeks Using Mixed Model for Repeated Measures	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 (weeks 4, 8, 12 and 16) average 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.	Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
Change From Baseline in Blood Eosinophil Count Over 16 Weeks Using Mixed Model for Repeated Measures	Blood eosinophil counts were measured using a standard complete blood count (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. The during treatment (weeks 4, 8, 12 and 16) average eosinophil counts were 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.	Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16
Participants With Adverse Events	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. 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).	Day 1 (post-dose) to Week 29
Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Abnormal Lab Values	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 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).	Day 2 to Week 29
Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Vital Signs Values	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 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).	Day 2 to Week 29
Shifts From Baseline to Endpoint in Electrocardiogram Findings	Participant counts in each category of shift from baseline to endpoint of ECG finding. Findings summarized as normal or abnormal.	Weeks -4 to -2 (Screening Visit), Week 16
Participants With a Positive Anti-Reslizumab Antibody Status at Baseline, Week 8, Week 16, Endpoint, and Overall	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). Endpoint =week 16 or early withdrawal.	Day 1 (pre-dose), week 8, 16 and endpoint

Collaborators and Investigators

• Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
• Investigators: Study Director: Sponsor's Medical Expert, Senior Director - Worldwide Clinical Research, MD, Cephalon

Publications and helpful links

General Publications

• Bjermer L, Lemiere C, Maspero J, Weiss S, Zangrilli J, Germinaro M. Reslizumab for Inadequately Controlled Asthma With Elevated Blood Eosinophil Levels: A Randomized Phase 3 Study. Chest. 2016 Oct;150(4):789-798. doi: 10.1016/j.chest.2016.03.032. Epub 2016 Apr 4.

Study record dates

Study Major Dates

• Study Start: February 1, 2011
• Primary Completion (Actual): September 1, 2013
• Study Completion (Actual): September 1, 2013

Study Registration Dates

• First Submitted: December 29, 2010
• First Submitted That Met QC Criteria: January 3, 2011
• First Posted (Estimate): January 5, 2011

Study Record Updates

• Last Update Posted (Estimate): June 6, 2016
• Last Update Submitted That Met QC Criteria: April 28, 2016
• Last Verified: April 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Immune System Diseases; Lung Diseases; Hypersensitivity, Immediate; Hematologic Diseases; Bronchial Diseases; Lung Diseases, Obstructive; Respiratory Hypersensitivity; Hypersensitivity; Leukocyte Disorders; Eosinophilia; Hypereosinophilic Syndrome; Asthma; Pulmonary Eosinophilia; Anti-Asthmatic Agents; Respiratory System Agents; Reslizumab
• Other Study ID Numbers: C38072/3081; 2010-023342-67 (EudraCT Number)