A Study to Evaluate the Efficacy and Safety of Reslizumab in Patients With Eosinophilic Asthma

Eosinophilic Asthma Clinical Trial

Official title:

A 12-Month, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of Reslizumab (3.0 mg/kg) in the Reduction of Clinical Asthma Exacerbations in Patients (12-75 Years of Age) With Eosinophilic Asthma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01285323
• Other study ID #: C38072/3083
• Secondary ID: 2010-024006-35
• Status: Completed
• Phase: Phase 3
• Start date: March 2011
• Est. completion date: April 2014

Study information

• Verified date: November 2021
• Source: Teva Branded Pharmaceutical Products R&D, Inc.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The primary objective of this study is to determine whether reslizumab is more effective than placebo in reducing the number of clinical asthma exacerbations (CAEs) in patients with eosinophilic asthma.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 464
• Est. completion date: April 2014
• Est. primary completion date: April 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 75 Years

Eligibility

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 Germany, India, Argentina, and Korea; patients 66 through 75 years of age are excluded from participating in India and Korea.
• The patient has had at least 1 asthma exacerbation requiring oral, intramuscular (im), or intravenous (iv) corticosteroid use for at least 3 days over the past 12 months before screening.
• The patient has a current blood eosinophil level of at least 400/µL.
• The patient has airway reversibility of at least 12% to beta-agonist administration.
• The patient has an ACQ score of at least 1.5 5 at the screening and baseline (before the 1st dose of study drug) visits.
• The patient is taking inhaled fluticasone at a dosage of at least 440 µg, or equivalent, daily. Chronic oral corticosteroid use (no more than 10 mg/day prednisone or equivalent) is allowed. If a patient is on a stable dose, eg, 2 weeks or more of oral corticosteroid treatment at the time of study enrollment, the patient must remain on this dose throughout the study. The patient's baseline asthma therapy regimen (including, but not limited to, inhaled corticosteroids, oral corticosteroids up to a maximum dose of 10 mg prednisone daily or equivalent, leukotriene antagonists, 5-lipoxygenase inhibitors, or cromolyn) must be stable for 30 days prior to screening and baseline and must continue without dosage changes throughout the study.
• All female patients must be surgically sterile, 2 years postmenopausal, or must have a negative pregnancy test (ß-human chorionic gonadotropin [ß-HCG]) 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 participation in the study. Acceptable methods of contraception include barrier method with spermicide, abstinence, intrauterine device (IUD), or steroidal contraceptive (oral, transdermal, implanted, and injected). NOTE: Partner sterility alone is not acceptable for inclusion in the study.
• Written informed consent is obtained. Patients 12 through 17 years old, where participating, must provide assent.
• The patient is in reasonable health (except for diagnosis of asthma) as judged by the investigator, and as determined by a medical history, medical examination, ECG evaluation (at screening), serum chemistry, hematology, and urinalysis.
• The patient must be willing and able to understand and comply with study restrictions, requirements, and procedures, as specified by the study center, and to remain at the study center for the required duration during the study period, and willing to return to the study center for the follow-up evaluation as specified in this protocol.
• Patients who experience an asthma exacerbation during the screening period will be considered to have failed screening and cannot be randomly assigned to study drug. Patients may be rescreened 1 time only.

Exclusion Criteria:

• The patient has a clinically meaningful co-morbidity that would interfere with the study schedule or procedures, or compromise the patient's safety.
• The patient has known hypereosinophilic syndrome.
• The patient has another confounding underlying lung disorder (eg, chronic obstructive pulmonary disease, pulmonary fibrosis, or lung cancer). Patients with pulmonary conditions with symptoms of asthma and blood eosinophilia (eg, Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis) will also be excluded.
• The patient is a current smoker (ie, has smoked within the last 6 months prior to screening).
• The patient is using systemic immunosuppressive, immunomodulating, or other biologic agents (including, but not limited to, anti-immunoglobulin E (IgE) mAb, methotrexate, cyclosporin, interferon-a, or anti-tumor necrosis factor [anti-TNF] mAb) within 6 months prior to screening.
• The patient has previously received an anti-hIL-5 monoclonal antibody (eg, reslizumab, mepolizumab, or benralizumab).
• The patient has any aggravating medical factors that are inadequately controlled (eg, rhinitis, gastroesophageal reflux disease, and uncontrolled diabetes).
• 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 6 months prior to screening.
• Other exclusion criteria apply.

Related Conditions & MeSH terms

• Asthma
• Eosinophilic Asthma
• Pulmonary Eosinophilia

Intervention

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

Locations

Country	Name	City	State
Argentina	Teva Investigational Site 121	Ciudad Autonoma de Buenos Aire
Argentina	Teva Investigational Site 126	Ciudad Autonoma de Buenos Aire
Argentina	Teva Investigational Site 123	Rosario-Santa Fe
Argentina	Teva Investigational Site 120	San Miguel De Tucuman - Tucuma
Brazil	Teva Investigational Site 150	Florianopolis
Brazil	Teva Investigational Site 140	Porto Alegre
Brazil	Teva Investigational Site 144	Porto Alegre
Brazil	Teva Investigational Site 145	Porto Alegre
Brazil	Teva Investigational Site 143	Porto Alegre, RS
Brazil	Teva Investigational Site 142	Santo André, São Paulo
Canada	Teva Investigational Site 104	Newmarket
Canada	Teva Investigational Site 102	Pointe-Claire
Canada	Teva Investigational Site 105	Windsor
France	Teva Investigational Site 343	Grenoble
France	Teva Investigational Site 342	Marseille
France	Teva Investigational Site 341	Montpellier
Germany	Teva Investigational Site 360	Bad Wörishofen
Germany	Teva Investigational Site 361	Berlin
Germany	Teva Investigational Site 362	Berlin
Germany	Teva Investigational Site 366	Berlin
Germany	Teva Investigational Site 371	Bochum
Germany	Teva Investigational Site 365	Dresden
Germany	Teva Investigational Site 369	Frankfurt
Germany	Teva Investigational Site 370	Hamburg
Germany	Teva Investigational Site 372	Koblenz
Germany	Teva Investigational Site 367	Leipzig
Germany	Teva Investigational Site 368	Leipzig
Germany	Teva Investigational Site 363	Mainz
Germany	Teva Investigational Site 364	Mainz
Greece	Teva Investigational Site 381	Alexandroupolis
Greece	Teva Investigational Site 380	Athens
Greece	Teva Investigational Site 382	Heraklion, Crete
Korea, Republic of	Teva Investigational Site 682	Gwangju
Korea, Republic of	Teva Investigational Site 680	Seoul
Korea, Republic of	Teva Investigational Site 681	Seoul
Korea, Republic of	Teva Investigational Site 683	Seoul
Korea, Republic of	Teva Investigational Site 686	Seoul
Korea, Republic of	Teva Investigational Site 685	Suwon
Mexico	Teva Investigational Site 205	Ciudad De México
Mexico	Teva Investigational Site 203	Distrito Federal
Mexico	Teva Investigational Site 204	Guadalajara, JAL
Mexico	Teva Investigational Site 207	Mexico City
Mexico	Teva Investigational Site 209	Monterrey
Mexico	Teva Investigational Site 202	Tijuana, B.C.
Peru	Teva Investigational Site 223	Cercado De Lima, Lima
Peru	Teva Investigational Site 220	Lima
Peru	Teva Investigational Site 221	Lima
Peru	Teva Investigational Site 222	Lima
Peru	Teva Investigational Site 225	Lima
Peru	Teva Investigational Site 226	Lima
Peru	Teva Investigational Site 227	Lima
Peru	Teva Investigational Site 229	Lima
Romania	Teva Investigational Site 523	Bucharest
Romania	Teva Investigational Site 524	Bucharest
Romania	Teva Investigational Site 520	Cluj-Napoca
Romania	Teva Investigational Site 521	Iasi
Romania	Teva Investigational Site 522	Targu Mures
Russian Federation	Teva Investigational Site 543	Moscow
Russian Federation	Teva Investigational Site 544	Moscow
Russian Federation	Teva Investigational Site 554	Moscow
Russian Federation	Teva Investigational Site 556	Moscow
Russian Federation	Teva Investigational Site 558	Moscow
Russian Federation	Teva Investigational Site 559	Moscow
Russian Federation	Teva Investigational Site 557	Novosibirsk
Russian Federation	Teva Investigational Site 541	St. Petersburg
Russian Federation	Teva Investigational Site 540	St.Petersburg
Slovakia	Teva Investigational Site 563	Bradejov
Slovakia	Teva Investigational Site 561	Levice
Slovakia	Teva Investigational Site 560	Spisska Nova Ves
Slovakia	Teva Investigational Site 562	Topolcany
Taiwan	Teva Investigational Site 764	Kaohsiung
Taiwan	Teva Investigational Site 765	Taichung
Taiwan	Teva Investigational Site 760	Taipei
Taiwan	Teva Investigational Site 761	Taipei
Taiwan	Teva Investigational Site 763	Taoyuan
Ukraine	Teva Investigational Site 621	Dnipropetrovsk
Ukraine	Teva Investigational Site 629	Donetsk
Ukraine	Teva Investigational Site 635	Donetsk
Ukraine	Teva Investigational Site 630	Ivano-Frankivsk
Ukraine	Teva Investigational Site 620	Kharkiv
Ukraine	Teva Investigational Site 633	Kharkiv
Ukraine	Teva Investigational Site 622	Kyiv
Ukraine	Teva Investigational Site 623	Kyiv
Ukraine	Teva Investigational Site 624	Kyiv
Ukraine	Teva Investigational Site 625	Kyiv
Ukraine	Teva Investigational Site 628	Ternopil
Ukraine	Teva Investigational Site 626	Vinnytsya
Ukraine	Teva Investigational Site 631	Zaporizhzhia
Ukraine	Teva Investigational Site 632	Zaporizhzhia
United States	Teva Investigational Site 46	Bangor	Maine
United States	Teva Investigational Site 53	Clearwater	Florida
United States	Teva Investigational Site 44	Dallas	Texas
United States	Teva Investigational Site 47	Denver	Colorado
United States	Teva Investigational Site 69	El Paso	Texas
United States	Teva Investigational Site 67	Fort Mill	South Carolina
United States	Teva Investigational Site 41	Fresno	California
United States	Teva Investigational Site 25	Lawrenceville	Georgia
United States	Teva Investigational Site 59	Long Beach	California
United States	Teva Investigational Site 57	Metairie	Louisiana
United States	Teva Investigational Site 27	Miami	Florida
United States	Teva Investigational Site 48	Mobile	Alabama
United States	Teva Investigational Site 40	Saint Louis	Missouri
United States	Teva Investigational Site 45	San Antonio	Texas
United States	Teva Investigational Site 28	Waterbury	Connecticut

Sponsors (1)

Lead Sponsor	Collaborator
Teva Branded Pharmaceutical Products R&D, Inc.

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  France,  Germany,  Greece,  Korea, Republic of,  Mexico,  Peru,  Romania,  Russian Federation,  Slovakia,  Taiwan,  Ukraine, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Frequency of Clinical Asthma Exacerbations (CAEs) During 12 Months of Treatment	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.	Day 1 to Month 12
Primary	Frequency of Each of the Two Criteria for Clinical Asthma Exacerbations (CAEs)	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.	Day 1 to Month 12
Secondary	Change From Baseline in Forced Expiratory Volume in 1 Second (FEV1) At Week 16	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.	Day 1 (baseline, pre-dose), Week 16
Secondary	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. During study (Weeks 4, 8, 12 and 16) average value 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.	Day 1 (baseline, pre-dose), Weeks 4, 8, 12 and 16
Secondary	Change From Baseline in Asthma Quality of Life Questionnaire (AQLQ) to Week 16	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.	Day 1 (baseline, pre-dose), Week 16
Secondary	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
Secondary	Kaplan-Meier Estimates for Time to First Clinical Asthma Exacerbation (CAE)	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 (US or other).	Day 1 to Day 526 (longest treatment time plus 2 weeks)
Secondary	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; info obtained from questionnaire about asthma symptoms.; 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
Secondary	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
Secondary	Change From Baseline in Blood Eosinophil Count Over 16 Weeks and 52 Weeks Using Mixed Model for Repeated Measures	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. The 'over 16 weeks' value used data from Weeks 4, 8, 12 and 16. The 'over 52 weeks' value used all the during study time points listed in the Time Frame field.; Negative change from baseline values correlate to reduced asthma severity.	Day 1 (baseline, pre-dose), Weeks 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, 52 or early withdrawal
Secondary	Participants With Treatment-Emergent Adverse Events TEAE)	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.	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.
Secondary	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; 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	Week 4 to Week 52
Secondary	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 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	Week 4 to Week 52
Secondary	Participants With a Positive Anti-Reslizumab Antibody Status During Study	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.	Baseline visit (prior to reslizumab exposure), Weeks 16, 32, 48 and 52