Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of Reslizumab (3.0 mg/kg) as Treatment for Patients (12 Through 75 Years of Age) With Eosinophilic Asthma

Study Overview
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Brief Summary
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The primary objective of the study is to evaluate the long-term safety of reslizumab at a dosage of 3.0 mg/kg every 4 weeks for approximately 24 months in pediatric and adult patients with eosinophilic asthma as assessed by adverse events, physical examination findings, vital sign measurements, and concomitant medication usage throughout the study (every 4 weeks), clinical laboratory test results, and measurement of antidrug antibodies.

Detailed Description
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Study patients deemed eligible based on activities from the preceding Teva sponsored double blind study of reslizumab in eosinophilic asthma. Specifically, as per inclusion criterion c, patients must have either completed treatment in a previous Teva-sponsored study or have received at least 2 doses of study drug treatment in a pulmonary function study. Eligible patients could enroll in this study only after completion of the end of treatment visit in a Teva sponsored, randomized, placebo controlled, double blind study of reslizumab in eosinophilic asthma, which served as the screening/baseline visit for participation in this open label extension study. The use of systemic corticosteroids for asthma in any of the previous Teva sponsored double blind studies of reslizumab did not exclude patients from this study. The previous Teva studies were C38072/3081 (NCT01270464), C38072/3082 (NCT01287039), and C38072/3083 (NCT01285323).

Official Title
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An Open-Label Extension Study to Evaluate the Long-Term Safety and Efficacy of Reslizumab (3.0 mg/kg) as Treatment for Patients With Eosinophilic Asthma Who Completed a Prior Teva-Sponsored Study in Eosinophilic Asthma

Conditions
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Eosinophilic Asthma

Intervention / Treatment
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* Drug: Reslizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent is obtained. Patient must have completed treatment in a previous Cephalon-sponsored double-blind asthma exacerbation study or received at least 2 doses of study drug treatment in a pulmonary function study. The patient must be willing and able to comply with study restrictions and to remain at the clinic for the required duration during the study period, and willing to return to the clinic for the follow-up evaluation as specified in this protocol. other criteria may apply; please contact the investigator for more information. 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 another confounding underlying lung disorder (eg, chronic obstructive pulmonary disease, pulmonary fibrosis, or lung cancer). The patient is a current smoker. 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 (e.g., gastroesophageal reflux disease [GERD]). Female patients who are pregnant, or nursing, or, if of childbearing potential and not using a medically accepted, effective method of birth control (eg, spermicide, abstinence, intrauterine device [IUD], or steroidal contraceptive [oral, transdermal, implanted, and injected] in conjunction with a barrier method) are excluded from this study. The patient has a current infection or disease that may preclude assessment of asthma. other criteria may apply; please contact the investigator for more information.

Ages Eligible for Study
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Minimum Age: 12 Years
Maximum Age: 75 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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Reslizumab 3.0 mg/kg<br>Reslizumab 3.0 mg/kg administered intravenously once every 4 weeks ( +-7 days) for up to 24 months. | Drug: Reslizumab<br>* Reslizumab (3.0 mg/kg) administered intravenously by infusion every 28 days (±7 days), for approximately 24 months<br>* Other names: CEP-38072;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Participants With Treatment-Emergent 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. | 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. | 
| Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Abnormal Lab Values | Data represents participants with potentially clinically significant (PCS) abnormal serum chemistry, hematology, and urinalysis values on any of the during treatment lab analyses. Significance criteria: Blood urea nitrogen: >=10.71 mmol/L Creatinine: >=177 μmol/L Uric acid: M>=625, F>=506 μmol/L Aspartate aminotransferase: >=3*upper limit of normal (ULN). Normal range is 10-43 U/L Alanine aminotransferase: >=3*ULN. Normal range is 10-40 U/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- low: <=3.0*10^9/L White blood cells-high: >=20*10^9/L Hemoglobin: M<=115, F<=95 g/dL Hematocrit: M<0.37, F<0.32 L/L Platelets: >=700*10^9/L Absolute neutrophil count: <=1.0*10^9/L Eosinophils: >=10 Urinalysis: ketones, blood, glucose, and total protein: >=2 unit increase from baseline | Weeks 4, 8, 24 and 48 | 
| Participants With Treatment-Emergent Potentially Clinically Significant (PCS) Vital Signs Values | Data represents participants with PCS vital sign values during any of the during treatment visits or the follow-up visit. Significance criteria Sitting heart rate-high: >100 and increase of >= 30 beats/min (all ages) Sitting heart rate-low: <50 and decrease of >=30 beats/min Sitting systolic blood pressure (BP)-high: >130 and increase of >=30 mmHg (ages 12-17) Systolic BP-low: <90 and decrease of >=30 mmHg (ages >=18) Systolic BP-high: >160 and increase of >=30 mmHg (ages >=18) Sitting diastolic BP-low: <55 and decrease of >=12 mmHg (ages 12-17) Diastolic BP-high: >85 and increase of >=12 mmHg (ages 12-17) Diastolic BP-low: <50 and decrease of >=12 mmHg (ages >=18) Diastolic BP-high: >100 and increase of >=12 mmHg (ages >=18) Respiration rate: >20 and increase of >=10 breaths/minute (ages 12-17) Respiration rate: >24 and increase of >=10 breaths/minute (ages >=18) Body temperature-low: <96.5° Fahrenheit (all ages) Body temp-high: >100.5° F (all ages) | Week 4 to Week 65 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Forced Expiratory Volume In 1 Second (FEV1) at Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, End of Study and Endpoint | 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. | Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, end of study and endpoint | 
| Percent Predicted Forced Expiratory Volume In 1 Second (% Predicted FEV1) at Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, End of Study and 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. Percent predicted lung function values were transcribed directly from the lung function report to the CRF, without any calculation by Teva. | Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, end of study and endpoint | 
| Forced Vital Capacity (FVC) at Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, End of Study and Endpoint | The FVC is the volume of air that can be forcibly blown out after full inspiration, measured in liters. . | Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, end of study and endpoint | 
| Forced Expiratory Flow at 25% to 75% Forced Vital Capacity (FEF 25%-75%) at Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, End of Study and Endpoint | The FEF 25%-75% is the force expiratory flow at 25% to 75% of the Forced Vital Capacity (FVC), measured in liters/second . | Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, end of study and endpoint | 
| Average Daily Use of Short-Acting Beta-Agonist (SABA)Therapy at Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, End of Study and Endpoint | SABA are used for quick relief of asthma symptoms. To measure SABA use, at each clinical visit participants 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. . | Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, end of study and endpoint | 
| Asthma Symptom Utility Index (ASUI) Score at Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, End of Study and Endpoint | 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. . | Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, end of study and endpoint | 
| Asthma Control Questionnaire (ACQ) at Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, End of Study and 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 (the total scale is therefore 0-6). A higher score is an indication of poorer asthma control. | Weeks 4, 8, 12, 16, 24, 36, 48, 60, 72, 84, 96, end of study and endpoint | 
| Asthma Quality of Life Questionnaire (AQLQ) Total Score at Weeks 24, 48, 72, 96, End of Study and Endpoint | 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. | Weeks 24, 48, 72, 96, End of Study and Endpoint | 
| Participants With a Positive Anti-Reslizumab Antibody Status at Baseline, Weeks 24, 48, 72, 96, End of Study, Endpoint and Overall | Blood samples were collected for the determination of anti-drug antibody (ADAs) before study drug infusion at baseline and every 24 weeks until end of treatment visit or early withdrawal. Serum samples were analyzed by Teva (Teva Biopharmaceuticals USA, Rockville, Maryland, USA) using a validated homogeneous solution based bridging enzyme linked immune sorbent assay (Mikulsis et al 2011, Qui et al 2010). The analysis of anti-reslizumab antibody in patient serum consists of 3 tiers of assays for screening, confirmation, and titer analysis. If a participant had a treatment-emergent ADA response (ie, ADA positive at any of the postdose time points but negative at the predose time point) or if there was a treatment-boosted ADA response (defined as a greater than 4-fold increase from a positive baseline ADA response (Shankar et at 2014), the participant was classified as overall ADA positive. Predose samples for the reslizumab-experienced participants came from the previous studies. | Baseline, Weeks 24, 48, 72, 96, End of Study, Endpoint and Overall |