Conditions: Asthma
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 468
Healthy volunteers: no

Brief summary:
The primary objective of this study is to determine the effect of reslizumab (110 mg) administered subcutaneously every 4 weeks on clinical asthma exacerbations in adults and adolescents with asthma and elevated blood eosinophils who are inadequately controlled on standard-of-care asthma therapy.

Detailed description:

Arms:
arm 1: Reslizumab arm 2: Matching Placebo

Interventions: intervention 1: Reslizumab intervention 2: Placebo
Intervention descriptions: intervention 1: Reslizumab will be administered subcutaneously in a dose of 110 mg every 4 weeks. intervention 2: Matching Placebo

Protocol document:
Prot_000.pdf: 
 
 
 
 
Clinical Study Protocol with Amendment 04 
 
A 52-Week Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of 
Reslizumab 110 mg Fixed, Subcutaneous Dosing in Patients with Uncontrolled Asthma and 
Elevated Blood Eosinophils 
 
 
Study Number C38072-AS-30025 
 
NCT02452190 
 
Protocol with Amendment 04 Approval Date: 24 October 2016  
 


 
Placebo-Controlled Study–Asthma 
Clinical Study Protocol with Amendment 04 
C38072-AS-30025 
 
1 
 
 
 
Clinical Study Protocol with Amendment 04 
Study Number C38072-AS-30025 
A 52-Week Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of 
Reslizumab 110 mg Fixed, Subcutaneous Dosing in Patients with Uncontrolled Asthma and 
Elevated Blood Eosinophils 
Phase 3 
IND number: 101,399 
  
EudraCT number: 2015-000865-29 
Protocol Approval Date: 24 October 2016 
 
Sponsor  
Monitor 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States 
 
 
 
 
 
Authorized Representative 
 
 
Teva Branded Pharmaceutical Products R&D, Inc. 
 
Sponsor’s Medical Expert 
Sponsor’s Safety Representative 
 
 
 
 
Teva Global R&D 
 
 
 
Teva Branded Pharmaceutical Products 
R&D, Inc 
 
 
 
Confidentiality Statement 
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed by the 
provisions of the International Conference on Harmonisation (ICH); United States Code of Federal Regulations 
(CFR) and European Union Directives (as applicable in the region of the study); local country regulations; and the 
sponsor’s Standard Operating Procedures (SOPs).  
This document contains confidential and proprietary information (including confidential commercial information 
pursuant to 21CFR§20.61) and is a confidential communication of Teva Pharmaceuticals. The recipient agrees that 
no information contained herein may be published or disclosed without written approval from the sponsor. 
© 2016 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 


 
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AMENDMENT HISTORY 
The protocol for Study C38072-AS-30025 (original protocol dated 26 March 2015) has been 
amended and reissued as follows: 
Amendment 04 
24 October 2016 
468 patients enrolled to date 
Amendment 03 
25 July 2016 
368 patients enrolled to date 
Administrative Letter: 
Reiteration of eosinophil count 
21 March 2016 
85 patients enrolled to date 
Administrative Letter: 
Change in Medical Monitor  
08 March 2016 
67 patients enrolled to date 
Administrative Letter: 
Change in Sponsor’s Medical Expert  
26 February 2016 
57 patients enrolled to date 
Amendment 02 
25 January 2016 
24 patients enrolled to date 
Administrative Letter: 
Contraception Use 
22 July 2015 
0 patients enrolled to date 
Amendment 01 
 
04 May 2015 
0 patients enrolled to date 
Addendum Letter:  
Change in estimated total blood volume taken 
22 April 2015 
0 patients enrolled to date 
Administrative Letter :  
Change in Central Spirometry and ECG Vendor  
14 April 2015 
0 patients enrolled to date 


 
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INVESTIGATOR AGREEMENT 
 


 
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COORDINATING INVESTIGATOR AGREEMENT 
 


 
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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS 
Central Institutional Review Board 
 
 
 
Central Clinical Laboratory 
  
 
 
 
 
 
 
Electronic Data Capture 
 
 
 
 
 
Web and Phone Integrated Interactive Response Technology 
 
 
 
 
Bioanalytical Pharmacokinetics Evaluation  
Teva Pharmaceuticals 
Global Bioassay and Technology 
West Chester, PA 19380 


 
Placebo-Controlled Study–Asthma 
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Bioanalytical Immunogenicity Evaluation  
Teva Pharmaceuticals 
Global Bioassay and Technology 
West Chester, PA 19380 
Exploratory Asthma Biomarker Evaluation 
Teva Pharmaceuticals 
Global Bioassay and Technology 
West Chester, PA 19380 
Central Spirometry, e-diary and ECG 
 
Spirometry and e-diary:  
 
 
ECG:  
 
 
 


 
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CLINICAL STUDY PERSONNEL CONTACT INFORMATION 
For medical issues, contact the physician listed below:  
Oversight Lead Medical Monitor: 
 
 
For centers in North America 
 
 
 
 
For Centers in Latin America 
 
 
 
For centers in Europe and countries outside the Americas 
EMEA:  
 
 
 
 
 
APAC: 
 
 
 
 
 
 
 
For operational issues, contact the operational lead listed below:  
 
 
 
For serious adverse events: 
Send by e-mail to the local safety officer/contract research organization (LSO/CRO). The email 
address will be provided in the serious adverse event report form. In the event of difficulty 
transmitting the form, contact the sponsor’s study personnel identified above for further 
instruction. 


 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Study C38072-AS-30025 
Title of Study: A 52-Week Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of 
Reslizumab 110 mg Fixed, Subcutaneous Dosing in Patients with Uncontrolled Asthma and Elevated Blood 
Eosinophils 
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc  
IND Number: 101,399 
 EudraCT Number: 2015-000865-29 
Name of Active Ingredient: Reslizumab 
Name of Investigational Product: Reslizumab for subcutaneous injection, 110 mg/mL 
Phase of Clinical Development: 3 
Number of Investigational Centers Planned: ~275  
Countries Planned: ~30  
Planned Study Period: Q3 2015 to Q3 2017  
Number of Patients Planned: Approximately 225 patients per treatment group for a total of 450 patients. 
Study Population: Asthma patients 12 years of age and older (Patients 12 to <18 years of age are excluded from 
participating in South Korea and Argentina, and patients 66 years of age and older are excluded from participating in 
South Korea.) 
Primary Objective: The primary objective of this study is to determine the effect of reslizumab (110 mg) 
administered subcutaneously every 4 weeks on clinical asthma exacerbations (CAEs) in adults and adolescents with 
asthma and elevated blood eosinophils who are inadequately controlled on standard-of-care asthma therapy. 
Secondary Objectives: Secondary efficacy objectives are to evaluate the effects of reslizumab compared with 
placebo on a range of clinical markers of asthma control including pulmonary function (forced expiratory volume in 
1 second [FEV1]). 
Other Objectives: Other objectives of this study are to evaluate the safety, pharmacokinetics (PK), 
pharmacodynamics, and immunogenicity of reslizumab. 
Study Endpoints:  
Primary Efficacy Endpoint:  
The primary efficacy endpoint is the frequency of CAEs per patient during the 52-week treatment period. 
For this study, a CAE is defined as a clinically judged deterioration in asthma control as determined by the 
investigator and as evidenced by new or worsening asthma signs or symptoms based on the patient history, 
asthma control diary, physical examination, and/or ambulatory or clinic visit assessment of lung function and 
that results in a medical intervention, including at least 1 of the following: 
• 
use of systemic corticosteroids (oral or injection) or at least a doubling from a stable maintenance oral 
corticosteroid dose for at least 3 days 
• 
asthma-specific hospital admission 
• 
asthma-specific emergency department visit 
Additional medication and/or medical intervention that would satisfy the CAE definition occurring within 
7 days of the last day of a prior CAE event will be considered as part of the same event for analysis purposes. 
Secondary Efficacy Endpoints:  
The secondary efficacy endpoints are as follows: 
• 
change in pre-bronchodilator FEV1 from baseline/the day of randomization (DoR) at week 52 


 
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• 
change in Asthma Quality of Life Questionnaire for patients 12 years and older (AQLQ +12) score 
from baseline/DoR at week 52 
• 
change in 6-item Asthma Control Questionnaire (ACQ-6) score from baseline/DoR at week 52 
• 
change in total asthma symptom scores (day and night) from baseline at week 52 
• 
percentage of asthma control days from baseline/DoR to week 52 
• 
change in St. George’s Respiratory Questionnaire (SGRQ) score from baseline/DoR at week 32 
• 
time to first CAE during the 52-week treatment period 
• 
frequency of exacerbations requiring hospitalization or emergency department visits per patient during 
the 52-week treatment period 
• 
frequency of moderate exacerbations defined as exacerbations requiring additional asthma controller 
medication that was not a systemic corticosteroid and that did not result in an asthma-specific 
hospitalization or emergency department visit during the 52-week treatment period 
Target Biomarker Endpoints: The target biomarker endpoints are the blood eosinophil counts at 
baseline/DoR; weeks 2, 4, 8, 12, 16, 32, 52 or early withdrawal; and the follow-up visit (approximately 
week 64).  
Immunogenicity Endpoints: Samples for immunogenicity assessment for development of anti-drug antibodies 
will be obtained before the administration of study drug at DoR; weeks 4, 16, 32, 52 or early withdrawal; and 
the follow-up visit (approximately week 64). An additional sample will be obtained at the late follow-up visit 
(approximately week 76).  
Pharmacokinetic Endpoints: The PK endpoints are the serum reslizumab concentrations at baseline/DoR; 
weeks 1 (patients in US study centers only), 2, and prior to study drug administration at weeks 4, 8, 12, 16, 20, 
32, 48, 52 or early withdrawal; and the follow-up visit (approximately week 64). An additional PK sample will 
be taken at long term follow-up (approximately week 76) at the same time for anti-drug antibody (ADA) sample 
collection. (These data may be presented in a clinical study report addendum.) 


 
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Safety Endpoints 
The safety endpoints for this study are as follows: 
• 
adverse events throughout the study 
• 
vital signs (pulse, respiratory rate, and blood pressure) throughout the study 
• 
concomitant medication usage throughout the study 
• 
physical examination findings throughout the study 
• 
clinical laboratory evaluations at screening, baseline/DoR, and periodically throughout the study 
• 
electrocardiogram (ECG) evaluation at screening and week 24, 36, and 52 or early withdrawal 
General Design and Methodology: This is a 52-week, Phase 3, multicenter, randomized, double-blind, 
placebo-controlled study to evaluate the safety and efficacy of reslizumab, at a fixed dose of 110 mg, administered 
subcutaneously every 4 weeks in patients aged 12 years and older with asthma and elevated blood eosinophils, who 
are inadequately controlled on at least a medium total daily ICS dose and a second asthma controller. Evidence of 
inadequate asthma control will include a history of at least 2 exacerbations requiring systemic corticosteroids (oral 
or injection) in the previous 12 months, a suboptimal screening ACQ score (≥1.5), and persistent symptoms during 
run-in on the patient’s usual asthma controller regimen. The study’s duration is approximately 69 weeks, including 
up to a 2-week (±3 days) screening period, a minimum 3-week run-in period, a 52-week treatment period. If the 
patient enrolls in an available open-label, long-term safety study, then adults (age 18 years and older) may wait to 
complete the early and late follow-up visits until the end of the open-label study; however, adolescents (ages 12 to 
<18 years) should complete the early follow-up visit at 12 weeks as part of this current study before starting an 
open-label study. 
At the start of run-in, patients will begin daily self-monitoring at home using an asthma control diary and PEF meter, 
while taking their usual asthma medications, in order to establish their baseline level of asthma control based on the 
frequency of symptoms, use of reliever SABA, nighttime awakenings due to asthma, and ambulatory lung function 
measurement. Improvement in asthma control during the treatment period will primarily be assessed by a reduction 
in the rate of clinically significant asthma exacerbations with reslizumab versus placebo during the 52-week 
treatment period. Pulmonary function; AQLQ +12, ACQ, and SGRQ scores; asthma symptoms; use of reliever 
SABA; nighttime awakenings due to asthma; safety measures; PK; immunogenicity; and health care utilization 
events will be assessed periodically; final assessments will be made at the end of treatment visit (week 52) or at 
early withdrawal. Patients who withdraw from the study before completing the 52-week evaluation period will have 
visit-17 (week 52 or early withdrawal) procedures and assessments performed at their final visit. Patients will return 
12 weeks after the end of treatment visit for follow-up hematology, PK, immunogenicity, and safety assessments. If 
a patient elects to withdraw (or is discontinued from treatment by the Investigator), every attempt will be made to 
continue the assessments subsequent to their withdrawal from the study drug.  
Method of Blinding and Randomization: This is a randomized, double-blind, placebo-controlled study. Patients 
who meet all inclusion criteria and none of the exclusion criteria will be randomly assigned to receive reslizumab 
110 mg subcutaneously or matching placebo (approximately 225 patients per treatment group) in a 1:1 ratio. 
Randomization will be stratified by age (12 to <18 and ≥18 years), and blood eosinophil levels at screening (300/μL 
to <400/μL and ≥400/μL). Patients will be randomly assigned to the treatment groups by means of a 
computer-generated randomization list using interactive response technology after confirmation of all eligibility 
criteria. The sponsor’s clinical personnel involved in the study will be blinded to the study drug identity until the 
database is locked for analysis and the treatment assignment is revealed, with the exception of the bioanalytical 
group, who will not be blinded to facilitate PK and ADA sample analysis. Eosinophils and monocytes will be 
redacted from the post-baseline differential cell count reports to avoid the possibility of unblinding patients. Both 
reslizumab and placebo will be provided as clear solutions essentially free of particulate matter. 
Study Drug Dose, Mode of Administration, and Administration Rate: Reslizumab for subcutaneous injection 
will be provided as a sterile solution containing 110 mg (1.0 mL) reslizumab per syringe, formulated at 110 mg/mL 
in 
 sodium acetate, with 
 sucrose, 
 polysorbate 80, pH 5.5 buffer. Reslizumab will be administered 
subcutaneously in a dose of 110 mg (1.0 mL) every 4 weeks. 
Investigational Product: Reslizumab 


 
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Reference Therapy:  
Placebo: Diluent solution administered subcutaneously 
Comparison Drug: None 
Duration of Patient Participation: Approximately 69 weeks, including up to a 2-week (±3 days) screening period, 
minimum 3-week run-in period, 52-week treatment period, and 12-week follow-up visit. An additional, late follow-
up for immunogenicity testing will be performed 28 weeks (±2 weeks) after the last dose of study drug.  
Criteria for Inclusion: Patients may be included in the study only if they meet all of the following criteria: 
a. 
Written informed consent is obtained. A patient 12 through <18 years of age must provide assent, and 
their parent(s) or legal guardian(s) must provide consent. 
b. The patient is male or female, 12 years of age and older, with a diagnosis of asthma. (Patients 
12 to <18 years of age are excluded from participating in South Korea and Argentina, and patients 
66 years of age and older are excluded from participating in South Korea.) 
c. 
The patient has had at least 2 documented asthma exacerbations requiring the use of systemic (oral, 
intramuscular, or intravenous) corticosteroids within 12 months of signing the Informed Assent 
Form/Informed Consent Form. 
d. The patient has an ACQ-6 score of at least 1.5 at screening (visit 1). 
e. 
The patient has a blood eosinophil level of at least 300/µL during the screening period (ie, before 
visit 2). (A maximum of 30% of the patients [60 patients per treatment group] with blood eosinophil 
levels of 300/μL to <400/μL will be enrolled. When this 30% threshold has been reached, only patients 
with blood eosinophil levels of ≥400/μL will then be enrolled.) 
f. 
The patient has an FEV1 reversibility of at least 12% after administration of inhaled SABA according 
to standard American Thoracic Society (ATS) or European Respiratory Society (ERS) protocol. 
Documented historical reversibility within 12 months of signing the Informed Assent Form/Informed 
Consent Form is acceptable.  
g. The patient has required at least a medium total daily inhaled corticosteroid (ICS) dose based on 
Global Initiative for Asthma 2016 clinical comparability table (Protocol Appendix A) for at least 3 
months. For ICS/LABA combination preparations, the mid-strength approved maintenance dose in the 
local country will meet this ICS criterion. 
h. The patient has required an additional asthma controller medication (eg, long-acting beta-2-agonist 
[LABA], long-acting muscarinic antagonist [LAMA], leukotriene receptor antagonist [LTRA], or 
theophylline preparations), besides inhaled corticosteroids, for at least 3 months or a documented 
failure in the past 12 months of an additional asthma controller medication for at least 3 successive 
months. 
i. 
Females of childbearing potential (not surgically sterile by hysterectomy, bilateral salpingectomy, 
bilateral oophorectomy, or 2 years postmenopausal) must have exclusively same-sex partners or use 
medically acceptable methods of birth control and must agree to continue use of this method for the 
duration of the study and for 5 months after the last study drug dose. Acceptable methods of birth 
control include intrauterine device, systemic hormonal contraceptive (oral, implanted, transdermal, or 
injected), barrier method with spermicide, abstinence, bilateral fallopian tube occlusion, and partner 
vasectomy. Contraception is further clarified in an administrative letter in Protocol Section 17.4.1. 


 
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j. 
The patient must be willing and able to comply with study restrictions, perform requisite procedures 
and remain at the clinic for the required duration during the study period, and be willing to return to the 
clinic for the follow-up evaluation as specified in this protocol.  
k. The patient must maintain their usual asthma controller regimen without change throughout the 
screening and run-in periods. A patient who experiences an asthma exacerbation during this time that 
requires additional medication, beyond increased SABA use, will be considered to have failed 
screening/run-in and cannot undergo randomization. A patient may be rescreened for this reason 1 time 
only. The duration between the date of Screen Failure and the re-screening must be >30 days. 
l. 
In order to be randomized, a patient must demonstrate the following: 
− 
inadequate asthma control at baseline/DoR as evidenced by:  
○ 
daytime asthma symptom score >0 on >2 of the previous 7 days based on the asthma 
control diary received at run-in OR 
○ 
need for reliever SABA use on >2 of the previous 7 days OR 
○ 
≥1 nighttime awakening due to asthma over the previous 7 days OR 
○ 
pre-bronchodilator FEV1 <80% predicted at baseline/DoR 
○ 
 
AND 
− 
completion of at least 4 days of diary entries or equivalent during the last 7 days of run-in. 
A patient may be rescreened for this reason 1 time only. 
Please refer to Protocol Section 3.16.1 and Section 3.16.2 for further guidance on rescreening if the 
above inclusion criteria are not met initially. The eosinophil count and reversibility test may each be 
repeated once during the Screening period, and subjects may also be rescreened for either of these 
reasons. The duration between the date of Screen Failure and the re-screening must be >30 days. 
Criteria for Exclusion: Patients will be excluded from participating in this study if they meet any of the following 
criteria:  
a. 
The patient has any clinically significant, uncontrolled medical condition (treated or untreated) that 
would interfere with the study schedule or procedures, interpretation of efficacy results, or compromise 
the patient’s safety. 
b. The patient has another confounding underlying lung disorder (eg, chronic obstructive pulmonary 
disease, interstitial lung disease, bronchiectasis, eosinophilic granulomatosis with polyangiitis [EGPA, 
also known as Churg-Strauss syndrome], or allergic bronchopulmonary aspergillosis [ABPA]).  
c. 
The patient has a known hypereosinophilic syndrome. 
d. The patient has a diagnosis of malignancy within 5 years of the screening visit, except for treated and 
cured non-melanoma skin cancers.  
e. 
The patient is a pregnant or lactating woman, or intends to become pregnant during the study or within 
5 months after the last dose of study drug. Any woman becoming pregnant during the study will be 
withdrawn from the study. 
f. 
The patient required treatment for an asthma exacerbation within 4 weeks of screening or during the 
screening/run-in period. 
g. The patient is a current smoker (ie, has smoked within the last 6 months before screening) or has a 
smoking history ≥10 pack years. 
h. The patient is currently using any systemic immunosuppressive or immunomodulatory biologic (eg, 
anti-immunoglobulin E monoclonal antibody or other monoclonal antibody [eg, mepolizumab] or 
soluble receptors) or non-biologic (eg, methotrexate or cyclosporine), except maintenance oral 


 
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corticosteroids for the treatment of asthma (up to and including 10 mg of prednisone daily or 
equivalent). Note: Previous use of such agents that occurred >5 half-lives from the initial screening 
visit may be allowed, if approved by the medical monitor.  
i. 
The patient participated in a clinical trial within 30 days or 5 half-lives of the investigational drug 
before screening, whichever is longer. 
j. 
The patient was previously exposed to benralizumab within 12 months of screening. 
k. The patient was previously exposed to reslizumab. 
l. 
The patient has a history of an immunodeficiency disorder including HIV.  
m. The patient has current or suspected drug and alcohol abuse. 
n. The patient has an active helminthic parasitic infection or was treated for one within 6 months of 
screening.  
o. The patient has a history of allergic reaction or hypersensitivity to any component of the study drug. 
p. The patient has a history of latex allergy. (The current prefilled syringe device has a natural rubber 
component to the needle shield.)  
Measures and Time Points:  
Primary Efficacy Measure and Time Point: The primary efficacy measure for this study is frequency of 
CAEs for each patient during the 52-week treatment period.  
Secondary Efficacy Measures and Time Points: The secondary efficacy measures and their time points for 
this study include the following: 
• 
pre-bronchodilator spirometry (at baseline/DoR and week 52 or early withdrawal)  
• 
AQLQ +12 at baseline/DoR and week 52 or early withdrawal 
• 
ACQ-6 at baseline/DoR and week 52 or early withdrawal 
• 
asthma symptoms based on the daily asthma control diary at baseline and week 52 or early withdrawal 
• 
asthma control days from baseline/DoR to week 52 or early withdrawal 
• 
SGRQ at baseline/DoR and week 32 


 
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Safety Measures and Time Points: The following safety measures will be implemented throughout the study 
and evaluated at the following time points: 
• 
inquiries about adverse events at every visit including screening, run-in, and follow-up 
• 
clinical laboratory tests (serum chemistry at screening; baseline/DoR; and weeks 16, 32, and 52 or 
early withdrawal and hematology at screening; baseline/DoR; weeks 2, 4, 8, 12, 16, 32, 52 or early 
withdrawal; and follow-up (approximately week 64) (a sample for CPK measurement only, will also 
be collected on weeks 1, 2, 4, 8, 12, and 20). 
• 
vital signs (respiratory rate, blood pressure, and pulse) at screening, run-in; baseline/DoR; and weeks 
2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52 or early withdrawal 
• 
ECGs at screening and weeks 24, 36, and 52 or early withdrawal 
• 
physical examinations, including body weight measurements. These will include both full physical 
examinations including height and weight (at screening and week 52 or early withdrawal) and brief 
physical examinations (at baseline/DoR and weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, and 48). 
• 
inquiries about concomitant medication usage at every visit including screening, run-in, and follow-up 
Pharmacokinetics/Biomarkers/ Immunogenicity and Other Ancillary Studies Measures and Time Points:  
Pharmacokinetics: Pharmacokinetic samples at baseline/DoR; weeks 1 (patients in US study centers only), 2, 
prior to study drug administration at weeks 4, 8, 12, 16, 20, 32, 48, and 52 or early withdrawal; and follow-up 
(approximately week 64). An additional PK sample will be taken at long term follow-up (approximately 
week 76) at the same time for ADA sample collection. 
Target biomarkers: Blood eosinophils will be determined from blood samples at specified time points. 
Immunogenicity: Serum anti-reslizumab antibodies will be determined from blood samples collected from 
each patient at baseline/DoR; prior to study drug administration at weeks 4, 16, 32, and 52 or early withdrawal; 
and follow-up (approximately week 64). An additional sample will be collected at late follow-up 
(approximately week 76). 
Allowed and Disallowed Medications Before and During the Study: The following medications will not be 
allowed during this study: any immunosuppressive or immunomodulatory agents (excluding systemic 
corticosteroids prescribed for asthma and maintenance allergen immunotherapy), all biologic therapies, and all 
nonbiologic investigational drugs. 
Statistical Considerations:  
Sample Size Rationale:  
Power calculations were based on the below assumptions: 
• 
Negative binomial (NB) distribution for the number of exacerbations with a mean of 2.9 exacerbations 
per patient per year for the placebo group 
• 
Dispersion parameter of 1.2 
• 
Treatment effect of 45% between the reslizumab group and the placebo group 
• 
Alpha level of 0.05 
Based on the assumptions above, 225 patients per arm (450 total) will provide >99% power to detect significant 
treatment effect of reslizumab over placebo in the reduction of exacerbation rate. The sample size was increased 
beyond the minimal sample size required to provide 90% power in order to allow sufficient number of patients to 
assess safety and immunogenicity and to ensure adequate enrollment in the adolescent subset. The current sample 
size also provide higher power for other efficacy endpoints. 
Analysis of Primary Endpoint: The primary analysis of frequency of CAEs will use the NB regression model. The 
primary NB model will include the treatment group, randomization stratification factors, and number of 
exacerbations in the previous year as model factors and an offset variable. The offset variable will be calculated as 
the logarithm of follow-up duration minus the summed duration of exacerbations. The ratio of CAE rate between the 
treatment groups and its 95% confidence interval (CI) will be estimated from the NB model. 
Data from all randomized patients will be used in the primary analyses regardless of whether they early withdrew 
from treatment or completed the treatment phase. 
Analysis of Secondary Endpoints: Analysis of pulmonary function tests, AQLQ +12, ACQ-6, total asthma 
symptom scores, and SGRQ will use the mixed model repeated measures model with treatment group, visit, 


 
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treatment and visit interaction, baseline value, and stratification factors as fixed effects and patient as a random 
effect. Analysis of percentage of asthma control days will use an analysis of variance (ANOVA) model with 
treatment group and stratification factors.  
Additional covariates or factors may be added to the statistical model. These will be detailed in the statistical 
analysis plan. 
The Kaplan-Meier (KM) method will be used to estimate and compare the distributions of time to first CAEs 
between treatment groups. Differences will be compared using a log rank test adjusting for the stratification factors. 
The frequency of exacerbations requiring hospitalization or emergency department visits and the frequency of 
moderate exacerbations will be examined separately. The analysis will use similar methodology to that described for 
the primary analysis. 
Multiple Comparisons and Multiplicity: A fixed sequence multiple testing procedure will be implemented to test 
the primary and secondary variables while controlling the overall Type I error rate at 0.05. If the resulting two-sided 
p-value from the primary comparison is ≤0.05, then the next comparison of interest (first secondary variable) will be 
interpreted inferentially at 0.05. This process continues through the secondary variables until either all comparisons 
of interest are interpreted inferentially, or until the point at which the resulting two-sided p-value for a comparison 
of interest is >0.05. At the point where p>0.05, no further comparisons will be interpreted inferentially. 
No multiplicity adjustments will be made for other efficacy and exploratory efficacy analyses. 
Analysis of Other Endpoints: All efficacy variables will be summarized by treatment group. For continuous 
variables, the summary statistics will include n, mean, SD, standard error (SE), median, minimum, and maximum. 
For categorical variables, counts and percentages will be provided. Categories for missing data will be presented if 
necessary. 
 
 Reslizumab concentration data will be summarized by treatment group, and blood 
eosinophil count data will be listed by treatment group. An attempt will be made to correlate serum concentrations 
of reslizumab with measures of efficacy and/or safety. Anti-reslizumab antibody information will be described for 
subjects who test positive.  
The baseline for diary variables will be the average of the run-in values over the 7 days preceding baseline/DoR. 
The baseline for clinic visit variables will be the last observed value before the first dose of study drug. The baseline 
for eosinophils levels analysis will be screening value. 
Safety Analyses: Safety and PK data will be summarized using descriptive statistics by treatment group. 


 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
AMENDMENT HISTORY .............................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................4 
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............5 
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................7 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................8 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................25 
1. 
BACKGROUND INFORMATION ...........................................................................27 
1.1. 
Introduction .................................................................................................................27 
1.2. 
Name and Description of Investigational Product ......................................................27 
1.3. 
Findings from Nonclinical and Clinical Studies .........................................................28 
1.3.1. 
Nonclinical Studies .....................................................................................................28 
1.3.2. 
Clinical Studies ...........................................................................................................28 
1.3.2.1. 
Clinical Pharmacology Studies ...................................................................................28 
1.3.2.2. 
Clinical Safety and Efficacy Studies ..........................................................................29 
1.4. 
Known and Potential Risks and Benefits to Human Patients .....................................32 
1.4.1. 
Risks of Reslizumab ...................................................................................................32 
1.4.2. 
Benefits of Reslizumab ...............................................................................................32 
1.4.3. 
Overall Risk and Benefit Assessment for This Study ................................................32 
1.5. 
Selection of Drugs and Dosages .................................................................................33 
1.5.1. 
Justification for Dosage of Active Drug .....................................................................33 
1.5.2. 
Justification for Use of Placebo ..................................................................................34 
1.6. 
Compliance Statement ................................................................................................34 
1.7. 
Population To Be Studied and Justification ................................................................34 
1.8. 
Location and Timing of Study ....................................................................................35 
2. 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES .....................................36 
2.1. 
Purpose of the Study ...................................................................................................36 
2.2. 
Study Objectives .........................................................................................................36 
2.2.1. 
Primary Objective .......................................................................................................36 
2.2.2. 
Secondary Objectives .................................................................................................36 


 
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2.2.3. 
Other Objectives .........................................................................................................36 
2.3. 
Study Endpoints ..........................................................................................................36 
2.3.1. 
Primary Efficacy Endpoint .........................................................................................36 
2.3.2. 
Secondary Efficacy Endpoints ....................................................................................36 
2.3.3. 
37 
2.3.4. 
Target Biomarker Endpoints .......................................................................................37 
2.3.5. 
Immunogenicity Endpoints .........................................................................................38 
2.3.6. 
Pharmacokinetic Endpoints ........................................................................................38 
2.3.7. 
38 
2.3.8. 
Safety Endpoints .........................................................................................................38 
3. 
STUDY DESIGN .......................................................................................................39 
3.1. 
General Design and Study Schema.............................................................................39 
3.2. 
Justification for Study Design ....................................................................................41 
3.3. 
Primary and Secondary Efficacy Measures and Time Points .....................................42 
3.3.1. 
Primary Efficacy Measure and Time Points ...............................................................42 
3.3.2. 
Secondary Efficacy Measures and Time Points .........................................................42 
3.3.3. 
43 
3.4. 
Safety Measures and Time Points ...............................................................................43 
3.5. 
43 
3.6. 
Pharmacokinetic Measures and Time Points ..............................................................44 
3.7. 
Target Biomarker Measures and Time Points ............................................................44 
3.8. 
Immunogenicity Measures and Time Points ..............................................................44 
3.9. 
Randomization and Blinding ......................................................................................44 
3.10. 
Maintenance of Randomization and Blinding ............................................................44 
3.10.1. 
Randomization ............................................................................................................44 
3.10.2. 
Blinding/Unblinding ...................................................................................................45 
3.10.3. 
Data Monitoring Committee .......................................................................................45 
3.11. 
Drugs Used in the Study .............................................................................................45 
3.11.1. 
Investigational Product ...............................................................................................46 
3.11.2. 
Placebo ........................................................................................................................46 
3.12. 
Drug Supply and Accountability ................................................................................46 
3.12.1. 
Drug Storage and Security ..........................................................................................46 
3.12.2. 
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3.13. 
Duration of Patient Participation and Justification .....................................................46 
3.14. 
Stopping Rules and Discontinuation Criteria .............................................................47 
3.15. 
Source Data Recorded on the Case Report Form .......................................................47 
3.16. 
Study Procedures ........................................................................................................47 
3.16.1. 
Procedures for Screening and Start of Run-In Period (Visits 1 and 2) .......................52 
3.16.2. 
Procedures Before Study Drug Treatment (Baseline/Day of Randomization 
[Week 0, Visit 3]) .......................................................................................................54 
3.16.3. 
Procedures During Study Drug Treatment .................................................................55 
3.16.3.1. 
Double-Blind Treatment Period .................................................................................55 
3.16.4. 
Procedures After Study Drug Treatment ....................................................................57 
3.16.5. 
Unscheduled Visits .....................................................................................................58 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................59 
4.1. 
Patient Inclusion Criteria ............................................................................................59 
4.2. 
Patient Exclusion Criteria ...........................................................................................60 
4.3. 
Justification for Key Inclusion and Exclusion Criteria...............................................61 
4.4. 
Criteria and Procedures for Discontinuation of Study Treatment and/or 
Study Withdrawal .......................................................................................................61 
4.4.1. 
Discontinuation of Study Treatment ...........................................................................62 
4.4.2. 
Complete Withdrawal from Study ..............................................................................62 
5. 
TREATMENT OF PATIENTS ..................................................................................64 
5.1. 
Drugs Administered During the Study .......................................................................64 
5.2. 
Restrictions .................................................................................................................64 
5.3. 
Prior and Concomitant Therapy or Medication ..........................................................64 
5.4. 
Procedures for Monitoring Patient Compliance .........................................................65 
5.5. 
Total Blood Volume ...................................................................................................65 
6. 
ASSESSMENT OF EFFICACY ................................................................................66 
6.1. 
Primary Efficacy Measure and Justification ...............................................................66 
6.2. 
Spirometry ..................................................................................................................66 
6.3. 
PEF Monitoring ..........................................................................................................67 
6.4. 
Asthma Quality of Life Questionnaire for Patients 12 years and Older .....................67 
6.5. 
Asthma Control Questionnaire ...................................................................................67 
6.6. 
Asthma Symptom Assessment ...................................................................................67 
6.7. 
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6.8. 
St. George’s Respiratory Questionnaire .....................................................................67 
6.9. 
.68 
6.10. 
Asthma Rescue Medication Use .................................................................................68 
6.11. 
Nighttime Awakenings ...............................................................................................68 
6.12. 
68 
7. 
ASSESSMENT OF SAFETY .....................................................................................69 
7.1. 
Adverse Events ...........................................................................................................69 
7.1.1. 
Definition of an Adverse Event ..................................................................................69 
7.1.2. 
Recording and Reporting Adverse Events ..................................................................70 
7.1.3. 
Severity of an Adverse Event .....................................................................................70 
7.1.4. 
Relationship of an Adverse Event to the Study Drug .................................................71 
7.1.5. 
Serious Adverse Events ..............................................................................................71 
7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................71 
7.1.5.2. 
Expectedness ...............................................................................................................72 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................72 
7.1.6. 
Protocol-Defined Adverse Events for Expedited Reporting to Teva .........................74 
7.1.7. 
Specific Adverse Event Case Report Form Capturing ...............................................74 
7.1.7.1. 
Anaphylaxis/Hypersensitivity Reactions Case Report Form .....................................74 
7.1.7.2. 
Creatine Phosphokinase/Muscular Adverse Events Case Report Form .....................75 
7.1.8. 
Withdrawal Due to an Adverse Event ........................................................................75 
7.1.9. 
Overdose of Study Drug .............................................................................................76 
7.1.10. 
Protocol Deviations Because of an Adverse Event ....................................................76 
7.2. 
Pregnancy ...................................................................................................................76 
7.3. 
Clinical Laboratory Tests ...........................................................................................77 
7.3.1. 
Serum Chemistry ........................................................................................................77 
7.3.2. 
Hematology and Serology ..........................................................................................78 
7.3.3. 
Urinalysis ....................................................................................................................78 
7.3.4. 
Other Clinical Laboratory Tests .................................................................................79 
7.3.4.1. 
Human Chorionic Gonadotropin Tests .......................................................................79 
7.4. 
Vital Signs ..................................................................................................................79 
7.5. 
Electrocardiography ....................................................................................................79 
7.6. 
Physical Examinations ................................................................................................80 
7.7. 
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7.8. 
Methods and Timing of Assessing, Recording, and Analyzing Safety Data ..............80 
8. 
ASSESSMENT OF PHARMACOKINETICS, BIOMARKERS, AND 
IMMUNOGENICITY ................................................................................................81 
8.1. 
Pharmacokinetic Variables .........................................................................................81 
8.1.1. 
Specimen Sampling and Handling ..............................................................................81 
8.1.2. 
Shipment and Analysis of Samples ............................................................................81 
8.2. 
Biomarker Variables ...................................................................................................82 
8.2.1. 
Blood Eosinophil Counts ............................................................................................82 
8.2.2. 
82 
8.3. 
Immunogenicity ..........................................................................................................82 
8.3.1. 
Shipment and Analysis of Samples ............................................................................82 
9. 
STATISTICS ..............................................................................................................84 
9.1. 
Sample Size and Power Considerations .....................................................................84 
9.2. 
Analysis Sets ...............................................................................................................84 
9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................84 
9.2.2. 
Safety Analysis Set .....................................................................................................84 
9.2.3. 
Additional Analysis Sets.............................................................................................85 
9.2.3.1. 
Per-Protocol Analysis Set ...........................................................................................85 
9.3. 
Data Handling Conventions ........................................................................................85 
9.4. 
Study Population .........................................................................................................85 
9.4.1. 
Patient Disposition ......................................................................................................85 
9.4.2. 
Demographic and Baseline Characteristics ................................................................85 
9.5. 
Efficacy Analysis ........................................................................................................85 
9.5.1. 
Primary Endpoint ........................................................................................................85 
9.5.2. 
Secondary Endpoints ..................................................................................................86 
9.5.3. 
86 
9.5.4. 
87 
9.5.5. 
Target Biomarker Endpoints .......................................................................................87 
9.5.6. 
Planned Method of Analysis .......................................................................................87 
9.5.6.1. 
Primary Efficacy Analysis ..........................................................................................87 
9.5.6.2. 
Secondary Efficacy Analysis ......................................................................................88 
9.5.6.3. 
89 
9.5.6.4. 
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9.6. 
Multiple Comparisons and Multiplicity......................................................................89 
9.7. 
Safety Endpoints and Analysis ...................................................................................89 
9.7.1. 
Safety Endpoints .........................................................................................................89 
9.7.2. 
Safety Analysis ...........................................................................................................90 
9.7.3. 
Immunogenicity Endpoints .........................................................................................90 
9.8. 
Pharmacokinetic Analysis ..........................................................................................90 
9.9. 
Biomarker Analysis ....................................................................................................91 
9.10. 
Immunogenicity Analysis ...........................................................................................91 
9.11. 
Planned Interim Analysis ............................................................................................91 
9.12. 
Reporting Deviations from the Statistical Plan ..........................................................91 
10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................92 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................93 
11.1. 
Protocol Amendments and Protocol Deviations and Violations ................................93 
11.1.1. 
Protocol Amendments ................................................................................................93 
11.1.2. 
Protocol Violations .....................................................................................................93 
11.2. 
Information to Study Personnel ..................................................................................93 
11.3. 
Study Monitoring ........................................................................................................94 
11.4. 
Clinical Product Complaints .......................................................................................94 
11.4.1. 
Product Complaint Information Needed from the Investigational Center ..................95 
11.4.2. 
Handling the Study Drug at the Investigational Center ..............................................95 
11.4.3. 
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint ...................................................................................................................96 
11.4.4. 
Documenting a Product Complaint ............................................................................96 
11.5. 
Audit and Inspection ...................................................................................................96 
12. 
ETHICS ......................................................................................................................97 
12.1. 
Informed Consent/Assent ...........................................................................................97 
12.2. 
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards .........................................................................................................................97 
12.3. 
Confidentiality Regarding Study Patients ..................................................................98 
12.4. 
Declaration of the End of the Clinical Study ..............................................................98 
12.5. 
Registration of the Clinical Study...............................................................................98 
13. 
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING ...................................................................................................................99 


 
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13.1. 
Data Collection ...........................................................................................................99 
13.2. 
Data Quality Control ...................................................................................................99 
13.3. 
Archiving of Case Report Forms and Source Documents ........................................100 
13.3.1. 
Sponsor Responsibilities ...........................................................................................100 
13.3.2. 
Investigator Responsibilities .....................................................................................100 
14. 
FINANCING AND INSURANCE ...........................................................................102 
15. 
REPORTING AND PUBLICATION OF RESULTS ..............................................103 
16. 
REFERENCES .........................................................................................................104 
17. 
SUMMARY OF CHANGES TO PROTOCOL .......................................................106 
17.1. 
Amendment 04 Dated 24 October 2016 ...................................................................106 
17.2. 
Amendment 03 Dated 25 July 2016 .........................................................................107 
17.3. 
Amendment 02 Dated 25 January 2016 ....................................................................122 
17.4. 
Amendment 01 Dated 04 May 2015 .........................................................................146 
17.5. 
Clarification Letters ..................................................................................................148 
17.5.1. 
Administrative Letter Dated 22 July 2015 ................................................................148 
17.5.2. 
Addendum Letter Dated 22 April 2015 ....................................................................149 
17.5.3. 
Administrative Letter Dated 14 April 2015 ..............................................................151 
17.5.4. 
Administrative Letter Dated 26 February 2016 ........................................................152 
17.5.5. 
Administrative Letter Dated 08 March 2016 ............................................................153 
17.5.6. 
Administrative Letter Dated 21 March 2016 ............................................................154 
APPENDIX A. GLOBAL INITIATIVE FOR ASTHMA ICS CLINICAL 
COMPARABILITY TABLE....................................................................................155 
APPENDIX B. ASTHMA QUALITY OF LIFE QUESTIONNAIRE + 12 .............................156 
APPENDIX C. ASTHMA CONTROL QUESTIONNAIRE ...................................................162 
APPENDIX D. 
164 
APPENDIX E. 
165 
APPENDIX F. ST. GEORGE’S RESPIRATORY QUESTIONNAIRE ..................................168 
APPENDIX G. ASTHMA CONTROL DIARY .......................................................................174 
APPENDIX H. CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS ...................176 
APPENDIX I. OPPORTUNISTIC INFECTIONS ...................................................................177 


 
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LIST OF TABLES 
Table 1: 
Rationale for Protocol .................................................................................................41 
Table 2: 
Study Procedures and Assessments ............................................................................48 
Table 3: 
Changes to the Protocol ............................................................................................106 
Table 4: 
Changes to the Protocol ............................................................................................107 
Table 5: 
Changes to the Protocol ............................................................................................122 
Table 6: 
Changes to the Protocol ............................................................................................146 
Table 7: 
Medium or Higher Daily Doses of Inhaled Corticosteroids in Patients 12 
Years and Older ........................................................................................................155 
 


 
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LIST OF FIGURES 
Figure 1: 
Overall Study Schema ................................................................................................41 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table of Abbreviations 
Abbreviation 
Term 
ACQ 
Asthma Control Questionnaire 
ACQ-6 
6-item Asthma Control Questionnaire 
ADA 
anti-drug antibody 
ADR 
adverse drug reaction 
AQLQ +12 
Asthma Quality of Life Questionnaire for patients 12 years and older 
ANOVA 
analysis of variance 
AUC 
area under the plasma drug concentration by time curve 
AUC0–∞ 
area under the plasma drug concentration by time curve from time 0 to infinity 
AUC0–t 
area under the plasma drug concentration by time curve from time 0 to the time of the 
last measurable drug concentration 
BUN 
blood urea nitrogen 
CAE 
clinical asthma exacerbation 
CDMS 
clinical data management system  
CFR 
Code of Federal Regulations 
CPK 
creatine phosphokinase 
CRF 
case report form (refers to any media used to collect study data [ie, paper or 
electronic]) 
CRO 
contract research organization 
DoR 
day of randomization 
ECG 
electrocardiogram 
eDiary 
electronic diary 
EOT 
end-of-treatment (visit) 
FEF25%-75% 
forced expiratory flow at the 25% point to the 75% point of forced vital capacity 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 
HIV 
human immunodeficiency virus 
ICH 
International Conference on Harmonisation 
ICS 
inhaled corticosteroids 


 
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Abbreviation 
Term 
IEC 
Independent Ethics Committee 
IgA 
immunoglobulin A 
IgG 
immunoglobulin G 
IgM 
immunoglobulin M 
IL-5 
Interleukin-5 
IP 
Investigational product 
IRB 
Institutional Review Board 
IRT 
interactive response technology 
ITT 
intent-to-treat  
iv 
intravenous 
KM 
Kaplan-Meier 
LSLV 
Last Subject Last Visit 
LSO 
local safety officer  
mAb 
monoclonal antibody 
n 
number 
NB 
negative binomial 
PEF 
peak expiratory flow 
PK 
pharmacokinetic(s) 
SABA 
short-acting beta-agonist 
sc 
subcutaneous 
SD 
standard deviation 
SGRQ 
St. George’s Respiratory Questionnaire 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
ULN 
upper limit of normal 
WHO Drug 
World Health Organization (WHO) drug dictionary 


 
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1. 
BACKGROUND INFORMATION 
1.1. 
Introduction  
Asthma is a common, chronic lung disorder characterized by inflammation and narrowing of the 
airways. Symptoms of asthma include cough, breathlessness, and wheezing. The most recent 
estimates suggest that as many as 334 million people in the world have asthma (Global Asthma 
Network 2014).  
Asthma is a heterogeneous syndrome with distinct phenotypes and variable severity. Certain 
patients are prone to experiencing asthma exacerbations defined as an acute or sub-acute 
worsening in symptoms and lung function from the patient’s usual status (Global Initiative for 
Asthma [GINA] 2014) in patients who are unable to achieve control despite chronic use of 
inhaled corticosteroids (ICS) and other asthma medications. These patients are considered at 
high risk because of the morbidity and potential mortality associated with exacerbations. During 
acute asthma exacerbations, patients often require additional therapy, such as a course of 
systemic corticosteroids, which have substantial adverse effects (Walsh LJ et al 2001, Wardlaw 
et al 2000). 
Interleukin-5 (IL-5) is the prototypic maturation and survival factor for eosinophilic 
granulocytes, which has been strongly implicated in asthma pathogenesis (Wardlaw et al 2000). 
Eosinophils are major effector cells involved in initiation and propagation of diverse 
inflammatory responses. A high blood eosinophil count is a risk factor for increased future 
asthma exacerbations and excessive short-acting beta-agonist (SABA) use after adjustment of 
potential confounders in adults with persistent asthma, which suggests a higher disease burden in 
patients with asthma and high blood eosinophil counts (Tran et al 2014, Zeiger et al 2014).  
Therapies directed against IL-5 or its receptor (mepolizumab, reslizumab, and benralizumab) 
work by reducing eosinophil counts in the circulation and in the airway and have recently met a 
clinical proof of concept (reduction in asthma exacerbations, improved Asthma Control 
Questionnaire [ACQ] scores, or improved lung function) in Phase 2 and Phase 3 studies in 
primarily adult populations with asthma and elevated sputum or blood eosinophils (Castro et al 
2011, Haldar et al 2009, Molfino et al 2012, Nair et al 2009, Ortega et al 2014, Pavord et al 
2012). 
Reslizumab is a humanized anti-human IL-5 monoclonal antibody (mAb) of the immunoglobulin 
G (IgG) 4/κ isotype being developed for the treatment of uncontrolled asthma in patients with 
elevated blood eosinophils. Confirmatory Phase 3 safety and efficacy studies for administration 
of reslizumab by the intravenous (iv) route have concluded the clinical portion; preliminary 
results are notable for a significant reduction in clinical asthma exacerbations (CAEs) as well as 
improved lung function. 
1.2. 
Name and Description of Investigational Product 
Reslizumab (CEP 38072) is a humanized anti-human IL-5 mAb of the IgG4/κ isotype. 
Reslizumab is being developed for administration by the iv and subcutaneous (sc) routes. A more 
detailed description of the product is given in Section 3.11.  


 
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1.3. 
Findings from Nonclinical and Clinical Studies 
1.3.1. 
Nonclinical Studies  
A correlation between IL-5–induced eosinophilia and pulmonary hyper-reactivity was suggested 
by studies in IL-5 gene knockout mice (Foster et al 1996). When sensitized and challenged with 
allergen, mice lacking the IL-5 gene failed to develop airway eosinophilia, lung damage, or 
increased lung responsiveness. Otherwise, IL-5 gene knockout mice developed normally and had 
normal antibody and cytotoxic T-cell responses. 
In vivo, reslizumab showed biological activity in several species, including mouse, guinea pig, 
rabbit, and monkey. Reslizumab inhibited eosinophilia in lungs or skin and reduced airway 
hyper-responsiveness after antigenic challenge in sensitized animals. Inhibition of pulmonary 
eosinophilia was observed for up to 8 weeks post-dose in mice and for up to 6 months in 
monkeys. Reslizumab’s effects on eosinophilia in mice were additive with the effects of 
prednisolone. 
In single-dose iv toxicity studies with reslizumab, no adverse effects were observed at the 
maximum doses administered (500 mg/kg in mice and rats; 100 mg/kg in monkeys). In 
repeat-dose studies, reslizumab was well tolerated by mice and monkeys given 2 iv doses of 1, 5, 
or 25 mg/kg reslizumab 14 days apart; the no-observed-effect level was 5 mg/kg in male mice 
and at least 25 mg/kg in female mice and monkeys. The 6-month studies in mice and monkeys 
with once-monthly dosing showed no toxicity and a no-observed-effect level of at least 
25 mg/kg. The no-observed-effect level for evidence of reslizumab-related binding to nervous 
system tissues of monkeys was also at least 25 mg/kg. Reslizumab was not genotoxic and did not 
affect reproductive parameters. In safety pharmacology studies, reslizumab had no effect on 
parameters related to organ function.  
Nonclinical studies in male cynomolgus monkeys, mice, and rats were performed to assess the 
absolute bioavailability of reslizumab following single and multiple sc doses. It was found that 
absolute bioavailability following sc administration of reslizumab was high (>75%) in all 
species. Subcutaneous administration of reslizumab in these studies was well tolerated. Mild, 
focal, intramuscular macrophage infiltrates were found at the injection site in 1 monkey dosed 
with sc reslizumab. In addition, an acute sc irritation study in rats found that sc administration of 
reslizumab produced minimal to mild gross local tissue irritation. Following sc administration in 
nonclinical studies, approximately 20% to 50% of animals tested positive for anti-reslizumab 
antibodies. The antibody response correlated with decreased serum concentrations in some, but 
not all, of these animals.  
Further details may be found in the current Investigator’s Brochure.  
1.3.2. 
Clinical Studies 
1.3.2.1. 
Clinical Pharmacology Studies 
The pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and safety of iv 
reslizumab over the dose range of 0.03 mg/kg through 3 mg/kg have been characterized in 
14 studies in patients and in healthy subjects.  


 
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Systemic exposure to reslizumab increases in a dose-proportional manner over the range of 
0.03 to 3.0 mg/kg in patients with asthma and from 1.0 to 3.0 mg/kg in patients with nasal 
polyps. Serum concentration declines from peak in a biphasic manner with a mean elimination 
half-life ranging from 23 to 30 days. The volume of distribution for reslizumab is low 
(approximately 4 to 6 L), suggesting minimal distribution of reslizumab into extravascular 
tissues. Following a single 220 mg sc dose of reslizumab in adults, the bioavailability of 
reslizumab is approximately 67%, similar to other mAbs. Peak serum reslizumab concentrations 
are typically observed approximately 7 days after sc administration (range 12 hours to 20 days). 
As expected, the terminal PK profile following sc administration is qualitatively similar to that 
observed following iv administration and exhibits a biphasic decline from peak with a long 
terminal elimination half-life (approximately 26 days).  
Further details may be found in the current Investigator’s Brochure. 
1.3.2.2. 
Clinical Safety and Efficacy Studies 
The Phase 3 BREATH program in adult and adolescent asthma evaluated the safety and efficacy 
of reslizumab administered intravenously every 4 weeks at 3 mg/kg (16-week 
Studies C38072/3081 and C38072/3084, 52-week Studies C38072/3082 and C38072/3083, and 
open-label safety extension Study C38072/3085) and 0.3 mg/kg (Study 3081 only). A significant 
reduction in the annual rate of asthma exacerbations, and significant improvements in lung 
function, asthma related quality of life, and patient reported measures of asthma control (ACQ 
and ASUI) were observed for patients with eosinophilic asthma defined by a screening blood 
eosinophil count of ≥400/µL (Studies 3081, 3082, and 3083). In asthma patients without elevated 
blood eosinophils (Study 3084), reslizumab produced non-significant improvements in lung 
function and other measures of efficacy. In contrast in patients with blood eosinophil levels 
≥400/µL, reslizumab produced significant improvements in lung function and other measures of 
efficacy.  
A total of 2195 healthy volunteers and patients with moderate to severe asthma, eosinophilic 
esophagitis, eosinophilic gastritis, hypereosinophilic syndrome, or nasal polyposis had received 
at least 1 dose of reslizumab in 14 clinical studies.  
The safety of reslizumab was evaluated in adults and in children in clinical studies summarized 
in the current Investigator’s Brochure. Single or multiple doses of iv reslizumab from 0.03 
through 3.0 mg/kg were well tolerated with a common adverse event profile similar to placebo. 
The majority of adverse events were generally mild to moderate in severity, and most adverse 
events were assessed as unrelated to study drug, as determined by the investigator. Overall, the 
nature and occurrence of the reported study drug-related adverse events did not raise any specific 
safety concerns. 
The following summary relates to integrated adverse events data of the 5 asthma 
placebo-controlled completed studies (ie, Studies Res-5-0010, 3081, 3082, 3083, and 3084) that 
include the 3 mg/kg iv dose and every 4 weeks dosing regimen (up to 52 weeks). Serious adverse 
event and death cases from the open-label Study 3085 are also included in the relevant sections.  


 
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Common Adverse Events 
The most common preferred terms (reported in >5% of patients in the reslizumab 3.0 mg/kg 
group) were asthma (232 [23%] and 289 [40%] patients in the reslizumab 3.0 mg/kg and placebo 
groups, respectively), nasopharyngitis (103 [10%] and 103 [14%] patients, respectively), upper 
respiratory tract infection (96 [9%] and 69 [10%] patients, respectively), headache (78 [8%] and 
62 [9%] patients, respectively), and sinusitis (57 [6%] and 51 [7%] patients, respectively). There 
were no adverse events in the reslizumab-treated group with an incidence higher than the placebo 
group by at least 1%.  
Serious Adverse Events 
The incidence of serious adverse events was similar in the reslizumab 3.0 mg/kg treatment group 
(6%) compared with the placebo treatment group (9%). The serious adverse event reported with 
the highest incidence was asthma (preferred terms of asthma, asthma crisis, and status 
asthmaticus), reported by 24 (3%) patients in the placebo group and 24 (2%) patients in the 
reslizumab 3.0 mg/kg group.  
Deaths 
There were 4 deaths in the clinical development plan: one death occurred in a placebo-treated 
patient and 3 deaths occurred in the ongoing open-label study (Study C38072/3085). None of the 
deaths were considered related to reslizumab. 
Laboratory Findings 
No clinically meaningful changes in clinical laboratory values, vital signs measurements, 
electrocardiogram (ECG), or physical examination findings were noted in the completed studies 
with the exception of a decrease in eosinophil counts in the reslizumab groups, which was dose 
related and is expected in view of the mechanism of action of reslizumab. Small decreases in the 
mean values of total white blood cell counts were also observed in some studies and have been 
assessed as reflecting the decrease in the eosinophil component of differential cell counts. The 
mean values of eosinophil and white blood cell counts returned to baseline values at the end of 
study follow-up visit (4 months after the last dose of reslizumab). 
Adverse Drug Reactions 
Anaphylaxis related to reslizumab infusion has been reported and is considered an adverse drug 
reaction (ADR). All cases of anaphylaxis early in the drug development occurred in the 
eosinophilic esophagitis studies and were deemed by the investigator as related to known food 
allergies, and not to reslizumab. Three infusion-related reactions, reported as anaphylaxis, 
occurred during or shortly after reslizumab infusion in the BREATH studies and were 
characterized variously by skin or mucosal involvement, dyspnea, wheezing, gastrointestinal 
symptoms, and chills. The 3 events were treated at the study site, and patients were withdrawn 
from the study. 
Myalgia (without evidence for muscle injury) was reported at a slightly higher rate in the 
reslizumab 3.0-mg/kg group (1%) than in the placebo group (0.5%) and is considered an ADR of 
reslizumab. 


 
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Additional Safety Considerations 
Malignancy 
As of February 2015, there were 27 treatment-emergent adverse events reported by 24 patients 
related to malignancy for the entire clinical program, including placebo-treated patients. 
Malignancies in reslizumab-treated patients were of diverse tissues (colon, anal, 
melanoma, prostate, breast, lung, plasmacytoma, lymphoma, lung metastasis of a previous 
resected colon cancer, ovarian adenocarcinoma, borderline ovarian tumor, and non-melanoma 
skin cancer cases).  
In the asthma placebo-controlled studies utilizing the 3.0-mg/kg dose, incidence of overall 
malignancies was 6 patients (0.58%; 1 patient had both prostate cancer and skin squamous cell 
carcinoma) in the reslizumab 3.0-mg/kg treatment group and 2 patients (0.27%) in the placebo 
group. All malignancies in reslizumab-treated patients were diagnosed within less than 6 months 
from first reslizumab dosing, except for the skin squamous cell carcinoma.  
In the combined placebo-controlled studies and long-term, open-label, safety extension 
Study C38072/3085, malignancies were reported in 21 patients. These included 5 cases of 
non-melanoma skin cancer. Most malignancies were diagnosed within less than 6 months after 
starting reslizumab treatment, and in 5 cases, there was a previous medical history of 
malignancy.  
A thorough analysis of malignancy cases did not suggest a causal relationship between 
reslizumab and cancer risk. 
Infections 
The immune response to parasitic infections may involve eosinophils; therefore, the clinical 
course of existing or new parasitic infections could potentially be complicated by a mechanism 
of action that lowers blood and tissue eosinophils. The iv reslizumab clinical protocols contained 
an exclusion criterion for patients with active or suspected helminth infestation/infection. The 
asthma Phase 3 studies were conducted in geographic regions in which helminth infections are 
prevalent, including South and Central America, Africa, and Asia. There were no helminth 
infections reported, and no difference was documented between the treatment groups in regards 
to adverse events that could be associated with gastrointestinal helminth infections.  
The overall rate of infection adverse events was lower for reslizumab versus placebo-treated 
patients, with the types of infection events reported consistent with what would be expected in a 
primarily adult patient population with an underlying condition of asthma. No potential 
opportunistic infections were reported. 


 
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Pregnancy 
The safety of reslizumab in pregnant women or developing fetus has not been studied, but 
nonclinical and clinical studies raised no specific concerns. As of December 2015, there have 
been 10 pregnancies during the entire clinical development of reslizumab, 2 of which occurred 
during the screening period of the study and 8 in patients receiving reslizumab. All patients were 
withdrawn from the study. Two pregnancies were terminated by an elective abortion with no 
complications, and 5 led to the birth of full-term infants with no malformations and no obstetric 
or perinatal complications. One male newborn had a neonatal jaundice that was reported as an 
unrelated adverse event and was assessed as a physiological jaundice. One pregnancy case was 
lost to follow-up, and the outcome is unknown. 
Immunogenicity 
Anti-drug antibody (ADA) responses were observed in 3.3% to 11.8% of patients in the 
completed Phase 3 studies in patients with asthma (iv administration every 4 weeks, 
>1000 patients evaluated for ADA). In general, the ADA responses were low in titer and often 
transient and were not associated with an effect on reslizumab concentration, eosinophil count, 
or specific clinical manifestations (including hypersensitivity reactions).  
Further details may be found in the current Investigator’s Brochure. 
1.4. 
Known and Potential Risks and Benefits to Human Patients  
Information regarding risks and benefits of reslizumab to human patients may be found in the 
current Investigator’s Brochure. 
1.4.1. 
Risks of Reslizumab 
Most clinical safety data for reslizumab are based on the experience with iv administration of the 
drug. As described in Section 1.3.2, iv reslizumab has been generally well tolerated over the 
range of doses evaluated (ie, from 0.03 through 3 mg/kg). Systemic severe reactions (including 
anaphylaxis) and myalgia are considered as ADRs of iv reslizumab.  
There are limited safety data regarding sc administration of reslizumab. In Study C38072/1107 
(Study 1107), 45 healthy volunteers received a single 220-mg sc injection of reslizumab. All 
adverse events were mild-moderate in severity. There were no deaths, serious adverse events, 
treatment-related adverse events, or withdrawals due to adverse events reported in this study. 
1.4.2. 
Benefits of Reslizumab 
As described in Section 1.3.2, results from clinical studies indicate improved asthma control and 
FEV1, and a medically meaningful decreased rate of CAEs with reslizumab. 
1.4.3. 
Overall Risk and Benefit Assessment for This Study 
Improvement in lung function has been confirmed in 3 Phase 3 clinical trials with the iv dosage 
form. In addition to improved lung function, 2 Phase 3 clinical trials demonstrated a significant 
reduction in CAEs over 52 weeks in patients with moderate to severe asthma and elevated blood 
eosinophils. 


 
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In completed studies, reslizumab was generally well-tolerated over the dosage range 0.03 to 
3.0 mg/kg. The majority of adverse events in reslizumab-treated patients were mild to moderate 
in severity, considered to be unrelated to study drug treatment, as determined by the investigator, 
and (as expected) associated with underlying asthma disease. There were no significant 
differences in the adverse event profile between patients treated with reslizumab and patients 
treated with placebo with the exception of the following ADRs: “systemic severe reactions 
(including anaphylaxis)” and “myalgia.” Three anaphylaxis reactions related to reslizumab 
infusions were reported during the BREATH asthma program; none of the patients were positive 
for ADA. All cases resolved with standard treatment, and treatment with reslizumab was 
permanently discontinued. Myalgia (without evidence for muscle injury) was reported at a 
slightly higher rate in the reslizumab 3.0-mg/kg group (1%) than in the placebo group (0.5%). 
The protocol includes measures to closely monitor and promptly address these ADRs to mitigate 
any potential harm to patients. 
Consideration of the accumulated data on the clinical effects of reslizumab in patients with 
asthma suggests that patients with elevated blood eosinophils benefit the most from anti-human 
IL-5 therapy. The safety profile accumulated throughout the clinical development of reslizumab 
suggests that reslizumab would have a favorable benefit-risk profile in treating patients with 
asthma and elevated blood eosinophils whose symptoms remain inadequately controlled on 
standard of care asthma therapy. 
1.5. 
Selection of Drugs and Dosages  
A detailed description of study drug administration is presented in Section 5.1. 
1.5.1. 
Justification for Dosage of Active Drug 
The platform of evidence that supports the range of the reslizumab dose response is based on 
observed effects on lung function and other clinical endpoints in patients with eosinophilic 
asthma (Studies P00290 [0.3 and 1 mg/kg doses], Res-5-0010 [3-mg/kg dose], and 3081 
[0.3- and 3-mg/kg doses]), on eosinophil depletion in the blood in healthy subjects (Study 1102 
[0.3-, 1-, 2-, and 3-mg/kg doses]) and in the blood and affected tissue in patients with asthma 
(Studies I96-350, 3081 and P00290), and eosinophilic esophagitis (Study Res-5-0002 [1-, 2-, and 
3-mg/kg doses]). Please refer to the Investigator’s Brochure for summary and comprehensive 
presentation of these data. Briefly, treatment with reslizumab 0.3 mg/kg produced substantially 
smaller and less durable reductions in the number of blood or tissue eosinophils (ie, sputum) than 
doses ≥1 mg/kg. In contrast, the magnitude of reductions in blood or tissue eosinophils at doses 
≥1 mg/kg (ie, 1, 2, or 3 mg/kg) were slight. Improvements for patients in the reslizumab 
0.3 mg/kg treatment group for FEV1 were 0.129 L at week 16 (p=0.0481), but other efficacy 
endpoint results were more variable (eg, no treatment effect on FVC and FEF25%-75% was 
observed for patients in the reslizumab 0.3 mg/kg treatment group). Therefore, doses of 
≥1 mg/kg are anticipated to be clinically effective in most patients. Based on these clinical and 
eosinophil pharmacodynamic data, Teva has chosen reslizumab 110 mg administered every 
4 weeks as the fixed dose to study in the sc program. This approximates a 1 mg/kg iv dose for 
the average patient (ie, 70 kg) when adjusted to account for sc bioavailability (ie, 67%, as 
determined by Study 1107). Modeling and simulation demonstrate that steady-state trough serum 
concentrations of reslizumab following administration of the proposed 110 mg sc dosing regimen 
are expected to fall within the range of exposures that produced meaningful effects on both blood 


 
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eosinophils and FEV1 in patients with eosinophilic asthma. Therefore, a fixed dose of 110 mg sc 
every 4 weeks is anticipated to provide sufficient efficacy. 
1.5.2. 
Justification for Use of Placebo 
A placebo control design is scientifically appropriate because placebo will be compared against 
reslizumab added on to an established treatment regimen. Patients will not be taken off their 
standard of care asthma therapy for this study. 
1.6. 
Compliance Statement 
This study will be 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, Title 21 Code of Federal Regulations 
[21CFR] Parts 11, 50, 54, 56, 312, and 314, European Union Directive 2001/20/EC on the 
approximation of the laws, regulations, and administrative provisions of the Member States 
relating to the implementation of GCP in the conduct of clinical trials on medicinal products for 
human use). Any episode of noncompliance will be documented. 
The investigator is responsible for performing the study in accordance with this protocol and the 
applicable GCP guidelines referenced above for collecting, recording, and reporting the data 
accurately and properly. Agreement of the investigator to conduct and administer this study in 
accordance with the protocol will be documented in separate study agreements with the sponsor 
and other forms as required by national authorities in the country where each investigational 
center is located.  
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the study and must ensure that trained personnel are immediately available in the event 
of a medical emergency. The investigator and the applicable study staff must be familiar with the 
background and requirements of the study and with the properties of the study drug(s) as 
described in the Investigator’s Brochure or prescribing information.  
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the study at that center and for contacts with study management, 
with the Independent Ethics Committee/Institutional Review Board (IEC/IRB), and with local 
authorities. 
1.7. 
Population To Be Studied and Justification 
The study will enroll male and female patients, 12 years of age and older, with asthma and 
elevated blood eosinophils who are inadequately controlled on at least a medium total daily ICS 
dose and a second asthma controller. (Patients 12 to <18 years of age are excluded from 
participating in South Korea and Argentina, and patients 66 years of age and older are excluded 
from participating in South Korea.) Adolescents are included in this study because they follow 
the same treatment recommendations as adults according to widely cited asthma guidelines 
(GINA 2014, ERP-3 2007). Elevated blood eosinophils have been associated with poor asthma 
control and increased risk of exacerbation (Tran et al 2014, Zeiger et al 2014). 


 
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1.8. 
Location and Timing of Study  
This study is planned to be conducted in approximately 30 countries at approximately 
275 centers. It is expected to start in Q3 2015 and have a duration of approximately 2 years. 
Additional centers will be added, if needed. Expected duration of the study may also be extended 
dependent on enrollment rate and other factors.  


 
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2. 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1. 
Purpose of the Study 
The purpose of this study is to establish the safety and efficacy of the sc formulation of 
reslizumab in patients with uncontrolled asthma and elevated blood eosinophils.  
2.2. 
Study Objectives 
2.2.1. 
Primary Objective 
The primary objective of this study is to determine the effect of reslizumab (110 mg) 
administered sc every 4 weeks on CAEs in adults and adolescents with asthma and elevated 
blood eosinophils who are inadequately controlled on standard-of-care asthma therapy. 
2.2.2. 
Secondary Objectives 
Secondary efficacy objectives are to evaluate the effects of reslizumab compared with placebo 
on a range of clinical markers of asthma control including pulmonary function (forced expiratory 
volume in 1 second [FEV1]). 
2.2.3. 
Other Objectives 
Other objectives of this study are to evaluate the safety, PK, PD, and immunogenicity of 
reslizumab. 
2.3. 
Study Endpoints  
2.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the frequency of CAEs per patient during the 52-week 
treatment period. Refer to Section 6.1 for additional details regarding the definition of CAE. 
2.3.2. 
Secondary Efficacy Endpoints  
The secondary efficacy endpoints are as follows: 
• change in pre-bronchodilator FEV1 from baseline/the day of randomization (DoR) at 
week 52 
• change in Asthma Quality of Life Questionnaire for patients 12 years and older 
(AQLQ +12) score from baseline/DoR at week 52 
• change in 6-item Asthma Control Questionnaire (ACQ-6) score from baseline/DoR at 
week 52 
• change in total asthma symptom scores (day and night) from baseline at week 52 
• percentage of asthma control days from baseline/DoR to week 52 
• change in St. George’s Respiratory Questionnaire (SGRQ) from baseline/DoR at 
week 32 


 
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• time to first CAE during the 52-week treatment period 
• frequency of exacerbations requiring hospitalization or emergency department visits 
per patient during the 52-week treatment period 
• frequency of moderate exacerbations defined as exacerbations requiring additional 
asthma controller medication that was not a systemic corticosteroid and that did not 
result in an asthma-specific hospitalization or emergency department visit during the 
52-week treatment period 
2.3.4. 
Target Biomarker Endpoints 
The target biomarker endpoints are the blood eosinophil counts at baseline/DoR; weeks 2, 4, 8, 
12, 16, 32, 52 or early withdrawal; and the follow-up visit (approximately week 64).  


 
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2.3.5. 
Immunogenicity Endpoints 
Samples for immunogenicity assessment for development of anti-drug antibodies will be 
obtained before the administration of study drug at DoR; prior to study drug administration at 
weeks 4, 16, 32, 52 or early withdrawal; and the follow-up visit (approximately week 64). 
Additional samples will be collected at the late follow-up visit (approximately week 76).  
2.3.6. 
Pharmacokinetic Endpoints 
The PK endpoints are the serum reslizumab concentrations at baseline/DoR; weeks 1 (patients in 
US study centers only), 2, and prior to study drug administration at weeks 4, 8, 12, 16, 20, 32, 
48, 52 or early withdrawal; and the follow-up visit (approximately week 64). An additional PK 
sample will be taken at long term follow-up (approximately week 76) at the same time for ADA 
sample collection. 
2.3.8. 
Safety Endpoints 
The safety endpoints for this study are as follows: 
• adverse events throughout the study 
• vital signs (pulse, respiratory rate, and blood pressure) throughout the study 
• concomitant medication usage throughout the study 
• physical examination findings throughout the study 
• clinical laboratory evaluations at screening, baseline/DoR, and periodically 
throughout the study 
• ECG evaluation at screening and week 24, 36, and 52 or early withdrawal 


 
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3. 
STUDY DESIGN 
3.1. 
General Design and Study Schema 
This is a 52-week, Phase 3, multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the safety and efficacy of reslizumab, at a fixed dose of 110 mg, administered sc every 
4 weeks in patients aged 12 years and older with asthma and elevated blood eosinophils, who are 
inadequately controlled on at least a medium total daily ICS dose and a second asthma controller. 
Evidence of inadequate asthma control will include a history of at least 2 exacerbations requiring 
systemic corticosteroids (oral or injection) in the previous 12 months, a suboptimal screening 
ACQ-6 score (≥1.5), and persistent symptoms during run-in on the patient’s usual asthma 
controller regimen. At least one of the historical exacerbations must have been previously 
documented in the medical or pharmacy record; additional exacerbations may have been 
documented in either the medical or pharmacy record, or may be documented by the study site at 
the time of screening history. For all exacerbations, which fulfill inclusion criterion ‘c’, the 
approximate dates of systemic corticosteroid therapy and the name of the systemic corticosteroid 
taken should be recorded in source documents. The study consists of a screening period of up to 
2 weeks to satisfy essential screening inclusion criteria (ie, confirmation of asthma with elevated 
blood eosinophils), a minimum 3-week run-in period on usual care to establish the patient’s 
baseline level of control and a 52-week double-blind treatment period. If the patient enrolls in an 
available open-label, long-term safety study, then adults (age 18 years and older) may wait to 
complete the early and late follow-up visits until the end of the open-label study; however, 
adolescents (ages 12 to <18 years) should complete the early follow-up visit at 12 weeks as part 
of this current study before starting an open-label study. 
Patients will begin screening up to approximately 5 weeks (±1 week) before DoR. During the 
screening period, a signed and dated informed consent form (and an assent form for children 
ages 12 through <18 years of age in accordance with local standards) will be obtained before a 
diagnosis of asthma is confirmed on the basis of patient history and by demonstration of airway 
reversibility. The patients will also be asked about their asthma medication compliance and to 
demonstrate their inhaler use technique. If the inhaler use technique is not optimal, patients will 
be taught the appropriate inhaler use technique during the screening period and should be 
reassessed before run-in. The patient will also have a complete blood count determined. If the 
patient’s eosinophil count is 300 eosinophils/μL or greater, and if the patient’s medication 
compliance and inhaler use technique are optimal, the patient will be eligible to continue in the 
study. Patient medical history, 12-lead ECG, physical examination, hematology and chemistry 
tests, urinalysis, vital signs measurements, beta-human chorionic gonadotropin serum pregnancy 
test (for all females of childbearing potential), and concomitant medication history will also be 
assessed at screening. 
To be eligible to enroll in the study, a patient will have an ACQ-6 score of at least 1.5, airway 
FEV1 reversibility of at least 12% to beta-agonist administration, blood eosinophil count of at 
least 300/μL, and a current fluticasone propionate dosage of at least a medium total daily ICS 
dose with a second asthma controller and will have met all the inclusion and none of the 
exclusion criteria at screening. The goal is to recruit a maximum of 30% of the patients 
(60 patients per treatment group) with eosinophil levels of 300/μL to <400/μL. 


 
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Patients who meet screening eligibility requirements will return to the research facility 3 weeks 
before baseline/DoR to confirm eligibility and begin the run-in period. At the start of run-in, 
patients will begin daily self-monitoring at home using an asthma control diary and PEF meter, 
while taking their usual asthma medications, in order to establish their baseline level of asthma 
control based on the frequency of symptoms, use of reliever SABA, nighttime awakenings due to 
asthma, and ambulatory lung function measurement. Improvement in asthma control during the 
treatment period will primarily be assessed by a reduction in the rate of clinically significant 
asthma exacerbations with reslizumab versus placebo over the 52-week treatment period. 
Pulmonary function; AQLQ +12, ACQ, and SGRQ scores; asthma symptoms; use of reliever 
SABA; nighttime awakenings due to asthma; safety measures; PK; immunogenicity; and health 
care utilization events will be assessed periodically; final assessments will be made at the EOT 
visit (week 52) or at early withdrawal. Patients who withdraw from the study before completing 
the 52-week evaluation period will have visit-17 (week 52 or early withdrawal) procedures and 
assessments performed at their final visit. Patients will return 12 weeks after the EOT visit for 
follow-up hematology, PK, immunogenicity, and safety assessments. An additional, late 
follow-up for immunogenicity testing will be performed 28 weeks (±2 weeks) after the last dose 
of study drug (ie, approximately week 76). 
The assessments and procedures performed during each study visit are detailed in Table 2 and 
Section 3.16. If a patient elects to withdraw (or is discontinued from treatment by the 
Investigator), every attempt will be made to continue the assessments subsequent to their 
withdrawal from the study (see Section 4.4). 
A total of 450 patients are planned to be randomized in a 1:1 ratio (approximately 225 patients 
within each treatment group) to receive reslizumab 110 mg or matching placebo every 4 weeks 
for 52 weeks. 
The study schema is presented in Figure 1. 


 
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Figure 1: 
Overall Study Schema 
 
*A maximum of 30% of the patients (60 patients per treatment group) with blood eosinophil levels of 300/μL to 
<400/μL will be enrolled. When this 30% threshold has been reached, only patients with blood eosinophil levels of 
≥400/μL will then be enrolled. 
Note: An additional, late follow-up for immunogenicity testing will be performed 28 weeks (±2 weeks) after the last 
dose of study drug (ie, approximately week 76). 
ACQ6 = 6-item Asthma Control Questionnaire; BKGD = background; CBC = complete blood count; 
DoR = day of randomization; EOT = end of treatment; F/U = follow up; ICS = inhaled corticosteroid; 
IP = investigational product; PK = pharmacokinetic; q4 weeks = once every 4 weeks; V = visit. 
3.2. 
Justification for Study Design 
The rationale for the design of the study is summarized in Table 1.  
Table 1: 
Rationale for Protocol 
Area 
Rationale 
Study population 
Representative of the uncontrolled asthma 
population with elevated blood eosinophils and 
history of exacerbations 
Investigational product dosage regimen and 
duration of treatment 
Subcutaneous dose and regimen are based on data 
and modeling from the BREATH intravenous 
program; fixed subcutaneous dosage form more 
convenient for patients 
Choice of comparison drug(s) (placebo, active) 
Placebo control is essential to establish efficacy  
Number of patients (including number per 
treatment group) 
Number of patients was based on power 
considerations and exacerbation data from 
BREATH Studies 3082 and 3083 
Treatment blinding (ie, rationale for blinded or 
open-label design) 
Double-blinding and randomized treatment 
allocation to prevent bias in pivotal efficacy trial 


 
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Area 
Rationale 
Primary analysis (measure, variable, time point, 
statistical test) 
Reduction in the rate of asthma exacerbations is 
important to patients, health care professionals, and 
payers and constitutes the essential claim 
Inclusion of ancillary studies: pharmacokinetics, 
target biomarker/pharmacodynamics, 
pharmacogenomics, and immunogenicity 
• 
Pharmacokinetics and target blood 
eosinophil pharmacodynamics are 
important for correlating with efficacy 
results, and will provide a basis for future 
pediatric dosing. 
• 
 
 
. 
• 
Immunogenicity assessments are essential 
to understanding the safety and efficacy of 
reslizumab.  
Safety Assessments 
Standard measures consistent with intravenous 
reslizumab studies in eosinophilic esophagitis and 
eosinophilic asthma  
 
3.3. 
Primary and Secondary Efficacy Measures and Time Points 
A description of the efficacy measures is provided in Section 6. 
3.3.1. 
Primary Efficacy Measure and Time Points 
The primary efficacy measure for this study is CAEs, which will be evaluated at the time points 
indicated in Table 2. If a patient experiences worsening of his or her asthma symptoms, the 
patient is to call the study center within 48 hours (if possible) to be evaluated for his or her 
asthma symptoms. A diary alert, based on a sustained fall in peak flow from baseline, will also 
help support the patient’s subjective experience. Procedures and assessments to be performed if 
an unscheduled visit occurs are described in Section 3.16.1. Refer to Section 6.1 for additional 
details regarding the definition of CAE. 
3.3.2. 
Secondary Efficacy Measures and Time Points 
The secondary efficacy measures for this study include the following. These measures will be 
evaluated at the time points indicated in Table 2. 
• pre-bronchodilator spirometry 
• AQLQ +12 
• ACQ-6 
• asthma symptoms based on the daily asthma control diary 


 
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• asthma control days 
• SGRQ 
3.4. 
Safety Measures and Time Points 
The following safety measures will be implemented throughout the study and evaluated at the 
time points indicated in Table 2. 
• inquiries about adverse events 
• clinical laboratory (serum chemistry and hematology) tests  
• vital signs (respiratory rate, blood pressure, and pulse)  
• ECGs  
• physical examinations, including body weight measurements. These will include both 
full physical examinations including height and weight and brief physical 
examinations.  
• inquiries about concomitant medication usage 
A description of the safety measures is provided in Section 7. 


 
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3.6. 
Pharmacokinetic Measures and Time Points 
Serum reslizumab concentration will be determined from serum samples collected from 
drug-treated patients at the time points indicated in Table 2. 
3.7. 
Target Biomarker Measures and Time Points 
Blood eosinophils will be determined from blood samples collected at the time points indicated 
in Table 2. 
3.8. 
Immunogenicity Measures and Time Points 
Anti-reslizumab antibody responses will be determined from serum samples collected from 
drug-treated patients at the time points indicated in Table 2. 
3.9. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Patients who meet all inclusion 
criteria and none of the exclusion criteria will be randomly assigned to receive reslizumab 
110 mg sc or matching placebo (approximately 225 patients per treatment group) in a 1:1 ratio. 
Patients and investigators will remain blinded to treatment assignment during the study. 
Randomization will be stratified by age (12 to <18 and ≥18 years), and blood eosinophil levels at 
screening (300/μL to <400/μL and ≥400/μL). This system is used to ensure a balance across 
treatment groups. The goal is to recruit a maximum of 30% of the patients (60 patients per 
treatment group) with eosinophil levels of 300/μL to <400/μL. 
The randomization list and treatment will be assigned to the relevant treatment groups through a 
qualified contract research organization (CRO), eg, via Interactive Voice Response System 
(IVRS)/ Interactive Web Response System (IWRS). The generation of the medication list and 
management of the IRT system will be done by a qualified CRO under the oversight of Teva’s 
Clinical Supply Chain. 
The sponsor’s clinical personnel involved in the study will also be blinded to the study drug 
identity after the run-in period until the database is locked for analysis and the treatment 
assignment is revealed, with the exception of the bioanalytical group who will not be blinded to 
facilitate PK and ADA sample analysis. Eosinophils and monocytes will be redacted from the 
post-baseline differential cell count reports to avoid the possibility of unblinding patients.  
Each patient will receive either one 1.0-mL sc injection containing 110 mg of reslizumab or one 
1.0-mL sc injection containing sterile placebo solution on each dosing day. Both reslizumab and 
placebo will be provided as clear solutions essentially free of particulate matter. 
3.10. 
Maintenance of Randomization and Blinding 
3.10.1. 
Randomization  
Patient randomization codes will be maintained in a restricted access area within Teva Global 
Biometrics or in a secure manner with the vendor contracted to create the list. At the time of 
analysis, when treatment codes are needed, the Teva statistician assigned to the study will make 
a request to unblind and will receive the unblinded codes. 


 
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3.10.2. 
Blinding/Unblinding 
In order to complete the data analysis for PK, it may be necessary to assay samples before 
database lock. If so, the individuals responsible for sample analysis will know which patients 
received study drug and which patients received placebo. The randomization codes will be 
provided to personnel responsible for bioanalysis according to a process that will be predefined 
in the unblinding plan form (GBP_RD_703_FRM_02) according to Teva Standard Operating 
Procedure (SOP) GBP_RD_703. The form will be signed at the study initiation stage by the 
responsible Teva statistician, CRO statistician, and randomization code generator. After 
authorization has been obtained to release the codes, the randomization code generator at the 
CRO will provide the codes directly to the bioanalysis team; the statisticians (at Teva and the 
CRO) will not be unblinded. Personnel responsible for bioanalysis will not have access to 
clinical safety and efficacy data and will provide concentration data to any other personnel who 
may require it in a manner that will not identify individual patients (ie, a dummy patient 
identifier will be linked to an individual patient’s concentration data). 
For information about personnel who may be aware of treatment assignments, see Section 3.9. 
These individuals will not be involved in conduct of any study procedures or assessment of any 
adverse events, safety, or efficacy data. 
In case of a serious adverse event or pregnancy, in which knowledge of the study drug 
assignment is needed to make treatment decisions, the investigator may unblind the patient’s 
drug assignment as deemed necessary, mainly in emergency situations. Individual treatment 
codes, indicating the treatment randomization for each randomized patient, will be available to 
the investigator(s) and/or pharmacist(s) at the study center via the IRT, both via telephone and 
internet. If possible, the sponsor should be notified of the event before breaking of the code. If 
this is not possible, the sponsor should be notified immediately afterwards, and the patient’s drug 
code assignment should not be revealed. Breaking of the treatment code can always be 
performed by the site without prior approval by the sponsor. 
When a blind is broken, the patient will be withdrawn from the study, and the event will be 
recorded onto the case report form (CRF). The circumstances leading to the breaking of the code 
should be fully documented in the investigator’s study files and in the patient’s source 
documentation. Treatment assignment should not be recorded in any study documents or source 
document. 
In blinded studies, for adverse events that are defined as: Suspected, Unexpected, Serious, 
Adverse Reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety 
and Pharmacovigilance may independently request that the treatment code be revealed (on a 
case-by-case basis) to comply with regulatory requirements. The report will be provided in an 
unblinded manner for regulatory submission. If this occurs, blinding will be maintained for other 
personnel (eg, the investigator) and the patient will not be withdrawn from the study. 
3.10.3. 
Data Monitoring Committee 
Not applicable. 
3.11. 
Drugs Used in the Study  
A description of administration procedures is given in Section 5.1.  


 
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Additional details may also be found in the current version of the Investigator’s Brochure for 
reslizumab.  
3.11.1. 
Investigational Product  
Reslizumab for sc injection will be provided as a sterile solution containing 110 mg (1.0 mL) 
reslizumab per syringe, formulated at 110 mg/mL in 
 sodium acetate, with 
 sucrose, 
 polysorbate 80, pH 5.5 buffer. The needle shields of the prefilled syringes contain natural 
rubber latex. 
Reslizumab will be administered subcutaneously at a dose of 110 mg (1.0 mL) every 4 weeks. A 
more detailed description of administration procedures is given in Section 5.1. 
3.11.2. 
Placebo  
Placebo will be provided as a sterile solution of 
 sodium acetate, with 
 sucrose, 
 polysorbate 80, pH 5.5 buffer, presented as 1 mL per syringe. The needle shields of the 
prefilled syringes contain natural rubber latex. 
Placebo will be administered subcutaneously as a 1.0-mL injection. A more detailed description 
of administration procedures is given in Section 5.1. 
3.12. 
Drug Supply and Accountability 
3.12.1. 
Drug Storage and Security 
Reslizumab and matching placebo must be stored in a refrigerator at controlled temperature (2°C 
to 8°C) and should not be frozen and should be protected from light. Reslizumab and placebo 
supplies must be kept in a secure area (eg, locked refrigerator). The site should have a process 
for monitoring the storage temperature of unused study drug. 
3.12.2. 
Drug Accountability 
Each study drug shipment will include a packing slip listing the contents of the shipment, a 
temperature monitoring device, and any applicable forms. 
Each investigator is responsible for ensuring that deliveries of study drug and other study 
materials from Teva are correctly received and recorded, handled and stored safely and properly 
in accordance with the Code of Federal Regulations (CFR) or local regulations and used in 
accordance with this protocol.  
A record of study drug accountability (ie, study drug and other materials received, used, retained, 
returned, or destroyed) must be prepared and signed by the principal investigator or designee, 
with an account given for any discrepancies. Empty, partially used, and unused study drug will 
be disposed of or returned to the sponsor’s designee. 
3.13. 
Duration of Patient Participation and Justification 
This study will consist of up to a 2-week (±3 days) screening period, minimum 3-week run-in 
period and a 52-week double-blind treatment period. Patients are expected to participate in this 
study for approximately 69 weeks. An additional, late follow-up for immunogenicity testing will 
be performed 28 weeks after the last dose of study drug. If the patient enrolls in an available 


 
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open-label, long-term safety study, then adults (age 18 years and older) may wait to complete the 
early and late follow-up visits until the end of the open-label study; however, adolescents (ages 
12 to <18 years) should complete the early follow-up visit at 12 weeks as part of this current 
study before starting an open-label study. See Section 12.4 for the definition of the end of the 
study. 
3.14. 
Stopping Rules and Discontinuation Criteria 
Other than pregnancy, there are no formal rules for study drug discontinuation in this study. 
During the conduct of the study, adverse events will be reviewed by the sponsor (see 
Section 7.1.5) as they are reported from the investigational center to identify safety concerns. 
The study may be terminated by the sponsor at any time for reasons including, but not limited to 
a safety concern.  
A patient may discontinue participation in the study at any time for any reason (eg, lack of 
efficacy, consent withdrawn, and adverse event). The investigator and/or sponsor can withdraw a 
patient from the study for reasons including, but not limited to, a change in the medical condition 
or an adverse event that alters the patient’s benefit/risk (eg, pregnancy, a related severe 
hypersensitivity, or related severe myalgia/muscle event), a protocol violation or deviation as 
defined in Section 11.1.2, or noncompliance. 
3.15. 
Source Data Recorded on the Case Report Form 
All patient data must have supportive original source documentation in the medical records, or 
equivalent, before they are transcribed onto the CRF. Data may not be recorded directly onto the 
CRF and considered as source data unless the sponsor provides written instructions specifying 
which data are permitted to be recorded directly onto the CRF.  
If data are processed from other institutions (eg, clinical laboratory, central image center, 
electronic diary [eDiary] data), the results will be sent to the investigational center, where they 
will be retained but not entered into the CRF unless otherwise noted in the protocol. These data 
may also be sent electronically to the sponsor (or organization performing data management) for 
direct entry into the clinical database (see Section 13.1). All data from other institutions will be 
available to the investigator. 
The CRFs are filed in the sponsor’s central file.  
3.16. 
Study Procedures 
Study procedures and assessments with their timing are summarized in Table 2. Detailed by-visit 
information is provided in the sections following the table. Detailed descriptions of each 
assessment are provided in Section 6 (efficacy assessments), Section 7 (safety assessments), and 
Section 8 (PK and other assessments). 


 
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Table 2: 
Study Procedures and Assessments 
Study period 
Pretreatment 
Double-blind treatment period 
Follow-up 
Late 
follow-up 
Visit number 
V1 
Start of 
screening 
perioda 
V2 
Start of 
run-in 
periodb 
V3 
DoR 
VPK V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 V14 V15 V16 
V17 
EOT or 
early 
withdrawal 
V18 
EOS 
V19 
Procedures and 
assessments 
Week 
-5 (±1 wk) 
Week 
-3 
0 
W1 
±3d 
W2 
±3d 
W4 
±7d 
W8 
±7d 
W12 
±7d 
W16 
±7d 
W20 
±7d 
W24 
±7d 
W28 
±7d 
W32 
±7d 
W36 
±7d 
W40 
±7d 
W44 
±7d 
W48 
±7d 
W52 
±7d 
EOT 
+12wk 
±14d 
W76 
±2wk 
Informed 
assent/consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion 
criteria 
X 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
testingd 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with 
differentiale 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
Serum chemistry 
testsf 
X 
 
X 
Xg 
Xg 
Xg 
Xg 
Xg 
X 
Xg 
 
 
X 
 
 
 
 
X 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full physical 
examinationh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Brief physical 
examinationh 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signsh 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Heighti and 
weight 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 


 
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Table 2: 
Study Procedures and Assessments (Continued) 
Study period 
Pretreatment 
Double-blind treatment period 
Follow-up 
Late 
follow-up 
Visit number 
V1 
Start of 
screening 
perioda 
V2 
Start of 
run-in 
periodb 
V3 
DoR 
VPK V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 V14 V15 V16 
V17 
EOT or 
early 
withdrawal 
V18 
EOS 
V19 
Procedures and 
assessments 
Week 
-5 (±1 wk) 
Week 
-3 
0 
W1 
±3d 
W2 
±3d 
W4 
±7d 
W8 
±7d 
W12 
±7d 
W16 
±7d 
W20 
±7d 
W24 
±7d 
W28 
±7d 
W32 
±7d 
W36 
±7d 
W40 
±7d 
W44 
±7d 
W48 
±7d 
W52 
±7d 
EOT 
+12wk 
±14d 
W76 
±2wk 
ECGh 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Reversibility 
testingj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-
bronchodilator 
spirometryk 
 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Post-
bronchodilator 
spirometry 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Provide and 
collect PEF 
meter 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Provide/collect 
asthma control 
diary; reinforce 
diary and PEF 
compliance. 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ACQl  
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AQLQ +12  
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
SGRQ 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 


 
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Table 2: 
Study Procedures and Assessments (Continued) 
Study period 
Pretreatment 
Double-blind treatment period 
Follow-
up 
Late 
follow-up 
Visit number 
V1 
Start of 
screening 
perioda 
V2 
Start of 
run-in 
periodb 
V3 
DoR 
VPK 
V4 
V5 
V6 
V7 
V8 
V9 
V10 V11 V12 V13 V14 V15 V16 
V17 
EOT or early 
withdrawal 
V18 
EOS 
V19 
Procedures and 
assessments 
Week 
-5 
(±1 wk) 
Week 
-3 
0 
W1 
±3d 
W2 
±3d 
W4 
±7d 
W8 
±7d 
W12 
±7d 
W16 
±7d 
W20 
±7d 
W24 
±7d 
W28 
±7d 
W32 
±7d 
W36 
±7d 
W40 
±7d 
W44 
±7d 
W48 
±7d 
W52 
±7d 
EOT 
+12wk 
±14d 
W76 
±2wk 
Assess asthma 
exacerbations and 
related HCUm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK samples 
(ALL) 
 
 
X 
Xn 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
Blood for ADAo 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Blood for hepatitis 
B, hepatitis C, and 
HIV testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phadiatop allergy 
test and total serum 
IgE 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event 
inquiryp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitant 
medication inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IP administration 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Injection site 
evaluation 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 


 
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V = visit; DoR = day of randomization; PK = pharmacokinetic; EOT = end of treatment; EOS = end of study; TERM = termination; wk, W = week; d = day; ACQ = Asthma 
Control Questionnaire; ACQ-6 = 6-item Asthma Control Questionnaire; CBC = complete blood count; CPK = creatine phosphokinase; CRF = case report form; 
ECG = electrocardiogram; eDiary = electronic diary; PEF = peak expiratory flow; IP = investigational product; HCU = health care utilizations; AQLQ +12 = Asthma Quality of 
Life Questionnaire for patients 12 years and older; 
 SGRQ = St. George’s Respiratory Questionnaire; 
 ADA = anti-drug antibody; HIV = human immunodeficiency virus; FEV1 = forced expiratory volume in 1 second. 
a The screening visit (visit 1) will take place approximately 5 weeks (±1 week) before the baseline/DoR visit. It is understood that not all procedures can be completed on the same 
day. In particular, the patient may need to return to satisfy the medication hold for screening pre-bronchodilator FEV1 (see note “k” for timing). 
b A minimum of 3 weeks run-in (extension allowed up to 4 weeks) on stable doses of the patient’s usual asthma medication is required to establish a baseline level of control 
before randomization. 
c Diary control inclusion must be met at baseline/DoR in order for the patient to be randomized. If the control criteria are not met, the patient should not be randomized and should 
be discontinued at that time; the run-in may only be extended up to 4 weeks. 
d Beta-human chorionic gonadotropin serum pregnancy tests will be performed at screening (female patients who are not 2 years postmenopausal or surgically sterile only). Urine 
pregnancy tests will be performed at baseline/DoR, before study drug injection at each administration visit and at week 52, or early withdrawal, and at follow-up V18. Pregnancy 
tests are not required for female patients who are 2 years postmenopausal or surgically sterile. 
e The blood eosinophil count must meet the ≥300/μL inclusion criterion during the screening period. Given the known variability in this measure, the eosinophil count may be 
repeated once during screening (total of 2 attempts), at the discretion of the Investigator, in order to fulfill this inclusion criterion. 
f CPK is collected with serum chemistry tests at scheduled visits. If a potentially clinically significant CPK level (≥3.1 × ULN) is reported, initiate the CPK/myalgia CRF and 
clinical monitoring as outlined in Protocol Section 7.1.7.2. 
g CPK measurement only. CPK will be collected with PK sample. 
h Physical examination, vital signs, and ECG should be obtained before spirometry procedures and IP administration. 
i Patients aged 21 years and over will have their height and weight assessed at screening only. Patients aged 12 to 21 years will have height and weight assessed at screening, week 
24, and EOT. 
j A failed reversibility test may be repeated once, within the 2-week (±3 days) screening period. Reversibility testing will be confirmed before entering the run-in period. 
Documented historical reversibility within 12 months of signing the Informed Assent Form/Informed Consent Form is acceptable as per inclusion criterion f. 
k Pre-bronchodilator spirometry assessments should only be performed after withholding short-acting bronchodilators (ie, inhaled short-acting beta-adrenergic agonists and/or 
short-acting anticholinergics) for at least 6 hours and long-acting bronchodilators (ie, inhaled long-acting beta-adrenergic agonists and long acting anticholinergic agents) for at 
least 12 or 24 hours, according to their labeled dose schedule. Spirometry should be performed prior to IP administration, if applicable. 
l The ACQ will be completed by the patient at the clinic. ACQ should be completed through question 6. NOTE: The screening V1 ACQ-6 score must be ≥1.5 in order to continue 
in this study. A screening visit ACQ score <1.5 may not be repeated and the patient should be screen-failed at that time. 
m If a patient experiences worsening of his or her asthma symptoms, the patient is to call the study center within 48 hours (if possible) to be evaluated for his or her asthma 
symptoms. A diary alert, based on a sustained fall in peak flow from baseline, will also help support the patient’s subjective experience. Procedures and assessments to be 
performed if an unscheduled visit occurs are described in Protocol Section 3.16.5. 
n Patients at sites in the United States will return for a PK assessment at approximately 1 week, which corresponds approximately to maximum plasma drug concentration (Cmax) 
for subcutaneous reslizumab. 
Note: All blood sampling (including hematology and chemistry) will be drawn before administration of IP unless otherwise indicated. 
o Blood for ADA assessment will be collected at baseline/DoR, and other scheduled time points, and upon observation of any severe hypersensitivity reaction (eg, anaphylaxis). 
Blood for ADA assessment will be collected before dosing, if both occur on the same day. An additional, late follow-up for immunogenicity testing will be performed 28 weeks 
(±2 weeks) after the last dose of study drug (~week 76). 
p Adverse event inquiry will occur before and after study drug administration at V3 to V16. Follow-up any prior messages from the post-injection eDiary symptom inquiry, as 
necessary. For systemic or severe hypersensitivity reactions possibly related to the study drug, initiate the anaphylaxis CRF. When such reactions are observed after study drug 
administration in the clinic, vital signs must be monitored using the unscheduled vital signs CRF. At the time of myalgia/muscular adverse events, CPK should be collected 
(initiate myalgia CRF). 


 
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3.16.1. 
Procedures for Screening and Start of Run-In Period (Visits 1 and 2) 
A signed and dated informed consent form will be obtained from all patients 18 years of age or 
older before screening procedures commence (see Section 12.1). For patients 12 through 
<18 years of age, a signed and dated informed consent form will be obtained from each 
parent/legal guardian, and a signed and dated assent form will be obtained from each patient 
before screening procedures commence, according to local IEC/IRB requirements. Evaluations 
obtained as part of routine medical care and performed during the screening period may be used 
in place of the study-specific evaluations. In addition, disease-specific assessments performed 
before informed consent may be used for the study. Patients 18 years of age or older and 
parents/legal guardians for patients 12 through <18 years of age will acknowledge and agree to 
the possible use of this information for the study by giving informed consent. 
After informed consent is obtained, patients who are screened will be assigned an 8-digit 
permanent identification number such that all patients from each investigational center are given 
consecutive identification numbers in successive order of inclusion. The first 2 digits of the 
screening number will be the number assigned to the country where the investigational center is 
located, the next 3 digits will be the designated investigator center number, and the last 3 digits 
will be assigned at the investigator center (eg, if the number assigned to the country is 01, the 
3rd patient screened at center 5 would be given the number of 01005003). 
Patients who do not initially meet the eosinophil or spirometry/reversibility criteria during the 
Screening period may have these tests repeated once, prior to excluding the subject from further 
study participation.  A patient who is screened but not randomized (eg, because entry criteria 
were not met or enrollment did not occur within the specified time), may be considered in the 
future for screening again, once more, if, eg, there is a change in the patient’s medical 
background or a modification of study entry criteria. The duration between the date of Screen 
Failure and re-screening must be >30 days. 
The screening visit (visit 1) will take place approximately 5 weeks (±1 week) before the 
baseline/DoR visit. The following procedures will be performed at visit 1: 
• Obtain written informed consent before any other study-related procedures are 
performed. 
• Review medical history. 
• Review medication history. 
• Review inclusion/exclusion criteria. 
• Perform serum pregnancy testing (female patients who are not 2 years 
postmenopausal or surgically sterile). 
• Perform clinical laboratory tests (chemistry, hematology, urinalysis). Only those 
patients with an eosinophil count of 300 eosinophils/µL or greater at screening will be 
eligible to continue in the study. Eosinophil testing may be repeated once during the 
2-week (±3 days) screening period. 
• Perform full physical examination. 


 
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• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Measure height and weight. 
• Perform ECG. 
• Complete asthma-specific tests. 
− Perform reversibility testing if long-acting and short-acting inhaled 
bronchodilators were held for the specified time; if not, the patient should be 
brought back on another day to complete. Reversibility testing may be repeated 
once within the 2-week (±3 days) screening period. Airway reversibility will be 
demonstrated by measuring the change in FEV1 before and after inhalation of 
SABA; reversibility testing should only be attempted after withholding 
short-acting bronchodilators (ie, inhaled short-acting beta-adrenergic agonists 
and/or short-acting anticholinergics) for at least 6 hours and long-acting 
bronchodilators (ie, inhaled long-acting beta-adrenergic agonists and long-acting 
anticholinergic agents) for at least 12 or 24 hours, according to their labeled dose 
schedule. SABAs, such as salbutamol or albuterol, administered via a metered 
dose inhaler should be used for reversibility testing. Four separate doses (eg, 
albuterol 360 μg or salbutamol 100 μg ex-valve) should be given by metered dose 
inhaler, as tolerated. Post-bronchodilator spirometry should be completed a 
minimum of 15 minutes after dosing of SABA. If a patient’s FEV1 improves at 
least 12% between the 2 tests, then they will be deemed as having airway 
reversibility and will continue the screening process.  
− Complete the ACQ-6. 
− Assess asthma exacerbations and related health care utilizations. 
• Collect blood for human immunodeficiency virus (HIV) antigen/antibody, hepatitis B 
surface antigen, and hepatitis C antibody testing. 
• Perform adverse event inquiry. 
• Perform concomitant medication inquiry. 
The start of run-in period visit (visit 2) will take place 3 weeks before the baseline/DoR visit. 
The following procedures will be performed at visit 2: 
• Review inclusion/exclusion criteria. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Provide PEF meter to patient. 
• Provide asthma control diary to patient. 
• Assess asthma exacerbations and related health care utilizations. 
• Perform concomitant medication inquiry. 
• Perform adverse event inquiry 


 
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For a minimum of 3 weeks after visit 2, patients will continue on their usual asthma medications 
and complete daily self-monitoring of symptoms using an asthma control diary and PEF meter. 
Level of asthma control will be established based on the frequency of symptoms, use of a SABA, 
nighttime awakenings due to asthma, and ambulatory lung function. 
3.16.2. 
Procedures Before Study Drug Treatment (Baseline/Day of Randomization 
[Week 0, Visit 3]) 
Patients who continue to meet the inclusion/exclusion criteria at visit 2 will continue to visit 3, 
when baseline/DoR evaluations will be conducted. 
The following procedures will be performed at visit 3 before reslizumab or placebo 
administration: 
• Review inclusion/exclusion criteria. 
• Perform urine pregnancy testing (female patients who are not 2 years postmenopausal 
or surgically sterile only). 
• Perform clinical laboratory tests (chemistry and hematology). 
• Perform brief physical examination. 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Perform concomitant medication inquiry. 
• Perform adverse event inquiry. 
• Complete asthma-specific tests. 
− If patient has withheld inhaled long acting and short-acting bronchodilators for 
the requisite time period, perform pre-bronchodilator spirometry, including FEV1, 
FVC, and FEF25%-75%, and post-bronchodilator spirometry, including FEV1. If 
inhaled bronchodilators were used during the specified withhold window, lung 
function testing should be delayed until the withhold time is met if feasible, or the 
visit should be rescheduled. 
− Collect and review daily asthma control diary, and reinforce diary and PEF 
compliance. Patients must meet asthma control inclusion criteria. 
− Complete the ACQ-6. 
− Complete the AQLQ +12. 
− Complete the SGRQ. 
− Assess asthma exacerbations and related health care utilizations. 
• Collect blood for serum reslizumab concentration determination (PK assessment) 
from all patients. 


 
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• Collect blood sample for immunogenicity (ADA) assessment. 
• Collect blood for Phadiatop allergy test and total serum IgE (Vidal et al 2005). 
• 
. 
A patient who is not randomly assigned to treatment on the basis of results of baseline/DoR 
assessments (eg, because entry criteria were not met or enrollment did not occur within the 
specified time) may be considered for screening again if there is a change in the patient’s 
medical background, a modification of study entry criteria, or other relevant change. A patient 
who does not complete at least 4 days of diary entries or equivalent during the last 7 days of run-
in may also be considered for screening again. A patient may be rescreened for these reasons 1 
time only. The duration between the date of Screen Failure and the re-screening must be 
>30 days. Patients may be screened again if they did not meet spirometry/reversibility criteria 
initially, and they may also be screened again if they did not meet the eosinophil criterion during 
the initial Screening. 
Patients who continue to meet the inclusion/exclusion criteria will be assigned a permanent 
unique randomization number and a treatment number generated by IRT. These two newly 
assigned numbers will be entered into the CRF, and study drug will be dispensed. The following 
procedures/assessments will be performed during and after administration of study drug: 
• Patients will be observed for 1 hour after study injection/baseline/DoR assessments  
• Evaluation of injection site for reaction at approximately 1 hour after dosing using the 
injection site CRF. Clinically significant injection site reactions should be recorded as 
an adverse event. 
• If, during post-study drug observation, the patient develops clinical symptoms, vital 
signs should be collected. The patient should be assessed for 
anaphylaxis/hypersensitivity reactions as detailed in Section 7.1.7. 
Remind the patients that they will receive a post-injection symptom inquiry via the eDiary. 
3.16.3. 
Procedures During Study Drug Treatment 
3.16.3.1. Double-Blind Treatment Period  
Study drug will be administered at approximately the same time in the morning on the days 
indicated in Table 2. (Note: Patients must be observed for a minimum of 1 hour after study drug 
administration.) 
3.16.3.1.1. Week 1 (Pharmacokinetic Visit) 
Patients at sites in the US will return to the research facility approximately 1 week after 
administration of the first dose of study drug. A blood sample will be collected for serum 
reslizumab concentration determination and measurement of CPK at this visit. Adverse events, 
concomitant medications, and asthma exacerbations and related health care utilizations will also 
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3.16.3.1.2. Other On-Treatment Visits (Visits 4 through 17 [EOT]) 
During the double-blind treatment period, patients will return to the study center at week 2 and 
week 4 and then once every 4 weeks (±7 days) thereafter (relative to baseline/DoR) for 
administration of study drug and assessments until 4 weeks after the final administration of study 
drug (week 52 or early withdrawal). 
The following procedures/assessments will be performed before administration of study drug at 
each of these visits, unless otherwise indicated: 
• Perform urine pregnancy testing (female patients who are not 2 years postmenopausal 
or surgically sterile only) (excluding week 2 [visit 4]). 
• Perform hematology tests (weeks 2, 4, 8, 12, 16, 32, and 52 or early withdrawal only). 
• Perform serum chemistry tests (weeks 16, 32, and 52 or early withdrawal only) (a 
sample for CPK measurement only, will also be collected on weeks 2, 4, 8, 12, and 20). 
• Perform full physical examination (week 52 or early withdrawal only). 
• Perform brief physical examination (excluding week 52 or early withdrawal). 
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Measure height and weight (weeks 24 and 52 or early withdrawal only; patients 12 to 
21 years of age only). 
• Perform ECG (week 24, 36, and 52 or early withdrawal only). 
• Perform concomitant medication inquiry. 
• Perform adverse event inquiry. 
• Complete asthma-specific tests. 
− If patient has withheld inhaled long acting and short-acting bronchodilators for 
the requisite time period, perform pre-bronchodilator spirometry, including FEV1, 
FVC, and FEF25%-75% (weeks 2, 4, 8, 12, 16, 32, and 52 or early withdrawal only). 
− Perform post-bronchodilator spirometry, including FEV1 (weeks 16, 32, and 52 or 
early withdrawal only). If inhaled bronchodilators were used within the specified 
withhold window, lung function testing should be delayed until the withhold time 
is met if feasible, or the visit should be rescheduled. If neither option is feasible 
for the patient, the test may proceed and the deviation recorded. 
− Collect PEF meter (week 52 or early withdrawal only). 
− Collect and review daily asthma control diary, and reinforce diary and PEF 
compliance (excluding week 2). 
− Complete the ACQ-6 (may be completed after study drug administration during 
the 1-hour observation period.) 
− Complete the AQLQ +12 (weeks 4, 8, 12, 16, 32, and 52 or early withdrawal 
only) (AQLQ+12 may be completed after study drug administration during the 
1-hour observation period.) 
− Complete the SGRQ (weeks 32 and 52) (may be completed after study drug 
administration during the 1-hour observation period.) 


 
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− Assess asthma exacerbations and related health care utilizations. 
• Collect blood for serum reslizumab concentration determination (PK assessment) 
from all patients (weeks 2, 4, 8, 12, 16, 20, 32, 48, and 52 or early withdrawal only). 
• Collect blood sample for immunogenicity (ADA) assessment (weeks 4, 16, 32, and 
52 or early withdrawal only). 
• 
 
The following procedures/assessments will be performed during and after administration of 
study drug: 
• Patients will be observed for 1 hour after study injection. 
• Evaluation of injection site for reaction at approximately 1 hour after dosing using the 
injection site CRF. Clinically significant injection site reactions should be recorded as 
an adverse event. 
• If, during post-study drug observation, the patient develops clinical symptoms, vital 
signs should be collected. The patient should be assessed for 
anaphylaxis/hypersensitivity reactions as detailed in Section 7.1.7. 
Remind the patients that they will receive a post-injection symptom inquiry via the eDiary.  
3.16.4. 
Procedures After Study Drug Treatment 
Patients who participate in the study in compliance with the protocol for at least 52 weeks of 
double-blind treatment will be considered to have completed the treatment period. Patients who 
complete the follow-up visit (week 64) will be considered as having completed the study. An 
exception to this may be adult patients who enroll in an available open-label, long-term safety 
study and complete the early and late follow-up visits as part of that study. These adult patients 
may be considered as having completed the current study at the time of the 52-week visit (end of 
treatment period). See Section 12.4 for the definition of the end of the study. 
For patients who complete the treatment period, final evaluations will be performed at the end-of 
treatment/week 52 visit and the follow-up visit.  
Patients who discontinue treatment prematurely must be encouraged to continue to attend the 
regular scheduled visits, and complete the prescribed safety and efficacy evaluations through the 
end-of-treatment/early withdrawal visit and the follow-up visit, if at all possible (see 
Section 4.4). 
Patients who both discontinue treatment and also withdrawal from the study should have final 
evaluations performed on the last day the patient receives the study drug, or as soon as possible 
thereafter. The patient should also return for the follow-up visit and procedures if at all possible 
(see Section 4.4).  


 
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Procedures for patients who withdraw prematurely from the study are described in Section 4.4. 
Following termination of the study, patients should be treated according to the standard of care, 
and as guided by the Principal Investigator. 
Patients with ongoing adverse events or clinically significant abnormal laboratory test results (as 
interpreted by the investigator) will be monitored as described in Section 7.1.2.  
The following procedures/assessments will be performed at the follow-up visit (EOT +12 weeks 
±14 days, end of study visit): 
• Perform hematology tests. 
• Assess asthma exacerbations and related health care utilizations. 
• Collect blood for serum reslizumab concentration determination (PK assessment) 
from all patients. 
• Collect blood sample for immunogenicity (ADA) assessment. 
• Perform adverse event inquiry. 
• Perform concomitant medication inquiry. 
• Perform urine pregnancy test. 
3.16.5. 
Unscheduled Visits 
An unscheduled visit may be performed at any time during the study at the patient’s request or as 
deemed necessary by the investigator. The date and reason for the unscheduled visit, as well as 
any other data obtained (eg, adverse events, concomitant medications and treatments, and results 
from procedures or tests), will be recorded on the CRF and noted within the patient’s source 
notes. 
Procedures performed during unscheduled visits include the following:  
• Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate). 
• Perform adverse event inquiry. 
• Perform concomitant medication inquiry. 
• Perform study compliance review. 
Other procedures may be performed at the discretion of the investigator. As outlined in 
Section 4.4, subjects who discontinue study treatment will have all visit 17 procedures performed 
at an unscheduled visit. This visit should be scheduled as soon as possible after the time of 
treatment discontinuation. 


 
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4. 
SELECTION AND WITHDRAWAL OF PATIENTS 
Prospective waivers (exceptions) from study eligibility criteria to allow patients to enter a study 
are not granted by Teva (see Section 11.1.2). 
4.1. 
Patient Inclusion Criteria 
Patients may be included in this study only if they meet all of the following criteria: 
a. Written informed consent is obtained. A patient 12 through <18 years of age must 
provide assent, and their parent(s) or legal guardian(s) must provide consent. 
b. The patient is male or female, 12 years of age and older, with a diagnosis of asthma. 
(Patients 12 to <18 years of age are excluded from participating in South Korea and 
Argentina, and patients 66 years of age and older are excluded from participating in 
South Korea.) 
c. The patient has had at least 2 documented asthma exacerbations requiring the use of 
systemic (oral, intramuscular, or iv) corticosteroids within 12 months of signing the 
Informed Assent Form/Informed Consent Form. 
d. The patient has an ACQ-6 score of at least 1.5 at screening (visit 1). 
e. The patient has a blood eosinophil level of at least 300/µL during the screening 
period (ie, before visit 2). (A maximum of 30% of the patients [60 patients per 
treatment group] with blood eosinophil levels of 300/μL to <400/μL will be enrolled. 
When this 30% threshold has been reached, only patients with blood eosinophil levels 
of ≥400/μL will then be enrolled.) 
f. The patient has an FEV1 reversibility of at least 12% after administration of inhaled 
SABA according to standard American Thoracic Society (ATS) or European 
Respiratory Society (ERS) protocol. Documented historical reversibility within 
12 months of signing the Informed Assent Form/Informed Consent Form is 
acceptable.  
g. The patient has required at least a medium total daily ICS dose based on GINA 2016 
clinical comparability table (Appendix A) for at least 3 months. For ICS/LABA 
combination preparations, the mid-strength approved maintenance dose in the local 
country will meet this ICS criterion. 
h. The patient has required an additional asthma controller medication (eg, long-acting 
beta-2-agonist [LABA], long-acting muscarinic antagonist [LAMA], leukotriene 
receptor antagonist [LTRA], or theophylline preparations), besides ICS, for at least 
3 months or a documented failure in the past 12 months of an additional asthma 
controller medication for at least 3 successive months. 
i. Females of childbearing potential (not surgically sterile by hysterectomy, bilateral 
salpingectomy, bilateral oophorectomy, or 2 years postmenopausal) must have an 
exclusively same-sex partner or use a medically acceptable method of contraception, 
and must agree to continue use of this method for the duration of the study and for 5 
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intrauterine device (IUD), steroidal contraceptive (oral, implanted, transdermal, or 
injected), barrier method with spermicide, abstinence, bilateral fallopian tube 
occlusion, and partner vasectomy. Contraception is further clarified in an 
administrative letter in Section 17.5.1. 
j. The patient must be willing and able to comply with study restrictions, perform 
requisite procedures 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.  
k. The patient must maintain their usual asthma controller regimen without change 
throughout the screening and run-in periods. A patient who experiences an asthma 
exacerbation during this time that requires additional medication, beyond increased 
SABA use, will be considered to have failed screening/run-in and cannot undergo 
randomization. A patient may be rescreened for this reason 1 time only. The duration 
between the date of Screen Failure and the re-screening must be >30 days. 
l. In order to be randomized, a patient must demonstrate the following: 
− inadequate asthma control at baseline/DoR as evidenced by 1 of the 4 criteria 
below: 
○ daytime asthma symptom score >0 on >2 of the previous 7 days based on the 
asthma control diary received at run-in OR 
○ need for reliever SABA use on >2 of the previous 7 days OR 
○ ≥1 nighttime awakening due to asthma over the previous 7 days OR 
○ pre-bronchodilator FEV1 <80% predicted at baseline/DoR 
AND 
− completion of at least 4 days of diary entries or equivalent during the last 7 days 
of run-in. A patient may be rescreened for this reason 1 time only. 
4.2. 
Patient Exclusion Criteria 
Patients will be excluded from participating in this study if they meet any of the following 
criteria:  
a. The patient has any clinically significant, uncontrolled medical condition (treated or 
untreated) that would interfere with the study schedule or procedures, interpretation 
of efficacy results, or compromise the patient’s safety. 
b. The patient has another confounding underlying lung disorder (eg, chronic 
obstructive pulmonary disease, interstitial lung disease, bronchiectasis eosinophilic 
granulomatosis with polyangiitis [EGPA, also known as Churg-Strauss syndrome], or 
allergic bronchopulmonary aspergillosis [ABPA]).  
c. The patient has a known hypereosinophilic syndrome. 
d. The patient has a diagnosis of malignancy within 5 years of the screening visit, except 
for treated and cured non-melanoma skin cancers.  


 
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e. The patient is a pregnant or lactating woman, or intends to become pregnant during 
the study or within 5 months after the last dose of study drug. Any woman becoming 
pregnant during the study will be withdrawn from the study. 
f. The patient required treatment for an asthma exacerbation within 4 weeks of 
screening or during the screening/run-in period. 
g. The patient is a current smoker (ie, has smoked within the last 6 months before 
screening) or has a smoking history ≥10 pack years. 
h. The patient is currently using any systemic immunosuppressive or 
immunomodulatory biologic (eg, anti-immunoglobulin E mAb or other mAb or 
soluble receptors) or other monoclonal antibody [eg, mepolizumab] or soluble 
receptors) or non-biologic (eg, methotrexate or cyclosporine), except maintenance 
oral corticosteroids for the treatment of asthma (up to and including 10 mg of 
prednisone daily or equivalent). Note: Previous use of such agents that occurred 
>5 half-lives from the initial screening visit may be allowed, if approved by the 
medical monitor.  
i. The patient participated in a clinical trial within 30 days or 5 half-lives of the 
investigational drug before screening, whichever is longer. 
j. The patient was previously exposed to benralizumab within 12 months of screening. 
k. The patient was previously exposed to reslizumab. 
l. The patient has a history of an immunodeficiency disorder including HIV.  
m. The patient has current or suspected drug and alcohol abuse. 
n. The patient has an active helminthic parasitic infection or was treated for one within 
6 months of screening.  
o. The patient has a history of allergic reaction or hypersensitivity to any component of 
the study drug. 
p. The patient has a history of latex allergy. (The current prefilled syringe device has a 
natural rubber component to the needle shield.)  
4.3. 
Justification for Key Inclusion and Exclusion Criteria 
The inclusion and exclusion criteria select for an asthma phenotype that remains uncontrolled on 
standard of care asthma medications that may benefit from a targeted therapy such as reslizumab, 
while also ensuring that enrolled patients are of sufficient overall health to safely participate in 
this study and not assume unnecessary risk. 
4.4. 
Criteria and Procedures for Discontinuation of Study Treatment 
and/or Study Withdrawal 
In accordance with the Declaration of Helsinki (in accordance with the applicable country’s 
acceptance), patients may voluntarily discontinue study treatment (ie, refuse study treatment but 
continue with study participation) or completely withdraw from the study (ie, with no further 
study participation or contact) at any time. The investigator also has the right to discontinue a 


 
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patient from study treatment and/or withdraw a patient from the study in the event of intercurrent 
illness, adverse events, pregnancy (see Section 7.2), or other reasons concerning the health or 
well-being of the patient, or in the event of lack of cooperation.  
If a patient withdraws consent, every attempt will be made to determine the reason. If the reason 
for withdrawal is adverse event or a potentially clinically significant abnormal laboratory test 
result, monitoring will be continued until the event has resolved or stabilized, until the patient is 
referred to the care of a health care professional, or until a determination of a cause unrelated to 
the study drug or study procedure is made. The specific event or test result must be recorded on 
the source documentation and transcribed onto the CRF. 
4.4.1. 
Discontinuation of Study Treatment 
If premature discontinuation of study treatment occurs for any reason, the patient should 
continue attending remaining study visits while off study treatment. The patient should not be 
considered withdrawn from the study due to interruption or discontinuation of study treatment. 
For this study, it is very important to continue collecting data from all patients whether or not 
they complete treatment. 
If premature discontinuation of study treatment occurs, the patient should return to the clinic as 
soon as possible for a study treatment discontinuation visit. All evaluations should be performed 
as an unscheduled visit and include all the assessments specified in the protocol for the early 
withdrawal visit (see Table 2). The investigator must determine the reason for and the date of 
discontinuation of study treatment and record this information in both the source documentation 
and the Study Drug Treatment Completion CRF. The patient’s continued participation in the 
study must be discussed by the investigator and site staff with the patient; the investigator and 
site staff must also request the patient to continue attending study visits according to the study 
visit schedule with all assessments completed up to week 52 (visit 17). The CAE event status and 
safety assessments at week 52 (visit 17) are the priority assessments for patients that prematurely 
discontinue study treatment. At a minimum, the investigator should make every effort to obtain 
information regarding serious adverse events, CAE events, and survival status at week 52. A 
safety follow-up visit (visit 18) should be conducted 12 weeks after visit 17. 
4.4.2. 
Complete Withdrawal from Study 
If a patient decides to completely withdraw from the study (ie, refuses any further study 
participation or contact), all study participation for that patient will cease and all data to be 
collected at subsequent visits will be considered missing. If a patient decides to completely 
withdraw from the study, the patient should return to the clinic as soon as possible to complete 
the early withdrawal visit (see Table 2). A complete final evaluation at the time of the patient’s 
withdrawal should be made, including an explanation of why the patient is withdrawing from the 
study. The reason for and date of withdrawal from the study must be recorded in the source 
documentation and the Double-Blind Treatment Period Completion CRF. 
For patients who are lost to follow-up (ie, patients whose status is unclear because they fail to 
appear for study visits without stating an intention to withdraw), the investigator should make 
appropriate efforts to re-establish contact with patient; attempts to contact the patient should be 
documented in the source documents. If contact has not been re-established, efforts should still 
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events, and survival status at the end of the 52-week treatment period. A patient should only be 
designated as lost to follow-up if the site is unable to establish contact with the patient after 
3 documented attempts via 2 different methods (phone, text, e-mail, certified letter, etc). 


 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Drugs Administered During the Study  
After successfully meeting entry criteria, eligible patients will be randomly assigned to study 
drug (110 mg of reslizumab or placebo) with stratification based on blood eosinophil count 
(300/μL to <400/μL or ≥400/μL) and age (12 to <18 years or ≥18 years) at baseline/DoR, using 
IRT, which utilizes computerized central randomization. Study drug will be administered by 
qualified study personnel as a sc injection every 4 weeks for a total of 13 doses. Patients within 
each treatment group (placebo and 110 mg) will be randomly allocated to a particular sequence 
of injection sites: 
a. upper arm (A)→abdomen (B)→thigh (C) 
b. abdomen (B)→thigh (C)→upper arm (A) 
c. thigh (C)→upper arm (A)→abdomen (B) 
Study drug will be administered as a single sc injection containing either placebo (1.0 mL) or 
110 mg of reslizumab (1.0 mL).  
The pre-filled syringe has a staked 27G ½” needle. Subcutaneous injections can be given at a 90° 
angle or at a 45° angle. The injection can be given at a 90° angle if 2 inches of skin can be 
grasped between the thumb and first finger. If only 1 inch of skin can be grasped, the injection 
should be done at a 45° angle. Product should be removed from the refrigerator and allowed to 
equilibrate at room temperature for 15 to 30 minutes before administration. 
Study drug will be administered by qualified study personnel who will ensure that the study drug 
is administered in accordance with the protocol. The needle shields of the prefilled syringes 
contain natural rubber latex, which may cause allergic reactions; see exclusion criterion (p). 
Additional information regarding study drug can be found in the Pharmacy Manual.  
A more detailed description of the reslizumab drug product is provided in Section 3.11. Study 
drug exposure will be measured and compliance to study drug administration will be monitored. 
5.2. 
Restrictions 
Medications prohibited before and/or during the study are described in Section 5.3. Restrictions 
in regard to sexual activity and required laboratory values are provided in the inclusion and 
exclusion criteria. 
5.3. 
Prior and Concomitant Therapy or Medication 
Any prior or concomitant therapy, medication, or procedure a patient has had 4 weeks before 
study drug administration and up to the end of the study period, including follow-up, will be 
recorded on the CRF. Generic or trade name, indication, and dosage will be recorded. The 
sponsor will encode all therapy and medication according to the World Health Organization drug 
dictionary (WHO Drug).  
Of note, prior asthma medications such as ICS, leukotriene pathway modifiers, long acting 
bronchodilators, and mast cell stabilizers may be taken concomitantly and should not be altered 


 
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during the study unless patient safety is at risk. Any changes in background maintenance therapy 
must be discussed with the medical monitor. 
The following medications will not be allowed during this study: 
• any immunosuppressive or immunomodulatory agents (biological and 
non-biological), including, but not limited to methotrexate, cyclosporine, and 
interferon (excluding systemic corticosteroids prescribed for asthma and maintenance 
allergen immunotherapy) 
• all biologic therapies, including, but not limited to omalizumab (Xolair®), 
mepolizumab, benralizumab, lebrikizumab, and anti-tumor necrosis factor 
monoclonal antibodies 
• all nonbiologic investigational drugs 
At each clinic visit after the screening visit, the investigator will ask patients whether they have 
taken any medications (other than study drug), including over-the-counter medications, vitamins, 
or herbal or nutritional supplements, since the previous visit. Indication, dosage, and start and 
end dates should be entered on the appropriate CRF.  
5.4. 
Procedures for Monitoring Patient Compliance 
The investigator will be responsible for monitoring patient compliance. If the investigator or the 
sponsor determines that the patient is not in compliance with the study protocol, the investigator 
and the sponsor should determine whether the patient should be withdrawn. The IEC/IRB should 
be notified. 
5.5. 
Total Blood Volume 
The estimated total blood volume withdrawn over the entire study (including screening) is 
approximately 120 mL per patient. To further reduce the volume of blood withdrawn, pediatric 
tubes will be used when possible. 


 
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6. 
ASSESSMENT OF EFFICACY  
6.1. 
Primary Efficacy Measure and Justification  
For this study, a CAE is defined as a clinically judged deterioration in asthma control as 
determined by the investigator and as evidenced by new or worsening asthma signs or symptoms 
based on the patient history, asthma control diary, physical examination, and/or ambulatory or 
clinic visit assessment of lung function AND that results in a medical intervention, including at 
least 1 of the following: 
• use of systemic corticosteroids (oral or injection) or at least a doubling from a stable 
maintenance oral corticosteroid dose for at least 3 days1 
• asthma specific hospital admission 
• asthma specific emergency department visit 
Additional medication and/or medical intervention that would satisfy the CAE definition 
occurring within 7 days of the last day of a prior CAE event will be considered as part of the 
same event for analysis purposes. 
The CAE start and stop dates will be collected in order to determine the exacerbation duration. 
The start date of a CAE will be the start date of the initial medical intervention (eg, use of 
systemic corticosteroids [oral or injection] or at least a doubling from a stable maintenance oral 
corticosteroid dose for at least 3 days, asthma specific hospital admission, or asthma specific 
emergency department visit, whichever comes first). The stop date is the last day of systemic 
corticosteroids or the last day of an asthma-specific hospitalization or emergency department 
visit, whichever is later. For patients who are on a stable maintenance oral corticosteroid dose 
and receive at least a doubling of that dose for 3 days, the stop date is when they return to their 
baseline dose. For patients receiving a new use of oral corticosteroids or at least a doubling from 
their stable maintenance oral corticosteroid dose for at least 3 days that did not return to baseline, 
a CAE stop date will be the day that they have been on a stable dose for at least 10 days. 
6.2. 
Spirometry 
Pre-bronchodilator FEV1, FVC, and FEF25%-75% and post-bronchodilator FEV1 will be measured 
using spirometry. The FEV1 is the volume of air which can be forcibly exhaled from the lungs in 
the first second, measured in liters. The FVC is the volume of air that can be forcibly blown out 
after full inspiration, measured in liters. The FEF25%-75% is the forced expiratory flow at 25% to 
75% forced vital capacity. For post-bronchodilatory spirometry, SABAs, such as salbutamol or 
albuterol, administered via a metered dose inhaler should be used. Four separate doses (eg, 
albuterol 360 μg or salbutamol 100 μg ex-valve) should be given by metered dose inhaler, as 
tolerated. Post-bronchodilator spirometry should be completed a minimum of 15 minutes after 
dosing of SABA. Spirometry will be done according to American Thoracic Society/European 
                                                 
1 A single depot corticosteroid injection would fulfill this criterion. 


 
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Respiratory Society 2005 procedural guidelines. The National Health and Nutrition Survey 
(NHANES) III reference equations will be used. 
6.3. 
PEF Monitoring 
AM (morning) ambulatory and PM (evening) ambulatory PEF will be measured. PEF will be 
measured using a PEF meter. PEF is the maximum speed of exhalation. AM (morning) 
ambulatory and PM (evening) ambulatory PEF will be measured by the patient and recorded in 
the asthma control diary. 
6.4. 
Asthma Quality of Life Questionnaire for Patients 12 years and 
Older 
The AQLQ +12 is a modified version of the standardized AQLQ, which was developed to 
measure functional impairments experienced by adults ≥17 years of age. The AQLQ +12 is valid 
for patients aged 12 to 70 years and includes 32 questions in 4 domains (symptoms, activity 
limitation, emotional function, and environmental stimuli) (Juniper et al 1992, Wyrwich et al 
2011). Patients are asked to recall their experiences during the previous 2 weeks and score each 
of the questions on a 7-point scale where 7 = no impairment and 1 = severe impairment 
(Appendix B).  
6.5. 
Asthma Control Questionnaire 
The ACQ is a validated asthma assessment tool that has been widely used (Juniper et al 1999). 
Six questions are self-assessments (completed by the patient). Each item on the ACQ has a 
possible score ranging from 0 to 6, and the total score is the mean of all responses (Appendix C). 
6.6. 
Asthma Symptom Assessment 
The asthma symptom score will be determined from the information recorded in the asthma 
control diary. A Likert-style scale will be used to quantify symptomatology. This scale has been 
used previously to assess changes in asthma symptoms in response to novel asthma treatments 
(Shapiro et al 2000). Every morning and evening, patients will indicate how much they are 
bothered by their asthma symptoms, as shown in Appendix G. 
6.7. 
Asthma Control Days 
An asthma control day is defined as a day on which the patient used ≤2 puffs of inhaled SABA, 
had no nighttime awakenings, and experienced no asthma exacerbations as defined in the 
protocol (Baumgartner et al 2003, Schulpher and Buxton 1993). 
6.8. 
St. George’s Respiratory Questionnaire  
The St. George's Respiratory Questionnaire (SGRQ) is a 50-item health status survey specific for 
chronic obstructive pulmonary disease and other respiratory diseases (Appendix F; Barr et al 
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6.10. 
Asthma Rescue Medication Use 
The number of times asthma rescue medication (number of inhalations/puffs) is used will be 
assessed by reviewing the asthma control diary. Note: SABA therapy used for exercise 
pretreatment should not be recorded. 
6.11. 
Nighttime Awakenings 
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7. 
ASSESSMENT OF SAFETY  
In this study, safety will be assessed by qualified study personnel by evaluating the following:  
• adverse events throughout the study 
• vital signs (pulse, respiratory rate, blood pressure) assessments throughout the study 
• concomitant medication usage throughout the study 
• physical examination findings throughout the study 
• laboratory evaluations at screening, the baseline visit/DoR, and periodically 
throughout the study 
• ECG at screening and week 24, 36, and 52 
7.1. 
Adverse Events  
7.1.1. 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a patient administered a pharmaceutical 
product, regardless of whether it has a causal relationship with this treatment.  
In this study, any adverse event occurring after the clinical study patient has signed the informed 
consent form should be recorded and reported as an adverse event.  
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study or of any concurrent disease, whether or not 
considered related to the study drug. Asthma exacerbation is an efficacy variable for this study 
and should be captured on the asthma exacerbation CRF; accordingly, asthma exacerbations 
should not be recorded as adverse events unless assessed as more severe than the patient's usual 
disease course. In this case, the investigator should determine if the adverse event is nonserious 
or serious based on seriousness criteria, as defined in Section 7.1.5. A new condition or the 
worsening of a pre-existing condition will be considered an adverse event. Stable chronic 
conditions (such as arthritis) that are present before study entry and do not worsen during this 
study will not be considered adverse events.  
Accordingly, an adverse event can include any of the following: 
• intercurrent illnesses 
• physical injuries 
• events possibly related to concomitant medication 
• significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions  
• drug interactions 
• laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
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event, or require medical treatment or further diagnostic work-up, or are considered 
by the investigator to be clinically significant (Note: Abnormal laboratory test results 
at the screening visit that preclude a patient from entering the study or receiving study 
treatment are not considered adverse events.)  
7.1.2. 
Recording and Reporting Adverse Events 
For adverse event recording, the study period is defined for each patient as that time period from 
signature of the informed consent form through the end of the follow-up period. For this study, 
the follow-up period is defined as 12 weeks after the EOT visit. Adverse events will be collected 
at each visit, including the follow-up visit, via adverse event inquiry.  
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the CRF, regardless of the severity or seriousness of the 
event or judged relationship to the study drug. For serious adverse events, the Serious Adverse 
Event Form must also be completed and the serious adverse event must be reported immediately 
(see Section 7.1.5.3.1). The investigator does not need to actively monitor patients for adverse 
events once the study has ended. Serious adverse events that occur to a patient after the end of 
study should be reported to the sponsor if the investigator becomes aware of them, following the 
procedures described in Section 7.1.5.3.1.  
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as, “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe.” In addition, the eDiary will be 
programmed to query the patient about symptoms potentially consistent with hypersensitivity 
occurring during the 24 hour period following study drug injection. All reported or observed 
signs and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings will be 
recorded collectively as a single diagnosis on the CRF and, if it is a serious adverse event, also 
on the Serious Adverse Event Form. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, returned to baseline, or until the patient is referred for continued care to another health 
care professional, or until a determination of a cause unrelated to the study drug or study 
procedure is made. 
The onset and end dates, duration (in case of adverse event duration of less than 24 hours), action 
taken regarding study drug, treatment administered, and outcome for each adverse event must be 
recorded on the source documentation and transcribed onto the CRF. The approximate time of 
onset for each adverse event that starts within 24 hours of study drug administration will be also 
recorded. The relationship of each adverse event to study drug treatment and study procedures, 
and the severity and seriousness of each adverse event, as judged by the investigator, must be 
recorded as described below. 
7.1.3. 
Severity of an Adverse Event 
The severity of each adverse event must be recorded as 1 of the choices on the following scale: 
Mild:  
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Moderate:  Some limitation of usual activities 
Severe:  
Inability to carry out usual activities 
7.1.4. 
Relationship of an Adverse Event to the Study Drug 
The relationship of an adverse event to the study drug is characterized as follows: 
Term 
Definition 
Clarification 
No reasonable 
possibility 
(not related) 
 
This category applies to adverse 
events that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc.) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the study drug. 
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply: 
• 
It does not follow a reasonable temporal sequence 
from the administration of the study drug. 
• 
It could readily have been produced by the patient’s 
clinical state, environmental, or toxic factors, or other 
modes of therapy administered to the patient. 
• 
It does not follow a known pattern of response to the 
study drug.  
• 
It does not reappear or worsen when the study drug is 
re-administered.  
Reasonable 
possibility 
(related) 
 
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the study drug administration cannot 
be ruled out with certainty. 
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply: 
• 
It follows a reasonable temporal sequence from 
administration of the study drug. 
• 
It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors or other modes of 
therapy administered to the patient. 
• 
It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear upon 
discontinuation of the study drug, yet a drug 
relationship clearly exists. 
• 
It follows a known pattern of response to the study 
drug. 
7.1.5. 
Serious Adverse Events 
7.1.5.1. 
Definition of a Serious Adverse Event 
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions: 
• death 
• a life-threatening adverse event (ie, the patient was at immediate risk of death from 
the event as it occurred); does not include an event that, had it occurred in a more 
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• inpatient hospitalization or prolongation of existing hospitalization, which means that 
hospital inpatient admission and/or prolongation of hospital stay were required for 
treatment of an adverse event, or that they occurred as a consequence of the event. 
Hospitalizations scheduled before study entry will not be considered serious adverse 
events, unless there was worsening of the preexisting condition during the patient’s 
participation in this study. Note: Hospitalizations due to asthma exacerbation will be 
reported as serious adverse events if the presentation or outcome is more severe than 
the patient’s known course of asthma 
• persistent or significant disability or incapacity (refers to a substantial disruption of 
one’s ability to conduct normal life functions) 
• a congenital anomaly/birth defect 
• an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or the 
development of drug dependency or drug abuse. Note: Any suspected transmission of 
an infectious agent via a medicinal product is considered an important medical event 
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event. 
7.1.5.2. 
Expectedness 
A serious adverse event that is not included in the adverse reaction section of the relevant 
reference safety information by its specificity, severity, outcome, or frequency is considered an 
unexpected adverse event. The reference safety information for this study is the Investigator’s 
Brochure. All serious adverse events will be evaluated for expectedness by the sponsor. 
7.1.5.3. 
Reporting a Serious Adverse Event 
7.1.5.3.1. Investigator Responsibility 
To satisfy regulatory requirements, all serious adverse events (as described in Section 7.1.5.1, 
including the protocol-defined follow-up period, described in Section 7.1.2), regardless of judged 
relationship to treatment with the study drug, must be reported to the sponsor by the investigator. 
The event must be reported within 24 hours of when the investigator learns about it. Completing 
the serious adverse event form and reporting the event must not be delayed, even if not all the 
information is available. The investigator does not need to actively monitor patients for adverse 
events once this study has ended. Serious adverse events occurring to a patient after the end of 
the study should be reported to the sponsor if the investigator becomes aware of them. 
The serious adverse event form should be sent to the local safety officer (LSO) or other 
designated personnel (a CRO in a country without a sponsor LSO) (contact information is in the 
Clinical Study Personnel Contact Information section); the LSO will forward the report to the 
sponsor’s Global Patient Safety & Pharmacovigilance Department. 
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• study number 
• investigator and investigational center identification 
• patient number 
• onset date and detailed description of adverse event 
• investigator’s assessment of the relationship of the adverse event to the study drug 
(no reasonable possibility, reasonable possibility) 
Additional information may include the following: 
• age and sex of patient 
• date of first dose of study drug 
• date and amount of last administered dose of study drug 
• action taken 
• outcome, if known 
• severity 
• explanation of assessment of relatedness 
• concomitant therapy (including doses, routes, and regimens) and treatment of the 
event 
• pertinent laboratory or other diagnostic test data  
• medical history 
• results of dechallenge/rechallenge, if known 
• for an adverse event resulting in death:  
− cause of death (whether or not the death was related to study drug as determined 
by the investigator) 
− autopsy findings (if available) 
Each report of a serious adverse event will be reviewed and evaluated by the investigator and the 
sponsor to assess the nature of the event and the relationship of the event to the study drug, study 
procedures, and to underlying disease. The sponsor will also evaluate the expectedness of all 
serious adverse events. 
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigational center within 24 hours of when it becomes 
known to the same address as the initial report.  
For all countries, the sponsor’s Global Patient Safety & Pharmacovigilance Department will 
distribute the Council for International Organizations of Medical Sciences (CIOMS) form/XML 
file to the LSO/CRO for local submission to the regulatory authorities, IEC/IRBs, and 
investigators, according to regulations. The investigator is responsible for ensuring that the 
IEC/IRB is also informed of the event, in accordance with local regulations. 


 
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The blinding will be maintained for the people who are involved directly in the study. Therefore, 
in case of a SUSAR, only the LSO/CRO will receive from PhV the unblinded report for 
regulatory submission; the others will receive a blinded report.  
Note: Although pregnancy is not a serious adverse event, the process for reporting a pregnancy is 
the same as that for reporting a serious adverse event, but using the pregnancy form (see 
Section 7.2).  
If possible, a blood sample for measurement of serum reslizumab concentrations will be obtained 
from patients experiencing a serious adverse event, an adverse event leading to withdrawal, an 
observation of any severe hypersensitivity reaction (eg, anaphylaxis), or an exacerbation of 
asthma symptoms. 
7.1.5.3.2. Sponsor Responsibility 
If a serious unexpected adverse event is believed to be related to the study drug or study 
procedures, the sponsor will take appropriate steps to notify all investigators participating in 
sponsored clinical studies of reslizumab and the appropriate regulatory authorities (and IEC/IRB, 
if appropriate).  
In addition to notifying the investigators and regulatory authorities (and IEC/IRB, if appropriate), 
other measures may be required, including the following:  
• altering existing research by modifying the protocol 
• discontinuing or suspending the study 
• altering the process of informed consent by modifying the existing consent form and 
informing current study participants of new findings 
• modifying listings of expected toxicities to include adverse events newly identified as 
related to reslizumab 
7.1.6. 
Protocol-Defined Adverse Events for Expedited Reporting to Teva 
For the purposes of this protocol, the following are considered protocol-defined adverse events 
for expedited reporting to Teva: anaphylaxis, newly-diagnosed malignancy, opportunistic 
infection, and parasitic helminth infection. Protocol-defined adverse events for expedited 
reporting can be either serious or nonserious according to the criteria outlined in Section 7.1.5.1. 
The process for reporting a protocol-defined adverse event for expedited reporting is the same as 
that for reporting a serious adverse event (see Section 7.1.5.3). A list of potential opportunistic 
infections is found in Appendix I. 
7.1.7. 
Specific Adverse Event Case Report Form Capturing 
7.1.7.1. 
Anaphylaxis/Hypersensitivity Reactions Case Report Form 
Information about all suspected anaphylaxis events will be recorded on the Suspected 
Anaphylaxis/Hypersensitivity Reactions CRF, which is based on the 2006 Joint NIAID/FAAN 
Second Symposium on Anaphylaxis (Sampson et al, 2006; Appendix H). The 
Anaphylaxis/Hypersensitivity Reactions CRF should be initiated in real time (along with vital 
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possible for suspect events outside the clinic. The process for reporting a protocol-defined 
adverse event is the same as that for reporting a serious adverse event (see Section 7.1.5.3). 
These events can be either serious or nonserious, according to the criteria outlined in 
Section 7.1.5.1.  
7.1.7.2. 
Creatine Phosphokinase/Muscular Adverse Events Case Report Form  
Potentially clinically significant creatine phosphokinase (CPK) elevations (with or without 
associated symptoms) or myalgia/muscle symptoms will be recorded as an adverse event and 
documented using the potentially clinically significant CPK/myalgia case report form. A 
potentially clinically significant CPK is defined as ≥3.1× upper limit of normal (ULN) (Grade 3 
based on the Food and Drug Administration [FDA] “Guidance for Industry Toxicity Grading 
Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative Vaccine Clinical 
Trials”). 
If a potentially clinically significant CPK level (≥3.1 × ULN) occurs, the patient should attend an 
unscheduled visit for a physical examination and additional testing if indicated per investigator 
judgement. CPK levels will be re-tested at a minimum of every 7 to 10 days until the elevation is 
resolved, or if agreed with the medical monitor that no further testing is indicated. For ≥10 × 
ULN elevations in CPK, repeat CPK level, urinalysis (including microscopy), serum electrolytes, 
BUN, and creatinine will be performed as soon as possible after receipt of the CPK result. 
Further testing of CPK levels should be undertaken as frequently as needed to manage patient 
care per investigator judgment, but should be at a minimum of every 7 to 10 days as above. Need 
for repeat urinalysis, serum electrolytes, BUN, and creatinine testing should be determined by 
the investigator. In addition, need for treatment (eg, administration of iv fluids and urine 
alkalinization) should be considered by the investigator.  
In cases deemed by the investigator to be treatment-related elevations in CPK ≥10 × ULN (eg, 
potentially rhabdomyolysis), study drug discontinuation should occur at least until CPK 
normalization or longer based on investigator clinical assessment.   
7.1.8. 
Withdrawal Due to an Adverse Event 
Any patient who experiences an adverse event may be withdrawn from the study or from study 
treatment at any time at the discretion of the investigator. If a patient is withdrawn wholly or in 
part because of an adverse event, both the adverse events page and termination page of the CRF 
will be completed at that time.  
The patient will be monitored at the discretion of the investigator (eg, until the event has 
resolved or stabilized, until the patient is referred to the care of a health care professional, or 
until a determination of a cause unrelated to the study drug or study procedure is made). The 
investigator must inform the medical monitor as soon as possible of all patients who are being 
considered for withdrawal due to adverse events. Additional reports must be provided when 
requested. 
If a patient is withdrawn from the study or study drug for multiple reasons that include adverse 
events, the termination page of the CRF should indicate that the withdrawal was related to an 
adverse event. An exception to this requirement will be the occurrence of an adverse event which 
in the opinion of the investigator is not severe enough to warrant discontinuation but which 
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such a case, the reason for discontinuation would be the need to take a prohibited medication, not 
the adverse event. 
A subject should only be designated as lost to follow-up if the site is unable to establish contact 
with the subject after 3 documented attempts via 2 different methods (phone, text, e-mail, 
certified letter, etc). 
7.1.9. 
Overdose of Study Drug  
Any dose of study drug (whether the investigational product, reference therapy, or a placebo), 
whether taken intentionally or unintentionally, in excess of that prescribed must be immediately 
reported to the sponsor. When the identification of the study drug must be known, the 
investigator must follow the procedures outlined in Section 3.10.  
Medication errors will be captured as protocol violations or deviations depending on the error. 
7.1.10. 
Protocol Deviations Because of an Adverse Event 
If a patient experiences an adverse event or medical emergency, departures from the protocol 
may be allowed on a case-by-case basis. After stabilization and/or treatment has been 
administered to ensure patient safety, the investigator or other physician in attendance must 
contact the medical monitor as soon as possible to discuss the situation. The investigator, in 
consultation with the sponsor, will decide whether the patient should continue to participate in 
the study. 
7.2. 
Pregnancy  
All pregnancies that occur during the study, or within 5 months after last investigational product 
(IP) injection, are to be reported immediately to the medical monitor, and the investigator must 
provide the Teva Global Pharmacovigilance Department with the pregnancy form. The process 
for reporting a pregnancy is the same as that for reporting a serious adverse event (see 
Section 7.1.5.3).  
Any patient becoming pregnant during the study will be withdrawn. All patients who become 
pregnant after first IP administration and within 5 months after last IP injection will be 
monitored to the completion or termination of the pregnancy. If the pregnancy continues to term, 
the outcome (health of the infant up to 8 weeks of age), including spontaneous or voluntary 
termination, details of birth, and presence or absence of any birth defect, congenital 
abnormalities, or maternal and newborn complications, will be reported to the sponsor. Any 
complication of pregnancy will be reported as an adverse event or serious adverse event, as 
appropriate. 
If the pregnancy does not continue to term, 1 of the following actions will be taken: 
• For a spontaneous abortion, report as a serious adverse event.  
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event. 
• For an elective abortion not due to developmental anomalies, report on the pregnancy 
form. 


 
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The pregnancy should be followed up to determine outcome, including spontaneous or voluntary 
termination, details of birth, and presence or absence of any birth defect, congenital 
abnormalities or maternal and newborn complications. Pregnancy follow-up reports, like 
pregnancy reports, should be forwarded to Pharmacovigilance for data-entry to the global safety 
database and are also recorded on a specific CRF provided by Local Clinical Management. 
The pregnancies reporting procedure should be the same as the serious adverse event reporting 
procedure. 
7.3. 
Clinical Laboratory Tests 
A laboratory test result that has significantly worsened (according to investigator's medical 
judgment) from the baseline/DoR result will be recorded on the source documentation and 
should be repeated. An adverse investigational event includes a laboratory or diagnostic test 
abnormality (once confirmed by repeat testing) that results in the withdrawal of the patient from 
the study, the temporary or permanent cessation of treatment with study drug, or medical 
treatment or further diagnostic work-up. And adverse clinical laboratory should be monitored as 
described in Section 7.1.2. See Section 7.1.1 for a description of laboratory results that will be 
reported as adverse events. 
In addition, potentially clinically significant values will be predefined by the sponsor for selected 
laboratory parameters and will be detailed in the statistical analysis plan.  
Clinical laboratory tests (serum chemistry, hematology, serology, and urinalysis) will be 
performed before IP administration at the time points detailed in Table 2. Clinical laboratory 
tests will be performed using the central laboratory. Specific laboratory tests to be performed are 
listed below.  
7.3.1. 
Serum Chemistry 
The following serum chemistry tests will be performed: 
• calcium 
• phosphorus 
• sodium 
• potassium 
• chloride 
• creatine phosphokinase (at scheduled visits as noted in Table 2) 
• bicarbonate or carbon dioxide 
• glucose 
• blood urea nitrogen (BUN) 
• creatine 
• cholesterol (at screening and week 52 or early withdrawal only) 
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• alanine aminotransferase 
• aspartate aminotransferase 
• lactic dehydrogenase 
• alkaline phosphatase 
• creatine phosphokinase 
• total protein 
• albumin 
• total bilirubin 
• direct bilirubin (only if total bilirubin is elevated) 
• indirect bilirubin (only if total bilirubin is elevated) 
7.3.2. 
Hematology and Serology 
The following hematology tests will be performed: 
• hemoglobin 
• hematocrit 
• platelet count 
• absolute neutrophil count 
• white blood cell count and differential count 
− polymorphonuclear leukocytes (neutrophils) 
− lymphocytes 
− eosinophils (blinded) 
− monocytes (blinded) 
− basophils 
7.3.3. 
Urinalysis 
Urinalysis will be performed at screening and will include testing for the following: 
• protein 
• glucose 
• ketones 
• blood (hemoglobin) 
• pH 
• specific gravity 
• microscopic 


 
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− bacteria 
− red blood cells 
− white blood cells 
− casts 
− crystals 
7.3.4. 
Other Clinical Laboratory Tests 
At screening, patients will be tested for hepatitis B surface antigen, hepatitis C antibody, and 
HIV.  
7.3.4.1. 
Human Chorionic Gonadotropin Tests 
Human chorionic gonadotropin serum tests will be performed for all females of childbearing 
potential at screening (visit 1). Urine pregnancy tests will be performed at baseline/DoR, before 
study drug injection at each administration visit and at week 52, or early withdrawal, and at 
follow-up V18. Any patient who becomes pregnant during the study will be withdrawn. 
Procedures for reporting the pregnancy are provided in Section 7.2.  
7.4. 
Vital Signs 
Vital signs will be measured at time points specified in Table 2, and before other assessments 
(eg, blood draw and pulmonary function testing) and study drug administration. Vital signs 
include the following: 
• pulse 
• blood pressure 
• body temperature 
• respiratory rate 
Before pulse and blood pressure are measured, the patient must be in a supine or 
semi-erect/seated position and resting for at least 5 minutes. The same position and arm should 
be used each time vital signs are measured for a given patient. For any abnormal vital sign 
finding, the measurement should be repeated as soon as possible. Any vital sign value that is 
judged by the investigator as a clinically significant change (worsening) from a baseline value 
will be considered an adverse event, recorded on the source documentation and transcribed onto 
the CRF, and monitored as described in Section 7.1.2. 
In addition, potentially clinically significant values will be predefined by the sponsor for selected 
vital parameters and will be detailed in the statistical analysis plan.  
7.5. 
Electrocardiography 
A 12-lead ECG will be conducted at screening (visit 1), week 24 (visit 10), week 36 (visit 13), 
and EOT or early withdrawal. ECGs should be obtained before other assessments (eg, blood 
draw and pulmonary function testing) and study drug administration. Standard ECGs parameters 
will be recorded using a centralized process, and the ECG will be interpreted locally by the 


 
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Principal Investigator (or qualified physician) as normal or abnormal. If the ECG is read as 
abnormal the Principal Investigator will indicate whether or not the abnormality is clinically 
significant (yes or no) and write in the detailed interpretation/diagnosis. Clinically significant 
abnormal ECG findings at baseline/DoR and screening should be recorded as part of the medical 
history. Any ECG finding that is judged by the investigator as a clinically significant change 
compared with a baseline/DoR value will be considered an adverse event, recorded on the source 
documentation and transcribed onto the CRF, and monitored as described in Section 7.1.2. 
In addition, potentially clinically significant values will be predefined by the sponsor for selected 
ECG parameters and will be detailed in the statistical analysis plan.  
7.6. 
Physical Examinations 
Physical examinations, including height and weight, will be performed at specified time points as 
outlined in Table 2. The “full” physical examination should include the following organ systems: 
General appearance; Head, Eyes, Ears, Nose, and Throat (HEENT); Chest and Lung; Heart; 
Abdomen; Musculoskeletal; Skin; Lymph Nodes; and Neurological. The “brief” physical 
examination should include at minimum the following organ systems: General appearance; 
HEENT; Chest and Lung; Heart; and Skin. Any physical examination finding that is judged by 
the investigator as a clinically significant change (worsening) compared with a baseline/DoR 
value will be considered an adverse event, recorded on the CRF, and monitored as described in 
Section 7.1.2.  
7.7. 
Concomitant Therapy or Medication 
Concomitant therapy or medication usage will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.3.  
7.8. 
Methods and Timing of Assessing, Recording, and Analyzing Safety 
Data 
All adverse events will be reviewed on a periodic basis by the clinical project physician/medical 
monitor according to the safety monitoring plan (eg, scheduled safety reviews for study drug) as 
interim/preliminary safety databases become available. Safety data will additionally be evaluated 
periodically and ad hoc (if necessary) in the Product Safety Group. 
Methods and timing of assessing safety data are discussed in Section 3.16. Procedures for 
recording safety data are discussed in Section 13.1 and methods of analyses are discussed in 
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8. 
ASSESSMENT OF PHARMACOKINETICS, BIOMARKERS, AND 
IMMUNOGENICITY 
8.1. 
Pharmacokinetic Variables 
Serum reslizumab concentration will be measured at the time points indicated in Table 2.  
8.1.1. 
Specimen Sampling and Handling 
Blood samples (3 mL) will be collected via venipuncture or indwelling catheter at the time points 
detailed in Table 2 for serum concentration measurements of reslizumab.  
Samples will be collected into labeled serum separator tubes and inverted slowly at least 5 times 
to thoroughly mix the blood with the clotting activation agent. Labels for samples should include 
study number, patient number, period, and nominal collection time. Blood samples will be left 
standing upright at room temperature (20°C to 25°C) to clot for approximately 30-60 minutes. 
Samples should then be centrifuged at a minimum of 1500 g for approximately 10 minutes at 
4°C (if available, or ambient if 4°C centrifuge is not available) until clot and serum are well 
separated. Samples may be centrifuged at ambient temperature at 1500 g for 10 minutes as long 
as measures are be taken as appropriate to prevent samples from heating significantly during 
centrifugation. Separated serum will be transferred in approximately equal portions into 2 
opaque, labeled, cryotubes (Aliquot A and B), immediately frozen in an upright position at a 
temperature within the range of –60ºC to –90ºC, and stored under these conditions until shipped 
to the bioanalytical facility. Storage at -15 to -25°C is acceptable for a period of up to 60 days if 
a ≤-65°C freezer is not available. The listed temperatures must be maintained. Labels for samples 
should include study number, patient number, period, nominal collection time, set (A or B), and 
indication that they are PK samples. 
The dates and exact times of study drug administration and of each PK sample will be recorded 
on the source documentation and transcribed onto the CRF. 
8.1.2. 
Shipment and Analysis of Samples 
Serum samples for all patients will be shipped from the investigational center to the central 
laboratory, where they will be stored until shipped to the sponsor or its designee for analysis. The 
central laboratory will be notified before the shipment of the samples and will be sent the 
shipping information when the samples are shipped.  
Set A samples will be transported with a temperature data logger and frozen with sufficient dry 
ice, by next-day courier to the central laboratory.  
Set B samples will either be sent to the same laboratory as that for set A on a later day by 
next-day courier, or be retained at the investigational center until the study is completed (unless 
shipment to another facility is requested by the sponsor).  
Samples from reslizumab-treated patients will be analyzed using an appropriate validated 
method. Samples from placebo-treated patients will not be analyzed. Timing of the initiation of 
sample analysis will be determined by the Teva Global Bioassays and Technology representative 
responsible for the bioanalysis. The bioanalytical team will not be blinded for this analysis. 


 
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8.2. 
Biomarker Variables 
8.2.1. 
Blood Eosinophil Counts 
Biomarker measures will include blood eosinophils and 
 
measured at the time points indicated in Table 2. Details of blood sampling and 
preparation are described in the Laboratory Manual provided in the study file documents. 
8.2.2. 
 
 
 
8.3. 
Immunogenicity 
Blood samples (5 mL) for assessment of ADA response will be taken before dosing at the time 
points indicated in Table 2. Unscheduled blood samples for anti-reslizumab antibody assessment 
will also be obtained from all patients (inside and outside of the United States) experiencing a 
serious adverse event, an adverse event leading to withdrawal, an observation of any severe 
hypersensitivity reaction (eg, anaphylaxis), or an exacerbation of asthma symptoms.  
Samples will be collected into labeled serum separator tubes and inverted slowly at least 5 times 
to thoroughly mix the blood with the clotting activation agent. Labels for samples should include 
study number, patient number, period, and nominal collection time. Blood samples will be left 
standing upright at room temperature (20°C to 25°C) to clot for approximately 30-60 minutes. 
Samples should then be centrifuged at a minimum of 1500 g for approximately 10 minutes at 
4°C until clot and serum are well separated. Samples may be centrifuged at ambient temperature 
at 1500 g for 10 minutes as long as measures are taken as appropriate to prevent samples from 
heating significantly during centrifugation.  
Separated serum will be transferred, in approximately equal portions, into two labeled cryovial 
tubes (primary aliquot A and back-up aliquot B) and stored in an ultralow freezer at ≤-65°C until 
shipped to a central or bioanalytical laboratory with temperature monitoring. Sample labels 
should include patient number, study number, collection date, and indication that it is an ADA 
sample aliquot (A or B). Storage at -15 to -20°C is acceptable for a period of up to 1 month if a 
≤-65°C freezer is not available. The listed temperatures must be maintained. The actual times 
and dates of sampling will be recorded on the CRF. 
8.3.1. 
Shipment and Analysis of Samples 
Serum samples for immunogenicity assessment for all patients will be shipped from the 
investigational center to the central laboratory, where they will be stored until shipped to the 
sponsor or its designee for analysis. Samples will be stored in an upright position at ≤–65ºC until 
assayed. The central laboratory will be notified before the shipment of the samples and will be 
sent the shipping information when the samples are shipped. Set A samples will be transported 
with a temperature data logger and frozen with sufficient dry ice by next-day courier to the 
central laboratory.  


 
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Set B samples will either be sent to the same laboratory as that for set A on a later day by 
next-day courier, or be retained at the investigational center until the study is completed (unless 
shipment to another facility is requested by the sponsor).  
Samples from reslizumab-treated patients will be analyzed using appropriate validated methods. 
Timing of the initiation of sample analysis will be determined by the Teva Pharmaceuticals 
bioanalytical department representative responsible for the bioanalysis. The bioanalytical team 
will not be blinded for this analysis. 
Additional details regarding the collection, handling, and shipment of samples for measurement 
of anti-drug antibodies are provided in the investigator laboratory manual and its associated 
specimen collection summary. 


 
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9. 
STATISTICS 
This section describes the statistical analysis as foreseen at the time of planning the study. 
Changes, additions, and further details about the analyses will be described in the statistical 
analysis plan. After finalization of the statistical analysis plan, any additional analyses or 
changes to analyses that may be required will be fully disclosed in the clinical study report. 
9.1. 
Sample Size and Power Considerations 
The primary efficacy variable for this study is the frequency of CAEs per patient during the 
52-week treatment period. The study will be considered positive if the primary efficacy measure 
indicates a statistically significant treatment effect of reslizumab versus placebo at the respective 
predefined significance level. 
Power calculations were based on the below assumptions: 
• Negative binomial (NB) distribution for the number of exacerbations with a mean of 
2.9 exacerbations per patient per year for the placebo group  
• Dispersion parameter of 1.2  
• Treatment effect of 45% between the reslizumab group and the placebo group  
• Alpha level of 0.05 
Based on the assumptions above, 225 patients per arm (450 total) will provide >90% power to 
detect significant treatment effect of reslizumab over placebo in the reduction of exacerbation 
rate. The sample size was increased beyond the sample size required to provide 90% power in 
order to allow sufficient number of patients to assess safety and immunogenicity and to ensure 
adequate enrollment in the adolescent subset. The current sample size also provides higher power 
for other efficacy endpoints. 
Patients with blood eosinophil levels of 300/μL to <400/µL will be limited to no more than 30% 
of patients (60 patients per treatment group). 
9.2. 
Analysis Sets 
9.2.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all randomized patients and will be used as the 
default population for primary efficacy analysis. In this population, treatment will be assigned 
based on the treatment to which patients were randomized, regardless of which treatment they 
actually received. 
9.2.2. 
Safety Analysis Set 
The safety analysis set will include all patients who receive at least 1 dose of study drug. In this 
population, treatment will be assigned based upon the treatment patients actually receive, 
regardless of the treatment to which they were randomized.  


 
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9.2.3. 
Additional Analysis Sets 
9.2.3.1. 
Per-Protocol Analysis Set 
The Per-Protocol (PP) Analysis Set is a subset of the ITT Analysis Set including only Patients 
without major protocol violations.  
Additional analysis sets may be detailed in the Statistical Analysis Plan.  
9.3. 
Data Handling Conventions 
The primary analysis will include multiple imputations for missing data as detailed in 
Section 9.5.6.1.  
The methodology and algorithm to be used for imputations will be detailed in the Statistical 
Analysis Plan. For all other variables, only the observed data from the patients will be used in the 
statistical analyses, ie, there is no plan to estimate missing data.  
9.4. 
Study Population 
The ITT analysis set (see Section 9.2.1) will be used for all study population summaries unless 
otherwise noted. Summaries will be presented by treatment group and for all patients. 
9.4.1. 
Patient Disposition 
Data from patients screened, patients screened but not randomized, patients randomized to 
treatment in the study, patients randomized but not treated, patients in the safety analysis set, 
patients in the per-protocol analysis set, patients who completed treatment period (week 52), and 
patients who complete the study (see Section 3.16.4 for definition of study completion), patients 
that did not complete treatment but were followed up until end of study will be summarized. 
Data from patients who withdraw from the study will also be summarized by reason for 
withdrawal using descriptive statistics, and the number of patients who discontinue treatment but 
continue to attend study visits will be tabulated. 
9.4.2. 
Demographic and Baseline Characteristics  
Patient demographic and baseline characteristics, including medical history, prior medications, 
and ECG findings, will be examined to assess the comparability of the treatment groups and will 
be summarized using descriptive statistics. For continuous variables, descriptive statistics 
(number [n], mean, standard deviation (SD), standard error, median, minimum, and maximum) 
will be provided. For categorical variables, patient counts and percentages will be provided. 
Categories for missing data will be presented if necessary. 
9.5. 
Efficacy Analysis  
9.5.1. 
Primary Endpoint  
The primary efficacy variable for this study is the frequency of CAEs per patient during the 
52-week treatment period. 


 
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9.5.2. 
Secondary Endpoints 
Secondary efficacy endpoints are as follows: 
• change in pre-bronchodilator FEV1 from baseline/DoR at week 52 
• change in AQLQ +12 score from baseline/DoR at week 52 
• change in ACQ-6 score from baseline/DoR at week 52 
• change in total asthma symptom scores (day and night) from baseline at week 52 
• percentage of asthma control days from baseline/DoR to week 52 
• change in SGRQ score from baseline/DoR at week 32 
• time to first CAE during the 52-week treatment period 
• frequency of exacerbations requiring hospitalization or emergency department visits 
per patient during the 52-week treatment period 
• frequency of moderate exacerbations defined as exacerbations requiring additional 
asthma controller medication that was not a systemic corticosteroid and did not result 
in an asthma-specific hospitalization or emergency department visit during the 
52-week treatment period 
The order of the secondary endpoints above is the order of hierarchy to be used for controlling 
type I error as described in Section 9.6. 


 
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9.5.5. 
Target Biomarker Endpoints 
The target biomarker endpoints are the blood eosinophil counts at baseline/DoR; weeks 2, 4, 8, 
12, 16, 32, 52 or early withdrawal; and the follow-up visit (approximately week 64). 
9.5.6. 
Planned Method of Analysis 
The ITT analysis set (see Section 9.2.1) will be used for all efficacy analyses. Summaries will be 
presented by treatment group. The per-protocol analysis set will be used as sensitivity analysis 
for the primary analysis.  
The baseline for diary variables will be the average of the run-in values over the 7 days 
preceding baseline/DoR. The baseline for clinic visit variables will be the last observed value 
before the first dose of study drug. The baseline for eosinophils levels analysis will be screening 
value. 
9.5.6.1. 
Primary Efficacy Analysis 
The primary analysis of frequency of CAEs will use the NB regression model. The primary NB 
model will include the treatment group, randomization stratification factors, and number of 
exacerbations in the previous year as model factors and an offset variable. The offset variable 
will be calculated as the logarithm of follow-up duration minus the summed duration of 
exacerbations. The ratio of CAE rate between the treatment groups and its 95% confidence 
interval (CI) will be estimated from the NB model. 
CAEs that occur between the completion of the 1st dose of study drug and 2 weeks after the end 
of treatment/early withdrawal visit will be counted towards the CAEs for analysis. 
The primary analysis will incorporate data from all randomized patients. The analysis will 
include the frequency of all exacerbations observed in 52 weeks, for patients completed the 
52 weeks treatment period and for patients withdrew from treatment earlier than 52 weeks. For 
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attempts to contact the patient, a multiple imputation will be performed for the frequency of 
exacerbation after withdrawal. The multiple imputations will utilize the post-withdrawal data 
observed for patients who withdrew early and for which the sponsor succeeded to retrieve the 
data. The methodology and algorithm to be used for imputations will be detailed in the Statistical 
Analysis Plan. 
Sensitivity analyses will include: 
• Analysis including the frequency of all exacerbations observed until treatment 
completion or until withdrawal from treatment, excluding exacerbations observed 
after withdrawing from treatment. 
• Repeating the primary analysis using an offset variable in the NB model calculated as 
the logarithm of total follow-up duration (not excluding the summed duration of 
exacerbations). 
• Repeating the primary analysis on the Per-protocol analysis set. 
• “Tipping point” multiple imputation analysis to assess deviations from missing at 
random (MAR). The details regarding this analysis will be provided in the SAP. 
Additional sensitivity analyses will be detailed in statistical analysis plan. 
In addition, to the analysis described above, subgroup analyses will be performed for: 
1. Age categories. Patients at ages 12 to <18 and patients ≥18 will be analyzed separately.  
2. 
 
 
3. Eosinophil levels at baseline categories. Patients with blood eosinophil levels at baseline 
of 300/μL to <400/μL and ≥400/μL will be analyzed separately. 
Additional subgroup analyses may be performed. These will be described and detailed in the 
statistical analysis plan. 
9.5.6.2. 
Secondary Efficacy Analysis 
All efficacy variables will be summarized by treatment group. For continuous variables, the 
summary statistics will include n, mean, SD, standard error (SE), median, minimum, and 
maximum.  
Analysis of pulmonary function tests, AQLQ +12, ACQ-6, total asthma symptom scores, and 
SGRQ use will use the mixed model repeated measures model with treatment group, visit, 
treatment and visit interaction, baseline value, and stratification factors as fixed effects and 
patient as a random effect.  
Analysis of percentage of asthma control days will use an analysis of variance (ANOVA) model 
with treatment group and stratification factors. 
The Kaplan-Meier (KM) method will be used to estimate and compare the distributions of time 
to first CAE between treatment groups. Differences will be compared using a log rank test 
adjusting for the stratification factors. 


 
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The frequency of exacerbations requiring hospitalization or emergency department visits and the 
frequency of moderate exacerbations will be examined separately. The analysis will use similar 
methodology to that described for the primary analysis.  
Additional covariates or factors may be added to the statistical models. These will be detailed in 
the statistical analysis plan. 
9.6. 
Multiple Comparisons and Multiplicity 
A fixed sequence multiple testing procedure will be implemented to test the primary and 
secondary variables while controlling the overall Type I error rate at 0.05. If the resulting 
two-sided p-value from the primary comparison is ≤0.05, then the next comparison of interest 
(first secondary variable) will be interpreted inferentially at 0.05. This process continues through 
the secondary variables until either all comparisons of interest are interpreted inferentially, or 
until the point at which the resulting two-sided p-value for a comparison of interest is >0.05. At 
the point where p>0.05, no further comparisons will be interpreted inferentially. The hierarchy of 
endpoints is as defined in Section 9.5.2. 
No multiplicity adjustments will be made for other efficacy and exploratory efficacy analyses. 
9.7. 
Safety Endpoints and Analysis 
Safety analyses will be performed on the safety analysis set. 
9.7.1. 
Safety Endpoints 
Safety measures and time points are provided in Section 3.4. The overall safety of reslizumab 
treatment will be assessed throughout the study by evaluating adverse events and the following 
additional safety variables: 
• adverse events throughout the study 
• vital signs (pulse, respiratory rate, and blood pressure) throughout the study 
• concomitant medication usage throughout the study 
• physical examination findings throughout the study 
• clinical laboratory evaluations at screening, baseline/DoR, and periodically 
throughout the study 
• ECG at screening and week 24, 36, and 52 or early withdrawal 


 
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9.7.2. 
Safety Analysis 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Each patient will be counted only once in each preferred term or system organ class 
category for the analyses of safety. Summaries will be presented for all adverse events that 
started after first study dosing (overall and by severity), adverse events determined by the 
investigator to be related to study treatment (ie, reasonable possibility; see Section 7.1.4) 
(defined as related or with missing relationship) (overall and by severity), serious adverse events, 
adverse events causing discontinuation from study treatment, adverse events with onset during 
the follow-up period (ie, after the cessation of study treatment), and adverse events that begin 
within 24 hours after injection. Summaries will be presented by treatment group and for all 
patients. In addition, summaries of adverse events will be presented separately for patients with 
ADA positive status and patients with ADA negative status. Patient listings of adverse events, 
serious adverse events, and adverse events leading to discontinuation will be presented. 
Changes in laboratory, ECG, and vital signs measurement data will be summarized descriptively. 
All values will be compared with prespecified boundaries to identify incidence of abnormalities 
and potentially clinically significant changes or values as well as shift analysis, and such values 
will be listed and summarized. 
The use of concomitant medications coded with WHO Drug will be summarized by therapeutic 
class using descriptive statistics. Concomitant medications will include all medications taken 
while the patient is treated with study drug. 
For continuous variables, descriptive statistics (n, mean, SD, median, minimum, and maximum) 
will be provided for actual values and changes from baseline/DoR to each time point. For 
categorical variables, patient counts and percentages will be provided.  
If any patient dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the patient narrative included in the clinical study report.  
9.7.3. 
Immunogenicity Endpoints 
Samples for immunogenicity assessment for development of anti-drug antibodies will be 
obtained before the administration of study drug at DoR; prior to study drug administration at 
weeks 4, 16, 32, 52 or early withdrawal; and the follow-up visit (approximately week 64). 
Additional samples will be collected at the late follow-up visit (approximately week 76). These 
data may be presented in a clinical study report addendum. 
9.8. 
Pharmacokinetic Analysis 
Reslizumab concentration data will be summarized by treatment group and time point. An 
attempt will be made to correlate serum concentrations of reslizumab with measures of safety 
and/or efficacy. The data will be pooled with data from other studies and analyzed using 
population PK and PK/PD analysis and reported in a separate report. An additional, a PK sample 
will be collected 28 weeks (±2 weeks) after the last dose of study drug (~week 76) for validation 
of the ADA assessment.  


 
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9.9. 
Biomarker Analysis 
Biomarker results will be summarized using descriptive statistics. Analyses correlating efficacy 
variables and biomarkers will be explored as appropriate  
9.10. 
Immunogenicity Analysis 
Anti-reslizumab antibody information will be described for subjects who test positive. Samples 
from placebo-treated patients will not be analyzed unless the patient elects to enroll into an 
available open-label safety study where the patient will receive reslizumab treatment. In this case 
the pre-dose (baseline) sample from the rolled-over placebo patient will be analyzed and reported 
along with post-treatment samples collected in the open-label safety study. Summaries will be 
provided if appropriate.  
9.11. 
Planned Interim Analysis 
No interim analysis is planned for this study. 
9.12. 
Reporting Deviations from the Statistical Plan 
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the clinical study report, or any 
combination of these, as appropriate, and in accordance with applicable local and regional 
requirements and regulations. 


 
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10. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The medical experts, study monitors, auditors, IEC/IRB, and health authority inspectors (or their 
agents) will be given direct access to source data and documentation (eg, medical charts/records, 
laboratory test results, printouts, videotapes) for source data verification, provided that patient 
confidentiality is maintained in accordance with local requirements. 
The investigator must maintain the original records (ie, source documents) of each patient’s data 
at all times. Examples of source documents are hospital records, office visit records, examining 
physician’s finding or notes, consultant’s written opinion or notes, laboratory reports, drug 
inventory, study drug label records, diary data, protocol-required worksheets, and CRFs that are 
used as the source (see Section 3.15). 
The investigator will maintain a confidential patient identification list that allows the 
unambiguous identification of each patient. All study-related documents must be kept until 
notification by the sponsor. 


 
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11. 
QUALITY CONTROL AND QUALITY ASSURANCE 
11.1. 
Protocol Amendments and Protocol Deviations and Violations 
11.1.1. 
Protocol Amendments 
No changes from the final approved (signed) protocol will be initiated without the prior written 
approval or favorable opinion of a written amendment by the IEC/IRB and local competent 
authorities as applicable, except when necessary to address immediate safety concerns to the 
patients or when the change involves only nonsubstantial logistics or administration. Each 
investigator and the sponsor will sign the protocol amendment.  
11.1.2. 
Protocol Violations 
A protocol deviation is any change, divergence, or departure from the study design or procedures 
defined in the protocol. 
Important protocol deviations, referred to as protocol violations, are a subset of protocol 
deviations that may significantly impact the completeness, accuracy, and/or reliability of the 
study data or that may significantly affect a patient's rights, safety, or well-being. Protocol 
violations include enrolling patients in violation of key eligibility criteria designed to ensure a 
specific patient population; failing to collect data necessary to interpret primary endpoints; 
noncompliance to study drug administration; use of prohibited medications; or any other 
deviations that may have an impact on the processes put in place for the care and safety of the 
patients or compromise the scientific value of the trial. 
Protocol violations will be identified and recorded by investigational center personnel on the 
CRF. All protocol violations will be reported to the responsible IEC/IRB, as required. 
When a protocol violation is reported, the sponsor will determine whether to discontinue the 
patient from the study or permit the patient to continue in the study, with a documented decision 
from the Sponsor’s medical representative. The decision will be based on ensuring the safety of 
the patient and preserving the integrity of the study.  
Deviations from the inclusion/exclusion criteria of the protocol are not prospectively granted by 
the sponsor. If investigational center personnel learn that a patient who did not meet protocol 
eligibility criteria was entered into a study, they must immediately inform the sponsor. If such 
patient has already completed the study or has withdrawn early, no action will be taken, but the 
incident will be recorded. If such patient is still participating in the study, a determination will be 
made by the sponsor and the investigator as to whether it is in the best interest of the patient to 
continue in the study. 
11.2. 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all staff members 
involved in the study or in any element of patient management, both before starting the study and 
during the course of the study (eg, when new staff become involved). The investigator must 
assure that all study staff members are qualified by education, experience, and training to 
perform their specific responsibilities. These study staff members must be listed on the 


 
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investigational center authorization form, which includes a clear description of each staff 
member’s responsibilities. This list must be updated throughout the study, as necessary. 
The study monitor is responsible for explaining the protocol to all study staff, including the 
investigator, and for ensuring they comply with the protocol. Additional information will be 
made available during the study when new staff become involved in the study and as otherwise 
agreed upon with either the investigator or the study monitor. 
11.3. 
Study Monitoring 
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable SOPs, the protocol, and other written instructions and regulatory 
guidelines. 
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor(s) are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all patients before they 
participate in the study and when changes to the consent form are warranted, in accordance with 
IEC/IRB approvals. 
The study monitor(s) will contact the investigator and visit the investigational center at regular 
intervals throughout the study. The study monitor will be permitted to check and verify the 
various records (CRFs and other pertinent source data records, including specific electronic 
source documentation [see Section 3.15]) relating to the study to verify adherence to the protocol 
and to ensure the completeness, consistency, and accuracy of the data being recorded. If 
electronic CRFs are used for the study, the study monitor will indicate verification by 
electronically applying source document verification flags to the CRF and will ensure that all 
required electronic signatures are being implemented accordingly. 
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting staff must agree to cooperate with the study monitor to resolve any problems, errors, or 
possible misunderstandings concerning the findings detected in the course of these monitoring 
visits and/or provided in follow-up written communication. 
11.4. 
Clinical Product Complaints 
A clinical product complaint is defined as a problem or potential problem with the physical 
quality or characteristics of clinical drug supplies and/or clinical device supplies used in a 
clinical research study sponsored by Teva. Examples of a product complaint include but are not 
limited to the following:  
• suspected contamination 
• questionable stability (eg, color change, flaking, crumbling, etc.) 
• defective components 


 
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• missing or extra units (eg, primary container is received at the site with more or less 
than the designated number of units inside) 
• incorrect packaging or incorrect or missing labeling/labels 
• unexpected or unanticipated taste or odor or both 
• device not working correctly or appears defective in some manner 
Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the Product Complaint Form provided by Teva and emailing it to 
 within 48 hours of becoming aware of the issue. 
For complaints involving a device or other retrievable item, it is required that the device (or 
item) be sent back to the sponsor for investigative testing whenever possible. For complaints 
involving a drug product, all relevant samples (eg, the remainder of the patient’s drug supply) 
should be sent back to the sponsor for investigative testing whenever possible.  
11.4.1. 
Product Complaint Information Needed from the Investigational Center 
In the event that the Product Complaint Form cannot be completed, the investigator will obtain 
the following information, as available: 
• investigational center number and principal investigator name 
• name, phone number, and address of the source of the complaint  
• clinical protocol number 
• patient identifier (patient study number) and corresponding visit numbers, if 
applicable 
• product name and strength for open-label studies 
• patient number, bottle, and kit numbers (if applicable) for double-blind or open-label 
studies 
• product available for return Yes/No 
• product was taken or used according to protocol Yes/No 
• description or nature of complaint 
• associated serious adverse event Yes/No 
• clinical supplies unblinded (for blinded studies) Yes/No 
• date and name of person receiving the complaint  
Note: Reporting a complaint must not be delayed because not all the required information can be 
immediately obtained. Known information must be immediately reported. The sponsor will 
collaborate with the investigator to obtain any outstanding information. 
11.4.2. 
Handling the Study Drug at the Investigational Center 
The investigator is responsible for retaining the product in question in a location separate from 
the investigator’s clinical study supplies. The sponsor may request that the investigator return the 


 
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product for further evaluation and/or analysis. If this is necessary, the clinical study monitor or 
designee will provide the information needed for returning the study drug. 
If it is determined that the investigational center must return all of the study drug, the sponsor 
will provide the information needed to handle the return. 
The integrity of the randomization code and corresponding blinded clinical supplies will be 
maintained whenever possible. A serious adverse event or the potential for a product quality 
problem existing beyond the scope of the complaint may be a reason to unblind the clinical 
supplies for an affected patient. 
11.4.3. 
Adverse Events or Serious Adverse Events Associated with a Product Complaint 
If there is an adverse event or serious adverse event, the protocol should be followed. 
11.4.4. 
Documenting a Product Complaint 
The investigator will record a description of the product complaint in the source documentation 
as well as any actions taken to resolve the complaint and to preserve the safety of the patient. 
Once the complaint has been investigated by the sponsor and the investigator, if necessary, an 
event closure letter may be sent to the investigational center where the complaint originated or to 
all investigational centers using the product. 
11.5. 
Audit and Inspection 
The sponsor may audit the investigational center to evaluate study conduct and compliance with 
protocols, SOPs, GCPs, and applicable regulatory requirements. The sponsor’s Global Clinical 
Quality Assurance department, independent of the Global Clinical Development department, is 
responsible for determining the need for (and timing of) an investigational center audit. 
The investigator must accept that regulatory authorities and sponsor representatives may conduct 
inspections to verify compliance with GCP guidelines. 


 
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12. 
ETHICS 
Details of compliance with regulatory guidances and applicable laws are provided in Section 1.6. 
12.1. 
Informed Consent/Assent 
For patients 18 years of age or older, the investigator, or a qualified person designated by the 
investigator, should fully inform the patient of all pertinent aspects of the study, including the 
written information approved by the IEC/IRB. All written and/or oral information about the 
study will be provided in a language as nontechnical as practical and understood by the patient. 
The patient should be given ample time and opportunity to inquire about details of the study and 
to decide whether or not to participate in the study. The above should be detailed in the source 
documentation. 
Written informed consent will be obtained from each patient before any study-specific 
procedures or assessments are done and after the aims, methods, anticipated benefits, and 
potential hazards are explained, according to the IEC/IRB requirements. The patient’s 
willingness to participate in the study will be documented in a consent form, which will be 
signed and personally dated by the patient and by the person who conducted the informed 
consent discussion. The investigator will keep the original consent forms, and copies will be 
given to the patients. It will also be explained to the patients that the patient is free to refuse entry 
into the study and free to withdraw from the study at any time without prejudice to future 
treatment. 
For patients 12 through <18 years of age, the investigator, or a qualified person designated by the 
investigator, should fully inform the patient and parent or other legally acceptable representative 
of all pertinent aspects of the study, including the written information approved by the IEC/IRB. 
All written and/or oral information about the study will be provided in a language as 
nontechnical as practical and understood by the parent or legally acceptable representative, and 
the patient as far as is practical. The patient and parent/legal representative should be given 
ample time and opportunity to inquire about details of the study and to decide whether or not to 
participate in the study. The above should be detailed in the source documentation. 
A personally signed and dated informed consent form will be obtained from each parent/legal 
representative and a signed and dated assent form will be obtained from each patient (if the 
patient is able) before any study-specific procedures or assessments are done and after the aims, 
methods, anticipated benefits, and potential hazards are explained; according to local IEC/IRB 
requirements. The forms will also be signed and dated by the person who conducted the 
informed consent discussion. The investigator will keep the original consent and assent forms, 
and copies will be given to the patients. It will also be explained to the patients (and parent/legal 
representative) that they are free to refuse entry into the study and free to withdraw from the 
study at any time without prejudice to future treatment. 
12.2. 
Health Authorities and Independent Ethics Committees/Institutional 
Review Boards 
Before this study starts, the protocol will be submitted to the national/local health authorities and 
to each IEC/IRB for review. As required, the study will not start at a given investigational center 


 
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before the IEC/IRB and health authority (where applicable) for the center give written approval 
or a favorable opinion. 
12.3. 
Confidentiality Regarding Study Patients 
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification code (ie, identification number). 
Personal medical information may be reviewed for the purpose of patient safety and/or verifying 
data in the source and transcribed onto the CRF. This review may be conducted by the study 
monitor, properly authorized persons on behalf of the sponsor, the quality assurance unit, and/or 
regulatory authorities. Personal medical information will always be treated as confidential. 
12.4. 
Declaration of the End of the Clinical Study 
Last Subject Last Visit (LSLV) treatment period is defined as end of treatment (week 52). LSLV 
late follow up for immunogenicity testing only, will be performed 28 weeks (±2 weeks) after the 
last dose of study drug (approximately week 76). This will be considered the end of the trial for 
the purposes of end of trial notification. 
For clinical investigational centers located in the EU, a declaration of the end of the clinical 
study will be made according to the procedures outlined in Directive 2001/20/ED, Article 10(c); 
for other countries, local regulations will be followed. 
12.5. 
Registration of the Clinical Study 
In compliance with local regulations and in accordance with Teva standard procedures, this 
clinical study may be registered on clinical trials registry websites. 


 
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13. 
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING 
13.1. 
Data Collection 
Data will be collected using CRFs that are specifically designed for this study. The data collected 
on the CRFs will be captured in a clinical data management system (CDMS) that meets the 
technical requirements described in 21CFR Part 11. The CDMS will be fully validated to ensure 
that it meets the scientific, regulatory, and logistical requirements of the study before it is used to 
capture data from this study. Before using the CDMS, all users will receive training on the 
system and study-specific training. After they are trained, users will be provided with individual 
system access rights. 
Data will be collected at the investigational center by appropriately designated and trained 
personnel, and CRFs must be completed for each patient who provided informed consent. Patient 
identity should not be discernible from the data provided on the CRF. Data will be verified using 
the data source by the study monitor, and reviewed for consistency by Data Management using 
both automated logical checks and manual review. All data collected will be approved by the 
investigator at the investigational center. This approval acknowledges the investigator’s review 
and acceptance of the data as being complete and accurate.  
If data are processed from other sources (eg, central laboratory, bioanalytical laboratory, central 
image center, eDiary data, ePRO Tablet), the results will be sent to the investigational center, 
where they will be retained but not entered into the CRF, unless otherwise specified in the 
protocol. These data may also be sent electronically to the sponsor (or organization performing 
data management) for direct entry into the clinical database. Laboratory test results will not be 
entered into the CRF unless otherwise noted in the protocol. All data from other sources will be 
available to the investigators. 
For patients who enter a study but do not meet entry criteria, at a minimum, data for screen 
failure reason, demography, and adverse events from the time of informed consent will be 
entered into the CRF.  
13.2. 
Data Quality Control  
Data Management is responsible for the accuracy, quality, completeness, and internal 
consistency of the data from this study. Data handling, including data quality control, will 
comply with international regulatory guidelines, including ICH GCP guidelines. Data 
management and control processes specific to this study, along with all steps and actions taken 
regarding data management and data quality control, will be described in a data management 
plan. 
Case report forms received will be processed and reviewed for completeness, consistency, and 
the presence of mandatory values. Applicable terms will be coded according to the coding 
conventions for this study. Logical checks will be implemented to ensure data quality and 
accuracy. Any necessary changes will be made in the clinical database, and data review and 
validation procedures will be repeated as needed. Data from external sources will be compared 
with the information available in the CDMS. Discrepancies found will be queried. 


 
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Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates and 
times of modifications, and authorized electronic approvals of the changes. 
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate. 
13.3. 
Archiving of Case Report Forms and Source Documents  
13.3.1. 
Sponsor Responsibilities 
The sponsor will have final responsibility for the processing and quality control of the data. Data 
management oversight will be carried out as described in the sponsor’s SOPs for clinical studies. 
Day to day data management tasks for this study are delegated to a contract organization, and 
these functions may be carried out as described in the SOPs for clinical studies at that 
organization. These SOPs will be reviewed by the sponsor before the start of data management 
activities. The original CRFs will be archived by the sponsor. Center-specific CRFs will be 
provided to the respective investigational centers for archiving.  
13.3.2. 
Investigator Responsibilities 
The investigator must maintain all written and electronic records, accounts, notes, reports and 
data related to the study and any additional records required to be maintained under country, 
state/province, or other local laws, including, but not limited to, the following:  
• full case histories 
• signed informed consent forms 
• patient identification lists 
• case report forms for each patient on a per-visit basis  
• data results from other sources (eg, central laboratory, bioanalytical laboratory, 
central image center, eDiary data) 
• safety reports 
• financial disclosure reports/forms 
• reports of receipt, use, and disposition of the study drug 
• copies of all correspondence with sponsor, the IRB/IEC, and any regulatory authority 
The investigator will retain all records related to the study until the CRO or sponsor sends 
written notification that records may be destroyed. If, after 10 years from study completion, or 
earlier in the case of the investigative center closing or going out of business, the investigator 
reasonably determines that study record retention has become unduly burdensome, and sponsor 
has not provided written notification of destruction, then the investigator may submit a written 
request to sponsor at least 60 days before any planned disposition of study records. Upon receipt 
of such request, the sponsor may make arrangements for appropriate archival or disposition, 


 
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including requiring that the investigator deliver such records to the sponsor. The investigator 
shall notify the sponsor of any accidental loss or destruction of study records.  


 
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14. 
FINANCING AND INSURANCE 
A separate clinical study agreement, including a study budget, will be entered into between each 
principal investigator and the sponsor (or the CRO designated by the sponsor) before the study 
drug is delivered. 
This clinical study is insured in accordance with the corresponding local legal provisions. The 
policy coverage is patient to the full policy terms, conditions, extensions, and exclusions. 
Excluded from the insurance cover are inter alia, damages to health, and worsening of previous 
existing disease that would have occurred or continued if the patient had not taken part in the 
clinical study. 
The policy of Clinical Trials Insurance will be provided to the investigational centers by the 
sponsor. 
For covered clinical studies (see 21CFR54), the investigator will provide the sponsor with 
financial information required to complete Form FDA 3454. Each investigator will notify the 
sponsor of any relevant changes during the conduct of the study and for 1 year after the study has 
been completed.  


 
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15. 
REPORTING AND PUBLICATION OF RESULTS 
The sponsor is responsible for ensuring that the public has access to the appropriate information 
about the study by conforming to local and regional requirements and regulations for registration 
and posting of results.  
The sponsor is responsible for the preparation of a clinical study report, in cooperation with the 
coordinating investigator. The final report is signed by the sponsor and, if applicable, by the 
coordinating investigator. 
When the sponsor generates reports from the data collected in this study for presentation to 
regulatory authorities, drafts may be circulated to the coordinating investigator for comments and 
suggestions. An endorsement of the final report will be sought from the coordinating 
investigator. 
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. The primary 
publication from this study will report the results of the study in accordance with the current 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (www.ICMJE.org). Publication of the results will occur in a timely manner 
according to applicable regulations. Authorship will be based on meeting all the following 
4 criteria: 
• substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work 
• drafting the work or revising it critically for important intellectual content 
• final approval of the version to be published 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved 
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement.  
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor. 


 
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16. 
REFERENCES 
Barr JT, Schumacher GE, Freeman S, LeMoine M, Bakst AW, Jones PW. American translation, 
modification, and validation of the St. George’s Respiratory Questionnaire. Clin Ther 
2000;22(9):1121-45. 
Baumgartner RA, Martinez G, Edelman JM, Rodriguez Gomez GG, Bernstein M, Bird S, et al. 
Montelukast Asthma Study Group. Distribution of therapeutic response in asthma control 
between oral montelukast and inhaled beclomethasone. Eur Respir J 2003;21(1):123-8. 
Castro M, Mathur S, Hargreave F, Boulet LP, Xie F, Young J, et al. Reslizumab for poorly 
controlled, eosinophilic asthma: a randomized, placebo-controlled study. Am J Respir Crit Care 
Med 2011;184(10):1125-32. 
Foster PS, Hogan SP, Ramsay AJ, Matthaei KI, Young IG. Interleukin 5 deficiency abolishes 
eosinophilia, airways hyperreactivity, and lung damage in a mouse asthma model. J Exp Med 
1996;183(1):195-201. 
The Global Asthma Report 2014. Auckland, New Zealand: Global Asthma Network, 2014. 
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 
2014.  
Global Strategy for Asthma Management and Prevention, Global Initiative for Asthma (GINA) 
2016. Available at: http://www.ginasthma.org. Accessed 06 June 2016. 
Haldar P, Brightling CE, Hargadon B, Gupta S, Monteiro W, Sousa A, et al. Mepolizumab and 
exacerbations of refractory eosinophilic asthma. N Engl J Med 2009;360(10):973-84. 
 
 
Juniper EF, Guyatt GH, Epstein RS, Ferrie PJ, Jaeschke R, Hiller TK. Evaluation of impairment 
of health related quality of life in asthma: development of a questionnaire for use in clinical 
trials. Thorax 1992;47(2):76-83. 
Juniper EF, O'Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a 
questionnaire to measure asthma control. Eur Respir J 1999;14(4):902-7. 
Molfino NA, Nowak R, Silverman RA, Rowe BH, Smithline H, Khan F, et al. Reduction in the 
Number and Severity of Exacerbations Following Acute Severe Asthma: Results of a Placebo-
Controlled, Randomized Clinical Trial with Benralizumab. Am J Respir Crit Care Med 
2012;185:A2753.  
Nair P, Pizzichini MM, Kjarsgaard M, Inman MD, Efthimiadis A, Pizzichini E, et al. 
Mepolizumab for prednisone-dependent asthma with sputum eosinophilia. N Engl J Med 
2009;360(10):985-93. 
Ortega HG1, Liu MC, Pavord ID, Brusselle GG, FitzGerald JM, Chetta A, et al. Mepolizumab 
treatment in patients with severe eosinophilic asthma. N Engl J Med 2014;371(13):1198-207. 


 
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Pavord ID, Korn S, Howarth P, Bleecker ER, Buhl R, Keene ON, et al. Mepolizumab for severe 
eosinophilic asthma (DREAM): a multicentre, double-blind, placebo-controlled trial. Lancet 
2012;380(9842):651-9. 
Sculpher MJ1, Buxton MJ. The episode-free day as a composite measure of effectiveness: an 
illustrative economic evaluation of formoterol versus salbutamol in asthma therapy. 
Pharmacoeconomics 1993;4(5):345-52. 
Shapiro GS, Klinger NM, Ekholm BP, Colice GL. Comparable bronchodilation with 
hydrofluoroalkane-134a (HFA) albuterol and chlorofluorocarbons-11/12 (CFC) albuterol in 
children with asthma. J Asthma 2000;37(8):667-75. 
Tran TN, Khatry DB, Ke X, Ward CK, Gossage D. High blood eosinophil count is associated 
with more frequent asthma attacks in asthma patients. Ann Allergy Asthma Immunol 
2014;113(1):19-24. 
US Department of Health and Human Services; National Institutes of Health; National Heart, 
Lung, and Blood Institute. National Asthma Education and Prevention Program Expert Panel 
Report 3 (ERP-3). Guidelines for the diagnosis and management of asthma. NIH publication 
number 08-5846. October 2007. 
Vidal C, Gude F, Boguete O, Fernández-Merino MC, Meijide LM, Rey J, et al. Evaluation of the 
phadiatop test in the diagnosis of allergic sensitization in a general adult population. J Investig 
Allergol Clin Immunol 2005;15(2):124-30. 
Walsh LJ, Wong CA, Oborne J, Cooper S, Lewis SA, Pringle M, et al. Adverse effects of oral 
corticosteroids in relation to dose in patients with lung disease. Thorax 2001; 56:279-84.  
Wardlaw AJ, Brightling C, Green R, Woltmann G, and Pavord I. Eosinophils in asthma and 
other allergic diseases. Br Med Bull 2000;56(4):985-1003. 
Wyrwich KW, Ireland AM, Navaratnam P, Nolte H, Gates DF Jr. Validation of the AQLQ12+ 
among adolescents and adults with persistent asthma. Qual Life Res 2011;20(6):903-12. 
Zeiger RS, Schatz M, Li Q, Chen W, Khatry DB, Gossage D, et al. High blood eosinophil count 
is a risk factor for future asthma exacerbations in adult persistent asthma. J Allergy Clin 
Immunol Pract 2014;2(6):741-50.e4. 


 
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17. 
SUMMARY OF CHANGES TO PROTOCOL 
17.1. 
Amendment 04 Dated 24 October 2016 
The revisions listed below have been made to the protocol Study C38072-AS-30025 and are 
considered substantial by the Teva Authorized Representative. 
Table 3: 
Changes to the Protocol 
Original text with changes shown 
New wording 
Reason/Justification 
for change 
Cover Page (Other sections affected by this change: Investigator Agreement page) 
 
 
 
Teva Branded Pharmaceutical Products 
R&D, Inc. 
 
 
Teva Branded Pharmaceutical Products R&D, 
Inc. 
 
Teva Branded Pharmaceutical Products 
R&D, Inc. 
Change in Sponsor 
Authorized 
Representative  
Cover Page 
 
 
Teva Global R&D 
 
 
 
 
Teva Global R&D 
 
Change in Sponsor’s 
medical expert phone 
number 
Section 2.3.4 Target Biomarker Endpoints (Other sections affected by this change: Synopsis, Section 2.3.5 
Immunogenicity Endpoints, Section 2.3.6 Pharmacokinetic Endpoints, Section 3.1 General Design and Study 
Schema, Figure 1 Overall Study Schema, Section 3.13 Duration of Patient Participation and Justification, 
Table 2 Study Procedures and Assessments, Section 3.16.4 Procedures After Study Drug Treatment, 
Section 4.4.1 Discontinuation of Study Treatment, Section 7.1.2 Recording and Reporting Adverse Events, 
Section 9.5.5 Target Biomarker Endpoints, and Section 9.7.3 Immunogenicity Endpoints) 
The target biomarker endpoints are the blood 
eosinophil counts at baseline/DoR; weeks 2, 4, 
8, 12, 16, 32, 52 or early withdrawal; and the 
follow-up visit (approximately week 6064). 
The target biomarker endpoints are the 
blood eosinophil counts at baseline/DoR; 
weeks 2, 4, 8, 12, 16, 32, 52 or early 
withdrawal; and the follow-up visit 
(approximately week 64). 
Early follow-up visit 
was changed from 8 
to 12 weeks after end 
of treatment based on 
the European 
Medicines Agency 
Decision, 
P/0256/2016, dated 
05 October 2016, on 
Pediatric 
Investigational Plan 
(PIP) modification 
EMEA-001202-
PIP02-13-M01.  


 
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Original text with changes shown 
New wording 
Reason/Justification 
for change 
Section 3.1 General Design and Study Schema (Other sections affected by this change: Synopsis, Section 3.13 
Duration of Patient Participation and Justification, and Section 3.16.4 Procedures After Study Drug 
Treatment) 
The patient may delay the early and/or late 
follow up visits if the patient enrolls in an 
open label, long term safety study after end of 
treatment, if available. If the patient enrolls in 
an available open-label, long-term safety 
study, then adults (age 18 years and older) 
may wait to complete the early and late 
follow-up visits until the end of the open-
label study; however, adolescents (ages 12 to 
<18 years) should complete the early follow-
up visit at 12 weeks as part of this current 
study before starting an open-label study. 
If the patient enrolls in an available open-
label, long-term safety study, then adults 
(age 18 years and older) may wait to 
complete the early and late follow-up visits 
until the end of the open-label study; 
however, adolescents (ages 12 to 
<18 years) should complete the early 
follow-up visit at 12 weeks as part of this 
current study before starting an open-label 
study. 
Revised per the 
European Medicines 
Agency Decision, 
P/0256/2016, dated 
05 October 2016, on 
PIP modification 
EMEA-001202-
PIP02-13-M01. 
17.2. 
Amendment 03 Dated 25 July 2016 
The revisions listed below have been made to the protocol Study C38072-AS-30025 and are 
considered substantial by the Teva Authorized Representative. 
Table 4: 
Changes to the Protocol 
Original text with changes shown 
New wording 
Reason/Justification 
for change 
Cover Page 
 
 
Teva Global R&D 
 
 
Teva Global R&D 
 
Sponsor Medical 
Expert changed. 
Clinical Study Personnel Contact Information  
For centers in North America 
 
 
 
 
For Centers in Latin America 
 
 
 
 
 
For centers in North America 
 
 
 
 
For Centers in Latin America 
 
 
 
 
Per administrative 
letter, the contact 
physicians for North 
American and Latin 
America were 
updated/clarified. 


 
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Original text with changes shown 
New wording 
Reason/Justification 
for change 
Study Synopsis - Number of Patients Planned; page 8 (Other sections affected by this change: Synopsis page 10, 
11, 14; Section 3.1 Study Design; Section 3.9 Randomization and Blinding; Section 4.1 Patient Inclusion 
Criteria; Section 9.1 Sample Size and Power Considerations) 
Number of Patients Planned: Approximately 
200225 patients per treatment group for a total 
of 400450 patients. 
Number of Patients Planned: 
Approximately 225 patients per treatment 
group for a total of 450 patients. 
The total enrollment 
of the study was 
increased in order to 
ensure adequate 
adolescent 
enrollment. 
Study Synopsis - Criteria for Inclusion; page 12 
l.  In order to be randomized, a patient must 
demonstrate the following: … 
… 
Please refer to Section 3.16.1 and 
Section 3.16.2 for further guidance on 
rescreening if the above inclusion criteria 
are not met initially. The eosinophil count 
and reversibility test may each be 
repeated once during the Screening 
period, and subjects may also be 
rescreened for either of these reasons. 
The duration between the date of Screen 
Failure and the re-screening must be 
>30 days. 
l.  In order to be randomized, a patient 
must demonstrate the following: … 
… 
Please refer to Section 3.16.1 and 
Section 3.16.2 for further guidance on 
rescreening if the above inclusion 
criteria are not met initially. The 
eosinophil count and reversibility test 
may each be repeated once during the 
Screening period, and subjects may also 
be rescreened for either of these 
reasons. The duration between the date 
of Screen Failure and the re-screening 
must be >30 days. 
Clarification to study 
synopsis added for 
completeness and to 
further articulate the 
rescreening 
possibilities. 
Section 1.3.2: Clinical Studies 
Additional Safety Issues Considerations 
Additional Safety Considerations 
Section renamed for 
clarity and 
inclusiveness. 
Malignancy 
As of February 2015, there were 27 treatment-
emergent adverse events reported by 24 
patients related to malignancy for the entire 
clinical program, including placebo-treated 
patients. 
Malignancy 
As of February 2015, there were 27 
treatment-emergent adverse events 
reported by 24 patients related to 
malignancy for the entire clinical program, 
including placebo-treated patients. 
Language was added 
to clarify that the 
number of reported 
events includes 
patients who received 
placebo in the overall 
clinical program. 
Malignancy 
Most malignancies were diagnosed within less 
than 6 months after starting reslizumab 
treatment, and in 4 5 cases, there was a 
previous medical history of malignancy. 
Malignancy 
Most malignancies were diagnosed within 
less than 6 months after starting 
reslizumab treatment, and in 5 cases, there 
was a previous medical history of 
malignancy. 
The number of cases 
with previous 
medical history of 
malignancy was 
corrected. 


 
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Original text with changes shown 
New wording 
Reason/Justification 
for change 
New Text 
Infections 
The immune response to parasitic 
infections may involve eosinophils; 
therefore, the clinical course of existing or 
new parasitic infections could potentially 
be complicated by a mechanism of action 
that lowers blood and tissue eosinophils. 
The iv reslizumab clinical protocols 
contained an exclusion criterion for 
patients with active or suspected helminth 
infestation/infection. The asthma Phase 3 
studies were conducted in geographic 
regions in which helminth infections are 
prevalent, including South and Central 
America, Africa, and Asia. There were no 
helminth infections reported, and no 
difference was documented between the 
treatment groups in regards to adverse 
events that could be associated with 
gastrointestinal helminth infections.  
The overall rate of infection adverse events 
was lower for reslizumab versus placebo 
treated patients, with the types of infection 
events reported consistent with what would 
be expected in a primarily adult patient 
population with an underlying condition of 
asthma. No potential opportunistic 
infections were reported. 
Additional safety 
consideration for 
infections added for 
clarity. 
Section 3: Study Design 
3.1 General Design and Study Schema (Other sections affected by this change: Synopsis) 


 
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Original text with changes shown 
New wording 
Reason/Justification 
for change 
Evidence of inadequate asthma control will 
include a history of recent exacerbation ( of at 
least 2 exacerbations requiring systemic 
corticosteroids (oral or injection) in the 
previous 12 months), a suboptimal screening 
ACQ-6 score (≥1.5), and persistent symptoms 
during run-in on the patient’s usual asthma 
controller regimen. At least one of the 
historical exacerbations must have been 
previously documented in the medical or 
pharmacy record; additional exacerbations 
may be documented in either the medical or 
pharmacy record, or documented by the 
study site at the time of screening history. 
For all exacerbations, which fulfill inclusion 
criterion ‘c’, the approximate dates of 
systemic corticosteroid therapy and the 
name of the systemic corticosteroid taken 
should be recorded in source documents. The 
study consists of up to 2 weeks to satisfy 
essential screening inclusion criteria (ie, 
confirmation of asthma with elevated blood 
eosinophils), a minimum 3-week run-in period 
on usual care to establish the patient’s baseline 
level of control and, a 52-week double-blind 
treatment period. , and follow up evaluation 
approximately 8 weeks after the end of
treatment (EOT) visit.  The patient may delay 
the early and/or late follow-up visits if the 
patient enrolls in an open-label, long-term 
safety study after end of treatment, if 
available. 
Evidence of inadequate asthma control will 
include a history of at least 2 exacerbations 
requiring systemic corticosteroids (oral or 
injection) in the previous 12 months, a 
suboptimal screening ACQ-6 score (≥1.5), 
and persistent symptoms during run-in on 
the patient’s usual asthma controller 
regimen. At least one of the historical 
exacerbations must have been previously 
documented in the medical or pharmacy 
record; additional exacerbations may be 
documented in either the medical or 
pharmacy record, or documented by the 
study site at the time of screening history. 
For all exacerbations, which fulfill 
inclusion criterion ‘c’, the approximate 
dates of systemic corticosteroid therapy 
and the name of the systemic 
corticosteroid taken should be recorded in 
source documents. The study consists of 
up to 2 weeks to satisfy essential screening 
inclusion criteria (ie, confirmation of 
asthma with elevated blood eosinophils), a 
minimum 3-week run-in period on usual 
care to establish the patient’s baseline level 
of control and a 52-week double-blind 
treatment period. The patient may delay 
the early and/or late follow-up visits if the 
patient enrolls in an open-label, long-term 
safety study after end of treatment, if 
available. 
Rewording of study 
design to provide 
clarification of 
screening and 
enrollment. 
 
Minor wording 
adjustment and 
language was added 
to clarify the timing 
of the follow-up 
evaluation in the 
circumstance that an 
open-label, long-term 
safety study becomes 
available to the 
patients. 
Patients will return 8 weeks after the EOT visit 
for follow-up hematology, PK, 
immunogenicity, and safety assessments. An 
additional, late follow-up for 
immunogenicity testing will be performed 28 
weeks (±2 weeks) after the last dose of study 
drug (ie, approximately week 76). 
Patients will return 8 weeks after the EOT 
visit for follow-up hematology, PK, 
immunogenicity, and safety assessments. 
An additional, late follow-up for 
immunogenicity testing will be performed 
28 weeks (±2 weeks) after the last dose of 
study drug (ie, approximately week 76). 
Clarification of study 
duration and 
milestones. 
Section 3.11: Drugs Used in the Study (Other sections affected by this change: Section 5.1) 
Section 3.11.1 Investigational Product 
Reslizumab for sc injection will be provided as 
a sterile solution containing 110 mg (1.0 mL) 
reslizumab per syringe, formulated at 
110 mg/mL in 
 sodium acetate, with 
 
sucrose
 polysorbate 80, pH 5.5 buffer. 
The needle shields of the prefilled syringes 
contain natural rubber latex. 
 
Section 3.11.1 Investigational Product 
Reslizumab for sc injection will be 
provided as a sterile solution containing 
110 mg (1.0 mL) reslizumab per syringe, 
formulated at 110 mg/mL in 
 
sodium acetate, with 
 sucrose, 
 
polysorbate 80, pH 5.5 buffer. The needle 
shields of the prefilled syringes contain 
natural rubber latex. 
Information 
regarding the natural 
rubber component of 
the prefilled syringe 
was added for 
transparency. 


 
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Original text with changes shown 
New wording 
Reason/Justification 
for change 
Section 3.11.2 Placebo 
Placebo will be provided as a sterile solution of 
 sodium acetate, with 
 sucrose, 
 polysorbate 80, pH 5.5 buffer, presented 
as 1 mL per syringe. The needle shields of the 
prefilled syringes contain natural rubber 
latex. 
Section 3.11.2 Placebo 
Placebo will be provided as a sterile 
solution of 
 sodium acetate, with 
 sucrose, 
 polysorbate 80, pH 5.5 
buffer, presented as 1 mL per syringe. The 
needle shields of the prefilled syringes 
contain natural rubber latex. 
Information 
regarding the natural 
rubber component of 
the prefilled syringe 
was added for 
transparency. 
3.13 Duration of Patient Participation and Justification 
This study will consist of up to a 2-week (±3 
days) screening period, minimum 3-week run-
in period, and a 52- week double-blind 
treatment period. , and 8 week follow up visit. 
Patients are expected to participate in this study 
for approximately 65 weeks. An additional, late 
follow up for immunogenicity testing will be 
performed 28 weeks after the last dose of study 
drug.  Patients are expected to participate in 
this study for approximately 65 weeks. An 
additional, late follow-up for 
immunogenicity testing will be performed 28 
weeks after the last dose of study drug. The 
patient may delay the early and/or late 
follow-up visits if the patient enrolls in an 
open-label, long-term safety study after end 
of treatment, if available. 
This study will consist of up to a 2-week 
(±3 days) screening period, minimum 3-
week run-in period and a 52- week 
double-blind treatment period. Patients are 
expected to participate in this study for 
approximately 65 weeks. An additional, 
late follow-up for immunogenicity testing 
will be performed 28 weeks after the last 
dose of study drug. The patient may delay 
the early and/or late follow-up visits if the 
patient enrolls in an open-label, long-term 
safety study after end of treatment, if 
available. 
Clarification of study 
duration and 
milestones. 
3.14 Stopping Rules and Discontinuation Criteria 
Other than pregnancy, there are no formal rules 
for early withdrawal from this study for study 
drug discontinuation in this study. During the 
conduct of the study, adverse events will be 
reviewed by the sponsor (see Section 7.1.5) as 
they are reported from the investigational 
center to identify safety concerns. The study 
may be terminated by the sponsor at any time 
for reasons including, but not limited to a safety 
concern.  
A patient may discontinue participation in the 
study at any time for any reason (eg, lack of 
efficacy, consent withdrawn, and adverse 
event). The investigator and/or sponsor can 
withdraw a patient from the study for reasons 
including, but not limited to, a change in the 
medical condition or an adverse event that 
alters the patient’s benefit/risk (e.g. pregnancy, 
a related severe hypersensitivity, or related 
severe myalgia/muscle event), a protocol 
violation or deviation as defined in Section 
11.1.2, or noncompliance. 
Other than pregnancy, there are no formal 
rules for study drug discontinuation in this 
study. During the conduct of the study, 
adverse events will be reviewed by the 
sponsor (see Section 7.1.5) as they are 
reported from the investigational center to 
identify safety concerns. The study may be 
terminated by the sponsor at any time for 
reasons including, but not limited to a 
safety concern.  
A patient may discontinue participation in 
the study at any time for any reason (eg, 
lack of efficacy, consent withdrawn, and 
adverse event). The investigator and/or 
sponsor can withdraw a patient from the 
study for reasons including, but not limited 
to, a change in the medical condition or an 
adverse event that alters the patient’s 
benefit/risk (e.g. pregnancy, a related 
severe hypersensitivity, or related severe 
myalgia/muscle event), a protocol 
violation or deviation as defined in Section 
11.1.2, or noncompliance. 
Wording adjusted to 
clarify that with 
regard to pregnancy, 
the administration of 
study drug should be 
discontinued, but the 
patient does not need 
to be withdrawn from 
the study for being 
pregnant. 
 
Additional language 
was added to describe 
reasons for patient 
withdrawal. 


 
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Reason/Justification 
for change 
Section 3.16: Study Procedures; Table 2: Study Procedures and Assessments (Other sections affected by this 
change: Sections 3.16.3.1.1 and 3.16.3.1.2). 
W76 
+2wk 
W76 
+2wk 
Time window added 
to Week 76 visit. 
Only upper limit so 
ensure ADA titer is 
obtained without 
residual drug on 
board. 
Addition of CPK assessments at Day 7, 
Weeks 2-12, and Week 20  
Addition of CPK assessments at Day 7, 
Weeks 2-12 and Week 20. 
Clarification added 
based on request by 
Health Authorities. 
Removal of Phadiatop allergy test and total 
serum IgE at Visit 17 (Week 52) 
Phadiatop allergy test and total serum IgE 
at Visit 17 (Week 52) was removed. 
The phadiatop 
assessment at 
Week 52 was 
removed because it is 
exclusively a baseline 
assessment. 
Addition of Injection site evaluation at Visit 
3 and Weeks 4-48. 
Injection site evaluation addition at Visit 3 
and Weeks 4-48. 
Row added aligning 
with IP visits for 
clarification of 
evaluation. 
f.  CPK is collected with serum chemistry tests 
at scheduled visits. If potentially clinically 
significant CPK (≥3.1x ULN) is reported, 
initiate the CPK/myalgia CRF. Urinalysis and 
selected chemistries, should be performed for 
10x elevations as per CRF instructions, and 
CPK levels should be re tested every 7 to 10 
days until the elevation is resolved or if 
agreed with the medical monitor that no 
further testing is indicated. and clinical 
monitoring as outlined in Protocol 
Section 7.1.7.2. 
f.  CPK is collected with serum chemistry 
tests at scheduled visits. If a potentially 
clinically significant CPK level (≥3.1x 
ULN) is reported, initiate the 
CPK/myalgia CRF and clinical 
monitoring required as outlined in 
Protocol Section 7.1.7.2. 
 
Footnote modified 
for clarity. 
--   
g.  CPK measurement only. CPK will be 
collected with PK sample. 
New footnote added 
to support the 
additional CPK 
collection. 


 
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k.  Pre-bronchodilator spirometry assessments 
should only be performed after withholding 
short-acting bronchodilators (ie, inhaled 
short-acting beta-adrenergic agonists and/or 
short-acting anticholinergics) for at least 6 
hours and long-acting bronchodilators (ie, 
inhaled long-acting beta-adrenergic agonists 
and long-acting anticholinergic agents) for at 
least 12 or 24 hours, according to their 
labeled dose schedule. Spirometry should be 
performed prior to IP administration, if 
applicable 
k.  Pre-bronchodilator spirometry 
assessments should only be performed 
after withholding short-acting 
bronchodilators (ie, inhaled short-acting 
beta-adrenergic agonists and/or short-
acting anticholinergics) for at least 6 
hours and long-acting bronchodilators 
(ie, inhaled long-acting beta-adrenergic 
agonists and long-acting anticholinergic 
agents) for at least 12 or 24 hours, 
according to their labeled dose schedule. 
Spirometry should be performed prior to 
IP administration, if applicable 
Clarification of 
timing for 
spirometry. 
3.16.1 Procedures for Screening and Start of Run-In Period (Visits 1 and 2) 
Patients who do not initially meet the 
eosinophil or spirometry/reversibility 
criteria during the Screening period may 
have these tests repeated once, prior to 
excluding the subject from further study 
participation.  A patient who is screened but 
not randomized (eg, because entry criteria 
were not met or enrollment did not occur within 
the specified time), may be considered in the 
future for screening again, once more, if, 
eg, there is a change in the patient’s medical 
background or a modification of study entry 
criteria. Patients may be screened again if they 
did not meet spirometry/reversibility criteria 
initially. The duration between the first visit 
during the screening period and the date of 
Screen Failure and re-screening must be 
>30 days. 
Patients who do not initially meet the 
eosinophil or spirometry/reversibility 
criteria during the Screening period may 
have these tests repeated once, prior to 
excluding the subject from further study 
participation.  A patient who is screened 
but not randomized, eg, because entry 
criteria were not met or enrollment did not 
occur within the specified time, may be 
considered in the future for screening 
again, once more, if, eg, there is a change 
in the patient’s medical background or a 
modification of study entry criteria. The 
duration between the date of Screen 
Failure and re-screening must be 
>30 days. 
Screening and re-
screening details 
clarified. 
• 
Perform clinical laboratory tests 
(chemistry, hematology, urinalysis). 
Only those patients with an eosinophil 
count of 300 eosinophils/µL or greater at 
screening will be eligible to continue in 
the study; .patients with historic 
eosinophil counts of 400 eosinophils/µL 
or greater will not be eligible. Eosinophil 
testing may be repeated once during the 
2-week (±3 days) screening period. 
• 
Perform clinical laboratory tests 
(chemistry, hematology, urinalysis). 
Only those patients with an 
eosinophil count of 300 
eosinophils/µL or greater at 
screening will be eligible to 
continue in the study. Eosinophil 
testing may be repeated once during 
the 2-week (±3 days) screening 
period. 
Change made to 
protocol reflecting 
changes from 
administrative letter 
issued previously. 


 
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3.16.2 Procedures Before Study Drug Treatment (Baseline/Day of Randomization [Week 0, Visit 3]) 
The duration between the first visit during the 
screening period and the re-screening must be 
>30 days. Patients may be screened again if 
they did not meet spirometry/reversibility 
criteria initially, and they may also be 
screened again if they did not meet the 
eosinophil criterion during the initial 
Screening. 
The duration between the first visit during 
the screening period and the re-screening 
must be >30 days. Patients may be 
screened again if they did not meet 
spirometry/reversibility criteria initially, 
and they may also be screened again if 
they did not meet the eosinophil criterion 
during the initial Screening. 
Screening and re-
screening details 
clarified. 
These two newly assigned numbers will be 
entered into the CRF, and study drug will be 
dispensed. The following 
procedures/assessments will be performed 
during and after administration of study 
drug: 
• 
Patients will be observed for 1 
hour after study 
injection/baseline/DoR 
assessments  
• 
Evaluation of injection site for 
reaction at approximately 1 
hour after dosing using the 
injection site CRF. Clinically 
significant injection site 
reactions should be recorded as 
an adverse event. 
• 
If, during post-study drug 
observation, the patient 
develops clinical symptoms, 
vital signs should be collected. 
The patient should be assessed 
for anaphylaxis/hypersensitivity 
reactions as detailed in Section 
7.1.7. 
Remind the patients that they will receive a 
post-injection symptom inquiry via the 
eDiary. 
 
These two newly assigned numbers will be 
entered into the CRF, and study drug will 
be dispensed. The following 
procedures/assessments will be performed 
during and after administration of study 
drug: 
• 
Patients will be observed for 
1 hour after study 
injection/baseline/DoR 
assessments  
• 
Evaluation of injection site 
for reaction at approximately 
1 hour after dosing using the 
injection site CRF. Clinically 
significant injection site 
reactions should be recorded 
as an adverse event. 
• 
If, during post-study drug 
observation, the patient 
develops clinical symptoms, 
vital signs should be 
collected. The patient should 
be assessed for 
anaphylaxis/hypersensitivity 
reactions as detailed in 
Section 7.1.7. 
Remind the patients that they will receive a 
post-injection symptom inquiry via the 
eDiary. 
 
Clarification of study 
procedures to reflect 
the schedule of 
assessments. 
3.16.3.1.1 Week 1 (Pharmacokinetic Visit) 
Patients at sites in the US will return to the 
research facility approximately 1 week after 
administration of the first dose of study drug. A 
blood sample will be collected for serum 
reslizumab concentration determination and 
measurement of CPK at this visit. Adverse 
events, concomitant medications, and asthma 
exacerbations and related health care 
utilizations will also be assessed. 
Patients at sites in the US will return to the 
research facility approximately 1 week 
after administration of the first dose of 
study drug. A blood sample will be 
collected for serum reslizumab 
concentration determination and 
measurement of CPK at this visit. Adverse 
events, concomitant medications, and 
asthma exacerbations and related health 
care utilizations will also be assessed. 
Edited to align with 
modification to 
schedule of 
assessments. 


 
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3.16.3.1.2 Other On-Treatment Visits (Visits 4 through 17 [EOT]) 
Perform serum chemistry tests (weeks 16, 32, 
and 52 or early withdrawal only) (a sample for 
CPK measurement only, will also be 
collected on weeks 2, 4, 8, 12, and 20). 
Perform serum chemistry tests (weeks 16, 
32, and 52 or early withdrawal only) (a 
sample for CPK measurement only, will 
also be collected on weeks 2, 4, 8, 12, and 
20). 
Edited to align with 
modification to 
schedule of 
assessments. 
Collect blood for Phadiatop allergy test and 
total serum IgE (week 52 or early withdrawal 
only; Vidal et al 2005). 
 - [removed] 
Removed to align 
with modification to 
schedule of 
assessments. 
The following procedures/assessments will be 
performed during and after administration of 
study drug: 
• 
Patients will be observed for 1 
hour after study injection. 
• 
Evaluation of injection site for 
reaction at approximately 1 
hour after dosing using the 
injection site CRF. Clinically 
significant injection site 
reactions should be recorded as 
an adverse event. 
• 
Perform adverse event inquiry. 
− 
If, during post-study drug 
observation, the patient 
develops clinical symptoms, 
vital signs should be 
collected. The patient should 
be assessed for 
anaphylaxis/hypersensitivity 
reactions as detailed in 
Section 7.1.67.1.7. 
Remind the patients that they will receive a 
post-injection symptom inquiry via the eDiary.  
The following procedures/assessments will 
be performed during and after 
administration of study drug: 
• 
Patients will be observed for 
1 hour after study injection. 
• 
Evaluation of injection site 
for reaction at approximately 
1 hour after dosing using the 
injection site CRF. Clinically 
significant injection site 
reactions should be recorded 
as an adverse event. 
• 
If, during post-study drug 
observation, the patient 
develops clinical symptoms, 
vital signs should be 
collected. The patient should 
be assessed for 
anaphylaxis/hypersensitivity 
reactions as detailed in 
Section 7.1.7. 
Remind the patients that they will receive a 
post-injection symptom inquiry via the 
eDiary.  
Added to align with 
modification to 
schedule of 
assessments and to 
fully outline the 
assessments required. 
4.1 Patient Inclusion Criteria (Other sections affected by these changes: Study Synopsis) 
g.  The patient has required at least a medium 
total daily ICS dose based on GINA 
20152016 clinical comparability table 
(Appendix A) for at least 3 months. For 
ICS/LABA combination preparations, the 
mid-strength approved maintenance dose in 
the local country will meet this ICS criterion 
g.  The patient has required at least a 
medium total daily ICS dose based on 
GINA 2016 clinical comparability table 
(Appendix A) for at least 3 months. For 
ICS/LABA combination preparations, 
the mid-strength approved maintenance 
dose in the local country will meet this 
ICS criterion 
GINA Guidance 
version updated. 


 
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i.  Females of childbearing potential (not 
surgically sterile by hysterectomy, 
bilateral salpingectomy, bilateral 
oophorectomy, or 2 years 
postmenopausal) must have an 
exclusively same-sex partner or use a 
medically acceptable method of 
contraception, and must agree to continue 
use of this method for the duration of the 
study and for 5 months after last study 
drug dose. Acceptable methods of 
contraception include intrauterine device 
(IUD), steroidal contraceptive (oral, 
implanted, transdermal, or injected), 
barrier method with spermicide, 
abstinence, bilateral fallopian tube 
occlusion, and partner vasectomy. 
Contraception is further clarified in an 
administrative letter in Section 17.4.1. 
i.  Females of childbearing potential (not 
surgically sterile by hysterectomy, 
bilateral salpingectomy, bilateral 
oophorectomy, or 2 years 
postmenopausal) must have an 
exclusively same-sex partner or use a 
medically acceptable method of 
contraception, and must agree to 
continue use of this method for the 
duration of the study and for 5 months 
after last study drug dose. Acceptable 
methods of contraception include 
intrauterine device (IUD), steroidal 
contraceptive (oral, implanted, 
transdermal, or injected), barrier 
method with spermicide, abstinence, 
bilateral fallopian tube occlusion, and 
partner vasectomy. Contraception is 
further clarified in an administrative 
letter in Section 17.4.1. 
Criterion revised for 
clarity and alignment 
with case report 
form. 
 
k.  The patient must maintain their usual 
asthma controller regimen without change 
throughout the screening and run-in 
periods. A patient who experiences an 
asthma exacerbation during this time that 
requires additional medication, beyond 
increased SABA use, will be considered 
to have failed screening/run-in and cannot 
undergo randomization. A patient may be 
rescreened for this reason 1 time only. 
The duration between the date of 
Screen Failure and the re-screening 
must be >30 days. Patients may be 
screened again if they did not meet 
spirometry/reversibility criteria 
initially. 
k.  The patient must maintain their usual 
asthma controller regimen without 
change throughout the screening and 
run-in periods. A patient who 
experiences an asthma exacerbation 
during this time that requires additional 
medication, beyond increased SABA 
use, will be considered to have failed 
screening/run-in and cannot undergo 
randomization. A patient may be 
rescreened for this reason 1 time only. 
The duration between the date of 
Screen Failure and the re-screening 
must be >30 days. Patients may be 
screened again if they did not meet 
spirometry/reversibility criteria initially. 
Criterion revised for 
clarity and alignment 
with case report form 
instructions. 
 
4.4.1 Disconinutation of Study Treatment (Other sections affected by these changes: 3.16.5) 
If premature discontinuation of study treatment 
occurs, the patient should return to the clinic as 
soon as possible for a study treatment 
discontinuation visit. All evaluations should be 
performed as an unscheduled visit and 
include all the assessments specified in the 
protocol for the early withdrawal visit. 
If premature discontinuation of study 
treatment occurs, the patient should return 
to the clinic as soon as possible for a 
study treatment discontinuation visit. All 
evaluations should be performed as an 
unscheduled visit and include all the 
assessments specified in the protocol for 
the early withdrawal visit. 
Clarification of 
assessments for an 
unscheduled visit. 


 
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4.4.2 Complete Withdrawal from Study (Other sections affected by these changes: 3.16.5) 
If a patient decides to completely withdraw 
from the study (ie, refuses any further study 
participation or contact), all study participation 
for that patient will cease and all data to be 
collected at subsequent visits will be 
considered missing. If a patient decides to 
completely withdraw from the study, the 
patient should return to the clinic as soon as 
possible to complete the early withdrawal 
visit (see Table 2). 
If a patient decides to completely 
withdraw from the study (ie, refuses any 
further study participation or contact), all 
study participation for that patient will 
cease and all data to be collected at 
subsequent visits will be considered 
missing. If a patient decides to completely 
withdraw from the study, the patient 
should return to the clinic as soon as 
possible to complete the early withdrawal 
visit (see Table 2). 
Clarification of 
assessments for an 
unscheduled visit. 
5.5 Total Blood Volume 
The estimated total blood volume withdrawn 
over the entire study (including screening) is 
approximately 115120 mL per patient 
The estimated total blood volume 
withdrawn over the entire study 
(including screening) is approximately 
120 mL per patient 
Increased to account 
for additional CPK 
draws. 
Section 7.1: Adverse Events 
7.1.1. Definition of an Adverse Event 
… 
An adverse event can, therefore, be any 
unfavorable and unintended physical sign, 
symptom, or laboratory parameter that develops 
or worsens in severity during the course of this 
study, or significant worsening of the disease 
under study or of any concurrent disease, 
whether or not considered related to the study 
drug. Asthma exacerbation is an efficacy 
variable for this study and should be 
captured on the asthma exacerbation CRF; 
accordingly, asthma exacerbations should 
not be recorded as adverse events unless 
assessed as more severe than the patient's 
usual disease course. In this case, the 
investigator should determine if the adverse 
event is nonserious or serious based on 
seriousness criteria, as defined in 
Section7.1.5. A new condition or the worsening 
of a pre-existing condition will be considered 
an adverse event. Stable chronic conditions 
(such as arthritis) that are present before study 
entry and do not worsen during this study will 
not be considered adverse events.  
Accordingly, an adverse event can include any 
of the following: 
 
7.1.1. Definition of an Adverse Event 
… 
An adverse event can, therefore, be any 
unfavorable and unintended physical sign, 
symptom, or laboratory parameter that 
develops or worsens in severity during the 
course of this study, or significant 
worsening of the disease under study or of 
any concurrent disease, whether or not 
considered related to the study drug. 
Asthma exacerbation is an efficacy 
variable for this study and should be 
captured on the asthma exacerbation CRF; 
accordingly, asthma exacerbations should 
not be recorded as adverse events unless 
assessed as more severe than the patient's 
usual disease course. In this case, the 
investigator should determine if the 
adverse event is nonserious or serious 
based on seriousness criteria, as defined in 
Section7.1.5. A new condition or the 
worsening of a pre-existing condition will 
be considered an adverse event. Stable 
chronic conditions (such as arthritis) that 
are present before study entry and do not 
worsen during this study will not be 
considered adverse events.  
Accordingly, an adverse event can include 
any of the following: 
Clarification of the 
reporting of the 
disease under study 
as an adverse event. 


 
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• 
intercurrent illnesses 
• 
physical injuries 
• 
events possibly related to 
concomitant medication 
• 
significant worsening (change in 
nature, severity, or frequency) of 
the disease under study or other 
pre-existing conditions (Note: A 
condition recorded as pre existing 
that is intermittently symptomatic 
[eg, headache] and that occurs 
during this study should be 
recorded as an adverse event.)  
• 
drug interactions 
• 
laboratory or diagnostic… 
Worsening of the disease under study (ie, 
asthma), including asthma exacerbations 
requiring additional controller medication, will 
be collected as an efficacy assessment in this 
study. The aforementioned worsening of 
asthma should be recorded as an adverse event 
only if the presentation or outcome is more 
severe than would typically be expected from 
the normal course of the disease in a particular 
patient. 
• 
intercurrent illnesses 
• 
physical injuries 
• 
events possibly related to 
concomitant medication 
• 
significant worsening 
(change in nature, severity, or 
frequency) of the disease 
under study or other 
pre-existing conditions  
• 
drug interactions 
• 
laboratory or diagnostic… 
 
 
Section 7.1.5.1 Definition of a Serious Adverse 
Event 
• 
inpatient hospitalization or 
prolongation of existing 
hospitalization, which means that 
hospital inpatient admission and/or 
prolongation of hospital stay were 
required for treatment of an adverse 
event, or that they occurred as a 
consequence of the event. 
Hospitalizations scheduled before 
study entry will not be considered 
serious adverse events, unless there 
was worsening of the preexisting 
condition during the patient’s 
participation in this study.  Note: 
Hospitalizations due to asthma 
exacerbation will be reported as 
serious adverse events only if the 
presentation or outcome is more 
severe than the patient’s known course 
of asthma.   
Section 7.1.5.1 Definition of a Serious 
Adverse Event 
• inpatient hospitalization or 
prolongation of existing 
hospitalization; which means that 
hospital inpatient admission and/or 
prolongation of hospital stay were 
required for treatment of an adverse 
event, or that they occurred as a 
consequence of the event. 
Hospitalizations scheduled before 
study entry will not be considered 
serious adverse events, unless there 
was worsening of the preexisting 
condition during the patient’s 
participation in this study. Note: 
Hospitalizations due to asthma 
exacerbation will be reported as 
serious adverse events if the 
presentation or outcome is more 
severe than the patient’s known 
course of asthma 
Alignment between 
protocol language, 
adverse event 
reporting 
instructions, and 
processes.  


 
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7.1.6: Protocol-Defined Adverse Events for Expedited Reporting to Teva (Other sections affected by this 
change: Appendix I) 
7.1.6: Protocol-Defined Adverse Events for 
Expedited Reporting to Teva 
For the purposes of this protocol, the following 
are considered protocol-defined adverse events 
for expedited reporting to Teva: anaphylaxis, 
newly-diagnosed malignancy, opportunistic 
infection, and parasitic helminth infection. 
Protocol-defined adverse events for expedited 
reporting can be either serious or nonserious 
according to the criteria outlined in 
Section 7.1.5.1. The process for reporting a 
protocol-defined adverse event for expedited 
reporting is the same as that for reporting a 
serious adverse event (see Section 7.1.5.3). A 
list of potential opportunistic infections is 
found in Appendix I. 
 
7.1.6: Protocol-Defined Adverse Events 
for Expedited Reporting to Teva 
For the purposes of this protocol, the 
following are considered protocol-defined 
adverse events for expedited reporting to 
Teva: anaphylaxis, newly-diagnosed 
malignancy, opportunistic infection, and 
parasitic helminth infection. Protocol-
defined adverse events for expedited 
reporting can be either serious or 
nonserious according to the criteria 
outlined in Section 7.1.5.1. The process for 
reporting a protocol-defined adverse event 
for expedited reporting is the same as that 
for reporting a serious adverse event (see 
Section 7.1.5.3). A list of potential 
opportunistic infections is found in 
Appendix I. 
A list of opportunistic 
infections was 
provided to increase 
investigators’ 
awareness of the 
potential for 
opportunistic 
infection during 
reslizumab treatment. 
7.1.7.2.  Creatine Phosphokinase/Muscular Adverse Events Case Report Form 
Potentially clinically significant creatine 
phosphokinase (CPK) elevations (with or 
without associated symptoms) or 
myalgia/muscle symptoms will be recorded as 
an adverse event and documented using the 
potentially clinically significant CPK/myalgia 
case report form. A potentially clinically 
significant CPK is defined as ≥3.1× upper limit 
of normal (Grade 3 based on the Food and Drug 
Administration [FDA] “Guidance for Industry 
Toxicity Grading Scale for Healthy Adult and 
Adolescent Volunteers Enrolled in Preventative 
Vaccine Clinical Trials”). 
If a potentially clinically significant CPK 
level (≥3.1 × ULN) occurs, the patient should 
attend an unscheduled visit for a physical 
examination and additional testing if 
indicated per investigator judgement. CPK 
levels will be re-tested at a minimum of 
every 7 to 10 days until the elevation is 
resolved, or if agreed with the medical 
monitor that no further testing is indicated. 
For ≥10 × ULN elevations in CPK, repeat 
CPK level, urinalysis (including 
microscopy), serum electrolytes, BUN, and 
creatinine will be performed as soon as 
possible after receipt of the CPK result. 
Further testing of CPK levels should be 
undertaken as frequently as needed to 
Potentially clinically significant creatine 
phosphokinase (CPK) elevations (with or 
without associated symptoms) or 
myalgia/muscle symptoms will be 
recorded as an adverse event and 
documented using the potentially clinically 
significant CPK/myalgia case report form. 
A potentially clinically significant CPK is 
defined as ≥3.1× upper limit of normal 
(Grade 3 based on the Food and Drug 
Administration [FDA] “Guidance for 
Industry Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers 
Enrolled in Preventative Vaccine Clinical 
Trials”). 
If a potentially clinically significant CPK 
level (≥3.1 × ULN) occurs, the patient 
should attend an unscheduled visit for a 
physical examination and additional 
testing if indicated per investigator 
judgement.  CPK levels will be re-tested at 
a minimum of  every 7 to 10 days until the 
elevation is resolved, or if agreed with the 
medical monitor that no further testing is 
indicated. For ≥10 × ULN elevations in 
CPK, repeat CPK level, urinalysis 
(including microscopy), serum 
electrolytes, BUN, and creatinine will be 
performed as soon as possible after receipt 
Requested edits from 
Health Authority and 
for overall clarity. 


 
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manage patient care per investigator 
judgment, but should be at a minimum of 
every 7 to 10 days as above. Need for repeat 
urinalysis, serum electrolytes, BUN, and 
creatinine testing should be determined by 
the investigator. In addition, need for 
treatment (eg, administration of iv fluids, 
urine alkalinization) should be considered by 
the investigator. 
In cases deemed by the investigator to be 
treatment-related elevations in CPK ≥10 × 
ULN (eg, potentially rhabdomyolysis), study 
drug discontinuation should occur at least 
until CPK normalization or longer based on 
investigator clinical assessment.   
of the CPK result. Further testing of CPK 
levels should be undertaken as frequently 
as needed to manage patient care per 
investigator judgment, but should be at a 
minimum of every 7 to 10 days as above. 
Need for repeat urinalysis, serum 
electrolytes, BUN, and creatinine testing 
should be determined by the investigator. 
In addition, need for treatment (eg, 
administration of iv fluids, urine 
alkalinization) should be considered by the 
investigator. 
In cases deemed by the investigator to be 
treatment-related elevations in CPK ≥10 × 
ULN (eg, potentially rhabdomyolysis), 
study drug discontinuation should occur at 
least until CPK normalization or longer 
based on investigator clinical assessment.   
9.10  Immunogenicity Analysis 
Anti-reslizumab antibody information will be 
described for subjects who test positive. 
Samples from placebo-treated patients will not 
be analyzed unless the patient elects to enroll 
into an available open-label safety study 
where the patient will receive reslizumab 
treatment. In this case the pre-dose 
(baseline) sample from the rolled-over 
placebo patient will be analyzed and 
reported along with post-treatment samples 
collected in the open-label safety study study. 
Summaries will be provided if appropriate. 
Anti-reslizumab antibody information will 
be described for subjects who test positive. 
Samples from placebo-treated patients will 
not be analyzed unless the patient elects to 
enroll into an available open-label safety 
study where the patient will receive 
reslizumab treatment. In this case the pre-
dose (baseline) sample from the rolled-
over placebo patient will be analyzed and 
reported along with post-treatment samples 
collected in the open-label safety study. 
Summaries will be provided if appropriate. 
Updated to 
accommodate 
baseline ADA testing 
in previous placebo 
patients. 
17.4.4. Administrative Letter Dated 
February 2016 
17.4.4. Administrative Letter Dated 
February 2016 
Letter added as 
reference. 
17.4.5. Administrative Letter Dated 08 
March 2016 
17.4.5. Administrative Letter Dated 08 
March 2016 
Letter added as 
reference. 
17.4.6. Administrative Letter Dated 21 
March 2016 
17.4.6. Administrative Letter Dated 21 
March 2016 
Letter added as 
reference. 
Appendix A 
Global Initiative for Asthma ICS Equivalency 
Table 
and  
Row added for fluticasone fuorate total daily 
dose 
Global Initiative for Asthma ICS 
Equivalency Table 
and  
Row added for fluticasone fuorate total 
daily dose 
Title amended for 
clarity. 
Additional row added 
to account for 
fluticasone fuorate 
total daily dose as per 
GINA 2016 
guidance. 


 
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Reason/Justification 
for change 
Appendix I 
Appendix I. Opportunistic Infections 
Appendix I. Opportunistic Infections 
Appendix added per 
Health Authority 
request. 


 
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17.3. 
Amendment 02 Dated 25 January 2016 
The revisions listed below have been made to the protocol Study C38072-AS-30025 and are 
considered substantial by the Teva Authorized Representative. 
Table 5: 
Changes to the Protocol 
Original text with changes shown 
New wording 
Reason/Justification for 
change 
Title Page: 
 
 
Teva Branded Pharmaceutical Products 
R&D, Inc 
 
 
 
Teva Branded Pharmaceutical Products 
R&D, Inc 
 
Sponsor’s Safety 
Representative was 
changed. 
Clinical Study Personnel Contact Information: 
 
 
 
 
 
 
Medical Monitor for North 
America was changed. 
EMEA:  
 
 
 
 
EMEA:  
 
 
 
 
The spelling of the EMEA 
Medical Monitor was 
corrected. 
Section 1: BACKGROUND INFORMATION 
Section 1.3.2.2: Clinical Safety and Efficacy Studies: 
A total of 2195 healthy volunteers and 
patients with moderate to severe asthma, 
eosinophilic esophagitis, eosinophilic 
gastritis, hypereosinophilic syndrome, or 
nasal polyposis had received at least 1 iv 
dose of reslizumab in 14 clinical studies. 
A total of 2195 healthy volunteers and 
patients with moderate to severe 
asthma, eosinophilic esophagitis, 
eosinophilic gastritis, hypereosinophilic 
syndrome, or nasal polyposis had 
received at least 1 dose of reslizumab 
in 14 clinical studies. 
IV was removed as the 
2195 subjects also included 
45 patients who received sc 
reslizumab in Study 1107. 
Serious adverse events and death cases from 
the ongoing open-label sStudy (3085) are 
also included in the relevant sections 
Serious adverse events and death cases 
from the open-label Study 3085 are 
also included in the relevant sections 
The language was updated, 
as Study 3085 has been 
completed since the last 
version of the protocol. 


 
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Serious Adverse Events 
… 
Deaths 
… 
Laboratory Findings 
No clinically meaningful changes in clinical 
laboratory values, vital signs measurements, 
electrocardiogram (ECG), or physical 
examination findings were noted in the 
completed studies with the exception of a 
decrease in eosinophil counts in the 
reslizumab groups, which was dose related 
and is expected in view of the mechanism of 
action orof reslizumab. MildSmall decreases 
in the mean values of total white blood cell 
counts waswere also observed in some 
studies and hashave been assessed as 
reflecting the decrease in the eosinophil 
component of differential cell counts in 
hypereosinophilic patients. The mean values 
of eosinophil and WBCwhite blood cell 
counts returned to baseline values at the end 
of study follow-up visit (4 months after the 
last dose of reslizumab). 
Adverse Drug Reactions 
As expected with administration of a 
monoclonal antibody, hypersensitivity/ 
anaphylactic injection reactions/Anaphylaxis 
wererelated to reslizumab infusion has 
been reported and is are considered an 
adverse drug reactions (ADR). All cases of 
anaphylaxis early in the drug development 
plan occurred in the eosinophilic esophagitis 
studies and were deemed by the 
investigator as related to known food 
allergies by the investigator, and not to 
reslizumab. There were 3 infusion-related 
anaphylaxis reactions related to reported as 
anaphylaxis that occurred during or shortly 
after reslizumab infusion in the reactions 
reported as anaphylaxis that occurred 
during or shortly after reslizumab infusion 
in the BREATH studies: that were 
characterized variously by skin or mucosal 
involvement, dyspnea, wheezing, 
gastrointestinal symptoms, and chills. aAll 3 
were treated at the study site and the 
patients were discontinued withdrawn from 
the study. 
Myalgia was reported at a slightly higher 
rate in the reslizumab 3.0-mg/kg group (1%) 
than in the placebo group (0.5%) and is 
considered an ADR. 
Serious Adverse Events 
… 
Deaths 
… 
Laboratory Findings 
No clinically meaningful changes in 
clinical laboratory values, vital signs 
measurements, electrocardiogram 
(ECG), or physical examination 
findings were noted in the completed 
studies with the exception of a decrease 
in eosinophil counts in the reslizumab 
groups, which was dose related and is 
expected in view of the mechanism of 
action of reslizumab. Small decreases 
in the mean values of total white blood 
cell counts were also observed in some 
studies and have been assessed as 
reflecting the decrease in the eosinophil 
component of differential cell counts. 
The mean values of eosinophil 
andwhite blood cell counts returned to 
baseline values at the end of study 
follow-up visit (4 months after the last 
dose of reslizumab). 
Adverse Drug Reactions 
Anaphylaxis related to reslizumab 
infusion has been reported and is 
considered an adverse drug reaction 
(ADR). All cases of anaphylaxis early in 
the drug development occurred in the 
eosinophilic esophagitis studies and 
were deemed by the investigator as 
related to known food allergies and 
not to reslizumab. There were 
3 infusion-related anaphylaxis 
reactions reported as anaphylaxis that 
occurred during or shortly after 
reslizumab infusion in the BREATH 
studies that were characterized 
variously by skin or mucosal 
involvement, dyspnea, wheezing, 
gastrointestinal symptoms, and chills. 
All 3 were treated at the study site and 
the patients were withdrawn from the 
study. 
Myalgia was reported at a slightly 
higher rate in the reslizumab 3.0-
mg/kg group (1%) than in the placebo 
group (0.5%) and is considered an ADR. 
This information was 
added and updated to 
provide details and update 
the organization of the 
section. 


 
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change 
Additional safety issues 
Malignancy 
As of September 2014February 2015, there 
were 2427 treatment-emergent adverse 
events reported by 2124 patients related to 
malignancy for the entire clinical program. 
The malignancies,Malignancies in the 
reslizumab-treated patients were of diverse 
tissue origin (1tissues ( colon, 1 anal, 3 
melanoma, 2 prostate, 3 breast, 2 lung, 
1 plasmacytoma, 1 lymphoma, 1 lung 
metastasis of a previous resected colon 
cancer, and 5ovarian adenocarcinoma, 
borderline ovarian tumor, 
and non-melanoma skin cancer cases 
reported as nonserious events). ).  
In the placebo-controlled asthma studies 
utilizing the 3.0-mg/kg dose, the incidence 
of the overall malignancies was 6 (0.58%) 
patients (0.58%; 1 patient had both prostate 
cancer and skin squamous cell carcinoma) in 
the reslizumab 3.0-mg/kg treatment group 
and 2 patients (0.27%) in the placebo group; 
all. All malignancies in the reslizumab-
treated patients were diagnosed within less 
than 6 months from first reslizumab dosing 
with the exception of, except for the skin 
squamous cell carcinoma.  
In the combined placebo-controlled studies 
and the long-term, open-label, safety 
extension Study C38072/3085, there were a 
total of 19 patients with malignancies were 
reported in 1921 patients., including These 
included , including 5 cases of 
non-melanoma skin cancer. Most 
malignancies were diagnosed within less than 
half a year6 months after starting reslizumab 
treatment, and in 54 of these cases, there was 
a previous medical history of malignancies 
malignancy. The A thorough analysis of 
malignancy cases (ie, comparison of the 
malignancy rate to the general population 
malignancy [using the National Cancer 
Institute Surveillance, Epidemiology, and 
End Results Program], time to diagnosis, and 
nature and types of malignancies) did not 
suggest association a causal relationship 
between reslizumab and malignancies cancer 
risk. 
Additional safety issues 
Malignancy 
As of February 2015, there were 24 
treatment-emergent adverse events 
reported by 21 patients related to 
malignancy for the entire clinical 
program. Malignancies in 
reslizumab-treated patients were of 
diverse tissues ( colon, anal, 
melanoma, prostate, breast, 
lung, plasmacytoma, lymphoma, lung 
metastasis of a previous resected colon 
cancer, ovarian adenocarcinoma, 
borderline ovarian tumor, 
and non-melanoma skin cancer cases).  
In the placebo-controlled asthma 
studies utilizing the 3.0-mg/kg dose, 
incidence of overall malignancies was 
6 patients (0.58%; 1 patient had both 
prostate cancer and skin squamous cell 
carcinoma) in the reslizumab 
3.0-mg/kg treatment group and 
2 patients (0.27%) in the placebo 
group. All malignancies in reslizumab-
treated patients were diagnosed within 
less than 6 months from first 
reslizumab dosing, except for the skin 
squamous cell carcinoma. 
In the combined placebo-controlled 
studies and long-term, open-label, 
safety extension Study C38072/3085, 
malignancies were reported in 
21 patients. These included 5 cases of 
non-melanoma skin cancer. Most 
malignancies were diagnosed within 
less than 6 months after starting 
reslizumab treatment, and in 5 cases, 
there was a previous medical history of 
malignancy.  
A thorough analysis of malignancy 
cases did not suggest a causal 
relationship between reslizumab and 
cancer risk. 
This information was 
added and updated to 
provide details and update 
the organization of the 
section. 


 
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Pregnancy 
The safety of reslizumab in pregnant women 
or in the developing fetus has not been 
studied, but nonclinical and completed and 
ongoing clinical studies raised no specific 
concerns. There wereTo date, there have 
been 10 pregnancies during the entire clinical 
development of reslizumab, 2 of which 
occurred during the screening period of the 
study and 8 were onin patients receiving 
reslizumab. All patients were withdrawn 
from the study. Two pregnancies ended 
inwere terminated by an elective abortion 
with no complications, and 5 concluded with 
led to the birth of full-term live births of 
infants with no malformations and no 
obstetric or perinatal complications. One 
male babynewborn had a neonatal jaundice 
that was reported as an unrelated adverse 
event and was assessed as a physiological 
jaundice. There was 1One pregnancy case 
that was lost to follow-up, and the outcome is 
unknown. 
Pregnancy 
The safety of reslizumab in pregnant 
women or developing fetus has not 
been studied, but nonclinical and 
clinical studies raised no specific 
concerns. To date, there have been 
10 pregnancies during the entire 
clinical development of reslizumab, 2 
of which occurred during the screening 
period of the study and 8 in patients 
receiving reslizumab. All patients were 
withdrawn from the study. Two 
pregnancies were terminated by an 
elective abortion with no 
complications, and 5 led to the birth of 
full-term infants with no malformations 
and no obstetric or perinatal 
complications. One male newborn had 
a neonatal jaundice that was reported as 
an unrelated adverse event and was 
assessed as a physiological jaundice. 
One pregnancy case was lost to follow-
up, and the outcome is unknown. 
This information was 
added and updated to 
provide details and update 
the organization of the 
section. 
Immunogenicity analysis showed anti 
Anti-drug antibody (ADA) responses were 
observed in 3.3% to 11.8% of patients in 
the completed Phase 3 studies in patients 
with asthma (iv administration every 
4 weeks, >1000  patients evaluated for ADA) 
were observed in 3.3% to 11.8% of patients.). 
In general, the ADA responses were low in 
titer and often transient and were not 
associated with an effect on reslizumab 
concentration or, eosinophil count, or 
associated with specific clinical 
manifestations,  (including hypersensitivity 
reactions. Myalgia, which was slightly higher 
in the reslizumab 3.0 mg/kg group (1%) than 
in the placebo group (0.5%), and anaphylaxis 
reactions are considered adverse drug 
reactions (ADRs).).  
Immunogenicity 
Anti-drug antibody (ADA) responses 
were observed in 3.3% to 11.8% of 
patients in the completed Phase 3 
studies in patients with asthma (iv 
administration every 4 weeks, 
>1000 patients evaluated for ADA). In 
general, the ADA responses were low 
in titer and often transient and were not 
associated with an effect on reslizumab 
concentration, eosinophil count or 
specific clinical manifestations 
(including hypersensitivity reactions). 
This information was 
added and updated to 
provide details and update 
the organization of the 
section. 


 
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change 
Section 1.4.1: Risks of Reslizumab 
Most clinical safety data for reslizumab 
are based on the experience with iv 
administration of the drug. As described in 
Section 1.3.2, iv reslizumab iv has been 
generally well tolerated over the range of 
doses evaluated (ie, from 0.03 through 
3 mg/kg). Systemic severe reactions 
(including Aanaphylaxis) and myalgia are 
considered as adverse drug reactions of iv 
reslizumab.  
There are limited safety data regarding sc 
administration of reslizumab. 
Most clinical safety data for reslizumab 
are based on the experience with iv 
administration of the drug. As 
described in Section 1.3.2, iv 
reslizumab has been generally well 
tolerated over the range of doses 
evaluated (ie, from 0.03 through 
3 mg/kg). Systemic severe reactions 
(including anaphylaxis) and myalgia 
are considered as adverse drug 
reactions of iv reslizumab.  
There are limited safety data regarding 
sc administration of reslizumab. 
This section was updated 
with information found in 
the current Investigator’s 
Brochure. 
Section 1.4.3. 
Overall Risk and Benefit Assessment for This Study: 
The majority of adverse events in 
reslizumab-treated patients was were mild to 
moderate in severity, and considered to be 
unrelated to study drug treatment, as 
determined by the investigator, and (as 
expected), associated with underlying asthma 
disease. There were no significant differences 
in the AEadverse event profile between 
patients treated with reslizumab and patients 
treated with placebo with the exception of 
the following ADRs: “systemic severe 
reactions (including anaphylaxis)” and 
“myalgia”. Three3 anaphylaxis reactions 
related to reslizumab infusions that were 
reported during the BREATH asthma 
program; Nnone of the patients were positive 
for ADA. All cases resolved with standard 
treatment, and treatment with reslizumab was 
permanently discontinued. This is an 
expected ADR and is listed in the IB. 
Myalgia (without evidence for muscle 
injury) was reported at a slightly higher 
rate in the reslizumab 3.0-mg/kg group 
(1%) than in the placebo group (0.5%). 
The protocol includes measures to closely 
monitor and promptly address these 
ADRs, to mitigate any potential harm to 
patients. 
Overall, the nature and occurrence of the 
reported study drug related adverse events 
did not raise any specific safety concerns. For 
the full ADR list, please refer to the IB. 
The majority of adverse events in 
reslizumab-treated patients were mild 
to moderate in severity, were 
considered to be unrelated to study 
drug treatment, as determined by the 
investigator, and as expected, were 
associated with underlying asthma 
disease. There were no significant 
differences in the adverse event profile 
between patient treated with reslizumab 
and patients treated with placebo with 
the exception of the following ADRs: 
“systemic severe reactions (including 
anaphylaxis)” and “myalgia”. Three 
anaphylaxis reactions related to 
reslizumab infusions were reported 
during the BREATH asthma program; 
none of the patients were positive for 
ADA. All cases resolved with standard 
treatment, and treatment with 
reslizumab was permanently 
discontinued. Myalgia (without 
evidence for muscle injury) was 
reported at a slightly higher rate in the 
reslizumab 3.0 mg/kg group (1%) than 
in the placebo group (0.5%). The 
protocol includes measures to closely 
monitor and promptly address these 
ADRs, to mitigate any potential harm 
to patients. 
The overall risks were 
updated and ADRs were 
further defined by this 
change. Text on myalgia 
was moved to this section. 


 
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Section 1.7: Population to be Studied and Justification (Other sections affected by this change: Clinical Study 
Protocol Synopsis, and Sections 3.1 and 4.1): 
The study will enroll male and female 
patients, 12 years of age and older, with 
asthma and elevated blood eosinophils who 
are inadequately controlled on at least 440 μg 
of inhaled fluticasone propionate or 
equivalenta medium total daily ICS dose 
and a second asthma controller. 
The study will enroll male and female 
patients, 12 years of age and older, with 
asthma and elevated blood eosinophils 
who are inadequately controlled on at 
least a medium total daily ICS dose and 
a second asthma controller. 
This change generalized 
the ICS requirements for 
subjects enrolled in the 
study. 
Section 2: PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
Section 2.3.2: Secondary Efficacy Endpoints (Other sections affected by this change: Clinical Study Protocol 
Synopsis and Section 9.5.2): 
• 
change in total asthma symptom scores 
(day and night) from baseline/DoR at 
week 52 
• 
change in percentage of asthma control 
days from baseline/DoR atto week 52 
• 
change in total asthma symptom 
scores (day and night) from baseline at 
week 52 
• 
percentage of asthma control days 
from baseline/DoR to week 52 
These changes creates 
clarity for the endpoints. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 2.3.4: Target Biomarker Endpoints (Other sections affected by this change: Clinical Study Protocol 
Synopsis and Section 9.5.5): 
The target biomarker endpoints are the blood 
eosinophil counts at baseline/DoR; weeks 2, 
4, 8, 12, 16, 20, 32, 52 or early withdrawal; 
and the follow-up visit (approximately week 
60). 
The target biomarker endpoints are the 
blood eosinophil counts at 
baseline/DoR; weeks 2, 4, 8, 12, 16, 32, 
52 or early withdrawal; and the follow-
up visit (approximately week 60). 
Change made for 
consistency with Table 2 
Study Procedures and 
Assessments. 


 
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Section 2.3.6: Pharmacokinetic Endpoints (Other sections affected by this change: Clinical Study Protocol 
Synopsis, Sections 2.3.5 and 9.7.3): 
The PK endpoints are the serum reslizumab 
concentrations at baseline/DoR; weeks 1 
(patients in US study centers only), 2, and 
prior to study drug administration at 
weeks 4, 8, 12, 16, 20, 32, 48, 52 or early 
withdrawal; and the follow-up visit 
(approximately week 60). An additional PK 
sample will be taken at long term follow-up 
(approximately week 76) at the same time 
for anti-drug antibody (ADA) sample 
collectionassessment. 
The PK endpoints are the serum 
reslizumab concentrations at 
baseline/DoR; weeks 1 (patients in US 
study centers only), 2, and prior to 
study drug administration at weeks 4, 8, 
12, 16, 20, 32, 48, 52 or early 
withdrawal; and the follow-up visit 
(approximately week 60). An 
additional PK sample will be taken at 
long term follow-up (approximately 
week 76) at the same time for anti-drug 
antibody (ADA) sample collection. 
This addition clarified that 
the sample collection was 
to be done prior to study 
drug administration at 
certain visits. 
Section 3: STUDY DESIGN 
Section 3.1: General Design and Study Schema (Other sections affected by this change: Table 2, Footnote a, 
3.16.1. Procedures for Screening and Start of Run-In Period [Visits 1 and 2]) 
Patients will begin screening up to 
approximately 5 weeks (±1 week) before 
prior to DoR. 
Patients will begin screening up to 
approximately 5 weeks (±1 week) 
before DoR. 
Clarifies the duration of the 
screening period and 
allows flexibility for 
scheduling around holidays 
and weekends. 
Section 3.1: General Design and Study Schema (Other sections affected by this change: Clinical Study Protocol 
Synopsis): 
Patients will return 8 weeks after the end of 
treatment visit (EOT visit) for follow-up 
hematology, PK, and immunogenicity, 
biomarker, lung function, and safety 
assessments. 
Patients will return 8 weeks after the 
end of treatment visit (EOT visit) for 
follow-up hematology, PK, and 
immunogenicity, and safety 
assessments. 
Biomarker in this case 
refers to eosinophils which 
falls under hematology 
which is already listed. 
Lung function will not be 
assessed during the follow-
up. The deletion makes this 
consistent with Table 2. 
Section 3.1: General Design and Study Schema: 
If a patient elects to withdraw (or is 
discontinued from treatment by the 
Investigator), every attempt will be made to 
continue the assessments subsequent to their 
withdrawal from the study (see 
Section 4.4)drug. 
If a patient elects to withdraw (or is 
discontinued from treatment by the 
Investigator), every attempt will be 
made to continue the assessments 
subsequent to their withdrawal from the 
study (see Section 4.4). 
Section link added for 
clarity. 
Section 3.1: General Design and Study Schema; Figure 1: Overall Study Schema: 
Figure 1: 
Reversibility ≥12% and absolute change of 
≥200 mL 
Figure 1: 
Reversibility ≥12% 
Deletions were made to 
improve clarity in the 
figure. 
Figure 1: 
(CBC, PK, immunogenicity, biomarker, AE, 
and FEV1safety assessment) 
Figure 1: 
(CBC, PK, immunogenicity, and safety 
assessment) 
Assessments at the follow-
up visit EOT + 8 weeks 
were clarified. 


 
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Section 3.1: General Design and Study Schema (Other sections affected by this change: Clinical Study Protocol 
Synopsis, and Sections 3.16.1 and 4.1): 
To be eligible to enroll in the study, a patient 
will have an ACQ-6 score of at least 1.5, 
airway FEV1 reversibility of at least 12% and 
an absolute change of at least 200 mL to 
beta-agonist administration, blood eosinophil 
count of at least 300/μL, and a current 
fluticasone propionate dosage of at least 
440 μg daily (or equivalent) with a second 
asthma controller and will have met all the 
inclusion and none of the exclusion criteria at 
screening. 
To be eligible to enroll in the study, a 
patient will have an ACQ-6 score of at 
least 1.5, airway FEV1 reversibility of 
at least 12% to beta-agonist 
administration, blood eosinophil count 
of at least 300/μL, and a current 
fluticasone propionate dosage of at 
least 440 μg daily (or equivalent) with a 
second asthma controller and will have 
met all the inclusion and none of the 
exclusion criteria at screening. 
This deletion was made for 
severe asthma patients on 
high GINA step therapy 
(ie, ICS plus another 
controller (s) including 
OCS ), it may be overly 
difficult to achieve both 
criteria. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
Section 3.9: Randomization and Blinding: 
The randomization list and treatment will be 
assigned to the relevant treatment groups 
through a qualified service provider contract 
research organization (CRO), eg, via 
Interactive Web Response System (IWRS). 
Generation of the medication list and 
management of the interactive response 
technology (IRT) system will be done by a 
qualified service providerCRO under the 
oversight of Teva’s Clinical Supply Chain. 
The randomization list and treatment 
will be assigned to the relevant 
treatment groups through a qualified 
CRO, eg, via Interactive Web Response 
System (IWRS). Generation of the 
medication list and management of the 
interactive response technology (IRT) 
system will be done by a qualified CRO 
under the oversight of Teva’s Clinical 
Supply Chain. 
Change wording from 
“service provider” to 
“CRO.” 
Section 3.9: Randomization and Blinding (Other sections affected by this change: Clinical Study Protocol 
Synopsis): 
In addition, tThe sponsor’s clinical personnel 
involved in the study will also be blinded to 
the study drug identity after the run-in period 
until the database is locked for analysis and 
the treatment assignment is revealed, with the 
exception of the bioanalytical group who will 
not be blinded to facilitate PK and ADA 
sample analysis. Eosinophils and monocytes 
will be redacted from the post-baseline 
differential cell count reports to avoid the 
possibility of unblinding patients. 
The sponsor’s clinical personnel 
involved in the study will also be 
blinded to the study drug identity after 
the run-in period until the database is 
locked for analysis and the treatment 
assignment is revealed, with the 
exception of the bioanalytical group 
who will not be blinded to facilitate PK 
and ADA sample analysis. Eosinophils 
and monocytes will be redacted from 
the post-baseline differential cell count 
reports to avoid the possibility of 
unblinding patients. 
This addition clarified that 
the external vendor 
responsible for PK/PD 
analyses will not receive 
randomization codes. 


 
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Section 3.10.2: Blinding/Unblinding 
In order to complete the bioanalysis of data 
analysis for PK within the demonstrated time 
window of stability of reslizumab in serum, it 
may be necessary to assay samples before 
database lock. If so, the individuals 
responsible for sample analysis will know 
which patients received study drug and which 
patients received placebo. The randomization 
codes will be provided to personnel 
responsible for bioanalysis and PK data 
analysis according to a process that will be 
predefined in the unblinding plan form 
(GBP_RD_703_FRM_02) according to Teva 
Standard Operating Procedure (SOP) 
GBP_RD_703. The form will be signed at 
the study initiation stage by the responsible 
Teva statistician, service providerCRO 
statistician and randomization code 
generator. Personnel responsible for 
bioanalysis and PK data analysis After 
authorization has been obtained to release 
the codes, the randomization code 
generator at the CRO will provide the 
codes directly to the bioanalysis team; the 
statisticians (at Teva and the CRO) will 
not be unblinded. Personnel responsible 
for bioanalysis will not have access to 
clinical safety and efficacy data and will 
provide concentration data to any other 
personnel who may require it (including 
investigators) in a manner that will not 
identify individual patients (ie, a dummy 
patient identifier will be linked to an 
individual patient’s concentration data). 
In order to complete the data analysis 
for PK, it may be necessary to assay 
samples before database lock. If so, the 
individuals responsible for sample 
analysis will know which patients 
received study drug and which patients 
received placebo The randomization 
codes will be provided to personnel 
responsible for bioanalysis according to 
a process that will be predefined in the 
unblinding plan form 
(GBP_RD_703_FRM_02) according to 
Teva Standard Operating Procedure 
(SOP) GBP_RD_703. The form will be 
signed at the study initiation stage by 
the responsible Teva statistician, CRO 
statistician and randomization code 
generator. After authorization has been 
obtained to release the codes, the 
randomization code generator at the 
CRO will provide the codes directly to 
the bioanalysis team; the statisticians 
(at Teva and the CRO) will not be 
unblinded. Personnel responsible for 
bioanalysis will not have access to 
clinical safety and efficacy data and 
will provide concentration data to any 
other personnel who may require it in a 
manner that will not identify individual 
patients (ie, a dummy patient identifier 
will be linked to an individual patient’s 
concentration data). 
These edits clarify that 
randomization codes will 
be provided directly to the 
bioanalysis team.  
The paragraph addition 
also clarifies Teva’s use of 
PK samples collected 
during the course of the 
study. 
For information about personnel who may be 
aware of treatment assignments, see 
Section 3.9. These individuals will not be 
involved in conduct of any study procedures 
or assessment of any adverse events, safety, 
or efficacy data. 
For information about personnel who 
may be aware of treatment 
assignments, see Section 3.9. These 
individuals will not be involved in 
conduct of any study procedures or 
assessment of any adverse events, 
safety, or efficacy data. 
This addition clarifies that 
individuals aware of 
treatment assignments will 
also not be involved with 
assessement of safety or 
efficacy data. 
Section 3.13: (Other sections affected by this change: Clinical Study Protocol Synopsis, Table 2 [Footnote i], 
Section 3.16.1, and Section 7.3.1): 
The study’s duration is approximately 
65 weeks, including up to a 2-week (±3 days) 
screening period, a minimum 3-week run-in 
period, a 52-week treatment period, and a 
follow-up visit approximately 8 weeks after 
the end of treatment visit. 
The study’s duration is approximately 
65 weeks, including up to a 2 week 
(±3 days) screening period, a minimum 
3 week run in period, a 52 week 
treatment period, and a follow-up visit 
approximately 8 weeks after the end of 
treatment visit. 
This change was made to 
allow scheduling flexibility 
for weekends and holidays.  


 
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Section 3.14 Stopping Rules and Discontinuation Criteria: 
Other than pregnancy, tThere are no formal 
rules for early withdrawal from this study. 
Other than pregnancy, there are no 
formal rules for early withdrawal from 
this study. 
This addition clarifies that 
pregnancy can lead to early 
withdrawal from the study. 
Section 3.16: Study Procedures; Table 2: Study Procedures and Assessments: 
Addition of column for Late follow-up 
(visit number V19 and week W76) 
Addition of column for Late follow-up 
and visit number V19 and week W76 
Clarification added. 
Additional day for pregnancy testing at 
V18 
Additional day for pregnancy testing 
(V18) 
Clarification added. 
Additional days for providing/collecting 
asthma control diary and reinforcing 
diary and PEF compliance at VPK and V4 
Additional days for 
providing/collecting asthma control 
diary and reinforcing diary and PEF 
compliance at VPK and V4 
Clarification added. 
d Beta-human chorionic gonadotropin serum 
pregnancy tests will be performed at 
screening (female patients who are not 2 
years postmenopausal or surgically sterile 
only). Urine pregnancy tests will be 
performed at baseline/DoR, before study 
drug injection at each administration visit and 
at week 52, or early withdrawal, and at 
follow-up V18. Pregnancy tests are not 
required for female patients who are 2 years 
postmenopausal or surgically sterile. 
d Beta-human chorionic gonadotropin 
serum pregnancy tests will be 
performed at screening (female patients 
who are not 2 years postmenopausal or 
surgically sterile only). Urine 
pregnancy tests will be performed at 
baseline/DoR, before study drug 
injection at each administration visit 
and at week 52, or early withdrawal, 
and at follow-up V18. Pregnancy tests 
are not required for female patients 
who are 2 years postmenopausal or 
surgically sterile. 
Text was updated to be 
consistent with Table 2. 
Serum chemistry testsf 
f CPK is collected with serum chemistry 
tests at scheduled visits. If potentially 
clinically significant CPK is reported, 
initiate CPK/myalgia CRF. Urinalysis and 
selected chemistries should be performed 
for 10x elevations as per CRF instructions, 
and CPK levels re-tested every 7 to 10 
days until the elevation is resolved or if 
agreed with the medical monitor that no 
further testing is indicated. 
Serum chemistry testsf 
f CPK is collected with serum 
chemistry tests at scheduled visits. If 
potentially clinically significant CPK is 
reported, initiate CPK/myalgia CRF. 
Urinalysis and selected chemistries 
should be performed for 10x elevations 
as per CRF instructions, and CPK 
levels re-tested every 7 to 10 days until 
the elevation is resolved or if agreed 
with the medical monitor that no 
further testing is indicated. 
Footnote f was added for 
Serum Chemistry Tests. 


 
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h i A failed reversibility test may be repeated 
once, within the 2-week (±3 days) screening 
period. Reversibility testing will be 
confirmed beforeprior to entering the run-in 
period. Documented historical reversibility 
within 12 months of signing the Informed 
Assent Form/Informed Consent Form is 
acceptable as per inclusion criterion f. 
i A failed reversibility test may be 
repeated once, within the 2-week 
(±3 days) screening period. 
Reversibility testing will be confirmed 
before entering the run-in period. 
Documented historical reversibility 
within 12 months of signing the 
Informed Assent Form/Informed 
Consent Form is acceptable as per 
inclusion criterion f. 
Clarification added. 
l An additional, late follow up for PK testing 
will be performed 28 weeks (±2 weeks) after 
the last dose of study drug (~week 76) for 
ADA assessment. 
The footnote was deleted. 
Clarification added. 
Adverse event inquiryo 
o Adverse event inquiry will occur before 
and after study drug administration at V3 
to V16. Follow-up any prior messages 
from the post-injection eDiary symptom 
inquiry, as necessary. For systemic or 
severe hypersensitivity reactions possibly 
related to the study drug, initiate the 
anaphylaxis CRF. When such reactions 
are observed after study drug 
administration in the clinic, vital signs 
must be monitored using the unscheduled 
vital signs CRF. At the time of 
myalgia/muscular adverse events, CPK 
should be collected (initiate myalgia CRF). 
Adverse event inquiryo 
o Adverse event inquiry will occur 
before and after study drug 
administration at V3 to V16. Follow-up 
any prior messages from the post-
injection eDiary symptom inquiry, as 
necessary. For systemic or severe 
hypersensitivity reactions possibly 
related to the study drug, initiate the 
anaphylaxis CRF. When such reactions 
are observed after study drug 
administration in the clinic, vital signs 
must be monitored using the 
unscheduled vital signs CRF. At the 
time of myalgia/muscular adverse 
events, CPK should be collected 
(initiate myalgia CRF). 
Footnote o was added for 
Adverse Event Inquiry. 
3.16.1. Procedures for Screening and Start of Run-In Period (Visits 1 and 2) Other sections affected by this 
change: Table 2 and Section 3.1): 
The screening visit (visit 1) will take place not 
more thanapproximately 5 weeks (±1 week) 
but not less than 3 weeks before the 
baseline/DoR visit. The following procedures 
will be performed at visit 1: 
The screening visit (visit 1) will take 
place approximately 5 weeks (±1 week) 
before the baseline/DoR visit. The 
following procedures will be 
performed at visit 1: 
This change clarifies the 
duration of the screening 
period and allows 
flexibility for scheduling 
around holidays and 
weekends. 
Section 3.16.1: Procedures for Screening and Start of Run-In Period (Visits 1 and 2) (Other sections affected by 
this change: Sections 3.16.2 and 3.16.3.1.2): 
Perform reversibility testing if long acting 
and short acting inhaled beta agonists 
bronchodilators were held for the specified 
time; if not, the patient should be brought 
back on another day to complete. 
Perform reversibility testing if long 
acting and short acting inhaled 
bronchodilators were held for the 
specified time; if not, the patient should 
be brought back on another day to 
complete. 
The wording “beta-
agonists” was changed to 
“bronchodilators.” 


 
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Section 3.16.1: Procedures for Screening and Start of Run-In Period (Visits 1 and 2): 
Reversibility testing may be repeated once 
within the 2-week (±3 days) screening 
period. Airway reversibility will be 
demonstrated by measuring the change in 
FEV1 before and after inhalation of 
albuterolSABA; reversibility testing should 
only be attempted after withholding 
longshort-acting bronchodilators (ie, 
inhaled short-acting beta-agonist therapy for 
at least 12 hours and SABA 
therapyadrenergic agonists and/or short-
acting anticholinergics) for at least 6 hours. 
Up and long-acting bronchodilators (ie, 
inhaled long-acting beta-adrenergic 
agonists and long-acting anticholinergic 
agents) for at least 12 or 24 hours, 
according to 4 puffs of SABA therapytheir 
labeled dose schedule. SABAs, such as 
salbutamol or albuterol, administered via 
a metered dose inhaler should be used for 
reversibility testing. Four separate doses 
(eg, albuterol 360 μg or salbutamol 100 μg 
ex-valve) should be given by metered dose 
inhaler, as tolerated. Post-bronchodilator 
spirometry should be completed a 
minimum of 15 minutes after dosing of 
SABA. 
Reversibility testing may be repeated 
once within the 2-week (±3 days) 
screening period. Airway reversibility 
will be demonstrated by measuring the 
change in FEV1 before and after 
inhalation of SABA; reversibility 
testing should only be attempted after 
withholding short-acting 
bronchodilators (ie, inhaled short-
acting beta-adrenergic agonists and/or 
short-acting anticholinergics) for at 
least 6 hours and long-acting 
bronchodilators (ie, inhaled long-acting 
beta-adrenergic agonists and long-
acting anticholinergic agents) for at 
least 12 or 24 hours, according to their 
labeled dose schedule. SABAs, such as 
salbutamol or albuterol, administered 
via a metered dose inhaler should be 
used for reversibility testing. Four 
separate doses (eg, albuterol 360 μg or 
salbutamol 100 μg ex-valve) should be 
given by metered dose inhaler, as 
tolerated. Post-bronchodilator 
spirometry should be completed a 
minimum of 15 minutes after dosing of 
SABA. 
To make consistent with 
the text provided Table 2 
Study Procedures and 
Assessments. 
Section 3.16.3.1: Double-Blind Treatment Period: 
Study drug will be administered at 
approximately 0800 (±2 hours)the same time 
in the morning on the days indicated in 
Table 2. 
Study drug will be administered at 
approximately the same time in the 
morning on the days indicated in 
Table 2. 
As this is an anti-
inflammatory drug with a 
long half-life, the exact 
hour not critical. 
Section 3.16.3.1.2: Other On-Treatment Visits (Visits 4 through 17 [EOT]): 
• Complete the ACQ-6 (may be completed 
after study drug administration during 
the 1-hour observation period.) 
• Complete the AQLQ +12 (weeks 4, 8, 12, 
16, 32, and 52 or early withdrawal only) 
(AQLQ+12 may be completed after 
study drug administration during the 
1-hour observation period.) 
• Complete the SGRQ (weeks 32 and 52) 
(may be completed after study drug 
administration during the 1-hour 
observation period.) 
• 
 
 
• Complete the ACQ-6 (may be 
completed after study drug 
administration during the 1-hour 
observation period.) 
• Complete the AQLQ +12 (weeks 4, 
8, 12, 16, 32, and 52 or early 
withdrawal only) (AQLQ+12 may be 
completed after study drug 
administration during the 1-hour 
observation period.) 
• Complete the SGRQ (weeks 32 and 
52) (may be completed after study 
drug administration during the 1-hour 
observation period.) 
• 
 
Clarification around timing 
of questionnaires was also 
added. 


 
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The following procedures/assessments will 
be performed during and after 
administration of study drug: 
• Patients will be observed for 1 hour 
after study injection 
• Perform adverse event inquiry 
− If, during post-study drug 
observation, the patient develops 
clinical symptoms, vital signs should 
be collected. The patient should be 
assessed for 
anaphylaxis/hypersensitivity reactions 
as detailed in Section 7.1.6. 
Remind the patients that they will receive a 
post-injection symptom inquiry via the 
eDiary. 
The following procedures/assessments 
will be performed during and after 
administration of study drug: 
• Patients will be observed for 1 hour 
after study injection 
• Perform adverse event inquiry 
− If, during post-study drug 
observation, the patient develops 
clinical symptoms, vital signs 
should be collected. The patient 
should be assessed for anaphylaxis/ 
hypersensitivity reactions as detailed 
in Section 7.1.6. 
Remind the patients that they will 
receive a post-injection symptom 
inquiry via the eDiary. 
These additions were added 
to clarify the procedures 
and assessments to be 
performed during and after 
administration of study 
drug, as well as 24 hours 
after administration of the 
study. 
Section 3.16.4: eDiary Procedures After Study Drug Treatment (Other sections affected by this change: 
Sections 3.1): 
Patients who discontinue treatment 
prematurely must be encouraged to continue 
to attend the regular scheduled visits, and 
complete the prescribed safety and efficacy 
evaluations through the end-of-
treatment/early withdrawal visit and the 
follow-up visit, if at all possible (see 
Section 4.4). 
Patients who discontinue treatment 
prematurely must be encouraged to 
continue to attend the regular scheduled 
visits, and complete the prescribed 
safety and efficacy evaluations through 
the end-of-treatment/early withdrawal 
visit and the follow-up visit, if at all 
possible (see Section 4.4). 
A cross-reference was 
added to improve clarity. 
The following procedures/assessments will 
be performed at the follow-up visit (EOT 
+8 weeks ±14 days, end of study visit): 
• 
Perform urine pregnancy test. 
The following procedures/assessments 
will be performed at the follow-up visit 
(EOT +8 weeks ±14 days, end of study 
visit): 
• 
Perform urine pregnancy test. 
Edit made for consistency 
with Table 2. 


 
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Section 4: SELECTION AND WITHDRAWAL OF PATIENTS 
Section 4.1: Patient Inclusion Criteria (Other sections affected by this change: Clinical Study Protocol 
Synopsis): 
g. The patient has required at least 440 μg 
ofa medium total daily ICS dose based on 
GINA 2015 clinical comparability table 
(Appendix A) inhaled fluticasone propionate 
or equivalent total daily dosefor at least 
3 months. 
g. The patient has required at least a 
medium total daily ICS dose based on 
GINA 2015 clinical comparability table 
(Appendix A) for at least 3 months. 
Clarification: intent is to 
encompass the medium 
(and higher) daily dose 
range for a given ICS 
formulation as per GINA 
2015 BOX 3-6 as adapted 
in new Appendix A (with 
an additional asthma 
controller as per 
inclusion h). 
i. Females of childbearing potential (not 
surgically sterile or 2 years postmenopausal) 
must have an exclusively same-sex partner or 
use a medically acceptable method of 
contraception, and must agree to continue use 
of this method for the duration of the study 
and for 45 months after discontinuation 
oflast study drug dose. Contraception is 
further clarified in an administrative letter 
in Section 17.3.1. 
i. Females of childbearing potential 
(not surgically sterile or 2 years 
postmenopausal) must have an 
exclusively same-sex partner or use a 
medically acceptable method of 
contraception, and must agree to 
continue use of this method for the 
duration of the study and for 5 months 
after last study drug dose. 
Contraception is further clarified in an 
administrative letter in Section 17.3.1. 
Correction of time point 
after last dose of study drug 
with regards to use of 
contraception. 
l. inadequate asthma control at baseline/DoR 
as evidenced by 1 of the 4 criteria below: 
l. inadequate asthma control at 
baseline/DoR as evidenced by 1 of the 
4 criteria below: 
This addition provides 
context to the text that 
follows. 
Section 4.2: Patient Exclusion Criteria (Other sections affected by this change: Clinical Study Protocol 
Synopsis): 
e. The patient is a pregnant or lactating 
woman, or intends to become pregnant 
during the study or within 5 months after 
the last dose of study drug. Any woman 
becoming pregnant during the study will be 
withdrawn from the study. 
e. The patient is a pregnant or lactating 
woman, or intends to become pregnant 
during the study or within 5 months 
after the last dose of study drug. Any 
woman becoming pregnant during the 
study will be withdrawn from the 
study. 
This addition specified the 
period after the last dose of 
the study drug during 
which patient may not 
become pregnant. 
Section 4.4: Criteria and Procedures for Discontinuation of Study Treatment and/or Study Withdrawal: 
Withdrawal Criteria and Procedures for 
Discontinuation of Study Treatment and/or 
Study Withdrawal 
Criteria and Procedures for 
Discontinuation of Study Treatment 
and/or Study Withdrawal 
The title for the section was 
updated. 
In accordance with the Declaration of 
Helsinki (in accordance with the applicable 
country’s acceptance), each patient is free 
topatients may voluntarily discontinue 
study treatment (ie, refuse study treatment 
In accordance with the Declaration of 
Helsinki (in accordance with the 
applicable country’s acceptance), 
patients may voluntarily discontinue 
study treatment (ie, refuse study 
These edits clarified the 
procedures for 
discontinuation or 
withdrawal from the study. 


 
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but continue with study participation) or 
completely withdraw from the study (ie, 
with no further study participation or 
contact) at any time. The investigator also 
has the right to discontinue a patient from 
study treatment and/or withdraw a patient 
from the study in the event of intercurrent 
illness, adverse events, pregnancy (see 
Section 7.2), or other reasons concerning the 
health or well being of the patient, or in the 
event of lack of cooperation. In addition, a 
patient may be withdrawn from the study as 
described in Sections 3.10, 3.14, 3.16.3.1, 
5.4, and 7.1.7.  
Should a patient decide to withdraw from 
the treatment period after administration of 
study drug(s), or should the investigator 
decide to withdraw the patient, all efforts 
will be made to complete and report all 
observations up to the time of withdrawal. A 
complete final evaluation at the time of the 
patient’s withdrawal should be made and an 
explanation given as to why the patient is 
withdrawing or being withdrawn from the 
study. The reason for and date of withdrawal 
from study drug treatment and the reason 
for and date of withdrawal from the study If 
a patient withdraws consent, every attempt 
will be made to determine the reason. If the 
reason for withdrawal is an adverse event or 
a potentially clinically significant abnormal 
laboratory test result, monitoring will be 
continued until the event has resolved or 
stabilized, until the patient is referred to the 
care of a health care professional, or until a 
determination of a cause unrelated to the 
study drug or study procedure is made. The 
specific event or test result must be 
recorded on the source documentation and 
transcribed onto the CRF. 
treatment but continue with study 
participation) or completely withdraw 
from the study (ie, with no further 
study participation or contact) at any 
time. The investigator also has the 
right to discontinue a patient from 
study treatment and/or withdraw a 
patient from the study in the event of 
intercurrent illness, adverse events, 
pregnancy (see Section 7.2), or other 
reasons concerning the health or well 
being of the patient, or in the event of 
lack of cooperation. 
If a patient withdraws consent, every 
attempt will be made to determine the 
reason. If the reason for withdrawal is 
adverse event or a potentially clinically 
significant abnormal laboratory test 
result, monitoring will be continued 
until the event has resolved or 
stabilized, until the patient is referred 
to the care of a health care 
professional, or until a determination 
of a cause unrelated to the study drug 
or study procedure is made. The 
specific event or test result must be 
recorded on the source documentation 
and transcribed onto the CRF. 
Section 4.4.1: Discontinuation of Study Treatment 
4.4.1: Discontinuation of Study Treatment 
If premature discontinuation of study 
treatment occurs for any reason the patient 
should continue attending remaining study 
4.4.1: Discontinuation of Study 
Treatment 
If premature discontinuation of study 
treatment occurs for any reason the 
This section was inserted to 
clarify discontinuation of 
study treatment. 


 
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visits while off study treatment. The patient 
should not be considered withdrawn from 
the study due to interruption or 
discontinuation of study treatment. For this 
study, it is very important to continue 
collecting data from all patients whether or 
not they complete treatment. 
If premature discontinuation of study 
treatment occurs, the patient should return 
to the clinic as soon as possible for a study 
treatment discontinuation visit. All 
protocol specified evaluations should be 
performed atas specified in the protocol for 
the early withdrawal visit (see Table 2). 
Patients who The investigator must 
determine the reason for and the date of 
discontinuation of study treatment and 
record this information in both the source 
documentation and the Study Drug 
Treatment Completion CRF. The patient’s 
continued participation in the study must 
be discussed by the investigator and site 
staff with the patient; the investigator and 
site staff must also request the patient to 
continue attending study visits according to 
the study visit schedule with all 
assessments completed up to week 52 (visit 
17). The CAE event status and safety 
assessments at week 52 (visit 17) are the 
priority assessments for patients that 
prematurely discontinue study treatment. 
At a minimum, the investigator should 
make every effort to obtain information 
regarding serious adverse events, CAE 
events, and survival status at week 52. A 
safety follow-up visit (visit 18) should be 
conducted 8 weeks after visit 17. 
patient should continue attending 
remaining study visits while off study 
treatment. The patient should not be 
considered withdrawn from the study 
due to interruption or discontinuation 
study treatment. For this study, it is 
very important to continue collecting 
data from all patients whether or not 
they complete treatment. 
If premature discontinuation of study 
treatment occurs, the patient should 
return to the clinic as soon as possible 
for a study treatment discontinuation 
visit. All evaluations should be 
performed as specified in the protocol 
for the early withdrawal visit (see 
Table 2). The investigator must 
determine the reason for and the date 
of discontinuation of study treatment 
and record this information in both the 
source documentation and the Study 
Drug Treatment Completion CRF. The 
patient’s continued participation in the 
study must be discussed by the 
investigator and site staff with the 
patient; the investigator and site staff 
must also request the patient to 
continue attending study visits 
according to the study visit schedule 
with all assessments completed up to 
week 52 (visit 17). The CAE event 
status and safety assessments at week 
52 (visit 17) are the priority 
assessments for patients that 
prematurely discontinue study 
treatment. At a minimum, the 
investigator should make every effort 
to obtain information regarding 
serious adverse events, CAE events, 
and survival status at week 52. A safety 
follow-up visit (visit 18) should be 
conducted 8 weeks after visit 17. 
4.4.2: Complete Withdrawal from Study 
If a patient decides to completely withdraw 
from the study will be asked to return to the 
clinical site for a follow up visit 8 weeks ±14 
4.4.2: Complete Withdrawal from 
Study 
If a patient decides to completely 
withdraw from the study (ie, refuses 
 


 
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days after the early(ie, refuses any further 
study participation or contact), all study 
participation for that patient will cease and 
all data to be collected at subsequent visits 
will be considered missing. If a patient 
decides to completely withdraw from the 
study, every effort should be made to 
complete and report the observations 
outlined in Section 4.4.1 (Discontinuation of 
Study Treatment) before withdrawal visit. 
All protocol specified evaluations should be 
performed at the follow up visit 8 weeks ±14 
days after the early. A complete final 
evaluation at the time of the patient’s 
withdrawal visit (see Table 2). A 
subjectshould be made, including an 
explanation of why the patient is 
withdrawing from the study. The reason for 
and date of withdrawal from the study 
must be recorded in the source 
documentation and the Double-Blind 
Treatment Period Completion CRF. 
For patients who are lost to follow-up (ie, 
patients whose status is unclear because 
they fail to appear for study visits without 
stating an intention to withdraw), the 
investigator should make appropriate 
efforts to re-establish contact with patient; 
attempts to contact the patient should be 
documented in the source documents. If 
contact has not been re-established, efforts 
should still be made to locate the patient 
and obtain information regarding serious 
adverse events, CAE events, and survival 
status at the end of the 52-week treatment 
period. A patient should only be designated 
as lost to follow-up if the site is unable to 
establish contact with the subjectpatient after 
3  documented attempts via 2 different 
methods (phone, text, e-mail, certified letter, 
etc). 
If the final visit is conducted more than 28 
(±7) days after the final dose of study drug, 
all safety evaluations will be performed, but 
efficacy evaluations will not be made (see 
Section 3.16.3.1). 
any further study participation or 
contact), all study participation for that 
patient will cease and all data to be 
collected at subsequent visits will be 
considered missing. If a patient decides 
to completely withdraw from the 
study, every effort should be made to 
complete and report the observations 
outlined in Section 4.4.1 
(Discontinuation of Study Treatment) 
before withdrawal. A complete final 
evaluation at the time of the patient’s 
withdrawal should be made, including 
an explanation of why the patient is 
withdrawing from the study. The 
reason for and date of withdrawal 
from the study must be recorded in 
the source documentation and the 
Double-Blind Treatment Period 
Completion CRF. 
For patients who are lost to follow-up 
(ie, patients whose status is unclear 
because they fail to appear for study 
visits without stating an intention to 
withdraw), the investigator should 
make appropriate efforts to re-establish 
contact with patient; attempts to contact 
the patient should be documented in the 
source documents. If contact has not 
been re-established, efforts should still 
be made to locate the patient and obtain 
information regarding serious adverse 
events, CAE events, and survival status 
at the end of the 52-week treatment 
period. A patient should only be 
designated as lost to follow-up if the 
site is unable to establish contact with 
the patient after 3 documented attempts 
via 2 different methods (phone, text, e-
mail, certified letter, etc). 
Section 5: TREATMENT OF PATIENTS 
Section 5.1. Drugs Administered During the Study 


 
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Study drug will be administered as a single sc 
injection containing either placebo (1.0 mL) 
or 110 mg of reslizumab (1.0 mL). In the 
CRF, injection sites will be labeled (eg, “A,” 
“B,” or “C”). 
Study drug will be administered as a 
single sc injection containing either 
placebo (1.0 mL) or 110 mg of 
reslizumab (1.0 mL). 
Text was deleted to provide 
additional clarity. 
Section 5.3: Prior and Concomitant Therapy or Medication: 
Indication, dosage, and start and end dates 
should be entered on the appropriate CRF. 
Indication, dosage, and start and end 
dates should be entered on the 
appropriate CRF. 
Clarification added. 
Section 6: ASSESSMENT OF EFFICACY 
Section 6.2. Spirometry 
For post-bronchodilatory spirometry, 
SABAs, such as salbutamol or albuterol, 
administered via a metered dose inhaler 
should be used. Four separate doses (eg, 
albuterol 360 μg or salbutamol 100 μg ex-
valve) should be given by metered dose 
inhaler, as tolerated. Post-bronchodilator 
spirometry should be completed a 
minimum of 15 minutes after dosing of 
SABA. 
For post-bronchodilatory spirometry, 
SABAs, such as salbutamol or 
albuterol, administered via a metered 
dose inhaler should be used. Four 
separate doses (eg, albuterol 360 μg or 
salbutamol 100 μg ex-valve) should be 
given by metered dose inhaler, as 
tolerated. Post-bronchodilator 
spirometry should be completed a 
minimum of 15 minutes after dosing of 
SABA. 
The doses of various beta-
agonists for spirometry 
were clarified by this 
addition. 
Spirometry will be done according to 
American Thoracic Society/European 
Respiratory Society 2005 procedural 
guidelines. 
Spirometry will be done according to 
American Thoracic Society/European 
Respiratory Society 2005 procedural 
guidelines. 
Year of guidance was 
specified for clarity. 
Section 6.10: Asthma Rescue Medication Use 
6.10: Short Acting Beta Agonist Asthma 
Rescue Medication Use 
The number of times SABA therapy asthma 
rescue medication (number of 
inhalataions/puffs) is used for rescue 
purposes will be assessed by reviewing the 
asthma control diary. 
6.10: Asthma Rescue Medication Use 
The number of times asthma rescue 
medication (number of 
inhalataions/puffs) is used will be 
assessed by reviewing the asthma 
control diary. 
SABA therapy was 
changed to asthma rescue 
medication and the title of 
the section was also 
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Section 7: ASSESSMENT OF SAFETY 
Section 7.1.2: Recording and Reporting Adverse Events: 
At each contact with the patient, the 
investigator or designee must question the 
patient about adverse events by asking an 
open-ended question such as, “Have you had 
any unusual symptoms or medical problems 
since the last visit? If yes, please describe.” 
In addition, the eDiary will be 
programmed to query the patient about 
symptoms potentially consistent with 
hypersensitivity occurring during the 24 
hour period following study drug 
injection. 
At each contact with the patient, the 
investigator or designee must question 
the patient about adverse events by 
asking an open-ended question such as, 
“Have you had any unusual symptoms 
or medical problems since the last 
visit? If yes, please describe.” In 
addition, the eDiary will be 
programmed to query the patient about 
symptoms potentially consistent with 
hypersensitivity occurring during the 
24 hour period following study drug 
injection. 
This change was to clarify 
that the patient will be 
queried by the eDiary 
24 hours after dosing with 
the study drug. 
Section 7.1.5.3.1: Investigator Responsibility (Other sections affected by this change: Section 8.3): 
If possible, a blood sample for 
measurement of serum reslizumab 
concentrations will be obtained from 
patients experiencing a serious adverse 
event, an adverse event leading to 
withdrawal, an observation of any severe 
hypersensitivity reaction (eg, anaphylaxis), 
or an exacerbation of asthma symptoms. 
If possible, a blood sample for 
measurement of serum reslizumab 
concentrations will be obtained from 
patients experiencing a serious adverse 
event, an adverse event leading to 
withdrawal, an observation of any 
severe hypersensitivity reaction (eg, 
anaphylaxis), or an exacerbation of 
asthma symptoms. 
This text was added to 
clarify that a blood sample 
to measure serum 
reslizumab will be 
collected for patients 
experiencing certain types 
of adverse events. 
cause of death (whether or not the death was 
related to study drug as determined by the 
investigator) 
cause of death (whether or not the 
death was related to study drug as 
determined by the investigator) 
Clarification added. 
Section 7.1.6: Protocol-Defined Adverse events for Expedited Reporting to Teva: 
For the purposes of this protocol, the 
following are considered protocol-defined 
adverse events for expedited reporting to 
Teva: anaphylaxis, (possibly related to the 
study drug), newly-diagnosed malignancy, 
and parasitic helminth infection. Protocol-
defined adverse events for expedited 
reporting can be either serious or 
nonserious according to the criteria 
outlined in Section 7.1.5.1. The process for 
reporting a protocol-defined adverse event 
for expedited reporting is the same as that 
for reporting a serious adverse event (see 
Section 7.1.5.3). 
For purposes of this protocol, the 
following are considered 
protocol-defined adverse events for 
expedited reporting to Teva: 
anaphylaxis, newly-diagnosed 
malignancy, and parasitic helminth 
infection. Protocol-defined adverse 
events for expedited reporting can be 
either serious or nonserious according 
to the criteria outlined in 
Section 7.1.5.1. The process for 
reporting a protocol-defined adverse 
event for expedited reporting is the 
same as that for reporting a serious 
adverse event (see Section 7.1.5.3). 
This addition clarified 
where all anaphylaxis 
events were to be recorded. 
Section 7.1.7 Specific Adverse Event Case Report Form Capturing 
Section 7.1.7.1 Anaphylaxis/Hypersensitivity Reactions Case Report Form 
Hypersensitivity reactions will be monitored 
Information about all suspected 
Section 7.1.7 and its 


 
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using the diagnostic createria for 
Information about all suspected 
anaphylaxis as outlined by events will be 
recorded on the Suspected 
Anaphylaxis/Hypersensitivity Reactions 
CRF, which is based on the 2006 Joint 
NIAID/FAAN Second Symposium on 
Anaphylaxis ([Sampson et al, 2006]; 
(Appendix H). The 
Anaphylaxis/Hypersensitivity Reactions 
CRF should be initiated in real time (along 
with vital sign assessment) for events 
occurring after study drug administration 
in the clinic, or as soon as possible for 
suspect events outside the clinic. 
anaphylaxis events will be recorded on 
the Suspected 
Anaphylaxis/Hypersensitivity 
Reactions CRF, which is based on the 
2006 Joint NIAID/FAAN Second 
Symposium on Anaphylaxis (Sampson 
et al, 2006; Appendix H). The 
anaphylaxis CRF should be initiated in 
real time (along with vital sign 
assessment) for events occurring after 
study drug administration in the clinic, 
or as soon as possible for suspect 
events outside the clinic. 
2 subsections were added 
to describe the capturing of 
specific adverse events on 
the CRF. 
Section 7.1.7.2: Creatine Phosphokinase/Muscular Adverse Events Case Report Form: 
Potentially clinically significant creatine 
phosphokinase (CPK) elevations (with or 
without associated symptoms) or 
myalgia/muscle symptoms will be recorded 
as an adverse event and documented using 
the potentially clinically significant 
CPK/myalgia case report form. A 
potentially clinically significant CPK is 
defined as ≥3.1× upper limit of normal 
(Grade 3 based on the Food and Drug 
Administration [FDA] “Guidance for 
Industry Toxicity Grading Scale for 
Healthy Adult and Adolescent Volunteers 
Enrolled in Preventative Vaccine Clinical 
Trials”). 
Potentially clinically significant 
creatine phosphokinase (CPK) 
elevations (with or without associated 
symptoms) or myalgia/muscle 
symptoms will be recorded as an 
adverse event and documented using 
the potentially clinically significant 
CPK/myalgia case report form. A 
potentially clinically significant CPK is 
defined as ≥3.1× upper limit of normal 
(Grade 3 based on the Food and Drug 
Administration [FDA] “Guidance for 
Industry Toxicity Grading Scale for 
Healthy Adult and Adolescent 
Volunteers Enrolled in Preventative 
Vaccine Clinical Trials”). 
This section was added to 
address the reporting of 
muscular adverse events. 
Section 7.1.9: Overdose of Study Drug: 
Medication errors will be captured as 
protocol violations or deviations 
depending on the error. 
Medication errors will be captured as 
protocol violations or deviations 
depending on the error. 
This text clarified how 
medication errors would be 
captured. 
Section 7.3.3.1: Urinalysis: 
Urinalysis will be performed at screening 
and will include testing for the following: 
Urinalysis will be performed at 
screening and will include testing for 
the following: 
Text was added that 
urinalysis was to be 
collected for an elevated 
CPK level. 
Section 7.3.4.1: Human Chorionic Gonadotropin Tests: 


 
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Human chorionic gonadotropin serum tests 
will be performed for all females of 
childbearing potential at screening (visit 1). 
Human chorionic gonadotropin urineUrine 
pregnancy tests will be performed for all 
females of childbearing potentialat 
baseline/DoR, before study drug injection at 
each administration visit and at week 52, or 
early withdrawal, and at follow-up V18. 
Any patient who becomes pregnant during 
the study will be withdrawn. Procedures for 
reporting the pregnancy are provided in 
Section 7.2. 
Human chorionic gonadotropin serum 
tests will be performed for all females 
of childbearing potential at screening 
(visit 1). Urine pregnancy tests will be 
performed at baseline/DoR, before 
study drug injection at each 
administration visit and at week 52, or 
early withdrawal, and at follow-up 
V18. Any patient who becomes 
pregnant during the study will be 
withdrawn. Procedures for reporting 
the pregnancy are provided in 
Section 7.2. 
These edits clarified the 
visits at which pregnancy 
tests would be performed.  
Section 9: STATISTICS 
Section 9.2.3.1: Per-Protocol Analysis Set: 
The Per-Protocol (PP) Analysis Set is a 
subset of the ITT Analysis Set including only 
Patients without major protocol violations. In 
this analysis set, treatment will be assigned 
based upon the treatment Patients actually 
received, regardless of the treatment to which 
they were randomized. 
The Per-Protocol (PP) Analysis Set is a 
subset of the ITT Analysis Set 
including only Patients without major 
protocol violations. 
These deletions add clarity 
to the definition of the per-
protocol analysis set. 
Section 9.5.6: Planned Method of Analysis: 
The baseline for diary variables will be the 
average of the run-in values over the 7 days 
preceding baseline/DoR. The baseline for 
clinic visit variables will be the last 
observedpredose, pre bronchodilator 
baseline/DoR value before the first dose of 
study drug. The baseline for eosinophils 
levels analysis will be screening value. 
The baseline for diary variables will be 
the average of the run-in values over 
the 7 days preceding baseline/DoR. The 
baseline for clinic visit variables will be 
the last observed value before the first 
dose of study drug. The baseline for 
eosinophils levels analysis will be 
screening value. 
Clarification of baseline 
values 
Section 9.5.6.1: Primary Efficacy Analysis: 
Section 9.5.6.1: Primary Efficacy Analysis (Other sections affected by this change: Clinical Study Protocol 
Synopsis): 
The primary analysis of frequency of CAEs 
will use the NB regression model. The 
primary NB model will include the treatment 
group,and randomization stratification 
factors, and number of exacerbations in the 
previous year as model factors and an offset 
variable. 
The primary analysis of frequency of 
CAEs will use the NB regression 
model. The primary NB model will 
include the treatment group, 
randomization stratification factors, and 
number of exacerbations in the 
previous year as model factors and an 
offset variable. 
This change clarified that 
the number of 
exacerbations in the 
previous year will also be 
included in the NB 
regression model. 
Section 9.5.6.2: Secondary Efficacy Analysis (Other sections affected by this change: Clinical Study Protocol 
Synopsis): 


 
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Analysis of percentage of asthma control 
days will use an analysis of covariance 
(ANCOVA) model with treatment group and 
stratification factors. Additional covariates or 
factors may be added to the model. These 
will be detailed in the Statistical Analysis 
Plan. 
Additional covariates or factors may be 
added to the statistical models. These will 
be detailed in the Statistical Analysis Plan. 
Analysis of percentage of asthma 
control days will use an analysis of 
variance (ANOVA) model with 
treatment group and stratification 
factors. 
Additional covariates or factors may be 
added to the statistical models. These 
will be detailed in the Statistical 
Analysis Plan. 
Updated based on 
statistical analysis plan and 
moved last 2 sentences 
from first paragraph to 
fourth paragraph for 
clarity. 
Section 9.7.2: Safety Analysis: 
Summaries will be presented for all adverse 
events that started after first study dosing 
(overall and by severity), adverse events 
determined by the investigator to be related 
to study treatment (ie, reasonable possibility; 
see Section 7.1.4) (defined as related or with 
missing relationship) (overall and by 
severity), serious adverse events, adverse 
events causing withdrawal from the 
studydiscontinuation from study 
treatment, adverse events with onset date 
after end of treatment visitduring the follow-
up period (ie, after the cessation of study 
treatment), and adverse events that begin 
within 24 hours after injection. Summaries 
will be presented by treatment group and for 
all patients. In addition, summaries of 
adverse events will be presented separately 
for patients with ADA positive status and 
patients with ADA negative status. Patient 
listings of adverse events, serious adverse 
events, and adverse events leading to 
withdrawal discontinuation will be 
presented. 
Summaries will be presented for all 
adverse events that started after first 
study dosing (overall and by severity), 
adverse events determined by the 
investigator to be related to study 
treatment (ie, reasonable possibility; see 
Section 7.1.4) (defined as related or 
with missing relationship) (overall and 
by severity), serious adverse events, 
adverse events causing discontinuation 
from study treatment, adverse events 
with onset during the follow-up period 
(ie, after the cessation of study 
treatment), and adverse events that 
begin within 24 hours after injection. 
Summaries will be presented by 
treatment group and for all patients. In 
addition, summaries of adverse events 
will be presented separately for patients 
with ADA positive status and patients 
with ADA negative status. Patient 
listings of adverse events, serious 
adverse events, and adverse events 
leading to discontinuation will be 
presented. 
Adverse events causing 
discontinuation were 
further clarified by these 
additions. 
Section 9.10: Immunogenicity Analysis (Other sections affected by this change: Clinical Study Protocol 
Synopsis): 
Anti-reslizumab antibody datainformation 
will be described for subjects who test 
positivelisted at a patient level. Samples from 
placebo-treated patients will not be analyzed. 
Anti-reslizumab antibody information 
will be described for subjects who test 
positive. Samples from placebo-treated 
patients will not be analyzed. 
Clarification added. 
Section 11: QUALITY CONTROL AND QUALITY ASSUARANCE 
Section 11.1.2: Protocol Violations: 


 
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When a protocol violation is reported, the 
sponsor will determine whether to withdraw 
the patient from the study or permit the 
patient to continue in the study, with a 
documented approvaldecision from the 
Sponsor’s medical representative. 
When a protocol violation is reported, 
the sponsor will determine whether to 
withdraw the patient from the study or 
permit the patient to continue in the 
study, with a documented decision 
from the Sponsor’s medical 
representative. 
Clarification added. 
If investigational center personnel learn that a 
patient who did not meet protocol eligibility 
criteria was entered into a study, they must 
immediately inform the sponsor of the 
protocol violation. If such patient has already 
completed the study or has withdrawn early, 
no action will be taken, but the 
violationincident will be recorded. 
If investigational center personnel learn 
that a patient who did not meet protocol 
eligibility criteria was entered into a 
study, they must immediately inform 
the sponsor. If such patient has already 
completed the study or has withdrawn 
early, no action will be taken, but the 
incident will be recorded. 
Clarification added. 


 
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Section 12: ETHICS 
Section 12.1: Informed Consent/Assent: 
For patients 18 years of age or older, the 
investigator, or a qualified person designated 
by the investigator, should fully inform the 
patient of all pertinent aspects of the study, 
including the written information approved 
by the IEC/IRB. 
For patients 18 years of age or older, 
the investigator, or a qualified person 
designated by the investigator, should 
fully inform the patient of all pertinent 
aspects of the study, including the 
written information approved by the 
IEC/IRB. 
Missing “years” added. 
Appendices A, B, C, D, and E: 
(Sample provided in this appendix is for 
reference only.) 
(Sample provided in this appendix is 
for reference only.) 
Clarification added. 


 
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17.4. 
Amendment 01 Dated 04 May 2015 
The revisions listed below have been made to the protocol Study C38072-AS-30025 and are not 
considered substantial by the Teva Authorized Representative. 
Table 6: 
Changes to the Protocol 
Original Text with changes shown 
New wording 
Reason/Justification for change 
Title Page: 
 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States 
Sponsor 
Teva Branded Pharmaceutical  
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States 
 
Monitor 
 
 
 
 
 
 
 
 
 This change was to clarify that Teva 
Branded Pharmaceutical Products 
R&D, Inc was incorrectly identified 
as a Monitor 
Title Page: Sponsor’s Safety Representative 
 
 
 
Teva Pharmaceuticals 
 
 
Sponsor’s Safety Representative 
changed 


 
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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS: 
Central Spirometry, e-diary and ECG 
 
 
Spirometry and e-diary:  
 
 
 
ECG:  
 
 
  
 
Central Spirometry, e-diary 
and ECG 
 
Spirometry and e-diary:  
 
 
 
ECG:  
 
 
  
 
Change in vendor for Spirometry 
and ECG measurements 
5.5 TOTAL BLOOD VOLUME:  
The estimated total blood 
volume withdrawn over the 
entire study (including 
screening) is approximately 
115 mL per patient. 
 An internal review identified that 
the estimated total blood volume 
was incorrect 
Appendix A 
 
AQLQ +12 Questionaire 
AQLQ +12 Questionaire is 
appropriate for patients in Study 


 
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17.5. 
Clarification Letters 
17.5.1. 
Administrative Letter Dated 22 July 2015 
 


 
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17.5.2. 
Addendum Letter Dated 22 April 2015 
 


 
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17.5.3. 
Administrative Letter Dated 14 April 2015 
 


 
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17.5.4. 
 Administrative Letter Dated 26 February 2016 
 


 
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17.5.5. 
Administrative Letter Dated 08 March 2016 
 


 
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17.5.6. 
Administrative Letter Dated 21 March 2016 
 


 
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APPENDIX A. GLOBAL INITIATIVE FOR ASTHMA ICS CLINICAL 
COMPARABILITY TABLE 
Table 7: 
Medium or Higher Daily Doses of Inhaled Corticosteroids in Patients 12 
Years and Older 
Drug 
Daily Dose (μg) 
Medium 
High 
Beclomethasone dipropionate (CFC)a 
>500 
>1000 
Beclomethasone dipropionate (HFA) 
>200 
>400 
Budesonide (DPI) 
>400 
>800 
Ciclesonide (HFA) 
>160 
>320 
Fluticasone fuorate (DPI) 
N/A 
≥200 
Fluticasone propionate (DPI) 
>250 
>500 
Fluticasone propionate (HFA) 
>250 
>500 
Mometasone furoate 
>220 
>440 
Triamcinolone acetonide 
>1000 
>2000 
Source: Adapted from Box 8 in GINA 2016 Update (www.ginasthma.org). 
a  Beclometasone dipropionate CFC is included for comparison with older literature. 
CFC = chlorofluorocarbon propellant; DPI = dry powder inhaler; HFA = hydrofluoroalkane propellant; N/A = not 
applicable. 


 
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APPENDIX B. ASTHMA QUALITY OF LIFE QUESTIONNAIRE + 12 
(Sample provided in this appendix is for reference only.) 
 


 
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APPENDIX C. ASTHMA CONTROL QUESTIONNAIRE 
(Sample provided in this appendix is for reference only.) 
 


 
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SOURCE: Juniper EF, O’Byrne PM, Guyatt GH, Ferrie PJ, King DR. Development and validation of a 
questionnaire to measure asthma control. Eur Respir J 1999;14:902-7. 


 
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APPENDIX F. ST. GEORGE’S RESPIRATORY QUESTIONNAIRE  
(Sample provided in this appendix is for reference only.) 
 


 
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APPENDIX G. ASTHMA CONTROL DIARY 
Asthma Symptom Score 
Please enter a single number for the asthma symptom score below. This will be the score that 
describes all of your symptoms each morning and evening. 
Each morning, indicate how you felt the previous night by recording your nighttime asthma 
symptom score in the box below. 
Nighttime Asthma Symptom Score 
(Determined in the morning) 
0 = No symptoms during the night 
1 = Symptoms causing me to wake once (or wake early) 
2 = Symptoms causing me to wake twice or more (including waking early) 
3 = Symptoms causing me to be awake for most of the night 
4 = Symptoms so severe that I did not sleep at all 
Your nighttime symptom score: 
Each evening, indicate how you felt during the day by recording your daytime asthma symptom 
score in the box below. 
Daytime Asthma Symptom Score 
(Determined in the evening) 
0 = No symptoms during the day 
1 = Symptoms for one short period during the day 
2 = Symptoms for two or more short periods during the day 
3 = Symptoms for most of the day that did not affect my normal daily activities 
4 = Symptoms for most of the day that did affect my normal daily activities 
5 = Symptoms so severe that I could not go to work or perform normal daily activities 
Your daytime symptom score: 
Peak Flow Meter 
• You will need to record your peak expiratory flow (PEF) reading every morning and 
evening. 
• Blow into your peak flow meter 3 times in the morning and 3 times in the evening. 
• Write down the highest reading for the morning and the highest for the evening. 
AM peak flow meter reading: 


 
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PM peak flow meter reading: 
Time taken: 
Time taken: 
Rescue Medication (Do not record SABA use for exercise pretreatment!) 
Total number of puffs (daily): 


 
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APPENDIX H. CLINICAL CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS 
Anaphylaxis is highly likely when any one of the following 3 criteria are fulfilled: 
a. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-
tongue-uvula) AND AT LEAST ONE OF THE FOLLOWING 
− Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
peak expiratory flow (PEF), hypoxemia) 
− Reduced blood pressure (BP) or associated symptoms of end-organ dysfunction 
(eg, hypotonia [collapse], syncope, incontinence) 
b. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours): 
− Involvement of the skin-mucosal tissue (eg, generalized hives, itch-flush, swollen 
lips-tongue-uvula) 
− Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF, hypoxemia) 
− Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, 
incontinence) 
− Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting) 
c. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours): 
− Infants and children: low systolic BP (age specific) or greater than 30% decrease 
in systolic BP 
− Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline 
Source: Modified from Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock 
SA, Branum A, et al. Second symposium on the definition and management of anaphylaxis: 
summary report--Second National Institute of Allergy and Infectious Disease/Food Allergy and 
Anaphylaxis Network symposium.[reprint in Ann Emerg Med. 2006 Apr;47(4):373-80; PMID: 
16546624]. Journal of Allergy & Clinical Immunology. 2006 Feb;117(2):391-7.


 
Placebo-Controlled Study–Asthma 
Clinical Study Protocol with Amendment 04 
Study C38072-AS-30025 
 
177 
 
APPENDIX I. OPPORTUNISTIC INFECTIONS 
Potential opportunistic infections include, but are not limited to, the following:  
• Acinetobacter infection 
• Aspergillosis 
• Blastomycosis, extrapulmonary 
• Burkitt’s lymphoma 
• Candidiasis of esophagus, bronchi, trachea, or lungs 
• Cervical cancer invasive 
• Coccidioidomycosis, dissemintaed or extrapulmonary 
• Cryptococcosis, extrapulmonary 
• Cryptosporidiosis infection, chronic intestinal (>1 month duration) 
• Cytomegalovirus disease (other than liver, spleen, or nodes) 
• Hepatitis B and C 
• Herpes simplex bronchitis, pneumonitis, or esophagitis 
• Herpes simplex ulcers chronic (>1 month) 
• Herpes zoster (Shingles) when 2 distinct episodes or more than 1 dermatome 
• Histoplasmosis disseminated or extrapulmonary 
• Human polyomavirus infection 
• Isosporiasis, chronic intestinal (>1 month’s duration) 
• Kaposi’s sarcoma 
• Listeriosis 
• Lymphoid interstitial pneumonia 
• Lymphoma immunoblastic 
• Lymphoma primary of brain 
• Mycobacterium avium complex or M. kansasii, disseminated or extrapulmonary 
Mycobacterium infections, other species or unidentified species, disseminated or 
extrapulmonary (eg, M. haemophilium, M. fortuitum, or M. marinum) 
• Mycobacterium tuberculosis, any site, latent or active 
• Nocardiosis 
• Pneumocystis jiroveci infection 
• Pneumonia, recurrent 


 
Placebo-Controlled Study–Asthma 
Clinical Study Protocol with Amendment 04 
Study C38072-AS-30025 
 
178 
 
• Polyomavirus (JC virus or BK virus)-associated nephropathy (including progressive 
multifocal leukoencephalopathy) 
• Salmonella sepsis 
• Salmonella septicemia, recurrent 
• Shingles 
• Toxoplasmosis of brain 
• Any active tuberculosis 
• Wasting secondary to human immunodeficiency virus (HIV) 
Source: Modified from the Panel on Opportunistic Infections in HIV-Infected Adults and 
Adolescents. Guidelines for the prevention and treatment of opportunistic infections in 
HIV-infected adults and adolescents: recommendations from the Centers from Disease Control 
and Prevention, the National Institutes of Health, and the HIV Medicine Association of the 
Infectious Disease Society of America. Available at 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. 

SAP_001.pdf: 
 
 
 
 
Statistical Analysis Plan with Amendment 02 
 
A 52-Week Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of 
Reslizumab 110 mg Fixed, Subcutaneous Dosing in Patients with Uncontrolled Asthma and 
Elevated Blood Eosinophils 
 
 
Study Number C38072-AS-30025 
 
NCT02452190 
 
Statistical Analysis Plan with Amendment 02 Approval Date: 01 May 2017  
 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
1 
 
 
 
 
 
TEVA BRANDED PHARMACEUTICAL PRODUCTS R&D, INC. 
STATISTICAL ANALYSIS PLAN 
 
 
A 52-Week Double-Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of 
Reslizumab 110 mg Fixed, Subcutaneous Dosing in Patients with Uncontrolled Asthma and 
Elevated Blood Eosinophils 
 
 
 
Study C38072-AS-30025 Phase 3 
 
 
Date: 01-May-2017 
Version: Amendment 02 
 
 
 
Prepared by: 
 
  


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
2 
 
TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7 
PREFACE 10 
1. 
STUDY OBJECTIVES ..............................................................................................11 
1.1. 
Primary Objective .......................................................................................................11 
1.2. 
Secondary Objectives .................................................................................................11 
1.3. 
Other Objectives .........................................................................................................11 
2. 
STUDY DESIGN .......................................................................................................12 
2.1. 
General Design and Study Schema.............................................................................12 
2.2. 
Primary and Secondary Measures and Endpoints ......................................................18 
2.2.1. 
Primary Efficacy Endpoint .........................................................................................18 
2.2.2. 
Secondary Efficacy Endpoints ....................................................................................18 
2.2.3. 
18 
2.2.4. 
Target Biomarker Endpoints .......................................................................................19 
2.2.5. 
Immunogenicity Endpoints .........................................................................................19 
2.2.6. 
Pharmacokinetic Endpoints ........................................................................................19 
2.2.7. 
19 
2.2.8. 
Safety Endpoints .........................................................................................................19 
2.3. 
Sample Size and Power Considerations .....................................................................20 
2.4. 
Randomization and Blinding ......................................................................................20 
2.5. 
Sequence of Planned Analyses ...................................................................................21 
2.5.1. 
Interim Analyses .........................................................................................................21 
2.5.2. 
Final Analyses and Reporting .....................................................................................21 
3. 
POPULATIONS/ANALYSIS SETS ..........................................................................22 
3.1. 
Intent-to-Treat Analysis Set ........................................................................................22 
3.1.1. 
ITT Analysis Set (Patients 12-70 Years) ....................................................................22 
3.2. 
Safety Analysis Set .....................................................................................................22 
3.3. 
Per-Protocol Analysis Set ...........................................................................................23 
3.3.1. 
Major Protocol Violations ..........................................................................................23 
3.4. 
Subgroup Analysis Sets ..............................................................................................24 
3.4.1. 
Age Strata ...................................................................................................................24 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
3 
 
3.4.2. 
Eosinophil Strata .........................................................................................................24 
3.4.3. 
24 
3.4.4. 
Asthma Background Medication ................................................................................24 
3.4.5. 
Other Subgroups .........................................................................................................25 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................26 
4.1. 
General ........................................................................................................................26 
4.2. 
Specification of Baseline Values ................................................................................26 
4.2.1. 
Diary ...........................................................................................................................26 
4.2.2. 
Lung Function .............................................................................................................26 
4.2.3. 
Patient Reported Outcomes ........................................................................................26 
4.2.4. 
Biomarkers ..................................................................................................................26 
4.2.5. 
Safety ..........................................................................................................................26 
4.3. 
Multiple Comparisons and Multiplicity......................................................................26 
4.4. 
Handling Withdrawals and Missing Data ...................................................................27 
4.5. 
Study Days and Visit Windows ..................................................................................27 
5. 
STUDY POPULATION .............................................................................................29 
5.1. 
General ........................................................................................................................29 
5.2. 
Patient Disposition ......................................................................................................29 
5.3. 
Demographics and Baseline Characteristics ...............................................................29 
5.4. 
Medical History ..........................................................................................................29 
5.5. 
Prior Medications ........................................................................................................30 
5.6. 
Electrocardiography ....................................................................................................30 
5.7. 
Physical Examinations ................................................................................................30 
5.8. 
Protocol Violations .....................................................................................................30 
5.9. 
Childbearing Potential ................................................................................................31 
6. 
EFFICACY ANALYSIS ............................................................................................32 
6.1. 
General ........................................................................................................................32 
6.2. 
Primary Efficacy Variable(s) and Analysis ................................................................32 
6.2.1. 
Variable Definition .....................................................................................................32 
6.2.2. 
Primary Analysis ........................................................................................................33 
6.2.3. 
Sensitivity Analyses for the Primary Variable ...........................................................33 
6.2.4. 
Component Analysis for the Primary Variable ..........................................................34 
6.2.5. 
Subgroup Analysis for the Primary Variable ..............................................................34 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
4 
 
6.2.6. 
Time to First Clinical Asthma Exacerbation ..............................................................34 
6.2.7. 
Moderate Exacerbations .............................................................................................35 
6.3. 
Secondary Efficacy Variable(s) and Analysis ............................................................36 
6.3.1. 
Secondary Variables ...................................................................................................36 
6.3.2. 
36 
6.3.3. 
Pulmonary Function Tests ..........................................................................................37 
6.3.3.1. 
Variable Definition .....................................................................................................37 
6.3.3.2. 
Analysis ......................................................................................................................38 
6.3.4. 
AQLQ +12 ..................................................................................................................38 
6.3.4.1. 
Variable Definition .....................................................................................................38 
6.3.4.2. 
Analysis ......................................................................................................................39 
6.3.5. 
ACQ-6 .........................................................................................................................39 
6.3.5.1. 
Variable Definition .....................................................................................................39 
6.3.5.2. 
Analysis ......................................................................................................................40 
6.3.6. 
SGRQ ..........................................................................................................................40 
6.3.6.1. 
Variable Definition .....................................................................................................40 
6.3.6.2. 
Analysis ......................................................................................................................41 
6.3.7. 
42 
6.3.7.1. 
42 
6.3.7.2. 
42 
6.3.8. 
42 
6.3.8.1. 
42 
6.3.8.2. 
42 
6.3.9. 
Asthma Control Diary .................................................................................................43 
6.3.9.1. 
Variable Definition .....................................................................................................43 
6.3.9.2. 
Analysis ......................................................................................................................43 
7. 
SAFETY ANALYSIS ................................................................................................45 
7.1. 
General ........................................................................................................................45 
7.2. 
Study Drug Administration.........................................................................................45 
7.3. 
Adverse Events ...........................................................................................................45 
7.3.1. 
Adverse Events of Special Interest .............................................................................46 
7.3.1.1. 
Administration Site Reactions ....................................................................................46 
7.3.1.2. 
Anaphylaxis and Hypersensitivity ..............................................................................46 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
5 
 
7.3.1.3. 
Malignancies ...............................................................................................................46 
7.3.1.4. 
Helminth infections ....................................................................................................46 
7.3.1.5. 
Muscle Disorders ........................................................................................................47 
7.3.1.6. 
Opportunistic Infections .............................................................................................47 
7.3.2. 
Adverse Events by Subgroup ......................................................................................50 
7.4. 
Deaths .........................................................................................................................50 
7.5. 
Clinical Laboratory Tests ...........................................................................................51 
7.6. 
Vital Signs ..................................................................................................................54 
7.7. 
Electrocardiography ....................................................................................................54 
7.8. 
Physical Examinations ................................................................................................55 
7.9. 
Other Safety Measures and Variables .........................................................................55 
7.9.1. 
Concomitant Therapy or Medication ..........................................................................55 
8. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS ..............................56 
8.1. 
Pharmacokinetic Analysis ..........................................................................................56 
8.2. 
Pharmacodynamic Analysis........................................................................................56 
8.2.1. 
Target Biomarker (Blood Eosinophil Counts) ............................................................56 
8.2.2. 
56 
8.3. 
Immunogenicity ..........................................................................................................56 
9. 
STATISTICAL SOFTWARE ....................................................................................58 
10. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ..........................................59 
11. 
REFERENCES ...........................................................................................................75 
APPENDIX A. IMPUTATION AND ANALYSIS STEPS FOR ANALYSIS OF THE 
FREQUENCY OF ASTHMA EXACERBATION ....................................................76 
APPENDIX B. TIPPING POINT ANALYSIS ..........................................................................78 
APPENDIX C. SGRQ – ITEM WEIGHTS FOR PROGRAMMING ........................................80 
 
LIST OF TABLES 
Table 1: 
Study Procedures and Assessments ............................................................................14 
Table 2: 
Major Protocol Violations ..........................................................................................23 
Table 3: 
Definition of Analysis Days for Diary Data ...............................................................28 
Table 4: 
Conversion of ICS to Fluticasone-Equivalent Doses .................................................30 
Table 5: 
List of Terms for Opportunistic Infections .................................................................47 
Table 6: 
Criteria for Potentially Clinically Significant Laboratory Values ..............................52 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
6 
 
Table 7: 
Criteria for Potentially Clinically Significant Vital Signs ..........................................54 
Table 8: 
Key Changes to the Statistical Analysis Plan, Amendment 01 ..................................60 
Table 9: 
Key Changes to the Statistical Analysis Plan, Amendment 02 ..................................68 
 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
7 
 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
ACQ 
Asthma Control Questionnaire 
ADA 
Anti-Drug Antibody 
AE 
Adverse Event 
ALT 
Alanine Aminotransferase 
AM 
Morning 
ANCOVA 
Analysis of Covariance 
ANOVA 
Analysis of Variance 
AQLQ 
Asthma Quality of Life Questionnaire 
AST 
Aspartate Aminotransferase 
ATS 
American Thoracic Society 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CAE 
Clinical Asthma Exacerbation 
CBC 
Complete Blood Count 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSP 
Clinical Study Protocol 
CSR 
Clinical Study Report 
CT 
Computed Tomography 
DoR 
Day of Randomization 
ECG 
Electrocardiogram 
EOT 
End of Treatment 
ERS 
European Respiratory Society 
FDA 
Food and Drug Administration 
FEF25%-75% 
Forced Expiratory Flow at the 25% point to the 75% point of Forced Vital Capacity 
FEV1 
Forced Expiratory Volume in 1 Second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
GINA 
Global Initiative for Asthma 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
8 
 
GLM 
Generalized Linear Model 
HLGT 
High Level Group Term 
HLT 
High Level Term 
ICF 
Informed Consent Form  
ICH 
International Conference on Harmonization 
ICS 
Inhaled Corticosteroid 
IgE 
Immunoglobulin E 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat 
iv 
Intravenous 
IVRS 
Interactive Voice Response System 
IWRS 
Interactive Web Response System 
KM 
Kaplan-Meier 
LABA 
Long-Acting Beta-Agonist 
LAMA 
Long-Acting Anti-Muscarinic Antagonist 
LLT 
Low Level Term 
LS 
Least Square 
LTE 
Long term extension 
LTRA 
Leukotriene Receptor Antagonist 
MAR 
Missing at Random 
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed Model Repeated Measures 
MNAR 
Missing Not at Random 
nAb 
Neutralizing Antibody 
NB 
Negative Binomial 
NHANES 
National Health and Nutrition Examination Survey 
OCS 
Oral Corticosteroid 
PCS 
Potentially Clinically Significant 
PD 
Pharmacodynamics 
PEF 
Peak Expiratory Flow 
PK 
Pharmacokinetics 
PM 
Evening 
PP 
Per-Protocol 
PT 
Preferred Term 
SABA 
Short-Acting Beta-Agonist 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
9 
 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis Software 
sc 
Subcutaneous 
SD 
Standard Deviation  
SE 
Standard Error 
SGRQ 
St. George’s Respiratory Questionnaire 
SMQ 
Standardized MedDRA Query 
SOC 
System Organ Class 
ULN 
Upper Limit of Normal 
US 
United States 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
10 
 
PREFACE 
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for TEVA 
Branded Pharmaceuticals Products R&D, Inc. Study C38072-AS-30025 (A 52-Week Double-
Blind, Placebo-Controlled, Parallel-Group Efficacy and Safety Study of Reslizumab 110 mg 
Fixed, Subcutaneous Dosing in Patients with Uncontrolled Asthma and Elevated Blood 
Eosinophils) and was written in accordance with SOP_GBP_RD_702 (Statistical Analysis Plan). 
This phase 3 study is being completed to assess the safety and efficacy of reslizumab sc dosing. 
The structure and content of this SAP provides sufficient detail to meet the requirements 
identified by the FDA and International Conference on Harmonization of Technical 
Requirements for Registration of Pharmaceuticals for Human Use (ICH): E9 Guidance on 
Statistical Principles in Clinical Trials. All work planned and reported for this SAP will follow 
internationally accepted guidelines, published by the American Statistical Association, and the 
Royal Statistical Society, for statistical practice. 
The following documents were reviewed in preparation of this SAP: 
• Clinical Study Protocol C38072-AS-30025 Amendment 04, issued 24 October 2016 
• Case Report Form (CRF) for Study C38072-AS-30025 
• ICH E9 Guidance on Statistical Principles for Clinical Trials 
• ICH E3 Structure and Content of Clinical Study Reports 
The reader of this SAP is encouraged to also read the clinical protocol for details on the conduct 
of this study, and the operational aspects of clinical assessments and timing for completing a 
patient in this study. When differences exist in descriptions or explanations provided in the 
protocol and this SAP, the SAP prevails and the discrepancies will be explained in the CSR.  


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
11 
 
1. 
STUDY OBJECTIVES 
1.1. 
Primary Objective  
The primary objective of this study is to determine the effect of reslizumab (110 mg) 
administered subcutaneously every 4 weeks on clinical asthma exacerbations in adults and 
adolescents with asthma and elevated blood eosinophils who are inadequately controlled on 
standard-of-care asthma therapy. 
1.2. 
Secondary Objectives  
Secondary efficacy objectives are to evaluate the effects of reslizumab compared with placebo 
on a range of clinical markers of asthma control including pulmonary function (forced expiratory 
volume in 1 second [FEV1]). 
1.3. 
Other Objectives  
Other objectives of this study are to evaluate the safety, pharmacokinetics, pharmacodynamics, 
and immunogenicity of reslizumab. 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
12 
 
2. 
STUDY DESIGN  
2.1. 
General Design and Study Schema 
This is a 52-week, Phase 3, multicenter, randomized, double-blind, placebo-controlled study to 
evaluate the safety and efficacy of reslizumab, at a fixed dose of 110 mg, administered sc every 4 
weeks in patients aged 12 years and older with asthma and elevated blood eosinophils, who are 
inadequately controlled on at least a medium total daily ICS dose and a second asthma controller. 
Evidence of inadequate asthma control will include a history of at least 2 exacerbations requiring 
systemic corticosteroids (oral or injection) in the previous 12 months, a suboptimal screening 
ACQ-6 score (≥1.5), and persistent symptoms during run-in on the patient’s usual asthma 
controller regimen. The study consists of up to 2 weeks to satisfy essential screening inclusion 
criteria (ie, confirmation of asthma with elevated blood eosinophils), a minimum 3-week run-in 
period on usual care to establish the patient’s baseline level of control, and a 52-week double-
blind treatment period. 
Patients will begin screening up to approximately 5 weeks (±1 week) before DoR. During the 
screening period, a signed and dated informed consent form (and an assent form for children 
ages 12 through <18 years in accordance with local standards) will be obtained before a 
diagnosis of asthma is confirmed on the basis of patient history and by demonstration of airway 
reversibility. The patients will also be asked about their asthma medication compliance and to 
demonstrate their inhaler use technique. If the inhaler use technique is not optimal, patients will 
be taught the appropriate inhaler use technique during the screening period and should be 
reassessed before run-in. The patient will also have a complete blood count determined. If the 
patient’s eosinophil count is 300 eosinophils/μL or greater, and if the patient’s medication 
compliance and inhaler use technique are optimal, the patient will be eligible to continue in the 
study. Patient medical history, 12-lead ECG, physical examination, hematology and chemistry 
tests, urinalysis, vital signs measurements, beta-human chorionic gonadotropin serum pregnancy 
test (for all females of childbearing potential), and concomitant medication history will also be 
assessed at screening. 
To be eligible to enroll in the study, a patient will have an ACQ-6 score of at least 1.5, airway 
FEV1 reversibility of at least 12% to beta-agonist administration, blood eosinophil count of at 
least 300/μL, and a current fluticasone propionate dosage of at least a medium total daily ICS 
dose with a second asthma controller and will have met all the inclusion and none of the 
exclusion criteria at screening. The goal is to recruit a maximum of 30% of the patients (60 
patients per treatment arm) with eosinophil levels of 300/μL to <400/μL. 
Patients who meet screening eligibility requirements will return to the research facility 3 weeks 
before baseline/DoR to confirm eligibility and begin the run-in period. At the start of run-in, 
patients will begin daily self-monitoring at home using an asthma control diary and PEF meter, 
while taking their usual asthma medications, in order to establish their baseline level of asthma 
control based on the frequency of symptoms, use of reliever SABA, nighttime awakenings due to 
asthma, and ambulatory lung function measurement. Improvement in asthma control during the 
treatment period will primarily be assessed by a reduction in the rate of clinically significant 
asthma exacerbations with reslizumab versus placebo over the 52-week treatment period. 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
13 
 
Pulmonary function; AQLQ +12, ACQ, and SGRQ scores; asthma symptoms; use of reliever 
SABA; nighttime awakenings due to asthma; safety measures; PK; immunogenicity; and health 
care utilization events will be assessed periodically; final assessments will be made at the EOT 
visit (week 52) or at early withdrawal. Patients who withdraw from the study before completing 
the 52-week evaluation period will have visit 17 (week 52 or early withdrawal) procedures and 
assessments performed at their final visit. Patients will return 12 weeks after the EOT visit for 
follow-up hematology, PK, immunogenicity, and safety assessments. 
The assessments and procedures performed during each study visit are detailed in Table 1. If a 
patient elects to withdraw (or is discontinued from treatment by the Investigator), every attempt 
will be made to continue the assessments subsequent to their withdrawal from the study (see 
Section 4.4 of the study protocol for additional information). 
A total of 450 patients are planned to be randomized in a 1:1 ratio (approximately 225 patients 
within each treatment group) to receive reslizumab 110 mg or matching placebo every 4 weeks 
for 52 weeks. 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
14 
 
Table 1: 
Study Procedures and Assessments 
Study 
period 
Pretreatment 
Double-blind treatment period 
Follow-
up 
Late 
follow-
up 
Visit 
number 
V1 
Start 
of 
screeni
ng 
period
a 
V2 
Start 
of 
run-
in 
perio
db 
V3 
Do
R 
VP
K 
V4 V5 V6 V7 V8 V9 V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
V1
5 
V1
6 
V17 
EOT or 
early 
withdra
wal 
V18 
EOS 
V19 
Procedures 
and 
assessment
s 
Week 
-5 (±1 
wk) 
Wee
k 
-3 
0 
W
1 
±3
d 
W
2 
±3
d 
W
4 
±7
d 
W8 
±7d 
W1
2 
±7d 
W1
6 
±7d 
W2
0 
±7d 
W2
4 
±7d 
W2
8 
±7d 
W3
2 
±7d 
W3
6 
±7d 
W4
0 
±7d 
W4
4 
±7d 
W4
8 
±7d 
W52 
±7d 
EOT 
+12W 
±14d 
W76 
+2wk 
Informed 
assent/cons
ent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medication 
history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion 
and 
exclusion 
criteria 
X 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
testingd 
X 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
CBC with 
differentiale 
X 
 
X 
 
X X 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
X 
 
Serum 
chemistry 
testsf 
X 
 
X Xg Xg Xg Xg Xg 
X 
Xg 
 
 
X 
 
 
 
 
X 
 
 
Urinalysis  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Full 
physical 
examinatio
nh 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Brief 
physical 
examinatio
nh 
 
 
X 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Vital signsh 
X 
X 
X 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Heighti and 
weight 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
X 
 
 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
15 
 
Study 
period 
Pretreatment 
Double-blind treatment period 
Follow-
up 
Late 
follow-
up 
Visit 
number 
V1 
Start 
of 
screeni
ng 
perioda 
V2 
Start 
of 
run-
in 
perio
db 
V3 
Do
R 
VP
K 
V4 V5 V6 V7 V8 V9 V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
V1
5 
V1
6 
V17 
EOT or 
early 
withdra
wal 
V18 
EOS 
V19 
Procedures 
and 
assessment
s 
Week 
-5 (±1 
wk) 
Wee
k 
-3 
0 
W
1 
±3
d 
W
2 
±3
d 
W
4 
±7
d 
W8 
±7d 
W1
2 
±7d 
W1
6 
±7d 
W2
0 
±7d 
W2
4 
±7d 
W2
8 
±7d 
W3
2 
±7d 
W3
6 
±7d 
W4
0 
±7d 
W4
4 
±7d 
W4
8 
±7d 
W52 
±7d 
EOT 
+12W 
±14d 
W76 
+2wk 
ECGh 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
X 
 
 
Reversibilit
y testingj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-
bronchodila
tor 
spirometryk 
 
 
X 
 
X X 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Post-
bronchodila
tor 
spirometry 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
Provide and 
collect PEF 
meter 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Provide/col
lect asthma 
control 
diary; 
reinforce 
diary and 
PEF 
compliance. 
 
X 
X 
X X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
ACQl  
X 
 
X 
 
X X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
AQLQ +12  
 
 
X 
 
 
X 
X 
X 
X 
 
 
 
X 
 
 
 
 
X 
 
 
SGRQ 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
16 
 
Study 
period 
Pretreatment 
Double-blind treatment period 
Follow
-up 
Late 
follow-
up 
Visit 
number 
V1 
Start 
of 
screen
ing 
period
a 
V2 
Start 
of 
run-
in 
perio
db 
V3 
Do
R 
VP
K 
V4 V5 V6 V7 V8 V9 V1
0 
V1
1 
V1
2 
V1
3 
V1
4 
V1
5 
V1
6 
V17 
EOT or 
early 
withdraw
al 
V18 
EOS 
V19 
Procedures 
and 
assessment
s 
Week 
-5 
(±1 wk
) 
Week 
-3 
0 W1 
±3d 
W2 
±3d 
W4 
±7d 
W8 
±7d 
W1
2 
±7d 
W1
6 
±7d 
W2
0 
±7d 
W2
4 
±7d 
W2
8 
±7d 
W3
2 
±7d 
W3
6 
±7d 
W4
0 
±7d 
W4
4 
±7d 
W4
8 
±7d 
W52 
±7d 
EOT 
+12W 
±14d 
W76 
+2wk 
Assess 
asthma 
exacerbatio
ns and 
related 
HCUm 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PK samples 
(ALL) 
 
 
X Xn X 
X 
X 
X 
X 
X 
 
 
X 
 
 
 
X 
X 
X 
X 
Blood for 
ADAo 
 
 
X 
 
 
X 
 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
X 
Blood for 
hepatitis B, 
hepatitis C, 
and HIV 
testing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Phadiatop 
allergy test 
and total 
serum IgE 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse 
event 
inquiryp 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Concomitan
t medication 
inquiry 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
IP 
administrati
on 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Injection 
site 
evaluation 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
a The screening visit (visit 1) will take place approximately 5 weeks (±1 week) before the baseline/DoR visit. It is understood 
that not all procedures can be completed on the same day. In particular, the patient may need to return to satisfy the medication 
hold for screening pre-bronchodilator FEV1 (see note “k” for timing). 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
17 
 
b A minimum of 3 weeks run-in (extension allowed up to 4 weeks) on stable doses of the patient’s usual asthma medication is 
required to establish a baseline level of control before randomization. 
c Diary control inclusion must be met at baseline/DoR in order for the patient to be randomized. If the control criteria are not 
met, the patient should not be randomized and should be discontinued at that time; the run-in may only be extended up to 4 
weeks. 
d Beta-human chorionic gonadotropin serum pregnancy tests will be performed at screening (female patients who are not 2 years 
postmenopausal or surgically sterile only). Urine pregnancy tests will be performed at baseline/DoR, before study drug 
injection at each administration visit and at week 52, or early withdrawal, and at follow-up V18. Pregnancy tests are not 
required for female patients who are 2 years postmenopausal or surgically sterile. 
e The blood eosinophil count must meet the ≥300/μL inclusion criterion during the screening period. Given the known variability 
in this measure, the eosinophil count may be repeated once during screening (total of 2 attempts), at the discretion of the 
Investigator, in order to fulfill this inclusion criterion. 
f CPK is collected with serum chemistry tests at scheduled visits. If a potentially clinically significant CPK level (≥3.1 × ULN) 
is reported, initiate the CPK/myalgia CRF and clinical monitoring as outlined in Protocol Section 7.1.7.2. 
g CPK measurement only. CPK will be collected with PK sample. 
h Physical examination, vital signs, and ECG should be obtained before spirometry procedures and IP administration. 
i Patients aged 21 years and over will have their height and weight assessed at screening only. Patients aged 12 to 21 years will 
have height and weight assessed at screening, week 24, and EOT. 
j A failed reversibility test may be repeated once, within the 2-week (±3 days) screening period. Reversibility testing will be 
confirmed before entering the run-in period. Documented historical reversibility within 12 months of signing the Informed 
Assent Form/Informed Consent Form is acceptable as per inclusion criterion f. 
k Pre-bronchodilator spirometry assessments should only be performed after withholding short-acting bronchodilators (ie, 
inhaled short-acting beta-adrenergic agonists and/or short-acting anticholinergics) for at least 6 hours and long-acting 
bronchodilators (ie, inhaled long-acting beta-adrenergic agonists and long acting anticholinergic agents) for at least 12 or 24 
hours, according to their labeled dose schedule. Spirometry should be performed prior to IP administration, if applicable. 
l The ACQ will be completed by the patient at the clinic. ACQ should be completed through question 6. NOTE: The screening 
V1 ACQ-6 score must be ≥1.5 in order to continue in this study. A screening visit ACQ score <1.5 may not be repeated and the 
patient should be screen-failed at that time. 
m If a patient experiences worsening of his or her asthma symptoms, the patient is to call the study center within 48 hours (if 
possible) to be evaluated for his or her asthma symptoms. A diary alert, based on a sustained fall in peak flow from baseline, 
will also help support the patient’s subjective experience. Procedures and assessments to be performed if an unscheduled visit 
occurs are described in Protocol Section 3.16.5. 
n Patients at sites in the United States will return for a PK assessment at approximately 1 week, which corresponds 
approximately to maximum plasma drug concentration (Cmax) for subcutaneous reslizumab. 
Note: All blood sampling (including hematology and chemistry) will be drawn before administration of IP unless otherwise 
indicated. 
o Blood for ADA assessment will be collected at baseline/DoR, and other scheduled time points, and upon observation of any 
severe hypersensitivity reaction (eg, anaphylaxis). Blood for ADA assessment will be collected before dosing, if both occur on 
the same day. An additional, late follow-up for immunogenicity testing will be performed 28 weeks (±2 weeks) after the last 
dose of study drug (~week 76). 
p Adverse event inquiry will occur before and after study drug administration at V3 to V16. Follow-up any prior 
messages from the post-injection eDiary symptom inquiry, as necessary. For systemic or severe hypersensitivity 
reactions possibly related to the study drug, initiate the anaphylaxis CRF. When such reactions are observed after 
study drug administration in the clinic, vital signs must be monitored using the unscheduled vital signs CRF. At 
the time of myalgia/muscular adverse events, CPK should be collected (initiate myalgia CRF).  
V = visit; DoR = day of randomization; PK = pharmacokinetic; EOT = end of treatment; EOS = end of study; 
TERM = termination; wk, W = week; d = day; ACQ = Asthma Control Questionnaire; ACQ-6 = 6-item Asthma 
Control Questionnaire; CBC = complete blood count; CPK = creatine phosphokinase; CRF = case report form; 
ECG = electrocardiogram; eDiary = electronic diary; PEF = peak expiratory flow; IP = investigational product; 
HCU = health care utilizations; AQLQ +12 = Asthma Quality of Life Questionnaire for patients 12 years and older; 
 SGRQ = St. George’s Respiratory 
Questionnaire; 
 ADA = anti-drug antibody; HIV = human 
immunodeficiency virus; FEV1 = forced expiratory volume in 1 second. 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
18 
 
2.2. 
Primary and Secondary Measures and Endpoints 
2.2.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the frequency of clinical asthma exacerbations (CAEs) per 
patient during the 52-week treatment period. Refer to Section 6.2.1 for additional details 
regarding the definition of CAE. 
2.2.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are as follows: 
• change in pre-bronchodilator FEV1 from baseline/DoR at week 52 
• change in Asthma Quality of Life Questionnaire for patients 12 years and older 
(AQLQ +12) score from baseline/DoR at week 52 
• change in 6-item Asthma Control Questionnaire (ACQ-6) score from baseline/DoR at 
week 52 
• change in total asthma symptom scores (day and night) from baseline at week 52 
• percentage of asthma control days from baseline/DoR to week 52 
• change in St. George’s Respiratory Questionnaire (SGRQ) from baseline/DoR at 
week 32 
• time to first clinical asthma exacerbation during the 52-week treatment period 
• frequency of exacerbations requiring hospitalization or emergency department visits 
per patient during the 52-week treatment period 
• frequency of moderate exacerbations defined as exacerbations requiring additional 
asthma controller medication that was not a systemic corticosteroid and that did not 
result in an asthma-specific hospitalization or emergency department visit during the 
52-week treatment period 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
19 
 
2.2.4. 
Target Biomarker Endpoints 
The target biomarker endpoints are the blood eosinophil counts at baseline/DoR; weeks 2, 4, 8, 
12, 16, 32, 52 or early withdrawal; and the follow-up visit (approximately week 64).  
2.2.5. 
Immunogenicity Endpoints 
Samples for immunogenicity assessment for development of anti-drug antibodies will be 
obtained before the administration of study drug at DoR; prior to study drug administration at 
weeks 4, 16, 32, 52 or early withdrawal; and the follow-up visit (approximately week 64). 
Additional samples will be collected at the late follow-up visit (approximately week 76). 
2.2.6. 
Pharmacokinetic Endpoints 
The PK endpoints are the serum reslizumab concentrations at baseline/DoR; weeks 1 (patients in 
US study centers only), 2, and prior to study drug administration at weeks 4, 8, 12, 16, 20, 32, 
48, 52 or early withdrawal; and the follow-up visit (approximately week 64). An additional PK 
sample will be taken at long term follow-up (approximately week 76) at the same time for ADA 
sample collection. 
2.2.8. 
Safety Endpoints 
The safety endpoints for this study are as follows: 
• adverse events throughout the study 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
20 
 
• vital signs (pulse, respiratory rate, and blood pressure) throughout the study 
• concomitant medication usage throughout the study 
• physical examination findings throughout the study 
• clinical laboratory evaluations at screening, baseline/DoR, and periodically 
throughout the study 
• ECG evaluation at screening and week 24, 36, and 52 or early withdrawal 
2.3. 
Sample Size and Power Considerations 
The primary efficacy variable for this study is the frequency of CAEs per patient during the 
52-week treatment period. The study will be considered positive if the primary efficacy measure 
indicates a statistically significant treatment effect of reslizumab versus placebo at the respective 
predefined significance level. 
Power calculations were based on the below assumptions: 
• Negative binomial (NB) distribution for the number of exacerbations with a mean of 
2.9 exacerbations per patient per year for the placebo group  
• Dispersion parameter of 1.2 
• Treatment effect of 45% between the reslizumab group and the placebo group  
• Alpha level of 0.05 
Based on the assumptions above, 225 patients per group (450 total) will provide >90% power to 
detect significant treatment effect of reslizumab over placebo in the reduction of exacerbation 
rate. The sample size was increased beyond the sample size required to provide 90% power in 
order to allow sufficient number of patients to assess safety and immunogenicity and to ensure 
adequate enrollment in the adolescent subset. The current sample size also provides higher power 
for other efficacy endpoints. 
Patients with blood eosinophil levels of 300/μL to <400/µL will be limited to no more than 30% 
of patients (60 patients per treatment group). 
2.4. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. Patients who meet all inclusion 
criteria and none of the exclusion criteria will be randomly assigned to receive reslizumab 110 
mg sc or matching placebo (approximately 225 patients per treatment group) in a 1:1 ratio. 
Patients and investigators will remain blinded to treatment assignment during the study. 
Randomization will be stratified by age (12 to <18 years and ≥18 years) and blood eosinophil 
levels at screening (300/μL to <400/μL and ≥400/μL). This system is used to ensure a balance 
across treatment groups. The goal is to recruit a maximum of 30% of the patients (60 patients per 
treatment group) with eosinophil levels of 300/μL to <400/μL. 
The randomization list and treatment will be assigned to the relevant treatment groups through a 
qualified contract research organization (CRO), eg, via Interactive Voice Response System 
(IVRS)/ Interactive Web Response System (IWRS). The generation of the medication list and 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
21 
 
management of the IRT system will be done by a qualified CRO under the oversight of Teva’s 
Clinical Supply Chain. 
The sponsor’s clinical personnel involved in the study will be blinded to the study drug identity 
after the run-in period until the database is locked for analysis and the treatment assignment is 
revealed, with the exception of the bioanalytical group who will not be blinded to facilitate PK 
and ADA sample analysis. Eosinophils and monocytes will be redacted from the post-baseline 
differential cell count reports to avoid the possibility of unblinding patients. 
2.5. 
Sequence of Planned Analyses 
2.5.1. 
Interim Analyses 
No interim analysis is planned for this study. 
2.5.2. 
Final Analyses and Reporting 
All final, planned analyses identified in this SAP will be performed only after the last patient has 
completed the study. The randomization codes will not be unblinded until this SAP has been 
approved. 
Any exploratory analyses completed to support study analyses, which were not identified in this 
SAP, will be documented and reported in appendices to the CSR. 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
22 
 
3. 
POPULATIONS/ANALYSIS SETS 
Site 
 was terminated due to numerous unresolved Good Clinical Practice (GCP) issues, 
including an overall lack of adequate source documentation (letter to FDA dated 2 December 
2016). The data from this site are deemed invalid and the 4 patients randomized at this site will 
be excluded from the efficacy analysis but will be included as part of the safety analysis. In 
addition, these patents will be summarized as randomized, but not analyzed, as part of the ITT 
analysis set in the disposition summary (Section 5.2). 
3.1. 
Intent-to-Treat Analysis Set 
The intent to treat (ITT) analysis set will include all randomized patients, with the exception of 
patients from Site 
 who will be excluded. In this population, treatment will be based on the 
treatment to which patients were randomized, regardless of which treatment they actually 
received. 
Two analytic approaches are planned using the ITT analysis set. 
• In the first approach, all data collected from patients will be included, regardless of 
continued adherence to their assigned study treatment. 
• In the second approach, data collected from patients during the treatment period will 
be included, up to the point at which patients discontinue from their assigned study 
treatment (on-treatment). For patients who completed treatment in this study, the 
treatment period will be defined from the first dose of study drug to the end of 
treatment (week 52) visit. For patients who prematurely discontinue treatment, the 
treatment period will be defined from the first dose of study drug to the last dose of 
study drug + 4 weeks. 
The analytic approach including all data collected from patients will be utilized as the primary 
approach to analysis for the primary endpoint (frequency of CAE). The on-treatment approach 
will be conducted as a sensitivity analysis for the primary endpoint. For the analysis of all other 
efficacy endpoints, the on-treatment approach will be utilized as the main approach to analysis. 
The analytic approach including all data collected from patients will additionally be conducted as 
sensitivity analyses for selected secondary endpoints. 
3.1.1. 
ITT Analysis Set (Patients 12-70 Years) 
Since AQLQ +12 has only been validated for patients aged 12 to 70 years, the analysis of this 
variable will be restricted to the subset of the ITT analysis set (excluding patients from Site 
) within the specified age range (12 to 70 years) at baseline. 
3.2. 
Safety Analysis Set 
The safety analysis set will include all patients who receive at least 1 dose of study drug 
(including patients from Site 
). In this population, treatment will be based upon the 
treatment patients actually received, regardless of the treatment to which they were randomized. 
Patients dosed in error, but who otherwise received at least 1 dose of reslizumab, will be 
assigned to reslizumab for the analysis of safety. 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
23 
 
In this analysis, data collected from patients during the treatment period will be included, up to 
the point at which patients discontinue from their assigned study treatment. For patients who 
completed treatment in this study, the treatment period will be defined from the first dose of 
study drug to the end of treatment (week 52) visit. For patients who prematurely discontinue 
treatment, the treatment period will be defined from the first dose of study drug to the last dose 
of study drug + 4 weeks. This analysis will be used as the default approach for all safety 
endpoints. 
3.3. 
Per-Protocol Analysis Set 
The per-protocol (PP) analysis set is a subset of the ITT analysis set (excluding patients from 
Site 
) including only patients without major protocol violations. The PP analysis set will 
only be presented for the primary endpoint. In this analysis, data collected from patients during 
the treatment period will be included, up to the point at which patients discontinue from their 
assigned study treatment. 
3.3.1. 
Major Protocol Violations 
Table 2 presents the planned list of major protocol violations prospectively identified as having 
the potential to influence and/or bias the primary efficacy results. A complete list of protocol 
violations resulting in exclusion of patients from the PP analysis will be determined at the end of 
the study based on team review of accumulated blinded study data. Updates to the following list 
will be documented in the minutes from the final Statistical Data Review meeting. 
Table 2: 
Major Protocol Violations 
Violation 
Approach to identifying protocol violations 
Patient does not have ≥2 asthma 
exacerbations within the past 12 months 
Inclusion criteria (c); disposition CRF 
Asthma/allergy history CRF 
Protocol violation CRF 
Patient does not have ACQ-6 score 
≥1.5 at screening (Visit 1) 
Inclusion criteria (d); disposition CRF 
Asthma control questionnaire CRF 
Protocol violation CRF 
Patient does not have blood eosinophil 
≥300/µL during the screening period 
(prior to Visit 2) 
Inclusion criteria (e); disposition CRF 
Laboratory data 
Protocol violation CRF 
Patient does not demonstrate FEV1 
reversibility (≥12%) after 
administration of inhaled SABA 
Inclusion criteria (f); disposition CRF 
Spirometry data 
Protocol violation CRF 
Note: Historical reversibility is acceptable. 
Patient was not on ICS at baseline (at 
least a medium total daily dose) 
Inclusion criteria (g); disposition CRF 
Medication CRF 
Protocol violation CRF 
Patient was not on an additional asthma 
controller medication (eg, LABA, 
LAMA, LTRA, or theophylline 
preparations) 
Inclusion criteria (h); disposition CRF 
Medication CRF 
Protocol violation CRF 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
24 
 
Violation 
Approach to identifying protocol violations 
Patients who were unblinded at any 
point during the study 
Protocol violation CRF 
Patients who received the incorrect 
study treatment at any point during the 
study 
Protocol violation CRF 
3.4. 
Subgroup Analysis Sets 
3.4.1. 
Age Strata 
Selected efficacy endpoints including CAEs (primary), pre-bronchodilator FEV1, AQLQ+12, 
ACQ-6, and blood eosinophils will be analyzed separately for patients aged 12 to <18 years and 
≥18 years. Age strata will be defined based on the age recorded in the clinical database. 
3.4.2. 
Eosinophil Strata 
Selected efficacy endpoints including CAEs (primary), pre-bronchodilator FEV1, AQLQ+12, 
ACQ-6, and blood eosinophils will be analyzed separately for patients with baseline blood 
eosinophil levels 300/μL to <400/μL and ≥400/μL. Eosinophil strata will be defined based on the 
baseline blood eosinophil level recorded in the clinical database. 
3.4.4. 
Asthma Background Medication 
Patient classifications based on Global Initiative for Asthma (GINA) guidelines (GINA 2015) 
will be derived. Selected efficacy endpoints including CAEs and pre-bronchodilator FEV1 will 
be examined for the following medication classes taken at baseline. Medications at baseline will 
be defined as those taken at the time of randomization. 
• GINA 4 – ICS/LABA+ (Yes, No)  
Note: “Yes” is defined as patients taking ICS (medium or high-dose); and LABA or 
leukotriene or xanthine as a second controller; and no OCS use 
− ICS/LABA (Yes, No)  
Note: “Yes” is defined as patients taking ICS (medium or high-dose); and LABA 
as a second controller; and no OCS use 
− High-dose ICS/LABA (Yes, No)  
Note: “Yes” is defined as patients taking ICS (high-dose); and LABA as a second 
controller; and no OCS use 
− Medium-dose ICS/LABA (Yes, No)  
Note: “Yes” is defined as patients taking ICS (medium-dose); and LABA as a 
second controller; and no OCS use 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
25 
 
• GINA 5 – OCS (Yes, No) 
Note: “Yes” is defined as patients taking OCS 
3.4.5. 
Other Subgroups 
Selected efficacy endpoints including CAEs (primary), pre-bronchodilator FEV1, AQLQ+12, 
ACQ-6, and blood eosinophils will also be examined for the following demographic subgroups: 
• Gender (Male, Female) 
• Race (White, Black, Asian, Other; Black, non-Black) 
• Region (North America, Eastern Europe, Western Europe, Latin America, 
Asia/Pacific, Middle East/Africa; US, non-US) 
• Phadiatop result (Positive, Negative) 
• Age of asthma onset (<40, ≥40 years) 
• BMI (<30, ≥30 kg/m2) 
• ADA status (Positive, Negative) – for reslizumab-treated patients only 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
26 
 
4. 
GENERAL ISSUES FOR DATA ANALYSIS 
4.1. 
General 
Descriptive statistics for continuous variables include number of patients (n), mean, standard 
deviation (SD), standard error (SE) of the mean, median, minimum, and maximum. If inferential 
statistics are computed, the least square (LS) mean and standard error of the LS mean will be 
included. Descriptive statistics for categorical variables include patient counts and percentages. 
4.2. 
Specification of Baseline Values 
4.2.1. 
Diary 
Baseline for diary variables (eg, PEF, total asthma symptom score, total reliever use) will be 
derived as the average of the run-in values over the 7 days preceding baseline/DoR (see Table 3 
for the definition of analysis days for diary data). At least 4 out of the 7 expected measurements 
need to be recorded for each diary variable; otherwise the baseline value for that variable will be 
treated as missing. 
4.2.2. 
Lung Function 
The baseline value for lung function variables (eg, pre-bronchodilator FEV1, FVC, FEF25%-75%) 
will be the last observed pre-bronchodilator value prior to the first dose of study drug. Baseline 
for post-bronchodilator FEV1 will be the last observed post-bronchodilator value prior to the first 
dose of study drug. 
4.2.3. 
Patient Reported Outcomes 
The baseline value for patient reported variables (eg, ACQ-6, AQLQ +12, SGRQ, 
) will 
be the last observed value prior to the first dose of study drug. 
4.2.4. 
Biomarkers 
The baseline value for blood eosinophil levels will be the maximum value of the observed 
assessments from the screening visit to baseline/DoR (inclusive). 
4.2.5. 
Safety 
The baseline value for all visit-based safety assessments (eg, laboratory, vital signs) will be the 
last observed value prior to the first dose of study drug. 
4.3. 
Multiple Comparisons and Multiplicity 
A fixed sequence multiple testing procedure will be implemented to test the primary and 
secondary variables while controlling the overall type I error rate at 0.05. If the resulting two-
sided p-value from the primary comparison is ≤0.05, then the next comparison of interest (first 
secondary variable) will be interpreted inferentially at 0.05. This process continues through the 
secondary variables until either all comparisons of interest are interpreted inferentially, or until 
the point at which the resulting two-sided p-value for a comparison of interest is >0.05. At the 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
27 
 
point where p>0.05, no further comparisons will be interpreted inferentially. The hierarchy of 
endpoints is as defined in Section 6.3.1. 
No multiplicity adjustments will be made for other efficacy and exploratory analyses. 
4.4. 
Handling Withdrawals and Missing Data 
The primary analysis will include multiple imputations for missing data as detailed in 
Section 6.2.2 and Appendix A. For all other variables, only the observed data from the patients 
will be used in the statistical analyses (ie, there is no plan to estimate missing data). 
4.5. 
Study Days and Visit Windows 
Study days will be numbered relative to the first day of study drug administration. The start of 
treatment (day 1) is defined as the date on which a patient takes the first dose of study drug, as 
recorded on the study drug diary. Days will be numbered relative to study start (ie, ..., –2, –1, 1, 
2, ...) with day 1 being the start of study drug and day –1 being the day before the start of study 
drug). 
For safety-by-visit summaries, if there are multiple assessments at a post-baseline visit then the 
last non-missing assessment at that visit will be used for the analysis. This includes assessments 
at the scheduled and unscheduled visits.  
‘Endpoint’ for safety analyses and summaries is the time point when the last observation was 
obtained during the treatment period. For patients who completed treatment in this study, the 
treatment period will be defined from the first dose of study drug to the end of treatment (week 
52) visit. For patients who prematurely discontinue treatment, the treatment period will be 
defined from the first dose of study drug to the last dose of study drug + 4 weeks. 
For efficacy-by-visit summaries, only the assessments at the scheduled visit will be summarized. 
The assessments at unscheduled visits will be listed. For the purpose of the efficacy analysis, 
assessments collected at an early termination visit will be considered as the next scheduled visit 
for that assessment if at least 3 but no more than 5 weeks elapsed since the date of the last 
medication intake. 
Efficacy-by visit summaries will be presented on-treatment. In this context, ‘endpoint’ will be 
defined as the last observation obtained at a scheduled or qualified early termination visit during 
the treatment period. For patients who completed treatment in this study, the treatment period 
will be defined from the first dose of study drug to the end of treatment (week 52) visit. For 
patients who prematurely discontinue treatment, the treatment period will be defined from the 
first dose of study drug to the last dose of study drug + 4 weeks. 
For selected variables, additional sensitivity analyses may be presented utilizing all data 
collected over the entire course of the study including data collected after withdrawal for patients 
who prematurely discontinue from treatment. In this context, ‘endpoint’ will be defined as the 
last observation obtained at any post-baseline scheduled or qualified early termination visit. 
For summaries of diary data (eg, rescue medication use, asthma symptom score), the day used 
for analysis will consist of the evening assessment for the day and the morning assessment for 
the following day, as illustrated in Table 3. Weekly average data will be generated using 7-day 
windows derived based on these analysis days. 


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Study C38072-AS-30025 
 
28 
 
Table 3: 
Definition of Analysis Days for Diary Data 
Study Period 
Diary Day 
Study Daya 
Time Point 
Baseline 
Day -7 
-7 
PM 
-6 
AM 
Day -6 
-6 
PM 
-5 
AM 
Day -5  
-5 
PM 
-4 
AM 
Day -4 
-4 
PM 
-3 
AM 
Day -3 
-3 
PM 
-2 
AM 
Day -2 
-2 
PM 
-1 
AM 
Day -1 
-1 
PM 
1 (pre-dose) 
AM 
Treatment 
Day 1 
1 
PM 
2 
AM 
Day 2 
2 
PM 
3 
AM 
Day 3 
3 
PM 
4 
AM 
… 
.. 
PM 
.. 
AM 
Day 364 
364 
PM 
365 
AM 
a Study Day 1 denotes the first dose of study drug; Study Day -1 is the day prior to the first dose of study drug. 


Statistical Analysis Plan with Amendment 02 
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5. 
STUDY POPULATION  
5.1. 
General 
The ITT analysis set will be used for all study population summaries, unless otherwise noted. 
Population summaries will be presented by treatment group and overall. 
5.2. 
Patient Disposition 
Data from patients screened, patients screened but not randomized, and the reason the patients 
were not randomized will be summarized overall (for all screened patients). Patients randomized 
(ITT analysis set), patients randomized but not treated, patients randomized but not analyzed 
(Section 3), patients in the safety analysis set, patients in the PP analysis set, patients who 
completed treatment (all 52 weeks while on study treatment), patients who completed the 
planned treatment phase (remained active in the study for the full 52 week duration, either on- or 
off-treatment), and patients who completed the study will be summarized. Patients will be 
categorized as completed the study if they either complete the study visits up to and including 
follow-up (Week 64, for patients not participating in the LTE study) or up to and including end 
of treatment (Week 52, for patients participating in the LTE study). Data from patients who 
withdrew early will be summarized by reason for withdrawal, and the number of patients who 
discontinued treatment but continued to attend study visits will be tabulated. 
KM plots will be provided for time to discontinuation from treatment to identify if there is a 
differential dropout pattern between the treatment groups. 
5.3. 
Demographics and Baseline Characteristics 
Baseline demographics (eg, age, sex, race, ethnicity) and patient characteristics (eg, spirometry, 
airway reversibility) including smoking history, medical history, phadiatop test results, and prior 
medications will be summarized to assess the comparability of the treatment groups. Baseline 
stratification factors (age and blood eosinophil counts) and patients taking the various classes of 
background asthma medication (defined in Section 3.4.4) will also be summarized. Baseline 
demographics and patient characteristics will also be summarized separately for patients who 
discontinue from treatment and patients who complete treatment to investigate whether patients 
with and without missing values may have different characteristics at baseline. 
Age will be calculated based on the date of birth relative to the screening visit (date of informed 
consent). If regional data regulations prohibit collection of a full date of birth, then the patient’s 
age should be recorded on the CRF, if possible. If only a year of birth has been collected (and 
age has not otherwise been reported) then the missing date of birth will be imputed as 30 June 
(30 June YYYY) in order to derive the patient’s age at baseline. 
5.4. 
Medical History 
All medical history abnormalities will be coded using the Medical Dictionary for Regulatory 
Activities (MedDRA). The incidence of medical history abnormalities will be summarized by 


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system organ class (SOC) and preferred term (PT). Patients are only counted once in each SOC 
and once in each PT. 
Asthma- and allergy-specific history will also be collected and reported. In addition, descriptive 
statistics will be provided for time since asthma diagnosis, time since most recent exacerbation, 
number of exacerbations within the last 12 months, and number of days missed school/work due 
to asthma in the past year. 
History of nasal polyp, whether sinus surgery was performed, time since sinus surgery, whether 
diagnosed by CT scan, time since CT scan, and anosmia will be summarized. 
5.5. 
Prior Medications 
All prior medications will be coded using the World Health Organization dictionary of medical 
codes (WHO Drug). The incidence of prior medications will be summarized by therapeutic class 
and preferred term. Patients are only counted once in each therapeutic class and once in each 
preferred term. Prior medications include all medications with a start date prior to the first day of 
study drug. 
Prior medications for asthma will be summarized separately. In addition, total ICS dose taken at 
baseline will be summarized. The reported ICS doses will be converted to fluticasone equivalents 
using the following conversion factors. ICS dose at baseline will be defined as the dose taken at 
the time of randomization. 
Table 4: 
Conversion of ICS to Fluticasone-Equivalent Doses 
Inhaled corticosteroid (mcg) 
Conversion factor 
Fluticasone 
1 
Fluticasone furoate 
2 
Mometasone 
1.14 
Budesonide a 
0.625 
Ciclesonide 
1.56 
Beclomethasone 
1.25 
Triamcinolone 
0.25 
 a Nebulized budesonide is typically recorded in mg and, if applicable, the reported dose (in mg) may need to first be 
converted to mcg (x1000) prior to applying the indicated conversion factor for budesonide. 
5.6. 
Electrocardiography 
Electrocardiogram findings (normal, abnormal) at baseline will be summarized. 
5.7. 
Physical Examinations 
Patients with at least 1 abnormal finding (overall) and abnormal findings for each category will 
be summarized at baseline. 
5.8. 
Protocol Violations  
Patients with at least 1 protocol violation for each category will be summarized. 


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5.9. 
Childbearing Potential  
For female patients, information related to childbearing potential, contraception, and menopause 
will be collected at screening. Information will be provided in the patient data listings. 


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6. 
EFFICACY ANALYSIS 
6.1. 
General 
The ITT analysis set will be used as the default patient population for all efficacy variables, 
unless otherwise noted. Summaries will be presented by treatment group as randomized. 
6.2. 
Primary Efficacy Variable(s) and Analysis 
Note: For consistency, all variables related to or derived from the primary efficacy variable 
(clinical asthma exacerbations) are discussed within this section. This includes the secondary 
efficacy variables of moderate exacerbations, the subset of exacerbations requiring 
hospitalization or emergency department visits, and the analysis of time to first exacerbation, all 
of which are otherwise listed in Section 6.3 (Secondary Efficacy Variable(s) and Analysis). 
6.2.1. 
Variable Definition  
The primary efficacy variable for this study is the frequency of CAEs per patient during the 52-
week treatment period. CAE is defined as a clinically judged deterioration in asthma control as 
determined by the investigator and as evidenced by new or worsening asthma signs or symptoms 
based on the patient history, asthma control diary, physical examination, and/or ambulatory or 
clinic visit assessment of lung function AND that results in a medical intervention, including at 
least 1 of the following: 
• use of systemic corticosteroids (oral or injection) or at least a doubling from a stable 
maintenance oral corticosteroid dose for at least 3 days 
• asthma-specific hospital admission 
• asthma-specific emergency department visit 
Additional medication and/or medical intervention that would satisfy the CAE definition 
occurring within 7 days of the last day of a prior CAE event will be considered as part of the 
same event for analysis purposes. 
The CAE start and stop dates will be collected in order to determine the exacerbation duration. 
The start date of a CAE will be the start date of the initial medical intervention (eg, use of 
systemic corticosteroids [oral or injection] or at least a doubling from a stable maintenance oral 
corticosteroid dose for at least 3 days, asthma-specific hospital admission, or asthma-specific 
emergency department visit, whichever comes first). The stop date is the last day of systemic 
corticosteroids or the last day of an asthma specific hospitalization or emergency department 
visit, whichever is later. For patients who are on a stable maintenance oral corticosteroid dose 
and receive at least a doubling of that dose for 3 days, the stop date is when they return to their 
baseline dose. For patients receiving a new use of oral corticosteroids or at least a doubling from 
their stable maintenance oral corticosteroid dose for at least 3 days that did not return to baseline, 
a CAE stop date will be the day that they have been on a stable dose for at least 10 days. 


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6.2.2. 
Primary Analysis  
The primary analysis of frequency of CAEs will be analyzed using the general 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 will include the treatment 
group, randomization stratification factors (age and blood eosinophil categories, as defined in 
Section 2.4), and the number of exacerbations in the previous year as model factors and an offset 
variable. The offset variable will be calculated as the logarithm of follow-up duration minus the 
summed duration of exacerbations during the follow-up. Age and blood eosinophil categories 
will be based on data recorded in the clinical database. 
The ratio of CAE rate between the treatment groups and its 95% confidence interval (CI) will be 
estimated from the NB model. Treatment effect will be evaluated using the likelihood based chi-
square test. Clinical asthma exacerbations that occur between the first dose of study drug and 2 
weeks after the end of treatment/early withdrawal visit will be counted towards the CAEs for 
analysis. 
The primary analysis will incorporate data from all randomized patients. The analysis will 
include all exacerbations observed over 52 weeks, for patients who completed the 52 week 
treatment period and for patients who withdrew from treatment earlier than 52 weeks but from 
whom the sponsor was able to collect data post withdrawal. For early withdrawal patients that 
the sponsor will fail to retrieve data post withdrawal despite all attempts to contact the patient, a 
multiple imputation will be performed for the frequency of exacerbation post withdrawal. The 
multiple imputations will utilize the post withdrawal data observed for patients who withdrew 
early and for which the sponsor succeeded to retrieve the data. The methodology and algorithm 
used for imputations is described in Appendix A. 
The following sample Statistical Analysis Software (SAS®) code pertains to the primary efficacy 
analysis of CAEs. 
     proc genmod data=<<>>; 
 
class treatment strata1 strata2; 
 
model cae=treatment strata1 strata2 nexac /dist=negbin link=log offset=log_futime; 
 
estimate “CAE rate ratio” treatment 1 -1; 
 
lsmeans treatment /diff exp cl; 
 
ods output lsmeans=<<>>; 
 
ods output lsmeandiffs=<<>>; 
     run; 
A frequency distribution bar graph will be provided for the number of CAEs by treatment group. 
6.2.3. 
Sensitivity Analyses for the Primary Variable 
The following list of sensitivity analyses are pre-specified for this study, with an aim toward 
assessing the robustness of the primary efficacy results: 
• The primary analysis with offset variable calculated as the logarithm of follow-up 
duration (ie, not excluding the summed duration of exacerbations). 
• The primary analysis with control variables for age and blood eosinophil categories 
based on data recorded in the IRT (as randomized). This analysis will only be 


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performed if the number of discrepancies between data recorded in the IRT and the 
clinical database are sufficiently large (eg, 5% of total population). 
• On-treatment: analysis of the primary endpoint including exacerbations during the 
treatment period (ie, observed until treatment completion or until withdrawal from 
treatment, excluding any exacerbations observed after withdrawing from treatment). 
− For patients who complete treatment, the treatment period will be defined from 
the first dose of study drug to the end of treatment (week 52) visit. For patients 
who prematurely discontinue treatment, the treatment period will be defined from 
the first dose of study drug to the last dose of study drug + 4 weeks. 
• Per-protocol: on-treatment analysis of the primary endpoint including exacerbations 
during the treatment period (ie, observed until treatment completion or until 
withdrawal from treatment, excluding any exacerbations observed after withdrawing 
from treatment), based on the PP analysis set. 
• “Tipping point” multiple imputation: analysis of the primary endpoint to assess 
deviations from missing at random (MAR). The details regarding this analysis are 
provided in Appendix B. 
6.2.4. 
Component Analysis for the Primary Variable 
The frequency of the following individual components of the composite CAE definition will be 
examined separately. 
• asthma exacerbations requiring use of systemic corticosteroids (oral or injection) or at 
least a doubling from a stable maintenance oral corticosteroid dose for at least 3 days 
• asthma exacerbations requiring either hospitalization or emergency department visit 
The following individual components will also be examined, however due to the low event rates 
expected, these events will only be presented descriptively. 
• asthma exacerbations requiring hospital admission 
• asthma exacerbations requiring an emergency department visit 
These analyses will be restricted to on-treatment events. 
6.2.5. 
Subgroup Analysis for the Primary Variable 
The primary efficacy variable will additionally be examined for the subgroups defined in 
Section 3.4. The analysis will be similar to the on-treatment analysis described for the primary 
endpoint (Section 6.2.3). An interaction p-value will be derived from a separate NB model 
including additional terms for subgroup and treatment by subgroup interaction. Subgroup 
analyses for the primary efficacy variable will be presented graphically using forest plots. 
6.2.6. 
Time to First Clinical Asthma Exacerbation 
The Kaplan-Meier (KM) method will be used to estimate and compare the distributions of time 
to first CAE between treatment groups. Time to first event will be analysed for on-treatment 
events.  


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The time period for the on-treatment analysis will extend from the date of first dose of study 
drug to the cessation of study treatment, defined as the date of the end of treatment (week 52) 
visit for patients who completed treatment and the date of last dose (+4 weeks) for patients who 
discontinued treatment early. Patients without an event during the treatment period will be 
censored at either the date of the end of treatment (week 52) visit for patients who completed 
treatment or at the date of last dose (+4 weeks) for patients who discontinued early. 
The hazard ratio (95% CI) and p-value will be estimated using a Cox proportional hazards 
regression model adjusting for the stratification factors. 
The following sample SAS® code pertains to the analysis of time to first CAE. 
     proc lifetest data=<<>> outsurv=<<>>; 
 
time ttcae*censor(0); 
 
strata treatment; 
 
ods output quartiles=<<>>; 
     run; 
     proc phreg data=<<>>; 
 
class treatment (ref=’PBO’); 
 
model ttcae*censor(0) = treatment / rl ties=discrete; 
 
strata strata1 strata 2; 
 
ods output parameterestimates=<<>>; 
 
ods output globaltests=<<>>; 
     run; 
A KM plot will be provided for the time to first CAE by treatment group. 
6.2.7. 
Moderate Exacerbations 
A moderate exacerbation is defined as a clinically judged deterioration in asthma control as 
determined by the investigator and as evidenced by new or worsening asthma signs or symptoms 
based on the patient history, asthma control diary, physical examination, and/or ambulatory or 
clinic visit assessment of lung function AND that results in a medical intervention requiring 
additional asthma controller medication that was not a systemic corticosteroid and did not result 
in an asthma-specific hospitalization or emergency department visit (ie, medical intervention that 
did not otherwise meet the criteria for the primary endpoint). 
Additional medication that would satisfy the moderate exacerbation definition occurring within 7 
days of the last day of a prior event will be considered as part of the same event for analysis 
purposes. Similarly, additional medication that would satisfy the moderate exacerbation 
definition occurring within 7 days prior to the start date of another event satisfying the definition 
of a CAE (or occurring concurrently with a CAE) will be considered part of the CAE event and 
will not be counted towards the analysis of moderate exacerbations. 
The analysis for moderate exacerbations will be similar to the on-treatment analysis described 
for the primary endpoint (Section 6.2.3). In addition, the analysis of moderate exacerbations will 
not exclude exacerbation duration from the offset. 


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6.3. 
Secondary Efficacy Variable(s) and Analysis 
As described previously in Section 4.5, an on-treatment approach will be adopted as the primary 
analysis for the efficacy variables assessed by-visit. In this analysis, the treatment period will be 
defined from the first dose of study drug to the end of treatment (week 52) visit for patients who 
completed treatment and from the first dose of study drug to the last dose of study drug (+4 
weeks) for patients who discontinued treatment early. Measurements collected outside of these 
defined timeframes will be excluded from the analyses and endpoint will be defined within these 
timeframes. All results will be included in the patient listings. For selected key variables, 
additional sensitivity analyses may also be performed in which all post-baseline measurements 
collected during the study will be included and endpoint will be defined within this extended 
timeframe. 
6.3.1. 
Secondary Variables 
The secondary efficacy endpoints are as follows: 
• change in pre-bronchodilator FEV1 from baseline/DoR at week 52 
• change in Asthma Quality of Life Questionnaire for patients 12 years and older 
(AQLQ +12) score from baseline/DoR at week 52 
• change in 6-item Asthma Control Questionnaire (ACQ-6) score from baseline/DoR at 
week 52 
• change in total asthma symptom scores (day and night) from baseline at week 52 
• percentage of asthma control days from baseline/DoR to week 52 
• change in St. George’s Respiratory Questionnaire (SGRQ) from baseline/DoR at 
week 32 
• time to first clinical asthma exacerbation during the 52-week treatment period 
• frequency of exacerbations requiring hospitalization or emergency department visits 
per patient during the 52-week treatment period 
• frequency of moderate exacerbations defined as exacerbations requiring additional 
asthma controller medication that was not a systemic corticosteroid and that did not 
result in an asthma-specific hospitalization or emergency department visit during the 
52-week treatment period 
Testing of the secondary variables will be performed using the sequential testing procedure in the 
order as specified above, as described in Section 4.3. 


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6.3.3. 
Pulmonary Function Tests 
6.3.3.1. 
Variable Definition 
Pulmonary function tests will be measured using spirometry, according to ATS/ERS 2005 
procedural guidelines. Pre-bronchodilator assessments (FVC, FEV1, FEF25%-75%) are measured at 
weeks 2, 4, 8, 12, 16, 32, and 52 and post-bronchodilator assessments (FEV1) are measured at 
weeks 16, 32, and 52. 
The FVC is the volume of air, in liters (L), that can be forcibly blown out after full inspiration. 
The FEV1 is the volume of air (L) that can be forcibly exhaled from the lungs in the first second. 
The FEF25%-75% is the forced expiratory flow (L/second) at 25% to 75% forced vital capacity. 
The percent (%) predicted FEV1 is derived as the actual FEV1 divided by the standard predicted 
FEV1 (multiplied by 100). The National Health and Nutrition Examination Survey (NHANES) 
III reference equations will be used. An additional correction factor will be applied for Asian 
patients (Hankinson et al 2010). 


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6.3.3.2. 
Analysis 
Summary statistics of actual values and change from baseline to each scheduled visit will be 
provided by treatment group. 
Analysis of the change from baseline to each scheduled visit will be performed using a mixed 
effect model for repeated measures (MMRM) including fixed effects for treatment, visit, 
treatment by visit interaction, age group (12 to <18 years and ≥18 years), blood eosinophil 
counts at enrollment (300 to <400/µL and ≥400/µL), and sex, height and baseline value as 
covariates, and patient as a random effect. Age and blood eosinophil categories will be based on 
data recorded in the clinical database. An unstructured covariance matrix will be used for the 
within patient correlation modeling. If the fit of the unstructured (UN) covariance matrix fails to 
converge, the following covariance structures will be tried in order until convergence is reached: 
first order autoregressive (AR[1]) and compound symmetry (CS). Based on the MMRM model, 
the treatment effect, the difference from placebo, and the associated 95% CI will be presented 
together with the corresponding p-value. 
The following sample SAS® code pertains to the MMRM analysis. 
     proc mixed data=<<>>; 
 
class patient visit treatment strata1 strata2 sex; 
 
model change=treatment strata1 strata2 sex height baseline visit treatment*visit  
                                     /ddfm=kr alpha=0.05; 
 
repeated visit /type=un subject=patient r; 
 
lsmeans treatment*visit / diff cl; 
 
ods output lsmeans=<<>>; 
 
ods output diffs=<<>>; 
     run; 
Model results will only be reported if there are at least 15 patients contributing to the analysis in 
each treatment group; otherwise only the descriptive statistics will be displayed. A line graph 
presenting the LS mean change from baseline over time (at each visit) will be provided for pre-
bronchodilator FEV1, 
 by treatment group. 
Pre-bronchodilator FEV1 at Week 52 will additionally be examined for the selected subgroups 
defined in Section 3.4. The analysis of subgroups will use a MMRM model similar to the one 
described above. Subgroups will be presented graphically using forest plots. 
The proportion of patients achieving an increase of ≥100 mL in FEV1 from baseline to each 
scheduled visit will be summarized. A stratified (based on randomization strata) Cochran-
Mantel-Haenszel (CMH) test will be used to analyze the proportion of patients achieving an 
increase of ≥100 mL in FEV1 from baseline to Week 52. 
6.3.4. 
AQLQ +12 
6.3.4.1. 
Variable Definition 
The AQLQ +12 is a modified version of the standardized AQLQ which measures functional 
impairments experienced by adults ≥17 years of age. The AQLQ +12 is valid for patients aged 
12-70 years. 


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The AQLQ +12 is a 32-item instrument administered as a self assessment at weeks 4, 8, 12, 16, 
32, and 52. Patients are asked to recall their experiences during the previous 2 weeks and to 
score each question on a 7-point scale (7 = no impairment, 1 = severe impairment). 
The 32 questions (items) in the AQLQ +12 are divided into 4 domains: 
• Activity limitations: Items 1-5, 11, 19, 25, 28, 31, 32 
• Symptoms: Items 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30 
• Emotional function: Items 7, 13, 15, 21, 27 
• Environmental stimuli: Items 9, 17, 23, 26 
6.3.4.1.1. Missing data handling and total score calculation 
The overall and domain scores of the AQLQ +12 are derived as the average of the corresponding 
items; the analysis will be based on the available data. 
For incomplete data, the overall AQLQ +12 score for a particular visit will not be calculated if 3 
or more responses are missing with no more than 1 per domain. For the symptom and activity 
domain total scores, calculation will require no more than 1 missing item. Total scores for the 
other 2 domains will be regarded as missing if 1 or more item is missing. 
6.3.4.2. 
Analysis 
Summary statistics of actual values and change from baseline to each scheduled visit will be 
provided by treatment group. 
Analysis of the change from baseline to each scheduled visit will use the same MMRM model 
described in Section 6.3.3.2 with the exception of inclusion of sex and height in the model. A 
line graph will be provided for the LS mean change from baseline over time (at each visit). 
AQLQ +12 at Week 52 will additionally be examined for the selected subgroups defined in 
Section 3.4. The analysis of subgroups will use a MMRM model similar to the one described 
above. Subgroups will be presented graphically using forest plots. 
The proportion of patients achieving an increase of ≥0.5 in the AQLQ +12 score from baseline to 
each scheduled visit will be summarized. A stratified (based on randomization strata) Cochran-
Mantel-Haenszel (CMH) test will be used to analyze the proportion of patients achieving an 
increase of ≥0.5 in the AQLQ +12 score from baseline to Week 52. 
6.3.5. 
ACQ-6 
6.3.5.1. 
Variable Definition 
The ACQ-6 was developed to measure asthma control. The ACQ-6 is a 6-item instrument; each 
item is scored on a scale of 0 to 6 (higher scores are an indication of poorer asthma control). At 
weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, the patient answers each of the 6 
questions, identifying the response that best describes how the patient has been during the past 
week. 


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6.3.5.1.1. Missing data handling and total score calculation 
The overall score of the ACQ-6 is derived as the average of the individual item scores; the 
analysis will be based on the available data. 
For incomplete data, the following rules will apply: 
1. Total score for the visit will not be calculated if Question 1 is left blank, irrespective of 
the completion of the remaining questions. 
2. A missing score on post screening questionnaire for Questions 2-6 will be imputed based 
on the total scores from the previous visit, as long as at least 3 out of the 5 questions have 
responses for the current visit (ie, at least half of the remaining questions are answered).  
The formula is: (total sum of non-missing scores for the current visit / total sum of scores 
for the previous visit for questions answered for the current visit) * (score for the missing 
question on the previous visit) 
3. Total score at screening will not be calculated if Question 1 or two or more among 
Questions 2-6 is left blank. A missing score for Questions 2-6 at screening will be 
replaced by an average of the available scores. 
6.3.5.2. 
Analysis 
Summary statistics of actual values and change from baseline to each scheduled visit will be 
provided by treatment group. 
Analysis of the change from baseline to each scheduled visit will use the same MMRM model 
described in Section 6.3.3.2 with the exception of inclusion of sex and height in the model. A 
line graph will be provided for the LS mean change from baseline over time (at each visit). 
ACQ-6 at Week 52 will additionally be examined for the selected subgroups defined in 
Section 3.4. The analysis of subgroups will use a MMRM model similar to the one described 
above. Subgroups will be presented graphically using forest plots. 
The proportion of patients achieving a reduction of ≥0.5 in the ACQ-6 score from baseline to 
each scheduled visit will be summarized. A stratified (based on randomization strata) CMH test 
will be used to analyze the proportion of patients achieving a reduction of ≥0.5 in the ACQ-6 
score from baseline to Week 52. 
6.3.6. 
SGRQ 
6.3.6.1. 
Variable Definition 
St. George’s Respiratory Questionnaire (SGRQ) is a health status survey specific for chronic 
obstructive pulmonary disease and other respiratory diseases. The SGRQ consists of 2 parts: Part 
1 produces a symptom score and Part 2 produces an activity and impacts score. A total score is 
also calculated. The SGRQ is administered as a self assessment at weeks 32 and 52. 
The questions in the SGRQ are divided into 3 domains: 
• Symptoms: Questions 1-8 
• Activity: Questions 11, 15 


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• Impacts: Questions 9-10, 12-14, 16-17 
The SGRQ requests a single response to each of Questions 1-10 and 17; whereas Questions 11-
16 each request multiple responses, resulting in a total of 50 responses across the questionnaire. 
6.3.6.1.1. Missing data handling and total score calculation 
Each questionnaire response has a unique empirically derived ‘weight’ (the lowest possible 
weight is 0 and the highest is 100). The weights associated with each response is provided in 
Appendix C. Derivation of each domain and total score is as follows: 
1. The weights for all items with a positive response are summed. 
2. The weights for missing items are deducted from the maximum possible weight for each 
domain (or total) score. The maximum possible weights for each domain and total score 
are 662.5 (symptoms), 1209.1 (activity), 2117.8 (impacts), and 3989.4 (total). 
3. The score is calculated by dividing the summed weights (from Step 1) by the adjusted 
maximum possible weight for the domain or total score (from Step 2) and expressing the 
result as a percentage: 
Score = 100 x (Sum of weights from positive items in the domain (or total) / Sum of 
weights for all items in the domain (or total)) 
Thus, scores are expressed as a percentage of overall impairment, where 100 represents the worst 
possible health status and 0 represents the best possible health status. The questionnaire requests 
a single response to each of Questions 1-10 and 17. If multiple responses are given to any one of 
these questions, then the weights for the positive responses for that question will be averaged. 
A score will only be calculated if at least 75% of the responses for the total and/or domain score 
are non-missing for a given visit. If more than 25% of the questions are missing, then the total 
and/or domain score will be considered missing for that visit. For the symptoms domain (8 total 
responses), this threshold translates to a maximum of 2 missed responses that can be tolerated. 
For the activity domain (16 total responses), a maximum of 4 missed responses can be tolerated. 
For the impacts domain (26 total responses), a maximum of 6 missed responses can be tolerated. 
For the total score (50 total responses), a maximum of 12 missed responses can be tolerated. 
6.3.6.2. 
Analysis 
Summary statistics of actual values and change from baseline to each scheduled visit will be 
provided by treatment group. 
Analysis of the change from baseline to each scheduled visit will use the same MMRM model 
described in Section 6.3.3.2 with the exception of inclusion of sex and height in the model. 
The proportion of patients achieving a reduction of ≥4 in the SGRQ score from baseline to each 
scheduled visit will be summarized. A stratified (based on randomization strata) CMH test will 
be used to analyze the proportion of patients achieving a reduction of ≥4 in the SGRQ score from 
baseline to Week 32. 


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6.3.9. 
Asthma Control Diary 
6.3.9.1. 
Variable Definition 
6.3.9.1.1. Asthma symptom scores 
The asthma symptom score will be determined every morning and evening by the patient and 
recorded in the daily asthma control diary. The asthma symptom score is used to measure how 
much patients are bothered by their asthma symptoms. Asthma symptom score will be rated on a 
scale, with higher scores indicating more severe symptoms. The daytime asthma symptom score 
(range: 0-5) will be assessed in the evening and indicate how the patient felt earlier that same 
day. The nighttime asthma symptom score (range: 0-4) will be assessed in the morning and 
indicate how the patient felt during the previous night. Total asthma symptom score (range: 0-9) 
will be derived as the sum of the daytime and nighttime symptom scores. 
6.3.9.1.2. Total reliever use 
The number of times SABA reliever therapy is used will be recorded by the patient, once in the 
morning and once in the evening. Total reliever use will be derived as the sum of the morning 
and evening counts. 
6.3.9.1.3. Nighttime awakenings 
Nighttime awakenings will be recorded daily in the morning to indicate whether the patient was 
awakened during the previous night due to asthma. An awakening-free night (y/n) is defined as a 
night during which the patient did not experience a nighttime awakening. 
6.3.9.1.4. Peak expiratory flow 
Peak expiratory flow (PEF) is the maximum speed of exhalation, measured by a PEF meter. 
Morning (AM) and evening (PM) ambulatory PEF will be measured daily by the patient and the 
maximum of 3 separate readings will be recorded in the asthma control diary. 
6.3.9.1.5. Asthma control days 
An asthma control day (y/n) is defined as a day on which the patient used ≤2 puffs of inhaled 
SABA therapy, had no nighttime awakenings, and experienced no CAEs or moderate 
exacerbations. 
6.3.9.2. 
Analysis 
Compliance with the daily diary assessments will be derived for each patient as an additional 
measure of protocol adherence. A diary compliant day will be defined as a day with non-missing 
values for all diary assessments, including AM/PM asthma symptom score, 
, 


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. Diary compliance will be derived as a percentage over 
the treatment period: 
• Diary compliance (%) = 100 x (total number of diary compliant days / total number 
of days during the treatment period) 
The treatment period for diary compliance extends from the first day of study drug to the last day 
of study drug. Note that, in this analysis, missing data will be treated as non-compliant (eg, if 
compliance cannot be assessed for a given day due to missing data, then the day will not be 
counted as a diary compliant day). 
 
 
A weekly average of the daily diary measures (
, total asthma symptom score, and 
) will be derived (see Table 3 for the definition of analysis days for diary data). 
The average will be calculated as the sum of all values divided by the number of non-missing 
assessments. There will be no imputation of missing data. At least 4 of the 7 measurements need 
to be recorded for a week to be included in the analysis; otherwise the week will be treated as 
missing. 
 and asthma control days will be derived and analyzed as percentages over 
the relevant analysis period, derived as: 
• Asthma control days (%) = 100 x (total number of asthma control days / total number 
of days during the analysis period) 
• 
 
 
The analysis periods are as defined in Section 6.3. Note that, in this analysis, missing data will be 
treated as non-responders (eg, if asthma control cannot be assessed for a given day due to 
missing data, then the day will not be counted as an asthma control day). 
Summary statistics of actual values and change from baseline to each week will be provided by 
treatment group. 
Analysis of the change from baseline to each week will use a similar MMRM model as described 
in Section 6.3.3.2 with the exception of inclusion of sex and height in the model. 
Analysis of the percentage of 
 and percentage of asthma control days will 
be performed using an analysis of variance (ANOVA) model with fixed effects for treatment, 
age group, and blood eosinophil counts at enrollment. 
A line graph presenting the LS mean change from baseline over time (at each week) will be 
provided for 
 total asthma symptom score, and 
 by 
treatment group. 


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45 
 
7. 
SAFETY ANALYSIS 
7.1. 
General 
The safety analysis set will be used for all safety analyses, unless otherwise noted. Summaries 
will be presented by treatment group actually received. 
In this study, patients are encouraged to remain in the study and complete the remaining study 
assessments even after withdrawing from treatment. The assessment of safety in this context will 
be based on measurements and events recorded during the treatment period (on-treatment). On-
treatment assessments will be defined as events and measurements occurring between the first 
dose of study drug and the end of treatment (week 52) visit for patients who complete treatment 
and between the first dose of study drug and the last dose of study drug + 4 weeks for patients 
who discontinued treatment early. 
7.2. 
Study Drug Administration 
The exposure to study drug will be characterized by duration of treatment and by the number of 
patients receiving at least 1, 2, 3, etc. injections. Total patient years will also be summarized. The 
summaries will be provided by treatment group and overall, and by baseline stratification factors. 
Duration of treatment period is defined separately for patients who completed/discontinued 
treatment. 
• Completed : 
End of treatment (week 52) visit date – first dose date + 1  
• Discontinued: 
Last dose date – first dose date + 29 
7.3. 
Adverse Events 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA); the final version number will be indicated in the summary tables.  
On-treatment advese event summaries will be presented by treatment group and overall, based on 
events with onset during the treatment period. If the AE start date is missing or partial, the event 
will be considered on-treatment unless there is evidence to the contrary (eg, month and year of 
AE start is present and is less than the month and year of the first dose of study drug). Post-
treatment adverse events with onset during the follow-up period (ie, AE start date greater than 
the upper bound of the treatment period, as described previously) will be summarized separately. 
Summaries will be presented by SOC and/or PT for all adverse events (overall and by severity), 
adverse events determined by the investigator to be related to study treatment (overall and by 
severity), serious adverse events, adverse events causing discontinuation from study treatment, 
and non-serious adverse events. Treatment related adverse event summaries will include events 
with missing relationship to study drug. For summaries by severity, patients will be counted at 
the greatest reported severity. Adverse events missing the flag indicating a serious adverse event 
will be excluded from the summary of serious adverse events, but included in the summary of 
non-serious adverse events. 


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In addition, adverse events that begin within 24 hours after study drug injection and injection-site 
adverse events (as recorded on the CRF) will each be summarized separately. 
Summaries for the most common adverse events (incidence ≥2% in reslizumab-treated patients) 
and adverse events occurring with greater frequency for reslizumab-treated patients compared to 
placebo will also be presented. 
All adverse events, including pre-treatment events, will be included in the patient listings. The 
mapping of MedDRA dictionary terms for adverse event descriptions will also be provided. 
7.3.1. 
Adverse Events of Special Interest 
7.3.1.1. 
Administration Site Reactions 
Administration site reactions will be defined based on: 
• MedDRA HLGT: Administration Site Reactions 
Summaries will be presented by high level term (HLT), preferred term, and treatment group. 
Patients will further be assessed on a 4-point Likert scale (none, mild, moderate, severe) for 
several domains of localized injection site tolerability including pain, tenderness, erythema, 
warmth, and swelling. The number and percentage of patients reported for each of the levels will 
be summarized descriptively for each domain by visit. 
7.3.1.2. 
Anaphylaxis and Hypersensitivity 
Anaphylaxis and hypersensitivity events will be defined based on:  
• MedDRA SMQ: Anaphylactic Reaction 
• MedDRA SMQ: Hypersensitivity 
Summaries will be presented separately for both the broad (broad+narrow) and narrow preferred 
terms by treatment group. 
Adverse events suspected by the investigator to be anaphylaxis events will be summarized by 
preferred term and treatment group. Supplemental information related to the relative timing, 
clinical manifestation, and treatment of these suspected events will be collected in a dedicated 
CRF and reported in the patient listings. 
7.3.1.3. 
Malignancies  
Malignancies will be defined based on: 
• MedDRA SMQ: Malignant Tumors 
Summaries will be presented by preferred term and treatment group. 
7.3.1.4. 
Helminth infections 
Helminth infections will be defined based on:  
• MedDRA HLGT: Ectoparasitic Disorders 
• MedDRA HLT: Parasite Identification and Serology 


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• MedDRA HLT: Parasitic Lower Respiratory Tract Infections 
• MedDRA HLT: Skin and Subcutaneous Arthropod and Parasitic Infestations 
Summaries will be presented by high level term (HLT), preferred term, and treatment group. 
7.3.1.5. 
Muscle Disorders 
Muscle disorders will be defined based on: 
• MedDRA HLGT: Muscle Disorder 
• MedDRA PT: Blood Creatine Phosphokinase Increased 
Summaries will be presented by high level term (HLT), preferred term and treatment group. 
7.3.1.6. 
Opportunistic Infections 
Opportunistic infections will be defined based on the following list of terms, derived from the 
preferred term (PT) or low level term (LLT) summarized in Table 5. The FDA terms provided 
are from the Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. 
Summaries will be presented by preferred term and treatment group. 
Table 5: 
List of Terms for Opportunistic Infections 
Term 
Code 
Level 
FDA term (if applicable) 
If LLT- under which 
PT  
Acinetobacter infection 
10051894 
PT 
Acinetobacter infection 
  
Aspergillus infection 
10074171 
PT 
Aspergillosis 
  
Blastomycosis 
10005098 
PT 
Blastomycosis, extrapulmonary 
  
Burkitt's lymphoma 
10006595 
PT 
Burkitt's lymphoma 
  
Oesophageal candidiasis 
10030154 
PT 
Candidiasis of esophagus 
  
Cerebral toxoplasmosis 
10057854 
PT 
Toxoplasmosis of brain 
  
Cervix carcinoma 
10008342 
PT 
Cervical cancer invasive 
  
Coccidioidomycosis 
10009825 
PT 
Coccidioidomycosis, 
dissemintaed or extrapulmonary 
  
Cryptococcosis 
10011490 
PT 
Cryptococcosis, extrapulmonary 
  
Cryptosporidiosis infection 
10011502 
PT 
Cryptosporidiosis infection, 
chronic intestinal (> 1 month 
duration) 
  
Cytomegalovirus chorioretinitis 
10048843 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus colitis 
10048983 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  


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Table 5: 
List of Terms for Opportunistic Infections (Continued) 
Cytomegalovirus duodenitis 
10049014 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus enteritis 
10049074 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus enterocolitis 
10049015 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus gastritis 
10049016 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus gastroenteritis 
10051349 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus gastrointestinal 
infection 
10052817 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus infection 
10011831 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus mononucleosis 
10011834 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus mucocutaneous 
ulcer 
10065036 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus 
myelomeningoradiculitis 
10065621 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus myocarditis 
10056261 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus oesophagitis 
10049018 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus pancreatitis 
10049566 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus pericarditis 
10056721 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus syndrome 
10056262 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus urinary tract 
infection 
10051350 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Cytomegalovirus viraemia 
10058854 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Disseminated cytomegaloviral 
infection 
10049075 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  


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Table 5: 
List of Terms for Opportunistic Infections (Continued) 
Encephalitis cytomegalovirus 
10014586 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Pneumonia cytomegaloviral 
10035676 
PT 
Cytomegalovirus disease (other 
than liver, spleen, or nodes) 
  
Hepatitis B 
10019731 
PT 
Hepatitis B 
  
Hepatitis C 
10019744 
PT 
Hepatitis C 
  
Herpes simplex skin chronic 
ulcers 
10058426 
LLT 
Herpes simplex ulcers chronic 
(>1mo) 
Under "Herpes dermatitis" PT 
Herpes simplex 
10019948 
PT 
Herpes simplex bronchitis 
  
Herpes simplex pneumonia 
10065046 
PT 
Herpes simplex pneumonitis 
  
Herpes simplex oesophagitis 
10074242 
PT 
Herpes simplex oesophagitis 
  
Shingles 
10040555 
LLT 
Shingles when 2 distinct episodes 
or more than 1 dermatome 
Under "Herpes zoster" PT 
Histoplasmosis 
10020141 
PT 
Histoplasmosis extrapulmonary 
  
Histoplasmosis disseminated 
10020144 
PT 
Histoplasmosis disseminated  
  
HIV wasting syndrome 
10050309 
PT 
Wasting secondary to HIV 
  
Human polyomavirus infection 
10057366 
PT 
Human polyomavirus infection 
  
Immunoblastic lymphoma 
10053574 
PT 
Lymphoma immunoblastic 
  
Isosporiasis 
10023076 
PT 
Isosporiasis, chronic intestinal (> 
1 month’s duration) 
  
Kaposi's sarcoma 
10023284 
PT 
Kapposi’s sarcoma 
  
Lymphoid interstitial pneumonia 
10062997 
LLT 
Lymphoid interstitial pneunmonia 
Under "Interstitial lung 
disease" PT 
Listeriosis 
10024641 
PT 
Listeriosis 
  
Mycobacterial infection 
10062207 
PT 
Mycobacterium infections, other 
species or unidentified species, 
disseminated or extrapulmonary 
(eg, M. haemophilium, M. 
fortuitum, or M. marinum) 
  
Mycobacterium avium complex 
infection 
10058806 
PT 
Mycobacterium avium complex 
disseminated or extrapulmonary 
  
Mycobacterium kansasii 
infection 
10028447 
PT 
M. Kansasii, disseminated or 
extrapulmonary 
  
Nocardiosis 
10029444 
PT 
Nocardiosis 
  


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Table 5: 
List of Terms for Opportunistic Infections (Continued) 
Pneumocystis jirovecii infection 
10073756 
PT 
Pneumocystis jirovecii infection 
  
Pneumonia recurrent 
10066727 
LLT 
Pneumonia recurrent 
Under "Pneumonia" PT 
Polyomavirus-associated 
nephropathy 
10065381 
PT 
Polyomavirus (JC virus or BK 
virus)-associated nephropathy 
(including progressive multifocal 
leukoencephalopathy) 
  
Primary central nervous system 
lymphoma 
10036685 
LLT 
Lymphoma primary of brain 
 
Candidiasis of bronchi 
10064443 
LLT 
Candidiasis of bronchi 
Under "Respiratory 
moniliasis" PT 
Candidiasis of trachea 
10064459 
LLT 
Candidiasis of trachea 
Under "Respiratory 
moniliasis" PT 
Candidiasis of lung 
10007155 
LLT 
Candidiasis of lungs 
Under "Respiratory 
moniliasis" PT 
Salmonella sepsis 
10058878 
PT 
Salmonella sepsis 
  
Salmonella septicemia 
10039445 
LLT  
Salmonella septicemia, recurrent 
Under "Salmonella sepsis" PT 
Salmonella sepsis recurrent 
10066745 
LLT 
Salmonella sepsis if recurrent 
Under "Salmonella sepsis" PT 
Active tuberculosis 
10071157 
LLT 
Any active TB 
Under "Tuberculosis" PT 
Mycobacterium tuberculosis 
NOS 
10028461 
LLT 
Mycobacterium tuberculosis, any 
site, latent or active 
Under "Tuberculosis" PT 
7.3.2. 
Adverse Events by Subgroup 
Overall adverse event categories will be presented for selected subgroups defined in Section 3.4. 
The categories of adverse events will include: 
• Patients with at least one AE 
• Patients with at least one treatment-related AE 
• Patients with at least one SAE 
• Patients with at least one SAE resulting in death 
• Patients with at least one AE leading to discontinuation 
Selected summaries will also be presented for adverse events by system organ class (SOC), 
preferred term and subgroup. 
7.4. 
Deaths 
If any patient dies during the study all relevant information will be discussed in the patient’s 
narratives included in CSR. A patient listing of deaths will be provided. 


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7.5. 
Clinical Laboratory Tests 
Analysis of laboratory tests will be based on on-treatment results, as described in Section 7.1. 
Measurements collected outside of the defined treatment periods will be excluded. All results 
will be included in the patient listings. 
Summary statistics for laboratory tests will be presented at baseline and at each scheduled visit. 
Actual values and changes from baseline to each visit will be summarized. Shifts (below, within, 
and above the normal range) from baseline to each visit will be summarized using patient counts 
and percentages. Shifts from baseline (Grade 0-4) will be provided for creatine phosphokinase 
(CPK) at each visit, based on the following grading scale: 
• Grade 0: <1.25 x ULN 
• Grade 1: 1.25 to 1.5 x ULN 
• Grade 2: 1.6 to 3 x ULN 
• Grade 3: 3.1 to 10 x ULN 
• Grade 4: >10 x ULN 
For CPK values ≥3.1xULN (Grade 3-4), investigators will be prompted to collect additional 
information from the patient related to symptoms associated with the elevation and any potential 
alternate causes. This supplemental data will be reported in the patient listings. 
The incidence of potentially clinically significant laboratory values will be summarized using the 
criteria specified in Table 6; criteria have been provided for adults and adolescents separately. 
Summaries of potentially clinically significant laboratory values will include all relevant post-
baseline values (including scheduled, unscheduled, and early termination visits). A post-baseline 
laboratory value will be considered potentially clinically significant only if it satisfies the 
specified criteria and is more extreme (farther from the limit) than the baseline value. Listings for 
potentially clinically significant laboratory data will be presented. If any patient has a positive 
pregnancy test, relevant information will be supplied in data listings. 
A scatter plot will be provided for the baseline and maximum on treatment value for CPK.


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Table 6: 
Criteria for Potentially Clinically Significant Laboratory Values 
 
Adults (≥18 years) 
Adolescents (12 to <18 Years) 
Test 
Criterion value 
Change from 
baseline 
Criterion value 
Change from 
baseline 
Serum chemistry 
 
 
 
 
  Alanine aminotransferase 
≥3xULN 
Increase >0 
≥3xULN 
Increase >0 
  Aspartate aminotransferase 
≥3xULN 
Increase >0 
≥3xULN 
Increase >0 
  Alkaline phosphatase 
≥3xULN 
Increase >0 
≥3xULN 
Increase >0 
  Gamma-glutamyl 
transpeptidase 
≥3xULN 
Increase >0 
≥3xULN 
Increase >0 
  Lactate dehydrogenase 
≥3xULN 
Increase >0 
≥3xULN 
Increase >0 
  Blood urea nitrogen 
≥10.71 mmol/L 
Increase >0 
≥10.71 mmol/L 
Increase >0 
  Creatinine 
≥177 µmol/L 
Increase >0 
≥177 µmol/L 
Increase >0 
  Uric acid: 
Men 
≥625 µmol/L 
Increase >0 
≥625 µmol/L 
Increase >0 
 
Women 
≥506 µmol/L 
Increase >0 
≥506 µmol/L 
Increase >0 
  Bilirubin (total) 
≥34.2 µmol/L 
Increase >0 
≥34.2 µmol/L 
Increase >0 
  Creatine phosphokinase 
Grade 3: 3.1 to 10 x 
ULN 
Grade 4: >10 x ULN 
Increase >0 
Grade 3: 3.1 to 10 x 
ULN 
Grade 4: >10 x ULN 
Increase >0 


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Table 6: 
Criteria for Potentially Clinically Significant Laboratory Values (Continued) 
 
Adults (≥18 years) 
Adolescents (12 to <18 Years) 
Test 
Criterion value 
Change from 
baseline 
Criterion 
value 
Change from 
baseline 
Hematology 
 
 
 
 
  Hematocrit: 
Men 
<0.37 L/L 
Decrease >0 
<0.30 L/L 
Decrease >0 
 
Women 
<0.32 L/L 
Decrease >0 
<0.30 L/L 
Decrease >0 
  Hemoglobin: 
Men 
≤115 g/L 
Decrease >0 
≤100 g/L 
Decrease >0 
 
Women 
≤95 g/L 
Decrease >0 
≤100 g/L 
Decrease >0 
  White blood cell counts 
≤3 x 109/L 
Decrease >0 
≤3 x 109/L 
Decrease >0 
 
≥20 x 109/L 
Increase >0 
≥20 x 109/L 
Increase >0 
  Eosinophils 
≥1.5 x 109/L 
Increase >0 
≥1.5 x 109/L 
Increase >0 
  Absolute neutrophil counts 
≤1 x 109/L 
Decrease >0 
≤1 x 109/L 
Decrease >0 
  Platelet counts 
≤75 x 109/L 
Decrease >0 
≤75 x 109/L 
Decrease >0 
 
≥700 x 109/L 
Increase >0 
≥700 x 109/L 
Increase >0 
Urinalysis 
 
 
 
 
  Blood (HGB) 
≥2 unit increase  
from baseline 
 
≥2 unit increase  
from baseline 
 
  Glucose 
≥2 unit increase  
from baseline 
 
≥2 unit increase  
from baseline 
 
  Ketones 
≥2 unit increase  
from baseline 
 
≥2 unit increase  
from baseline 
 
  Total protein 
≥2 unit increase  
from baseline 
 
≥2 unit increase  
from baseline 
 
ULN=upper limit of normal range. 
If both the baseline and post-baseline values are beyond the same PCS limit, then the post-baseline value will be 
considered PCS only if it is more extreme (farther from the limit) than the baseline value. If the baseline value is 
beyond the low PCS limit and the post-baseline value is beyond the high PCS limit (or vice-versa), then the post-
baseline value will be considered PCS. 


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7.6. 
Vital Signs 
Analysis of vital signs will be based on on-treatment results, as described in Section 7.1. 
Measurements collected outside of the defined treatment periods will be excluded. All results 
will be included in the patient listings. 
Summary statistics for vital signs will be presented at baseline and at each visit. Actual values 
and changes from baseline to each visit will be summarized. The incidence of potentially 
clinically significant vital signs will be summarized. Summaries of potentially clinically 
significant values will include all relevant post-baseline values (including scheduled, 
unscheduled, and early termination visits). A scatter plot will be provided for the baseline and 
the maximum on treatment value for weight. 
Table 7 specifies the criteria for identifying vital signs as potentially clinically significant for 
adults and adolescents. In order to be identified as potentially clinically significant vital sign, the 
result would need to meet both identified conditions (ie, satisfies the specified criteria and results 
in a change from baseline of at least the magnitude specified). A listing for potentially clinically 
significant vital signs will be presented. 
Table 7: 
Criteria for Potentially Clinically Significant Vital Signs 
 
Adults (≥18 years) 
Adolescents (12 to <18 Years) 
Vital Sign 
Criterion value 
Change from 
baseline 
Criterion value 
Change from baseline 
Heart rate 
>100 bpm 
Increase of ≥30 
>100 bpm 
Increase of ≥30 
 
<50 bpm 
Decrease of ≥30 
<60 bpm 
Decrease of ≥30 
Systolic BP 
>160 mmHg 
Increase of ≥30 
>130 mmHg 
Increase of ≥30 
 
<90 mmHg 
Decrease of ≥30 
<90 mmHg 
Decrease of ≥30 
Diastolic BP 
>100 mmHg 
Increase of ≥12 
>85 mmHg 
Increase of ≥12 
 
<50 mmHg 
Decrease of ≥12 
<55 mmHg 
Decrease of ≥12 
Respiratory rate 
>24 breaths/min 
Increase of ≥10 
>20 breaths/min 
Increase of ≥10 
 
<6 breaths/min 
Not applicable 
<10 breaths/min 
Not applicable 
Temperature 
>100.5°F 
Increase of ≥2 
>100.5°F 
Increase of ≥2 
 
<96.5°F 
Not applicable 
<96.5°F 
Not applicable 
7.7. 
Electrocardiography  
Analysis of ECG findings will be based on on-treatment results, as described in Section 7.1. 
Measurements collected outside of the defined treatment periods will be excluded. All results 
will be included in the patient listings. 
Shifts (normal and abnormal) from baseline to week 52 and to overall will be summarized using 
patient counts. For overall, the worst post-baseline finding (eg, the abnormal finding if there are 
both normal and abnormal findings) for the patient will be summarized. Summary statistics for 
ECG variables will be presented at week 52. Actual values and changes from baseline to each 


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visit will be summarized. ECG results at weeks 24 and 36 will be presented in the patient 
listings. 
The following categorical analyses represent the criteria for potentially clinically significant QTc 
results. Both QTc Bazett and Fridericia interval will be presented using descriptive statistics. 
• Absolute value at week 52 
− QTc interval >450 msec 
− QTc interval >500 msec 
• Change from baseline to week 52 
− QTc interval increase >30 msec 
− QTc interval increase >60 msec 
• Combined absolute value and change from baseline to week 52 
− QTc interval >450 msec and QTc interval increase >30 msec 
− QTc interval >450 msec and QTc interval increase >60 msec 
− QTc interval >500 msec and QTc interval increase >30 msec 
− QTc interval >500 msec and QTc interval increase >60 msec 
7.8. 
Physical Examinations 
Analysis of physical exam findings will be based on on-treatment results, as described in 
Section 7.1. Measurements collected outside of the defined treatment periods will be excluded. 
All results will be included in the patient listings. 
Shifts (normal and abnormal) from baseline to each visit will be summarized using patient counts 
and percentages for each category. Descriptive statistics for weight will be provided. 
7.9. 
Other Safety Measures and Variables 
7.9.1. 
Concomitant Therapy or Medication 
All concomitant medications will be coded using the WHO Drug. The incidence of concomitant 
medications will be summarized by therapeutic class and preferred term. Patients are only 
counted once in each therapeutic class and once in each preferred term.  
Concomitant medications include all medications taken during the treatment period. Medications 
with a start date greater than the upper bound of the treatment period will be considered post-
treatment. Medications will be categorized in every period (prior, concomitant, post-treatment) in 
which it was taken. If the medication start/stop date is missing or partial, the medication will be 
considered concomitant unless there is evidence to the contrary (eg, month and year of stop date 
is present and is less than the month and year of the first dose of study drug). 


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8. 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS 
The safety analysis set will be used for the following analyses, unless otherwise noted. 
8.1. 
Pharmacokinetic Analysis 
The PK endpoints are the serum reslizumab concentrations at baseline/DoR; weeks 1 (patients in 
US study centers only), 2, and prior to study drug administration at weeks 4, 8, 12, 16, 20, 32, 
48, 52 or early withdrawal; and the follow up visit (approximately week 64). An additional PK 
sample will be collected 28 weeks (±2 weeks) after the last dose of study drug (approximately 
week 76) for validation of the ADA assessment. 
Reslizumab concentration data will be summarized descriptively for reslizumab-treated patients 
by time point. Reslizumab concentration data will additionally be summarized by ADA status. 
Samples from placebo-treated patients will not be analyzed. Listings for reslizumab 
concentration data will be presented. 
The data will be pooled with data from other studies and analyzed using population PK and 
PK/PD analysis and reported in a separate report. 
8.2. 
Pharmacodynamic Analysis 
8.2.1. 
Target Biomarker (Blood Eosinophil Counts) 
The target biomarker endpoints are the blood eosinophil counts at baseline/DoR; weeks 2, 4, 8, 
12, 16, 32, 52 or early withdrawal; and the follow-up visit (approximately week 64). 
Summary statistics of actual values, change from baseline, and percent change from baseline to 
each scheduled visit will be provided by treatment group, using the ITT analysis set. A line graph 
will be provided summarizing the mean blood eosinophil counts at each visit. 
Blood eosinophils will additionally be examined for selected subgroups defined in Section 3.4. 
As described above, the analysis of eosinophils by subgroups will be summarized descriptively. 
8.3. 
Immunogenicity 
Samples for immunogenicity assessment for development of anti-drug antibodies will be 
obtained before the administration of study drug at DoR; prior to study drug administration at 
weeks 4, 16, 32, 52 or early withdrawal; and the follow-up visit (approximately week 64). 
Additional samples will be collected at the late follow-up visit (approximately week 76). These 
data may be presented in a CSR addendum. 


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Two types of antibody assay will be performed, an immunogenicity status assay (ADA) and 
neutralizing assay (NAb). For the ADA assay, a screening assessment will be performed which 
produces a positive or negative result. For samples with a positive result, a neutralizing assay 
will be performed, which also produces a positive or negative result; a titre value will be 
obtained to quantify the degree of binding. 
A patient will be classified as having a treatment-emergent ADA response if a sample tested 
positive at any of the post-baseline time points but not at the baseline time point, or if the post-
baseline ADA titer increased ≥4-fold from a positive baseline ADA sample (Shankar et al 2014). 
Anti-reslizumab antibody data, including neutralizing antibody and titer results for patients who 
have tested ADA positive, will be listed. The number of patients with positive/negative results 
will be summarized at each scheduled visit. Samples from placebo-treated patients will not be 
analyzed. 


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9. 
STATISTICAL SOFTWARE 
All data listings, summaries, and statistical analyses will be generated using SAS®. 


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59 
 
10. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES 
There are no changes to the analyses specified in the CSP, Amendment 04 to report.  
• Table 8 summarizes the key changes that have been implemented since the original 
approved SAP.  
• Table 9 summarizes the key changes that have been implemented since the approved 
SAP, Amendment 01.  
Only substantive changes have been included; editorial and/or administrative changes are 
generally not listed.


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
60 
 
Table 8: 
Key Changes to the Statistical Analysis Plan, Amendment 01 
SAP 
Section 
SAP Description 
Change 
Rationale 
3.2 
<<null>> 
Patients dosed in error, but who otherwise 
received at least 1 dose of reslizumab, will be 
assigned to reslizumab for the analysis of safety 
data. 
Clarified how safety analyses would be handled if a 
patient receives a combination of both treatments. 
3.3.1 (Table 
2) 
<<null>> 
• 
Patient was not on an ICS at baseline (at 
least a medium total daily dose) 
• 
Patients who received the incorrect study 
treatment at any point during the study 
Two additional protocol violations. 
3.4.1 
The primary efficacy endpoint will be 
analyzed separately for patients aged 12 
to <18 years and ≥18 years. 
Selected efficacy endpoints including CAEs 
(primary), pre-bronchodilator FEV1, and blood 
eosinophils will be analyzed separately for 
patients aged 12 to <18 years and ≥18 years. 
Subgroup analyses planned for FEV1 and 
eosinophils, in addition to CAE. 
Note: The same changes are applied to other 
subsequent subgroup sections (ie, 3.4.2, 3.4.5) 
3.4.3 
3.4.4 
<<null>> 
Asthma Background Medication 
Created new section for subgroups based on the 
identified classes of background asthma medication. 
3.4.5 
• 
Age group (<65, ≥65 years) 
• 
Race (White, Black, Asian, Other) 
 
• 
Region (US, non-US) 
 
• 
<<null>> 
• 
<<deleted>> 
• 
Race (White, Black, Asian, Other; Black, 
non-Black) 
• 
Region (North America, Europe, Latin 
America, Asia/Pacific; US, non-US) 
• 
ADA status (Positive, Negative) – for 
reslizumab-treated patients only 
Modifications to the race and region subgroups; 
removed additional subgroup category for age; 
included subgroup for ADA status. 
4.2.4 
The baseline value for blood eosinophil 
levels will be screening value (for 
The baseline value for blood eosinophil levels 
will be the maximum value of the observed 
Modified definition of baseline to potentially 
account for patients who fulfilled the eosinophil 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
61 
 
SAP 
Section 
SAP Description 
Change 
Rationale 
consistency with study entry criteria). 
assessments from the screening visit to 
baseline/DoR (inclusive). 
threshold prior to randomization, but not at the 
screening visit. 
5.3 
The baseline stratification factors (age 
and baseline blood eosinophil counts) 
will also be summarized. 
 
 
<<null>> 
The baseline stratification factors (age and 
baseline blood eosinophil counts) and patients 
taking the various classes of background 
medication at baseline (defined in Section 3.4.4) 
will also be summarized. 
Age will be calculated based on the date of birth 
relative to the screening visit (date of informed 
consent). If regional data regulations prohibit 
collection of a full date of birth, then the 
patient’s age should be recorded on the CRF, if 
possible. If only a year of birth has been 
collected (and age has not otherwise been 
reported) then the missing date of birth will be 
imputed as 30 June (30 June YYYY) in order to 
derive the patient’s age at baseline.  
Additional summaries based on the asthma 
medication classes. 
 
 
 
Clarification, since derivation of age may not 
always be possible due to partial birth dates. 
5.5 
<<null>> 
In addition, the total daily ICS dose taken at 
baseline will be summarized descriptively. The 
reported ICS doses will first be converted to 
fluticasone equivalents using the following 
conversion factors. 
Additional summary based on ICS dose at baseline; 
included Table 4 for ICS conversion factors. 
6.2.2 
Any clinical asthma exacerbations that 
occur between the completion  of the first 
dose of study drug and 2 weeks after the 
end of treatment/early withdrawal visit 
will be counted towards the CAEs for 
analysis. 
Any clinical asthma exacerbations that occur 
between the day of randomization and 2 weeks 
after the end of treatment/early withdrawal visit 
will be counted towards the CAEs for analysis. 
Clarified that the lower bound of treatment period 
will be the day of randomization (rather than first 
dose date), in the case that the day of randomization 
and first dose date do not coincide. 
Note: The same changes are applied to other 
sections (ie, 4.5, 6.2.3, 6.2.6, 6.3) 
6.2.3 
The primary analysis based on the per 
protocol analysis set. 
Per protocol analysis: on-treatment analysis of 
the primary endpoint based on the per protocol 
analysis set. 
Clarified that the per protocol analysis is based on 
on-treatment events. 
6.2.6 
Time-to-first event will be analysed 
separately for all exacerbation events and 
on-treatment events.  
Time-to-first event will be analysed for on-
treatment events.  
 
Time-to-first event only planned to be summarized 
for on-treatment events. 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
62 
 
SAP 
Section 
SAP Description 
Change 
Rationale 
The time period for the primary time-to-
event analysis will extend from the first 
dose of study drug to the end of 
treatment/early withdrawal visit (+2 
weeks). Patients without an event during 
this time frame will be censored at the 
date of the end of treatment/early 
withdrawal visit (+2 weeks). 
For the on-treatment analysis, only 
events occurring during the treatment 
period will be counted. Patients without 
an event during this time frame will be 
censored at either the date of the end of 
treatment (week 52) visit for patients 
who completed treatment and at the date 
of last dose (+4 weeks) for patients who 
discontinued early. 
<<deleted>> 
 
 
 
 
 
 
 
 
The time period for the on-treatment analysis 
will extend from the day of randomization to the 
cessation of study treatment, defined as the date 
of the end of treatment (week 52) visit for 
patients who completed treatment and the date 
of last dose (+4 weeks) for patients who 
discontinued treatment early. Patients without an 
event during the treatment period will be 
censored at either the date of the end of 
treatment (week 52) visit for patients who 
completed treatment or at the date of last dose 
(+4 weeks) for patients who discontinued early. 
6.3.3.2 
Summary statistics of actual values and 
change from baseline to each scheduled 
visit and to endpoint will be provided by 
treatment group. 
 
Analysis of the overall change from 
baseline over 52 weeks, and to each 
scheduled visit will be performed using a 
mixed effect model for repeated 
measures (MMRM) including fixed 
effects for treatment, visit, treatment by 
visit interaction, age group (12 to <18 
years and ≥18 years), blood eosinophil 
counts at enrollment (300 to <400/µL 
and ≥400/µL), baseline value as a 
covariate, and patient as a random effect. 
Summary statistics of actual values and 
change from baseline to each scheduled visit 
will be provided by treatment group. 
 
 
Analysis of the change from baseline to 
each scheduled visit will be performed using 
a mixed effect model for repeated measures 
(MMRM) including fixed effects for 
treatment, visit, treatment by visit 
interaction, age group (12 to <18 years and 
≥18 years), blood eosinophil counts at 
enrollment (300 to <400/µL and ≥400/µL), 
and sex, height and baseline value as 
Summaries at endpoint have been removed. 
 
 
 
 
Sex and height have been included as additional 
factors in the model for pulmonary function tests. 
Analysis of the overall change over 52 weeks has 
been removed. 
 
 
 
 
 
 
 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
63 
 
SAP 
Section 
SAP Description 
Change 
Rationale 
 
Analysis of change from baseline to 
endpoint will be performed using an 
analysis of covariance (ANCOVA) 
model … Based on the ANCOVA model 
… with the corresponding p-value. 
 
<<null>> 
covariates, and patient as a random effect. 
 
 
 
<<deleted>> 
 
 
 
 
 
Model results will only be reported if there 
are at least 15 patients contributing to the 
analysis in each treatment group; otherwise 
only descriptive statistics will be displayed. 
 
 
ANCOVA analysis at endpoint has been removed. 
 
 
 
 
Pre-specified the approach to analysis in the case of 
small sample sizes (eg, in subgroups). Analyses 
based on less than 15 patients may result in 
convergence issues or general issues with 
interpretability. 
 
Note: The same changes are applied to other 
subsequent efficacy sections (ie, 6.3.4.2, 6.3.5.2, 
6.3.6.2, 6.3.7.2, 6.3.8.2, 6.3.9.2). 
6.3.4.2 
A stratified (based on randomization 
strata) Cochran-Mantel-Haenszel (CMH) 
test will be used to analyze the 
proportion of patients achieving an 
increase of ≥0.5 in the AQLQ +12 score 
from baseline to each scheduled visit and 
endpoint. 
The proportion of patients achieving an increase 
of ≥0.5 in the AQLQ +12 score from baseline to 
each scheduled visit will be summarized. A 
stratified (based on randomization strata) 
Cochran-Mantel-Haenszel (CMH) test will be 
used to analyze the proportion of patients 
achieving an increase of ≥0.5 in the AQLQ +12 
score from baseline to Week 52. 
Clarified that the planned analysis (CMH) will be 
done at Week 52; the rest of the visits will be 
summarized descriptively. 
 
Note: The same changes are applied to other 
subsequent efficacy sections (ie, 6.3.5.2, 6.3.6.2, 
6.3.8.2). 
6.3.8.1 
6.3.8.2 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
64 
 
Table 8: 
Key Changes to the Statistical Analysis Plan, Amendment 01 (Continued) 
SAP 
Section 
SAP Description 
Change 
Rationale 
7.3 
<<null>> 
In addition, adverse events that begin within 
24 hours after study drug injection and 
injection-site adverse events (as recorded on 
the CRF) will each be summarized 
separately. 
 
Summaries for the most common adverse 
events (incidence ≥2% in reslizumab-treated 
patients) and adverse events occurring with 
greater frequency for reslizumab-treated 
patients compared to placebo will also be 
presented. 
Additional AE tables. 
7.3.1 
<<null>> 
Adverse events of special interest updated to 
include: 
• 
Administration Site Reactions 
• 
Anaphylaxis and 
Hypersensitivity 
• 
Malignancies 
• 
Helminth Infections 
• 
Muscle Disorders/CPK 
Categories of adverse events have been added, 
along with the derivations of each. 
7.3.2 
<<null>> 
Adverse events by subgroup 
Created separate section for subgroup analysis and 
clarified the analyses.  
7.5 
Summary statistics for laboratory tests 
will be presented at baseline, at each 
scheduled visit and endpoint. Actual 
values and changes from baseline to each 
visit and endpoint will be summarized. 
Summary statistics for laboratory tests will be 
presented at baseline and at each scheduled visit. 
Actual values and changes from baseline to each 
visit will be summarized. Shifts (below, within, 
and above the normal range) from baseline to 
Summaries at endpoint have been removed. 
Note: The same changes are applied to other 
subsequent safety sections (ie, 7.6, 7.7, 7.8). 
 
 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
65 
 
SAP 
Section 
SAP Description 
Change 
Rationale 
Shifts (below, within, and above the 
normal range) from baseline to each visit 
and 
endpoint will be summarized using 
patient counts and percentages. 
Shift tables of abnormal values (change 
from baseline: high/normal to low, 
low/normal to high, and other) will be 
provided for creatine phosphokinase 
(CPK) at each visit and endpoint. Shifts 
from baseline (Grades 0 to 4) to each 
visit and endpoint will also be 
summarized for CPK. 
each visit will be summarized using patient 
counts and percentages. 
 
 
Shifts from baseline (Grade 0-4) will be 
provided for creatine phosphokinase (CPK) at 
each visit. 
 
 
 
 
Additional shift table has been removed. 
7.5 
<<null>> 
 
 
 
 
 
Scatter plots of the maximum on 
treatment values for total bilirubin vs. 
alanine aminotransferase and for total 
bilirubin vs. aspartate aminotransferase 
(each presented as multiples of the ULN) 
will be provided. 
 
Table 4 and Table 5 
 
Grade 0: ≤1 x ULN 
Grade 1: >1 x ULN to ≤2.5 x ULN 
Grade 2: >2.5 x ULN to ≤5 x ULN 
Grade 3: >5 x ULN to ≤10 x ULN 
Grade 4: >10 x ULN 
 
≥1.0 x 109/L 
A  post-baseline laboratory value will be 
considered potentially clinically significant only 
if it satisfies the specified criteria and is more 
extreme (farther from the limit) than the baseline 
value. 
 
<<deleted>> 
 
 
 
 
 
 
 
Combined into one table (Table 4). 
 
Grade 0: <1.25 x ULN 
Grade 1: 1.25 x ULN to 1.5 x ULN 
Grade 2: 1.6 x ULN to 3 x ULN 
Grade 3: 3.1 x ULN to 10 x ULN 
Grade 4: >10 x ULN 
 
≥1.5 x 109/L 
Modified the definition of potentially clinically 
significant values to account for presence of 
abnormal results at baseline. 
 
 
 
Formal plots are not planned. 
 
 
 
 
 
 
 
Combined for ease of review. 
 
Updated the CPK toxicity grade classifications. 
 
 
 
 
 
Updated the PCS value for eosinophils. 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
66 
 
Table 8: 
Key Changes to the Statistical Analysis Plan, Amendment 01 (Continued) 
SAP 
Section 
SAP Description 
Change 
Rationale 
7.6 
<<null>> 
 
 
 
 
Table 6 and Table 7 
Summaries of potentially clinically significant 
values will include all post-baseline values 
(including scheduled, unscheduled, and early 
termination visits). 
 
Combined into one table (Table 5). 
Clarification 
 
 
 
 
Combined for ease of review. 
8.2.1 
Summary statistics of actual values 
and change from baseline to each 
scheduled visit and to endpoint will 
be provided by treatment group. 
 
 
Analysis of the overall change from 
baseline over 52 weeks and the 
change from baseline to each 
scheduled visit will use the MMRM 
model described in Section 6.3.3.2 
with the exception of inclusion of sex 
and height in the model. Analysis of 
the change from baseline to endpoint 
will be performed using the 
ANCOVA model described in 
Section 6.3.3.2 with the exception of 
inclusion of sex and height in the 
model. 
Summary statistics of actual values, change from 
baseline, and percent change from baseline to 
each scheduled visit will be provided by 
treatment group, using the ITT analysis set. 
 
<<deleted>> 
Clarified that analysis of eosinophils will be based 
on the ITT analysis set. Included summary of 
percent change from baseline and removed 
summaries at endpoint. 
 
 
Eosinophils will be summarized descriptively. 
8.2.3 
The number of patients with positive or 
negative phadiatop results will be 
summarized at baseline and week 52. 
<<deleted>> 
Phadiatop allergy test is considered a baseline 
patient characteristic and will be summarized only 
at baseline. 
8.3 
<<null>> 
Two types of antibody assay will be 
performed, an immunogenicity status assay 
(ADA) and neutralizing assay (NAb). For 
the ADA assay, a screening assessment will 
Clarified the process for ADA samples. 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
67 
 
SAP 
Section 
SAP Description 
Change 
Rationale 
be performed which produces a positive or 
negative result. For samples with a positive 
result, a neutralizing assay will be 
performed, which also produces a positive 
or negative result and a titre value will be 
obtained to quantify the degree of binding. 
 
A patient will be classified as having a 
treatment-emergent ADA response if a 
sample tested positive at any of the post-
baseline time points but not at the baseline 
time point, or if the post-baseline ADA titer 
increased ≥4-fold from a positive baseline 
ADA sample (Shankar et al 2014). 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
68 
 
Table 9: 
Key Changes to the Statistical Analysis Plan, Amendment 02 
SAP 
Section 
SAP Description 
Change 
Rationale 
2.1 
A total of 400 patients are planned to be 
randomized in a 1:1 ratio (approximately 200 
patients within each treatment group) to 
receive reslizumab 110 mg or matching 
placebo every 4 weeks for 52 weeks. 
A total of 450 patients are planned to be 
randomized in a 1:1 ratio (approximately 225 
patients within each treatment group) to 
receive reslizumab 110 mg or matching 
placebo every 4 weeks for 52 weeks. 
Sample size aligned with amended protocol 
2.3 
Based on the assumptions above, 200 patients 
per group (400 total) will provide more than 
90% power (99.6%) to detect significant 
treatment effect of reslizumab over placebo in 
the reduction of exacerbation rate. The 
sample size was increased beyond the sample 
size required to provide 90% power in order 
to allow sufficient number of patients to 
assess safety and immunogenicity. The 
current sample size also provides higher 
power for other efficacy endpoints. 
Based on the assumptions above, 225 patients 
per group (450 total) will provide >90 % 
power to detect significant treatment effect of 
reslizumab over placebo in the reduction of 
exacerbation rate. The sample size was 
increased beyond the sample size required to 
provide 90% power in order to allow sufficient 
number of patients to assess safety and 
immunogenicity and to ensure adequate 
enrollment in the adolescent subset. The 
current sample size also provides higher power 
for other efficacy endpoints. 
Sample size aligned with amended protocol 
2.4 
Patients who meet all inclusion criteria and 
none of the exclusion criteria will be 
randomly assigned to receive reslizumab 110 
mg sc or matching placebo (approximately 
200 patients per treatment group) in a 1:1 
ratio. 
Patients who meet all inclusion criteria and 
none of the exclusion criteria will be randomly 
assigned to receive reslizumab 110 mg sc or 
matching placebo (approximately 225 patients 
per treatment group) in a 1:1 ratio. 
Sample size aligned with amended protocol 
3 
<<null>> 
Site 
 was terminated due to numerous 
unresolved Good Clinical Practice (GCP) 
issues including an overall lack of adequate 
source documentation (letter to FDA dated 2 
December 2016). The data from this site are 
deemed invalid and patients  from this site will 
be excluded from the efficacy analysis but will 
be included as part of the safety analysis. In 
addition, these patents will be summarized as 
randomized, but not analyzed, as part of the 
Termination of Site 
 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
69 
 
SAP 
Section 
SAP Description 
Change 
Rationale 
ITT analysis set in the disposition summary 
(Section 5.2). 
3.1 
<<null>> 
Two analytic approaches are planned using the 
ITT analysis set. 
• 
In the first approach, all data 
collected from patients will be 
included, regardless of continued 
adherence to their assigned study 
treatment. 
• 
In the second approach, data 
collected from patients during the 
treatment period will be included, 
up to the point at which patients 
discontinue from their assigned 
study treatment (on-treatment). 
For patients who completed 
treatment in this study, the 
treatment period will be defined 
from the first dose of study drug 
to the end of treatment (week 52) 
visit. For patients who 
prematurely discontinue 
treatment, the treatment period 
will be defined from the first 
dose of study drug to the last 
dose of study drug + 4 weeks. 
The analytic approach including all data 
collected from patients will be utilized as the 
primary approach to analysis for the primary 
endpoint (frequency of CAE). The on-
treatment approach will be conducted as a 
sensitivity analysis for the primary endpoint. 
For the analysis of all other efficacy endpoints, 
the on-treatment approach will be utilized as 
the main approach to analysis. The analytic 
approach including all data collected from 
Clarification 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
70 
 
SAP 
Section 
SAP Description 
Change 
Rationale 
patients will additionally be conducted as 
sensitivity analyses for selected secondary 
endpoints. 
3.2 
<<null>> 
In this analysis, data collected from patients 
during the treatment period will be included, 
up to the point at which patients discontinue 
from their assigned study treatment. For 
patients who completed treatment in this study, 
the treatment period will be defined from the 
first dose of study drug to the end of treatment 
(week 52) visit. For patients who prematurely 
discontinue treatment, the treatment period 
will be defined from the first dose of study 
drug to the last dose of study drug + 4 weeks. 
This analysis will be used as the default 
approach for all safety endpoints. 
Clarification 
3.3 
<<null>> 
The PP analysis set will only be presented for 
the primary endpoint. In this analysis, data 
collected from patients during the treatment 
period will be included, up to the point at 
which patients discontinue from their assigned 
study treatment. 
Clarification 
3.4.1 
Selected efficacy endpoints including CAEs 
(primary), pre-bronchodilator FEV1, and 
blood eosinophils will be analyzed separately 
for patients aged 12 to <18 years and ≥18 
years. 
Selected efficacy endpoints including CAEs 
(primary), pre-bronchodilator FEV1, 
AQLQ+12, ACQ-6, and blood eosinophils will 
be analyzed separately for patients aged 12 to 
<18 years and ≥18 years. Age strata will be 
defined based on the age recorded in the 
clinical database. 
Inclusion of 2 additional efficacy endpoints and 
clarification regarding definition of age strata 
3.4.2 
Selected efficacy endpoints including CAEs 
(primary), pre-bronchodilator FEV1, and 
blood eosinophils will be analyzed separately 
for patients with baseline blood eosinophil 
levels 300/μL to <400/μL and ≥400/μL. 
Selected efficacy endpoints including CAEs 
(primary), pre-bronchodilator FEV1, 
AQLQ+12, ACQ-6, and blood eosinophils will 
be analyzed separately for patients with 
baseline blood eosinophil levels 300/μL to 
<400/μL and ≥400/μL. Eosinophil strata will 
Inclusion of 2 additional efficacy endpoints and 
clarification regarding definition of eosinophil 
strata 


Statistical Analysis Plan with Amendment 02 
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71 
 
SAP 
Section 
SAP Description 
Change 
Rationale 
be defined based on the baseline blood 
eosinophil level recorded in the clinical 
database. 
3.4.5 
Selected efficacy endpoints including CAEs 
(primary), pre-bronchodilator FEV1, and 
blood eosinophils will also be examined for 
the following demographic subgroups: 
Selected efficacy endpoints including CAEs 
(primary), pre-bronchodilator FEV1, 
AQLQ+12, ACQ-6, and blood eosinophils will 
also be examined for the following 
demographic subgroups: 
Inclusion of 2 additional efficacy endpoints. In 
addition, Europe region split into Eastern and 
Western Europe and region for Middle 
East/Africa added. 
4.5,  
6.2.2, 
6.2.3, 6.2.6,  
6.3, 6.3.9.2 
For patients who completed treatment in this 
study, the treatment period will be defined 
from the day of randomization to the end of 
treatment (week 52) visit. For patients who 
prematurely discontinue treatment, the 
treatment period will be defined from the day 
of randomization to the last dose of study 
drug + 4 weeks. 
For patients who completed treatment in this 
study, the treatment period will be defined 
from the first dose of study drug to the end of 
treatment (week 52) visit. For patients who 
prematurely discontinue treatment, the 
treatment period will be defined from the first 
dose of study drug to the last dose of study 
drug + 4 weeks. 
Reference start date changed from day of 
randomization to day of first dose of study drug 
administration 
5.2 
<<null>> 
 
 
 
 
 
 
 
<<null>> 
Patients will be categorized as completed the 
study if they either complete the study visits up 
to and including follow-up (Week 64, for 
patients not participating in the LTE study) or 
up to and including end of treatment (Week 52, 
for patients participating in the LTE study). 
 
KM plots  will be provided for time to 
discontinuation from treatment to identify if 
there is a differential dropout pattern between 
the treatment groups. 
Clarification, based on inclusion of the long term 
extension study 
 
 
 
 
 
 
New analysis added 
5.3 
<<null>> 
Baseline demographics and patient 
characteristics will also be summarized 
separately for patients who discontinue from 
treatment and patients who complete treatment 
to investigate whether patients with and 
without missing values may have different 
characteristics at baseline. 
New analysis added 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
72 
 
SAP 
Section 
SAP Description 
Change 
Rationale 
6.2.2, 
6.3.3.2 
<<null>> 
Age and blood eosinophil categories will be 
based on data recorded in the clinical database. 
Clarification 
6.2.3 
<<null>> 
The primary analysis with control 
variables for age and blood eosinophil 
categories based on data recorded in the 
IRT (as randomized). This analysis will 
only be performed if the number of 
discrepancies between data recorded in the 
IRT and the clinical database are 
sufficiently large (eg, 5% of total 
population). 
New analysis added 
6.2.3 
On-treatment analysis: analysis of the primary 
endpoint including all exacerbations observed 
until treatment completion or until withdrawal 
from treatment, excluding any exacerbations 
observed after withdrawing from treatment. 
 
Per-protocol analysis: on-treatment analysis 
of the primary endpoint based on the per-
protocol analysis set. 
On-treatment: analysis of the primary endpoint 
including exacerbations during the treatment 
period (ie, observed until treatment completion 
or until withdrawal from treatment, excluding 
any exacerbations observed after withdrawing 
from treatment). 
 
Per-protocol: on-treatment analysis of the 
primary endpoint including exacerbations 
during the treatment period (ie, observed until 
treatment completion or until withdrawal from 
treatment, excluding any exacerbations 
observed after withdrawing from treatment), 
based on the PP analysis set. 
Clarification 
6.2.5 
An interaction p-value will be derived from a 
separate NB model including terms for 
treatment, subgroup, and treatment by 
subgroup interaction. 
An interaction p-value will be derived from a 
separate NB model including additional terms 
for subgroup and treatment by subgroup 
interaction. 
Clarification 
6.3.3.2 
<<null>> 
The proportion of patients achieving an 
increase of ≥100 mL in FEV1 from baseline to 
each scheduled visit will be summarized. A 
New analysis added 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
73 
 
SAP 
Section 
SAP Description 
Change 
Rationale 
stratified (based on randomization strata) 
Cochran-Mantel-Haenszel (CMH) test will be 
used to analyze the proportion of patients 
achieving an increase of ≥100 mL in FEV1 
from baseline to Week 52. 
6.3.4.2 
<<null>> 
AQLQ +12 at Week 52 will additionally be 
examined for the selected subgroups defined in 
Section 3.4. The analysis of subgroups will use 
a MMRM model similar to the one described 
above. Subgroups will be presented 
graphically using forest plots. 
New analysis added 
6.3.5.2 
<<null>> 
ACQ-6 at Week 52 will additionally be 
examined for the selected subgroups defined in 
Section 3.4. The analysis of subgroups will use 
a MMRM model similar to the one described 
above. Subgroups will be presented 
graphically using forest plots. 
New analysis added 
6.3.6.2 
A stratified (based on randomization strata) 
CMH test will be used to analyze the 
proportion of patients achieving a reduction 
of ≥4 in the SGRQ score from baseline to 
Week 52. 
A stratified (based on randomization strata) 
CMH test will be used to analyze the 
proportion of patients achieving a reduction of 
≥4 in the SGRQ score from baseline to Week 
32. 
Updated the timepoint for SGRQ responder 
analysis to be aligned with protocol. 
7.3.1.6 
<<null>> 
Opportunistic Infections 
New section added 
7.5 
Table 6 
Table 6 
PCS (potentially clinically significant) 
criteria for CPK changed to Grades 3-4 
8.2.2 
Clarification 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
74 
 
SAP 
Section 
SAP Description 
Change 
Rationale 
 


Statistical Analysis Plan with Amendment 02 
Study C38072-AS-30025 
 
75 
 
11. 
REFERENCES 
GINA 2015. Global Initiative for Asthma (GINA) REPORT, 2015. The Global Strategy for 
Asthma Management and Prevention. Available at: http://www.ginasthma.org/documents. 
Hankinson JL, Kawut SM, Shahar E, Smith LJ, Stukovsky KH, Barr RG. Performance of 
American Thoracic Society-Recommended Spirometry Reference Values in a Multiethnic 
Sample of Adults. Chest 2010;137(1):138–145. 
Little RJA, Rubin DB. Statistical Analysis with Missing Data. 2nd ed. New York: John Wiley, 
2002. 
National Research Council 2010. The Prevention and Treatment of Missing Data in Clinical 
Trials. Panel on Handling Missing Data in Clinical Trials. Available at: http://www.nap.edu/ 
catalog/12955/the-prevention-and-treatment-of-missing-data-in-clinical-trials.  
Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the 
Prevention and Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents: 
Recommendations from the Centers from Disease Control and Prevention, the National Institutes 
of Health, and the HIV Medicine Association of the Infectious Disease Society of America. 
Available at: http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. 
SAS Institute Inc. 2012. SAS® 9.3 In-Database Products: User’s Guide, 4th ed. Cary, NC: SAS 
Institute Inc. 
Shankar G, Arkin S, Cocea L, Devanarayan V, Kirshner S, Kromminga A, Quarmby V, Richards 
S, Schneider CK, Subramanyam M, Swanson S, Verthelyi D, Yim S. Assessment and Reporting 
of the Clinical Immunogenicity of Therapeutic Proteins and Peptides-Harmonized Terminology 
and Tactical Recommendations. AAPS J. 2014;16:658-73. 


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APPENDIX A. IMPUTATION AND ANALYSIS STEPS FOR ANALYSIS 
OF THE FREQUENCY OF ASTHMA EXACERBATION 
The following represents an outline of the planned methodology for the multiple imputation 
procedure for the primary analysis of the CAE variable. Minor deviations from this outline can 
be addressed in the discussion of the results in the CSR. In the situation that more significant 
updates are warranted, changes will be addressed in a SAP amendment to be finalized prior to 
database lock. 
Step 1: Seed generation. 
The seed generation utilized the code below, resulting in a seed (40880) that will be used in the 
analysis after unblinding. 
data derived.seed; 
  seed = int(time());     
 
 
  put seed=; 
  call symput('seed', left(seed));    
run; 
Step 2: Classify patients with missing data. 
Patients in this study will be partitioned into the following 3 categories:  
1. ET0; patients who completed all 52 weeks of treatment 
2. ET1; patients who withdrew early from treatment but remained in the study contributing 
post-treatment follow-up data through Week 52  
3. ET2; patients who withdrew early from treatment but elected not to remain in the study 
through Week 52 
Step 3: Imputation of missing data.  
Using the dataset of ET1 patients for each treatment group, fit a negative binomial regression 
model to the period of time after treatment withdrawal and estimate the mean number of 
exacerbations and dispersion parameter k. Let λ denote the estimated rate parameter for one 
month of duration. For each patient with missing data, derive the duration of missing exposure 
(TM) for that patient calculated in months. 
Let λM denote the unknown rate of exacerbations during the missing exposure period. The 
exacerbation rate λM will be simulated using a Gamma distribution with parameters α=1/k and 
β=λ*k. Then, the number of events during the missing exposure period will be imputed using a 
negative binomial distribution with mean λM*TM and dispersion k. For each patient in ET2, sum 
the observed number of exacerbations during the treatment period with the simulated number 
during the missing exposure period to obtain the imputed number of exacerbations. This process 
will be repeated 10 times. 
After each iteration, the output dataset of imputed values for ET2 from Step 3 will be appended 
to the existing data from ET0 and ET1 (from Step 2) to generate 10 complete datasets. 
Step 4: Re-run the primary analysis model. 
The negative binomial model will be fitted to the complete set of data for each of the 10 datasets 
using the same covariates that were used for the primary analysis. The model will include 


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log(follow-up time) as an offset variable, either excluding/including the summed duration of 
exacerbations, depending on the analysis. For patients with imputed number of exacerbations, 
complete follow up of 1 year is assumed. The summed duration of exacerbations will be 
calculated as summed duration of any exacerbations observed prior to treatment withdrawal + 8 
days for each additional (imputed) exacerbation. The assumption of 8 days for the duration of 
exacerbations is consistent with the minimal duration of exacerbation as derived previously in 
the BREATH IV program. 
Step 5: Multiple imputation and associated combining rules applied to propagate imputation 
uncertainty (Little and Rubin 2002). 
The output datasets from Step 4 will contain inferential statistics for each imputation iteration. 
The SAS® procedure PROC MIANALYZE will be used to generate an overall p-value and 95% 
CI for the treatment difference; results will be exponentiated back to their original scale. 


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APPENDIX B. TIPPING POINT ANALYSIS 
The tipping point analysis evaluates several combinations of imputed missing data values until 
the analysis reaches a “tipping point” or point at which a particular combination of imputed 
missing data changes the study conclusions, as summarized by its p-value. This is a sensitivity 
analysis utilizing multiple imputations under the missing not at random (MNAR) assumption, 
and will only be conducted if a significant result (p≤0.05) is observed as part of the primary 
analysis. If the sensitivity analysis reveals that the tipping point consists of unreasonable values, 
then the robustness of the study results is supported. This is in accordance with the 
recommendation discussed in the "Prevention and Treatment of Missing Data in Clinical Trials 
Report" (National Research Council 2010). 
The following represents an outline of the planned methodology for the “tipping point” multiple 
imputation sensitivity analysis of the CAE variable. Minor deviations from this outline can be 
addressed in the discussion of the results in the CSR. In the situation that more significant 
updates are warranted, changes will be addressed in a SAP amendment to be finalized prior to 
database lock. 
Exacerbations will be imputed for patients who discontinued treatment prior to the endpoint of 
the study. Multiple imputation and associated combining rules will be applied to propagate 
imputation uncertainty (see Appendix A for additional details). In the following analysis, the 
number of exacerbations in the control group will be imputed assuming that missing data are 
MAR. For the treatment group, the number of exacerbations will be multiplied by a constant 
scale factor (>1) to allow for MNAR. In the treatment group, this scale will be progressively 
increased and the process repeated until the treatment effect is no longer significant at the 5% 
level. The value of the scale parameter at which the treatment effect is no longer significant is 
called the “tipping point”. 
The tipping point analysis will be performed according to the following steps. 
1. Values will be imputed assuming MAR in both treatment groups using the multiple 
impution procedures described in Appendix A (Steps 1-3). This process will be repeated 
10 times. 
2. To allow for MNAR in the reslizumab treatment group, a scale parameter will be used to 
adjust imputed values for the number of CAEs, by multiplying the imputed values by the 
scale parameter. The following pseudo-code can be used to demonstrate this concept, 
where OUTMI is the output dataset(s) from the Step 1, COMPLETER identifies the 
patients who discontinued treatment early with incomplete follow-up, NUMCAE is the 
number of exacerbations, and λ is the scale parameter. 
data outmi; 
   set outmi; 
   if armcd='RESLIZUMAB' and COMPLETER='N' then numcae=numcae*λ; 
run; 
After this step, 10 datasets with complete data have been created. 
3. The negative binomial model will be fitted to the complete set of data for each of the 10 
datasets using the same covariates that were used for the primary analysis, following the 
same outline described in Appendix A (Step 4). 


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4. Apply combining rules to the results from the 10 datasets using PROC MIANALYZE, as 
described in Appendix A (Step 5). 
5. Repeat Steps 1-4 (above) using escalating values for the scale parameter (eg, 1, 2, 3, 4, 
etc.) resulting in estimates of the CAE rate ratio and p-values for each scale parameter. 
The rate ratio of CAEs and associated p-value will be summarized corresponding to each 
selected scale value (eg, 1, 2, 3, 4, etc.) until the tipping point is achieved. 


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APPENDIX C. SGRQ – ITEM WEIGHTS FOR PROGRAMMING 


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