Clinical trial NCT02501629
Conditions: Asthma Elevated Blood Eosinophils Oral Corticosteroid Dependence
Keywords: Asthma Elevated Blood Eosinophils Oral corticosteroid dependence Reslizumab
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2015-09-29; Completion date: 2017-12-04
Enrollment: 177 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of the study is to determine the ability of reslizumab administered by subcutaneous injection to produce a corticosteroid-sparing effect in patients with oral corticosteroid (OCS)-dependent asthma and elevated blood eosinophils, without loss of asthma control.

Detailed description:

Arms: arm 1: Reslizumab was administered by subcutaneous injection (sc) in a dosage of 110 mg (1.0 mL) every 4 weeks for a total of six doses. arm 2: Matching placebo was administered by subcutaneous injection (sc) 1.0 mL every 4 weeks for a total of six doses.
Interventions: intervention 1: Reslizumab intervention 2: Placebo intervention 3: Non-Oral Corticosteroid (non-OCS) Asthma Medication intervention 4: Oral Corticosteroid (OCS)
Intervention descriptions: intervention 1: Reslizumab 110 mg was administered by qualified study personnel as subcutaneous injections in the upper arm(s) once every 4 weeks for a total of 6 doses. Drug was supplied in pre-filled syringes. intervention 2: Placebo was administered by qualified study personnel as subcutaneous injections in the upper arm(s) once every 4 weeks for a total of 6 doses. Drug was supplied in pre-filled syringes. intervention 3: Participants continue using their non-OCS background asthma medications without change during the study's treatment period. intervention 4: After screening and prior to study start, the participant's OCS dose was adjusted to determine the minimal effective OCS requirement.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol with Amendment 02
A Phase 3, 24-Week Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and
Safety Study of Reslizumab Subcutaneous Dosing (110 mg Every 4 Weeks) in Patients 
With Oral Corticosteroid Dependent Asthma and Elevated Blood Eosinophils
Study Number C38072-AS-30027
NCT02501629
Protocol with Amendment 02 Approval Date: 18 July 2016


Placebo-Controlled Study–Asthma
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1
 
Clinical Study Protocol
Study Number C38072-AS-30027
A Phase 3, 24-Week Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and 
Safety Study of Reslizumab Subcutaneous Dosing (110 mg Every 4 Weeks) in Patients With 
Oral Corticosteroid Dependent Asthma and Elevated Blood Eosinophils
Phase 3
IND number: 101,399
EudraCT number: 2015-001580-39
Protocol Approval Date: 18 July 2016
Sponsor (and 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 (US) Code of Federal 
Regulations (CFR) and European Union (EU) 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.
© 2015 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved.


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AMENDMENT HISTORY
The protocol for Study C38072-AS-30027 (original protocol dated 15 April 2015) has been 
amended and reissued as follows:
Amendment 02
18 July 2016
44 patients enrolled to date
Amendment 01
27 January 2016
2 patients enrolled to date


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INVESTIGATOR AGREEMENT


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


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Bioanalytical Immunogenicity Evaluation 
Teva Pharmaceuticals
Global Bioassays and Technology
West Chester, PA 19380
Teva Pharmaceuticals
Global Bioassays and Technology
West Chester, PA 19380
Central Spirometry, eDiary, PEF meters, and 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
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 (SAE) 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-30027 
Title of Study: A Phase 3, 24-Week Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy 
and Safety Study of Reslizumab Subcutaneous Dosing (110 mg Every 4 Weeks) in Patients With 
Oral Corticosteroid Dependent Asthma and Elevated Blood Eosinophils
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc
IND Number: 101,399
EudraCT Number: 2015-001580-39
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: ~155 
Countries Planned: ~19
Planned Study Period: Q3 2015 to Q3 2017
Number of Patients Planned: Approximately 76 patients per treatment group for a total of 
152 patients
Study Population: This study will enroll male and female patients, 12 years of age and older, 
with oral corticosteroid (OCS)-dependent asthma and elevated eosinophils. Patients 12 to <18 
years of age are excluded from participating in South Korea, the Netherlands, Bulgaria, 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 ability of reslizumab 
(110 mg) administered subcutaneously (sc) once every 4 weeks to produce a corticosteroid-
sparing effect (as demonstrated by percent reduction in daily OCS use) in patients with OCS-
dependent asthma and elevated blood eosinophils, without loss of asthma control.
Secondary Objective: To evaluate the clinical benefits of reslizumab in the context of OCS 
reduction
Other Objective: To evaluate the effect of reslizumab on standard asthma control measures 
during tapering of OCS in patients with OCS-dependent asthma.
Target Biomarker Objective: The target biomarker objective is to evaluate the effect of sc
dosing of reslizumab on blood eosinophil counts.
Immunogenicity Objective: The immunogenicity objective is to evaluate the potential of sc
dosing of reslizumab to raise anti-drug antibodies (ADAs).
Pharmacokinetic Objective: The pharmacokinetic (PK) objective is to characterize the PK of sc
reslizumab in the study population.


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Exploratory Objectives:
Safety Objective

To evaluate the safety of chronic sc dosing of reslizumab and tapering of OCS
Study Endpoints:
Primary Efficacy Endpoint:
The primary efficacy variable and endpoint for this study is the categorized percent reduction 
in the daily OCS dose during weeks 20 to 24 as compared with the dose at the end of the 
optimization phase. Percent reduction will be categorized as follows:

90% to 100%

75% to <90%

50% to <75%

>0% to <50%

No decrease in OCS, or loss of baseline asthma control during weeks 20 through 24, 
or discontinuation from study drug
Loss of baseline asthma control will be defined as a forced expiratory volume in 1 second 
(FEV1) value of less than 80% of baseline at the week 24 visit, or clinically significant 
worsening in Asthma Control Questionnaire (ACQ)-6 score (change in score of 0.5) at the 
week 24 visit compared with baseline, and/or clinical asthma exacerbation (CAE) 1 (as 
defined in the protocol) during weeks 20 through 24.
Secondary Efficacy Endpoints:
The secondary efficacy variables and endpoints for this study are as follows:

Proportion of patients achieving ≥50% reduction in OCS dose at weeks 20 to 24 
relative to the OCS dose at date of randomization (DoR)/baseline, while maintaining 
asthma control


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
Proportion of patients achieving dose reduction to ≤5 mg daily dose at weeks 20 to 
24, while maintaining asthma control

Percent change from DoR/baseline in OCS dose at weeks 20 to 24

Proportion of patients achieving less than 5 mg decrement in OCS dose (ie, the 
minimal and non-responders) at weeks 20 to 24 compared with the OCS dose at 
DoR/baseline, while maintaining asthma control

Clinical asthma exacerbation related:

Annualized rate of CAEs requiring a burst of systemic corticosteroid (injection, or 
if oral at least a doubling from the current OCS dose for at least 3 days); an 
asthma-specific hospital admission; or an asthma-specific emergency department 
visit during the treatment period (weeks 0 to 24)

Proportion of patients discontinuing OCS at weeks 20 to 24, while maintaining 
asthma control
Other Prespecified Efficacy Endpoints:
The other efficacy endpoints are as follows:

Time to first CAE

Other clinic lung functions including the following:

Pre-bronchodilator FEV1: change from DoR/baseline to weeks 4, 8, 12, 16, 20, 
and 24 or early withdrawal

Post-bronchodilator FEV1: change from DoR/baseline to weeks 4, 12, 20, and 24 
or early withdrawal

Ambulatory lung function: change in morning (AM) and evening (PM) peak 
expiratory flow (PEF) from run-in baseline at each week through week 24 or early 
withdrawal

Asthma Quality of Life (AQLQ) + 12 score: change from DoR/baseline to weeks 4, 8, 
12, 16, 20, and 24 or early withdrawal

ACQ-6 score: change from DoR/baseline to weeks 4, 8, 12, 16, 20, and 24 or early 
withdrawal 

Change in total inhalations of reliever bronchodilator (eg, short-acting beta-agonist,
SABA) (number of inhalations per 24 hours: day+night) from run-in baseline at each 
week through week 24 or early withdrawal

Number of nighttime awakenings due to asthma over the 24-week treatment period

Change in total asthma symptom score from run-in baseline at each week through 
week 24 or early withdrawal

European Quality of Life 5-dimension health state utility index (EQ-5D) score:
change from DoR/baseline to week 24 or early withdrawal


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
St. George’s Respiratory Questionnaire (SGRQ) score: change from DoR/baseline to 
weeks 12 and 24 or early withdrawal
Target Biomarker Endpoints: The target biomarker endpoints are the blood eosinophil 
counts at DoR/baseline; weeks 4, 8, 12, 16, 20, and 24 or early withdrawal; and at the follow-
up visit (approximately week 32).
Immunogenicity Endpoints: The immunogenicity endpoints are the immunogenicity 
incidence and the impact of ADA on clinical outcomes. The drug-emergent ADA response 
will be identified by analyzing ADA test results for serum samples obtained before the 
administration of study drug at DoR/baseline; weeks 4, 8 12, and 24 or early withdrawal; and 
at the follow-up visit (approximately week 32). An additional sample will be obtained at the 
late follow-up visit (approximately week 48).
Pharmacokinetic Endpoints: There are no specific endpoints related to PK. Measured 
concentrations will be used to characterize the PK of sc reslizumab in the studied population 
and to explore exposure-response relationships. Serum reslizumab concentrations will be 
determined from blood samples collected from each patient at DoR/baseline; and prior to 
study drug administration at weeks 4, 8 12, and 24 or early withdrawal; and at the follow-up 
visit (approximately week 32). An additional PK sample will be obtained at the late follow-
up visit (approximately week 48).
Exploratory Endpoints:
The exploratory endpoints are as follows:


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Safety Endpoints:
The safety endpoints for this study are as follows:

Occurrence of adverse events throughout the study, including the week 32 follow-up 
visit

Clinical laboratory evaluations of serum chemistry at screening, DoR, and 
periodically throughout the study

Clinical laboratory evaluations of hematology throughout the study

Vital signs (pulse, body temperature, respiratory rate, and blood pressure) 
measurements throughout the study

Electrocardiogram (ECG) evaluation at screening and week 24 or early withdrawal

Physical examination findings, including body weight measurements, throughout the 
study

Signs and/or symptoms of adrenal insufficiency (OCS withdrawal effects) throughout 
the study

Concomitant medication usage throughout the study, including the week 32 follow-up 
visit
General Design and Methodology:
This is a Phase 3, 24-week, double-blind, placebo-controlled, parallel-group study to evaluate the 
efficacy and safety of sc reslizumab treatment at a dosage of 110 mg every 4 weeks in patients 
12 years of age and older with OCS-dependent asthma and elevated blood eosinophils. The study 
will consist of a screening period of up to 2 weeks, followed by an optimization period of up to 
10 weeks, a run-in period of at least 2 weeks, a 24-week double-blind treatment period, an 
8-week follow-up period, and an additional 16-week follow-up period to collect drug wash-out 
samples for immunogenicity assessments. 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.
During the optimization period, the patient’s minimal effective OCS requirement will be 
determined. The patient’s previous OCS will be standardized to an equivalent dose and regimen 
of prednisone to the nearest 2.5 mg daily. The patient’s previous non-OCS background asthma 
controller medications will be continued unchanged throughout the pre-randomization period and 
the entire study. At the beginning of the optimization period, an asthma symptom diary and 
electronic peak flow meter will be distributed where the patient will record asthma symptoms, 
number of reliever bronchodilator inhalations, nighttime awakenings due to asthma requiring 
rescue inhaler, and AM and PM PEF. For optimization, the OCS dose should be reduced at 1-
week intervals, for up to 10 weeks or until there is a worsening of asthma signs and symptoms
(minimum 1 day in optimization). When either a lung function or symptomatic deterioration 
occurs, the patient will be returned to the previously effective OCS level, which will then 
constitute the minimally effective dose for the purpose of run-in. If this previously effective dose 
is no longer effective, the investigator can determine the clinically appropriate, minimally 
effective dose for the purpose of run-in. Note: Patient may enter run-in (V12) on the same day as 


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optimization ended if the patient is on the minimally effective prednisone dose (did not require a 
prednisone burst at end-optimization).
Patients whose minimal effective OCS dose remains between ≥5 mg and ≤40 mg of prednisone 
daily at the end of optimization may advance to run-in. During run-in, patients will continue to 
keep their daily asthma control diary and a PEF meter to perform daily self-monitoring of asthma 
symptoms while maintaining their minimally effective OCS dose and previous background 
asthma medications unchanged. The last 7 days of run-in will constitute the baseline level of 
control for analysis and as the basis for OCS reduction algorithm to be used during the treatment 
period. The optimization period will be considered finished when patients experience a 
worsening of asthma signs and symptoms or if a patient optimizes to an OCS dose of <5 mg 
without a worsening of asthma signs and symptoms.
The post-randomization period consists of the treatment period, follow-up visit and late follow-
up visit. During the treatment period, the patient will continue his/her usual non-OCS 
background asthma medication without change; the OCS dose will be tapered per protocol. The 
treatment periods consist of an induction period and an OCS reduction period. During the 
induction period, the minimally effective dose of OCS will be maintained, unchanged, during the 
first 4 weeks of the treatment period. During the OCS reduction period, the minimally effective 
OCS dose will be reduced per protocol at scheduled clinic visits from the beginning of week 5 
(ie, end of the induction period) through week 20. If the OCS dose could not be decreased, it 
should be held constant, or may be increased to a previous level, at the investigator’s discretion, 
until the next study visit at which dose reduction criteria are met. This dose will be maintained 
for the final 4 weeks of the treatment period.
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 his/her withdrawal from the 
study.
Method of Blinding and Randomization: Patients will receive sc placebo or reslizumab 110 
mg on a 1:1 basis in a randomized, double-blind fashion. Randomization will be assigned using 
interactive response technology. After randomization, patients and investigators will remain 
blinded to randomized treatment assignment during the study. The sponsor’s 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 (Global Bioassays and Technology), who, in order to facilitate PK and ADA 
sample analysis, will not be blinded. Eosinophils and monocytes will be redacted from the from 
the post baseline differential cell count reports to avoid the possibility of removing the blind.
In order to achieve balance between treatment groups in regard to average daily OCS 
use/requirement, randomization will be stratified by optimized, average daily OCS dose of >10 
mg or ≤10 mg and age (12 to <18 years of age or ≥18 years of age) at baseline.
Study Drug Dose, Mode of Administration, and Administration Rate: Reslizumab will be 
administered as a fixed dose of 110 mg, as a sc injection in the upper arm(s) once every 4 weeks.
Investigational Product: Reslizumab for sc injection will be provided as a sterile solution 
presented as 110 mg (1 mL) per prefilled syringe, formulated at 110 mg/mL in 
sodium 
acetate, with 
 sucrose, 
 polysorbate 80, pH 5.5 buffer.


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Reference Therapy: 
Placebo: Diluent solution administered sc
Comparison Drug: None
Duration of Patient Participation: The duration of patient participation is up to 62 weeks, 
including up to 2 weeks to satisfy screening criteria, up to 10 weeks to optimize OCS dose, a 
minimum 2-week run-in period on the optimized OCS dose, a 24-week treatment period, and an
8-week follow-up visit. It is expected that the optimization period will be shorter than 10 weeks 
for those patients who are at or near their optimal corticosteroid dose at enrollment. An 
additional late follow-up visit for immunogenicity testing will be performed 28 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.
The patient is male or female, 12 years of age and older, with a previous diagnosis of 
asthma. Patients 12 to <18 years of age are excluded from participating in South 
Korea, the Netherlands, and Argentina, and patients 66 years of age and older are 
excluded from participating in South Korea.
b. Written informed consent is obtained. A patient 12 through <18 years of age must 
provide assent and his/her parent(s) or legal guardian(s) must provide consent.
c.
The patient continues to require an average daily maintenance dose of OCS for 
asthma of between 5 and 40 mg of prednisone or equivalent during the 3 months 
before screening. Patients on an OCS dose of >40 mg at screening who the 
investigator believes may be able to decrease OCS dose to ≤40 mg during the 
optimization period may also be enrolled. Note: every-other-day dosing that is within 
this daily average (ie, 10 to 80 mg) is allowed.
d. The patient has a documented blood eosinophil level of at least 300/L during the 
previous 12 months while on at least medium total daily dose of inhaled 
corticosteroid (ICS) based on Global Initiative for Asthma 2016 clinical 
comparability table (Appendix A of the  protocol), or ≥300/L at screening while on 
chronic OCS or that becomes manifest during the OCS optimization period or at the 
week -2 visit (end of optimization period/beginning of run-in period).
e.
The patient has required at least 880 μg of inhaled fluticasone propionate or 
equivalent daily PLUS another controller(s) (eg, long-acting beta-agonist [LABA], 
long-acting anti-muscarinic antagonist, leukotriene inhibitor, or theophylline), or 
documented intolerance to another controller, for at least 6 months before the 
screening visit. For a fixed-dose ICS/LABA preparation, the highest labeled dose in 
that region will satisfy this criterion. For patients 12 through <18 years of age, the 
ICS dose must correspond to at least a medium total daily ICS dose. Note: the dose 
and regimen of asthma controllers and any allergen immunotherapy should have been 
stable during the 30 days before signing the Informed Assent Form/Informed Consent 
Form (ICF).


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f.
The patient has FEV1 reversibility of at least 12% after administration of inhaled 
reliever medication according to the standard American Thoracic Society (ATS) or 
European Respiratory Society (ERS) protocol. Given the refractory nature of the 
disease in this population and the influence of high background controller 
medications on reversibility testing, documented FEV1 reversibility of 12% or a
provocation concentration producing a 20% fall in FEV1 for methacholine of ≤8 
mg/mL within 24 months of the screening visit, and performed according to the 
standard ATS/ERS procedures, would fulfill this criterion. Patients may be screened 
again if they did not meet spirometry/reversibility criteria initially. The duration 
between the date of Screen Failure and the re-screening must be >30 days.
g. 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. 
h. The patient must be willing and able to comply with study restrictions, willing and 
able to 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. 
i.
Except for the OCS, which will be adjusted per protocol, the patient must maintain 
his/her usual asthma controller regimen without change throughout the screening, 
optimization, run-in, and treatment periods. 
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 and 
interpretation of efficacy results or would 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 [also known as Churg-Strauss syndrome], or allergic 
bronchopulmonary aspergillosis). 
c.
The patient has a known hypereosinophilic syndrome.
d. The patient has a history of any malignancy within 5 years of the screening visit, 
except for treated and cured non-melanoma skin cancers. 
e.
The patient is pregnant or intends to become pregnant during the study or within 5 
months from last dose of study drug or is lactating. Any woman becoming pregnant
will be withdrawn from the study.
f.
The patient required treatment for an asthma exacerbation within 4 weeks of 
screening.


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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 [mAb] 
or other mAb [eg, mepolizumab] or soluble receptor) or non-biologic (eg, 
methotrexate, cyclosporine), except maintenance OCS for the treatment of asthma. 
Previous use of such agents that occurred >5 half-lives from the screening visit may 
be allowed, if approved by the medical monitor.
i.
The patient participated in a clinical study 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 immunodeficiency disorder including human 
immunodeficiency virus. 
m. The patient has current suspected drug and/or alcohol abuse.
n. The patient has had an active helminthic parasitic infection or was treated for one 
within 6 months of screening. 
o. The patient has a history of allergic reactions 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.)
Criteria for Randomization
After completion of the optimization/run-in period, patients may continue in the study if they 
meet all of the following criteria:
a.
The patient must be using an average daily dose of no less than 5 mg of prednisone
after OCS optimization. A patient requiring less than 5 mg of prednisone to maintain 
control should not be randomized.
b. The patient must be using an average daily dose of no more than 40 mg of prednisone
after OCS optimization. A patient requiring more than 40 mg of prednisone to 
maintain control should not be randomized.
c.
The patient should not have had an asthma exacerbation during the run-in period, 
defined as requiring a burst of systemic corticosteroid for an asthma worsening 
(injection, or if oral, at least a doubling from the current OCS dose for at least 3 
days); an asthma-specific hospital admission; or an asthma-specific emergency 
department visit.
d. The patient must have completed at least 4 days of diary entries (or any combination 
of 4 morning and 4 evening recordings) during the last 7 days of the run-in period.


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Measures and Time Points: 
Primary Efficacy Measure and Time Points
The primary efficacy measure and endpoint for this study is the percent reduction in the daily 
OCS during weeks 20 to 24 compared with the dose at the end of the optimization phase. 
Secondary Efficacy Measures and Time Points
The secondary efficacy measures and time points for this study are as follows:

≥50% reduction in OCS dose, while maintaining asthma control, at weeks 20 to 24 
relative to OCS dose at DoR/baseline

Reduction to ≤5 mg daily dose at weeks 20 to 24, while maintaining asthma control

OCS dose at weeks 20 to 24 relative to DoR/baseline

Less than 5 mg decrement in OCS dose (ie, the minimal and non-responders) at 
weeks 20 to 24, while maintaining asthma control

Clinical asthma exacerbation related:

Annualized rate of CAEs requiring a burst of systemic corticosteroid (injection, or 
if oral, at least a doubling from the current OCS dose for at least 3 days); an 
asthma-specific hospital admission; or an asthma-specific emergency department 
visit during the treatment period (weeks 0 to 24)

OCS discontinuations at weeks 20 to 24, while maintaining asthma control
Other Efficacy Measures and Time Points
The other efficacy measures and their time points for this study are as follows:

Time to first CAE

other clinic lung functions including the following:

Spirometry, including pre-bronchodilator FEV1 (at baseline/DoR; weeks 4, 8, 12, 
16, 20, and 24 or early withdrawal) and post-bronchodilator FEV1 (at 
baseline/DoR; weeks 4, 12, 20, and 24 or early withdrawal)

Ambulatory lung function including AM and PM PEF based on the PEF meter (run-in 
baseline and weekly averages)

AQLQ + 12 at DoR/baseline and weeks 4, 8, 12, 16, 20, and 24 or early withdrawal

ACQ-6 at DoR/baseline and weeks 4, 8, 12, 16, 20, and 24 or early withdrawal

Total reliever bronchodilator use (number of inhalations per 24 hours: day and night)
based on the daily asthma control diary (run-in baseline and weekly averages)

Nighttime awakenings due to asthma based on the daily asthma control diary (run-in 
baseline and weekly averages)

Asthma symptoms based on the daily asthma control diary (run-in baseline and 
weekly averages)


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
EQ-5D: baseline/DoR and week 24 or early withdrawal

SGRQ score at DoR/baseline; weeks 12 and 24 or early withdrawal
Target Biomarker, Immunogenicity, and Pharmacokinetics Measures and Time Points
Target biomarkers: Blood eosinophils will be determined from blood samples collected from 
each patient at DoR/baseline; weeks 4, 8, 12, 16, 20, and 24 or early withdrawal. Blood 
eosinophils will also be determined from samples collected at the follow-up visit (approximately 
week 32).
Immunogenicity: Serum ADAs will be determined from blood samples collected from each 
patient at DoR/baseline; prior to study drug administration at weeks 4, 8, 12, and 24 or early 
withdrawal; and at the follow-up visit (approximately week 32). An additional sample will be 
obtained at the late follow-up visit (approximately week 48).
Pharmacokinetics: Serum reslizumab concentrations will be determined from blood samples 
collected from each patient at DoR/baseline, prior to study drug administration at weeks 4, 8, 12, 
16, 20, and 24 or early withdrawal, and at the follow-up visit (approximately week 32). An 
additional PK sample will be obtained at the late follow-up visit (approximately week 48).
Exploratory Measures and Time Points
The following exploratory measures will be evaluated:
Safety Measures and Time Points
The following safety measures will be evaluated:

Inquiries about adverse events throughout the study

Clinical laboratory evaluations of serum chemistry at screening, DoR/baseline, and 
periodically throughout the study

Clinical laboratory evaluations of hematology throughout the study

Vital signs (pulse, body temperature, respiratory rate, and blood pressure) 
assessments throughout the study

ECG at screening and week 24 or early withdrawal


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
Physical examinations throughout the study

Monitoring and evaluation of any signs and/or symptoms of adrenal insufficiency 
(OCS withdrawal effects) throughout the study

Inquiries about concomitant medication usage throughout the study
Allowed and Disallowed Medications Before and During the Study:
Allowed: 

Inhaled fluticasone propionate at 880 μg or equivalent daily PLUS another 
controller(s) (eg, LABA, LAMA, leukotriene inhibitor, or theophylline), for at least 6 
months before the screening visit. For a fixed-dose ICS/LABA preparation, the 
highest labeled dose in that region will satisfy this criterion.

For patients 12 through <18 years of age, the ICS dose must correspond to at least a 
medium total daily dose for the formulation.

Allergen immunotherapy is allowed.

Inhaled reliever medications are allowed as needed for the relief of intermittent 
asthma symptoms.

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 during this study unless patient safety is at risk.
Disallowed During the Study:

Patients should refrain from using reliever inhalers for 6 hours before any study visit 
that includes spirometry or airway reversibility testing, including the screening visit.

If a patient is taking LABAs, these should be withheld for 12 hours before any study 
visit that includes spirometry or airway reversibility testing, including the screening 
visit.

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

Inhaled nicotine (including electronic cigarettes)
Statistical Considerations:
Sample Size Rationale: The sample size was calculated based on the following assumptions:

Categorical reduction in OCS dose after 24 weeks of treatment will have the 
following distribution for the placebo group: 


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
10.9% of patients will have 90% to 100% reduction

7.9% of patients will have 75% to <90% reduction

14.8% of patients will have 50% to <75% reduction

10.8% of patients will have 0% to <50% reduction

55.6% of patients will have no reduction, loss of asthma control, or 
discontinuation from study drug

The overall odds ratio between reslizumab and placebo based on proportional odds 
model will be 2.63.

Alpha level of 0.05
Based on the above assumptions, a sample size of 76 patients per group will provide 90% power 
to detect a significant effect of reslizumab over placebo on the probability for a higher 
categorical reduction of OCS dose.
Analysis of Primary Endpoint: For this study, the primary endpoint is the categorical reduction 
in OCS dose during weeks 20 to 24, compared with DoR/baseline dose, while maintaining 
asthma control. Five categories of reduction will be defined: 90% to 100% reduction, 75% to 
<90% reduction, 50% to <75% reduction, 0% to <50% reduction, and no decrease in OCS 
dose/loss of asthma control/discontinuation from study drug. This categorical endpoint will be 
analyzed using proportional odds model. The model will include the treatment group and 
randomization stratification factors as model factors and the OCS baseline dose and duration of 
historical OCS use (ie, before screening) as covariates. The overall odds ratio between 
reslizumab and placebo and its 95% confidence interval will be estimated.
For the primary analysis, patients who discontinue the study drug early will be considered as 
nonresponders and will be categorized in the lowest category of response.
Sensitivity analysis will use data collected after early discontinuation from the study drug. In this 
analysis, patients will be categorized according to the percent dose reduction at 24 weeks, 
regardless of whether they withdrew early from treatment or completed treatment.
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 his/her withdrawal from the 
study.
Analysis of Secondary Endpoints: All efficacy variables will be summarized by treatment 
group. For continuous variables, the summary statistics will include number, mean, standard 
deviation, standard error, median, minimum, and maximum. For categorical variables, patient 
counts and percentages will be provided. 
Proportion of patients achieving ≥50% reduction in OCS dose at weeks 20 to 24 while 
maintaining asthma control, proportion of patients achieving dose reduction to ≤5 mg daily dose 
at weeks 20 to 24 while maintaining asthma control, proportion of patients achieving less than 5 
mg decrement in OCS dose (ie, the minimal and non-responders) at weeks 20 to 24 while 
maintaining asthma control, and proportion of patients discontinuing OCS at weeks 20 to 24
while maintaining asthma control will be analyzed using a logistic regression model. The model 


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will include the treatment group and randomization stratification factors as model factors and the 
OCS baseline dose and duration of historical OCS use (ie, before screening) as covariates. 
For the categorical secondary analysis, patients who discontinue the study drug early will be 
considered as nonresponders and will be categorized in the lowest category of response
Analysis of the mean percentage change from baseline in OCS dose at weeks 20 to 24 will use an 
analysis of covariance model with treatment group and stratification factors as model factors and 
the OCS baseline dose and duration of historical OCS use (ie, before screening) as covariates.
The frequency of CAEs will use the negative binomial (NB) regression model. The primary NB 
model will include the treatment group and randomization stratification factors 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.
Additional covariates or factors may be added to the statistical models. These will be detailed in 
the statistical analysis plan.
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 2-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 will continue through the secondary variables either until all comparisons of interest are 
interpreted inferentially or until the point at which the resulting 2-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 of the protocol. 
No multiplicity adjustments will be made for other efficacy and exploratory efficacy analyses.
Analysis of Other/Exploratory Endpoints: Statistical modeling to be used for other and 
exploratory efficacy endpoints will be described and detailed in the statistical analysis plan.
Safety and PK Analyses: Safety and PK data will be summarized using descriptive statistics by 
time point and/or treatment group, as appropriate.


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TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
AMENDMENT HISTORY .............................................................................................................2
INVESTIGATOR AGREEMENT...................................................................................................3
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............4
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................6
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................7
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS................................................30
1.
BACKGROUND INFORMATION...........................................................................33
1.1.
Introduction.................................................................................................................33
1.2.
Name and Description of Investigational Product......................................................34
1.3.
Findings From Nonclinical and Clinical Studies........................................................34
1.3.1.
Nonclinical Studies.....................................................................................................34
1.3.2.
Clinical Studies...........................................................................................................35
1.3.2.1.
Clinical Pharmacology Studies...................................................................................35
1.3.2.2.
Clinical Safety and Efficacy Studies ..........................................................................36
1.4.
Known and Potential Risks and Benefits to Human Patients.....................................38
1.4.1.
Risks of Reslizumab ...................................................................................................39
1.4.2.
Benefits of Reslizumab...............................................................................................39
1.4.3.
Overall Risk and Benefit Assessment for This Study ................................................39
1.5.
Selection of Drugs and Dosages.................................................................................40
1.5.1.
Justification for Dosage of Active Drug.....................................................................40
1.5.2.
Justification for Use of Placebo..................................................................................41
1.6.
Compliance Statement................................................................................................41
1.7.
Population To Be Studied and Justification................................................................41
1.8.
Location and Timing of Study....................................................................................41
2.
PURPOSE OF THE STUDY AND STUDY OBJECTIVES.....................................42
2.1.
Purpose of the Study...................................................................................................42
2.2.
Study Objectives.........................................................................................................42
2.2.1.
Primary Objective.......................................................................................................42
2.2.2.
Secondary Objective...................................................................................................42
2.2.3.
Other Efficacy Objective ............................................................................................42


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2.2.4.
Target Biomarker Objective .......................................................................................42
2.2.5.
Immunogenicity Objective .........................................................................................42
2.2.6.
Pharmacokinetic Objective.........................................................................................42
2.2.7.
Exploratory Objectives ...............................................................................................42
2.2.8.
Safety Objective..........................................................................................................43
2.3.
Study Endpoints..........................................................................................................43
2.3.1.
Primary Efficacy Endpoint .........................................................................................43
2.3.2.
Secondary Efficacy Endpoints....................................................................................43
2.3.3.
Other Prespecified Efficacy Endpoints.......................................................................44
2.3.4.
Target Biomarker Endpoint........................................................................................45
2.3.5.
Immunogenicity Endpoints.........................................................................................45
2.3.6.
Pharmacokinetic Endpoints ........................................................................................45
2.3.7.
Exploratory Endpoints................................................................................................45
2.3.8.
Safety Endpoints.........................................................................................................46
3.
STUDY DESIGN .......................................................................................................47
3.1.
General Design and Study Schema.............................................................................47
3.1.1.
Screening Period.........................................................................................................47
3.1.2.
Optimization Period....................................................................................................47
3.1.3.
Run-In Period..............................................................................................................49
3.1.4.
Treatment Period ........................................................................................................49
3.1.4.1.
Handling of Asthma Exacerbations During the Treatment Period.............................51
3.2.
Justification for Study Design ....................................................................................53
3.3.
Primary and Secondary Measures and Time Points ...................................................53
3.3.1.
Primary Efficacy Measure and Time Points...............................................................53
3.3.2.
Secondary Efficacy Measures and Time Points .........................................................54
3.3.3.
Other Prespecified Efficacy Measures and Time Points ............................................54
3.4.
Target Biomarker Measures and Time Points ............................................................55
3.5.
Immunogenicity Measures and Time Points ..............................................................55
3.6.
Pharmacokinetic Measures and Time Points..............................................................55
3.7.
Exploratory Measures and Time Points......................................................................55
3.8.
Safety Measures and Time Points...............................................................................55
3.9.
Randomization and Blinding......................................................................................56
3.10.
Maintenance of Randomization and Blinding............................................................56


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3.10.1.
Randomization............................................................................................................56
3.10.2.
Blinding/Unblinding...................................................................................................56
3.11.
Drugs Used in the Study.............................................................................................57
3.11.1.
Investigational Product ...............................................................................................57
3.11.2.
Placebo........................................................................................................................58
3.12.
Drug Supply and Accountability ................................................................................58
3.12.1.
Drug Storage and Security..........................................................................................58
3.12.2.
Drug Accountability ...................................................................................................58
3.13.
Duration of Patient Participation and Justification.....................................................58
3.14.
Stopping Rules and Discontinuation Criteria .............................................................59
3.15.
Source Data Recorded on the Case Report Form.......................................................59
3.16.
Study Procedures ........................................................................................................59
3.16.1.
Procedures for Screening and Enrollment (Visit 1)....................................................64
3.16.2.
Procedures Before Study Drug Treatment..................................................................65
3.16.2.1.
Procedures During the Optimization Period (Weeks −12 through −3 
[Visits 2 through 11])..................................................................................................65
3.16.2.2.
Procedures During the Run-In Period (Week −2 [Visit 12])......................................66
3.16.2.3.
Procedures at Baseline/Day of Randomization (Week 0 [Visit 13])..........................66
3.16.3.
Procedures During Study Drug Treatment .................................................................68
3.16.3.1.
Double-Blind Treatment Period (Weeks 1 Through 24 [Visits 13 Through 
19])..............................................................................................................................68
3.16.4.
Procedures After Study Drug Treatment ....................................................................69
3.16.5.
Unscheduled Visits .....................................................................................................70
4.
SELECTION AND WITHDRAWAL OF PATIENTS..............................................72
4.1.
Patient Inclusion Criteria ............................................................................................72
4.2.
Patient Exclusion Criteria...........................................................................................73
4.3.
Justification for Key Inclusion and Exclusion Criteria...............................................74
4.4.
Randomization criteria................................................................................................74
4.5.
Criteria and Procedures for Discontinuation of Study Treatment and/or 
Study Withdrawal .......................................................................................................75
4.5.1.
Discontinuation of Study Treatment...........................................................................75
4.5.2.
Complete Withdrawal from Study..............................................................................76
5.
TREATMENT OF PATIENTS..................................................................................77


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5.1.
Drugs Administered During the Study .......................................................................77
5.2.
Restrictions .................................................................................................................77
5.3.
Prior and Concomitant Therapy or Medication..........................................................77
5.4.
Procedures for Monitoring Patient Compliance .........................................................78
5.5.
Total Blood Volume ...................................................................................................78
6.
ASSESSMENT OF EFFICACY AND IMMUNOGENICITY..................................79
6.1.
Primary Efficacy Measure and Justification...............................................................79
6.2.
Spirometry ..................................................................................................................79
6.3.
PEF monitoring...........................................................................................................79
6.4.
Asthma Quality of Life Questionnaire for Patients 12 Years and Older....................79
6.5.
Asthma Control Questionnaire ...................................................................................80
6.6.
Asthma Symptom Assessment ...................................................................................80
6.7.
Asthma Exacerbations ................................................................................................80
6.8.
European Quality of Life 5-Dimension Health State Utility Index............................81
6.9.
Inhaled Reliever Medication Use ...............................................................................81
6.10.
Nighttime Awakenings Requiring Rescue Inhaler Use..............................................81
6.11.
..81
6.12.
..81
6.13.
..81
6.14.
St. George’s Respiratory Questionnaire .....................................................................82
6.15.
Target Biomarker Measures .......................................................................................82
7.
ASSESSMENT OF SAFETY.....................................................................................83
7.1.
Adverse Events ...........................................................................................................83
7.1.1.
Definition of an Adverse Event..................................................................................83
7.1.2.
Recording and Reporting Adverse Events..................................................................84
7.1.3.
Severity of an Adverse Event .....................................................................................85
7.1.4.
Relationship of an Adverse Event to the Study Drug.................................................85
7.1.5.
Relationship of an Adverse Event to OCS Reduction................................................85
7.1.6.
Serious Adverse Events..............................................................................................86
7.1.6.1.
Definition of a Serious Adverse Event .......................................................................86
7.1.6.2.
Expectedness...............................................................................................................86
7.1.6.3.
Reporting a Serious Adverse Event............................................................................86
7.1.7.
Specific Protocol-Defined Adverse Events ................................................................88


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7.1.7.1.
Adrenal Insufficiency .................................................................................................88
7.1.7.2.
Protocol-Defined Adverse Events for Expedited Reporting to Teva .........................89
7.1.7.3.
Specific Adverse Event Case Report Form Capturing ...............................................89
7.1.8.
Withdrawal Due to an Adverse Event ........................................................................90
7.1.9.
Overdose of Study Drug .............................................................................................91
7.1.10.
Protocol Deviations Because of an Adverse Event ....................................................91
7.2.
Pregnancy ...................................................................................................................91
7.3.
Clinical Laboratory Tests ...........................................................................................92
7.3.1.
Serum Chemistry ........................................................................................................92
7.3.2.
Hematology.................................................................................................................93
7.3.3.
Other Clinical Laboratory Tests .................................................................................93
7.3.3.1.
Urinalysis....................................................................................................................93
7.3.3.2.
Hepatitis B, Hepatitis C, and HIV ..............................................................................94
7.3.3.3.
Human Chorionic Gonadotrophin Tests.....................................................................94
7.4.
Vital Signs ..................................................................................................................94
7.5.
Electrocardiography....................................................................................................94
7.6.
Physical Examinations................................................................................................95
7.7.
Concomitant Therapy or Medication..........................................................................95
7.8.
Methods and Timing of Assessing, Recording, and Analyzing Safety Data..............95
8.
ASSESSMENT OF PHARMACOKINETICS/PHARMACODYNAMICS, 
AND IMMUNOGENICITY.......................................................................................96
8.1.
Pharmacokinetic Variables.........................................................................................96
8.1.1.
Specimen Sampling and Handling..............................................................................96
8.1.2.
Shipment and Analysis of Samples ............................................................................96
8.2.
Pharmacodynamic Variables ......................................................................................97
8.2.1.
Blood Eosinophil Counts............................................................................................97
8.2.2.
Exploratory Biomarker Analysis ................................................................................97
8.3.
Immunogenicity Testing.............................................................................................97
8.3.1.
Blood Sampling and Handling....................................................................................97
8.3.2.
Shipment and Analysis of Samples ............................................................................98
8.4.
..98
8.4.1.
..98
8.4.2.
..99


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8.5.
...99
8.5.1.
...99
8.5.2.
...99
9.
STATISTICS ............................................................................................................100
9.1.
Sample Size and Power Considerations ...................................................................100
9.2.
Analysis Sets.............................................................................................................100
9.2.1.
Intent-to-Treat Analysis Set......................................................................................100
9.2.2.
Safety Analysis Set...................................................................................................101
9.2.3.
Additional Analysis Sets...........................................................................................101
9.2.3.1.
Per-Protocol Analysis Set.........................................................................................101
9.3.
Data Handling Conventions......................................................................................101
9.4.
Study Population.......................................................................................................101
9.4.1.
Patient Disposition....................................................................................................101
9.4.2.
Demographic and Baseline Characteristics ..............................................................101
9.5.
Efficacy Analysis......................................................................................................102
9.5.1.
Primary Endpoint......................................................................................................102
9.5.2.
Secondary Endpoints ................................................................................................102
9.5.3.
Other Secondary Efficacy Endpoints: ......................................................................103
9.5.4.
Exploratory Endpoints..............................................................................................103
9.5.5.
Target Biomarker Endpoint......................................................................................104
9.5.6.
Planned Method of Analysis.....................................................................................104
9.5.6.1.
Primary Efficacy Analysis........................................................................................104
9.5.6.2.
Sensitivity Analysis ..................................................................................................104
9.5.6.3.
Secondary Efficacy Analysis....................................................................................105
9.5.6.4.
Other Efficacy Analysis............................................................................................105
9.5.6.5.
Exploratory Efficacy Analysis..................................................................................105
9.6.
Multiple Comparisons and Multiplicity....................................................................105
9.7.
Safety Endpoints and Analysis .................................................................................106
9.7.1.
Safety Endpoints.......................................................................................................106
9.7.2.
Safety Analysis .........................................................................................................106
9.8.
Pharmacokinetic Analysis ........................................................................................107
9.9.
Biomarker Analysis ..................................................................................................107
9.10.
Pharmacodynamic Analysis......................................................................................107


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9.11.
Immunogenicity Analysis.........................................................................................107
9.12.
Planned Interim Analysis..........................................................................................107
9.13.
Reporting Deviations From the Statistical Plan........................................................107
10.
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.......................................108
11.
QUALITY CONTROL AND QUALITY ASSURANCE .......................................109
11.1.
Protocol Amendments and Protocol Deviations and Violations ..............................109
11.1.1.
Protocol Amendments ..............................................................................................109
11.1.2.
Protocol Violations...................................................................................................109
11.2.
Information to Study Personnel................................................................................109
11.3.
Study Monitoring......................................................................................................110
11.4.
Clinical Product Complaints.....................................................................................110
11.4.1.
Product Complaint Information Needed From the Investigational Center...............111
11.4.2.
Handling the Study Drug at the Investigational Center............................................111
11.4.3.
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint .................................................................................................................112
11.4.4.
Documenting a Product Complaint ..........................................................................112
11.5.
Audit and Inspection.................................................................................................112
12.
ETHICS ....................................................................................................................113
12.1.
Informed Consent/Assent .........................................................................................113
12.2.
Health Authorities and Independent Ethics Committees/Institutional Review 
Boards.......................................................................................................................113
12.3.
Confidentiality Regarding Study Patients ................................................................114
12.4.
Declaration of the End of the Clinical Study............................................................114
12.5.
Registration of the Clinical Study.............................................................................114
13.
DATA HANDLING, DATA QUALITY ASSURANCE, AND RECORD 
KEEPING .................................................................................................................115
13.1.
Data Collection.........................................................................................................115
13.2.
Data Quality Control.................................................................................................115
13.3.
Archiving of Case Report Forms and Source Documents........................................116
13.3.1.
Sponsor Responsibilities...........................................................................................116
13.3.2.
Investigator Responsibilities.....................................................................................116
14.
FINANCING AND INSURANCE...........................................................................118
15.
REPORTING AND PUBLICATION OF RESULTS..............................................119


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16.
REFERENCES .........................................................................................................120
17.
SUMMARY OF CHANGES TO PROTOCOL .......................................................122
17.1.
Amendment 02 Dated 18 JULY 2016 ......................................................................122
17.2.
Amendment 01 Dated 27 January 2016....................................................................135
APPENDIX A.
GLOBAL INITIATIVE FOR ASTHMA ICS EQUIVALENCY 
TABLE .....................................................................................................................160
APPENDIX B.
ASTHMA QUALITY OF LIFE QUESTIONNAIRE +12..............................161
APPENDIX C.
ASTHMA CONTROL QUESTIONNAIRE ...................................................167
APPENDIX D.
ASTHMA CONTROL DIARY.......................................................................169
APPENDIX E.
EUROPEAN QUALITY OF LIFE 5-DIMENSION HEALTH STATE 
UTILITY INDEX .....................................................................................................171
APPENDIX F.
..174
APPENDIX G.
ST. GEORGE’S RESPIRATORY QUESTIONNAIRE .................................175
APPENDIX H.
CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS...................181
APPENDIX I.
OPPORTUNISTIC INFECTIONS ...................................................................182


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LIST OF TABLES
Table 1:
Optimization Phase Prednisone Dose Reduction Algorithm......................................49
Table 2:
Eligibility Criteria for Scheduled Oral Corticosteroid Reductions During the 
Treatment Period (Must Meet All) .............................................................................50
Table 3:
Oral Corticosteroid Decrements During the Treatment Period..................................51
Table 4:
Rationale for Protocol.................................................................................................53
Table 5:
Study Procedures and Assessments............................................................................60
Table 6:
Changes to the Protocol............................................................................................122
Table 7:
Changes to the Protocol............................................................................................135
LIST OF FIGURES
Figure 1:
Overall Study Schema ................................................................................................52


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Abbreviation
Term
HCG
beta human chorionic gonadotropin
ACQ
Asthma Control Questionnaire
ADA
anti-drug antibody
ADR
adverse drug reaction
AE
adverse event
AM
morning
anti-hIL-5
humanized anti-human interleukin-5
AQLQ
Asthma Quality of Life
ATS
American Thoracic Society
BUN
blood urea nitrogen
CAE
clinical asthma exacerbation
CBC
complete blood count
CDMS
clinical data management system 
CFR
Code of Federal Regulations
CPK
creatine phosphokinase
CPP
clinical project physician
CRF
case report form (refers to any media used to collect study data [ie, paper or 
electronic])
CRO
contract research organization
DMC
Data Monitoring Committee 
DoR
date of randomization
ECG
electrocardiography, electrocardiogram
eDiary
electronic diary
EOT
end of treatment
EQ-5D
European Quality of Life 5-dimension health state utility index
ERS
European Respiratory Society
EU
European Union
FEV1
forced expiratory volume in 1 second
FEF25%-75%
forced expiratory flow at 25% and 75% of the forced vital capacity


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Abbreviation
Term
FDA
Food and Drug Administration
FVC
forced vital capacity
GCP
Good Clinical Practice
HCV 
hepatitis C 
HEENT
Head, Eyes, Ears, Nose, and Throat
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
ICS
inhaled corticosteroids
IEC
Independent Ethics Committee
IgG
Immunoglobulin G
IL
interleukin
im
intramuscular
IRB
Institutional Review Board
IRT
interactive response technology
ITT
intent-to-treat 
iv
intravenous
IWRS
Interactive Web Response System
LABA
long-acting beta-agonist
LSO
local safety officer 
LSLV
Last Subject Last Visit
mAb
monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities 
NB
negative binomial
NOEL
no-observed-effect level
OCS
oral corticosteroid
PD
pharmacodynamics/s
PEF
peak expiratory flow
PGx
pharmacogenomic(s)
PK
pharmacokinetic/s


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Abbreviation
Term
PM
evening
SABA
short-acting beta-agonist
sc
subcutaneous
SD
standard deviation
SDV
source document verification
SE
standard error
SGRQ
St. George’s Respiratory Questionnaire
SOP
standard operating procedure
SUSAR
suspected unexpected serious adverse reaction
ULN
upper limit of normal
US(A)
United States (of America)
WBC
white blood cell
WHO
World Health Organization
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 many as 334 million people in the world have asthma (Global 
Asthma Network 2014).
Inhaled corticosteroids (ICS) are the most effective treatment agents for the long-term control of 
asthma (see EPR-3 2007 and GINA 2014 for review). For patients whose asthma is not 
adequately controlled on daily ICS alone, the addition of long-acting beta- agonists (LABAs) or 
and/or other controller therapies often provides additional control. There are currently very few 
options for patients whose asthma is inadequately controlled on ICS/LABA. The most severely 
affected patients with asthma may require daily oral corticosteroid (OCS) doses to maintain 
asthma control (GINA 2014). Chronic use of daily OCS is associated with the severe adverse 
effects of an iatrogenic Cushing’s syndrome, including increased risk of infections, impaired 
growth in children, hyperglycemia, low bone density, elevated blood pressure, cataracts, and 
adrenal insufficiency (Walsh et al 2001, Stanbury and Graham 1998). Risk can be decreased by 
maintaining patients on the lowest possible dose of OCS and utilization of corticosteroid-sparing 
strategies.
Interleukin (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 the 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; 
results are notable for a significant reduction in clinical asthma exacerbations (CAEs) as well as 
improved lung function. The safety profile accumulated throughout the clinical development of 
reslizumab suggests that reslizumab may have a favorable benefit-risk profile in treating patients 
with asthma and elevated blood eosinophils. Therefore, this study was proposed to further 


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investigate the potential corticosteroid-reducing properties of reslizumab in patients with 
corticosteroid-dependent asthma and elevated eosinophils.
1.2.
Name and Description of Investigational Product
Reslizumab (CEP38072) is a humanized anti-human interleukin-5 (anti-hIL-5) mAb of the 
immunoglobulin G4/κ isotype being developed for administration by the iv and subcutaneous 
(sc) routes.
A more detailed description of the product is given in Section 3.11.
1.3.
Findings From Nonclinical and Clinical Studies
1.3.1.
Nonclinical Studies
A correlation between IL-5–induced eosinophilia and pulmonary hyperreactivity was suggested 
by studies in the IL-5 gene knockout mouse (Foster et al 1996). When sensitized and challenged 
with antigen, 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 
hyperresponsiveness 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. The effects of reslizumab 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 (NOEL) 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 NOEL of at least 25 mg/kg. The 
NOEL 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.
Available data indicate that reslizumab may bind to a human brain-specific brain link protein-1, 
which belongs to a superfamily of structural proteins that help bind cells to matrix by binding 
hyaluronic acid and negatively charged glycoproteins (Study D-38271).
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 (im) 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 


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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 (IB). 
1.3.2.
Clinical 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. 
1.3.2.1.
Clinical Pharmacology Studies
The PK of reslizumab are similar following iv administration in patients and in healthy subjects. 
Following iv administration, maximum serum reslizumab concentrations (Cmax) are typically 
attained at the end of the infusion and generally decline from peak in a biphasic manner. Mean 
terminal half-life (t½) of reslizumab following multiple dose administration is approximately 
24 days, resulting in an accumulation ratio of approximately 1.5- to 1.9-fold when administered 
every 4 weeks. Systemic exposure, as assessed by Cmax and area under the concentration curve 
(AUC), increases in an apparently dose proportional manner over the dose range of 0.3 mg/kg 
through 3.0 mg/kg.
Following a single sc dose, bioavailability of reslizumab is approximately 67%. Peak serum 
reslizumab concentrations are typically observed approximately 7 days after sc administration. 
As expected, the remainder of the 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 t½ (approximately 26 days). 
Reslizumab has a small volume of distribution (Vd, approximately 5 L), suggesting minimal 
distribution to extravascular tissues. Based on the characteristics of reslizumab, renal or hepatic 
impairment and use of concomitant medications is unlikely to affect systemic exposure to 
reslizumab. The lack of effect of mild or moderate renal impairment or Grade 1/2 elevations in 
liver function tests on the PK of reslizumab was confirmed in population PK (PPK) analyses in 
asthma patients. In vitro data indicate that IL-5 and reslizumab are unlikely to affect cytochrome 
P450 (CYP) enzymes commonly implicated in drug-drug interactions and the results of the PPK 
analyses confirmed that concomitant use of leukotriene antagonists or systemic corticosteroid 
classes, as well as the individual drugs prednisone and montelukast, did not impact systemic 
exposure to reslizumab.
Other than a study performed to compare the PK, PD, and immunogenicity of reslizumab in 
Japanese and non-Japanese subjects, there were no dedicated studies for the assessment of the 
effect of demographic characteristics on the PK of reslizumab. Results of PPK analyses 
demonstrated that age, sex, and race (Caucasian, Black, Asian, ‘other’) have no notable impact 
on the PK of reslizumab; however, body weight was found to impact exposure. The PPK 
analyses also demonstrated no clear indication of reduced exposure to reslizumab in patients who 
developed antibodies to reslizumab (ie, were anti-drug antibody [ADA] positive).
Further details may be found in the current IB.


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1.3.2.2.
Clinical Safety and Efficacy Studies
The Phase 3 BREATH program in adults and adolescents with asthma evaluated the safety and 
efficacy of reslizumab administered iv every 4 weeks at 3 mg/kg (16-week Studies C38072/3081 
and C38072/3084, 12-month 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 
Asthma Symptom Utility Index) were observed in patients with eosinophilic asthma defined by a 
screening blood eosinophil count of ≥400/µL (Studies 3081, 3082, and 3083).
In patients with asthma but without elevated blood eosinophils (Study 3084), reslizumab 
produced nonsignificant improvements in lung function and other measures of efficacy. In 
contrast, in patients with blood eosinophil levels ≥400/L, 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 IB. 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 
events and death cases from the open-label Study 3085 are also included in the relevant sections.
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 that had 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.


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Deaths
There were 4 deaths in the clinical development plan: 1 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 the 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. 
Additional Safety Considerations
Malignancy risk
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 nonmelanoma 
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 


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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.
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 physiological jaundice. One pregnancy case was lost 
to follow-up, and the outcome is unknown.
Immunogenicity
Anti-drug antibody 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 IB.


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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 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 to 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
forced expiratory volume in 1 second (FEV1) and a medically meaningful decreased rate of 
CAEs with reslizumab.
A reduction in OCS dose in OCS-dependent asthma with elevated eosinophils has been reported 
for the related anti-IL-5 investigational product, mepolizumab (Bel et al 2014), and is theorized 
to be a potential class effect. Additionally, the effect of reslizumab was pronounced in patients 
with severe asthma who were on OCS (Castro et al 2015).
In Studies Res-5-0010, 3081, 3082, 3083, and 3084, certain therapeutic classes of medications 
were used more frequently in the placebo group than in the reslizumab 3.0 mg/kg treatment 
group. These included antibacterials for systemic use (270 [26%] patients in the reslizumab 
3.0 mg/kg treatment group and 290 [40%] patients in the placebo group), antihistamines for 
systemic use (375 [36%] patients in the reslizumab 3.0 mg/kg treatment group and 
321 [44%] patients in the placebo group), corticosteroids for systemic use (246 [24%] patients in 
the reslizumab 3.0 mg/kg treatment group and 288 [39%] patients in the placebo group), and 
nasal preparations (325 [32%] patients in the reslizumab 3.0 mg/kg treatment group and 
268 [37%] patients in the placebo group). These imbalances in concomitant medication use most 
likely reflect the substantial benefits that reslizumab treatment provided in improving respiratory 
symptoms, resulting in less need for additional treatment in the reslizumab group.
1.4.3.
Overall Risk and Benefit Assessment for This Study
Improvement in lung function has been confirmed in 3 Phase 3 clinical studies with the iv dosage 
form. In addition to improved lung function, a significant reduction in CAEs over 52 weeks was 
observed in patients with moderate to severe asthma and elevated blood eosinophils in 2 Phase 3 
clinical studies. Modeling and simulation data 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 eosinophils and FEV1 in patients with eosinophilic asthma. Therefore, a fixed dose of 
110 mg sc once every 4 weeks is anticipated to provide sufficient efficacy.
In completed studies, reslizumab was generally well tolerated over the dose range 0.03 through 
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 


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differences in the adverse event profile between patients treated with reslizumab and patients 
treated with placebo, with the exception of the 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 
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 the 
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]). Refer to the IB for summary and comprehensive presentation of these data. 
Briefly, treatment with iv reslizumab at a dose of 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) was similar. Improvements in 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 forced vital capacity (FVC) and 
forced expiratory flow at 25% and 75% of the FVC (FEF25%-75%) was observed for patients in the 
reslizumab 0.3-mg/kg treatment group). Therefore, iv doses of ≥1 mg/kg are anticipated to be 
clinically effective in most patients. Based on these clinical and eosinophil PD data, Teva has 
chosen reslizumab 110 mg administered once 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%). 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 eosinophils and FEV1 in patients with eosinophilic asthma. 
Therefore, a fixed dose of 110 mg sc once every 4 weeks is anticipated to provide sufficient 
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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 
[CFR] Parts 11, 50, 54, 56, 312, and 314, European Union [EU] Directive 20/EC and 28/EC). 
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.
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 to, and requirements of, the study and with the properties of the study drug(s) as 
described in the IB 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
This study will enroll male and female patients, 12 years of age and older, with OCS-dependent 
asthma and elevated eosinophils. (Patients 12 to <18 years of age are excluded from participating 
in South Korea, the Netherlands, and Argentina, and patients 66 years of age and older are 
excluded from participating in South Korea.)
1.8.
Location and Timing of Study
This study is planned to be conducted in 19 countries at 155 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 OCS-dependent asthma and elevated blood eosinophils.
2.2.
Study Objectives
2.2.1.
Primary Objective
The primary objective of the study is to determine the ability of reslizumab (110 mg) 
administered sc once every 4 weeks to produce a corticosteroid-sparing effect (as demonstrated 
by percent reduction in daily OCS use) in patients with OCS-dependent asthma and elevated 
blood eosinophils, without loss of asthma control.
2.2.2.
Secondary Objective
The secondary objective of this study is to evaluate the clinical benefits of reslizumab in the 
context of OCS reduction.
2.2.3.
Other Efficacy Objective
Another efficacy objective of this study is to evaluate the effect of reslizumab on standard 
asthma control measures during tapering of OCS in patients with OCS-dependent asthma.
2.2.4.
Target Biomarker Objective
The target biomarker objective is to evaluate the effect of sc dosing of reslizumab on blood 
eosinophil counts.
2.2.5.
Immunogenicity Objective
The immunogenicity objective is to evaluate the potential of sc dosing of reslizumab to raise 
ADAs.
2.2.6.
Pharmacokinetic Objective
The PK objective is to characterize the PK of sc reslizumab in the study population.
2.2.7.
Exploratory Objectives


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2.2.8.
Safety Objective
The safety objective is to evaluate the safety of chronic sc dosing of reslizumab and tapering of 
OCS as assessed by the following:

occurrence of adverse events

clinical laboratory evaluations of serum chemistry and hematology

vital signs (pulse, respiratory rate, and blood pressure) measurements

ECG findings

physical examination findings, including body weight measurements

signs and/or symptoms of adrenal insufficiency (OCS withdrawal effects)

concomitant medication usage
2.3.
Study Endpoints
2.3.1.
Primary Efficacy Endpoint
The primary efficacy variable and endpoint for this study is the categorized percent reduction in 
the daily OCS dose during weeks 20 to 24 as compared with the dose at the end of the 
optimization phase. Percent reduction will be categorized as follows:

90% to 100%

75% to <90%

50% to <75%

>0% to <50%

No decrease in OCS, or loss of baseline asthma control during weeks 20 through 24, 
or discontinuation from study drug
Loss of baseline asthma control will be defined as FEV1 value of less than 80% of baseline at the 
week 24 visit, or clinically significant worsening in ACQ-6 score (change in score of 0.5) at the 
week 24 visit compared with baseline, and/or CAEs during weeks 20 through 24 (as defined in 
Section 6.7).
2.3.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints for this study are as follows:


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
Proportion of patients achieving ≥50% reduction in OCS dose at weeks 20 to 24 
relative to the OCS dose at the date of randomization (DoR)/baseline, while 
maintaining asthma control

Proportion of patients achieving dose reduction to ≤5 mg daily dose at weeks 20 to 
24, while maintaining asthma control

Percent change from DoR/baseline in OCS dose at weeks 20 to 24

Proportion of patients achieving less than 5 mg decrement in OCS dose (ie, the 
minimal and non-responders) at weeks 20 to 24 compared with the OCS dose at 
DoR/baseline, while maintaining asthma control

Clinical asthma exacerbation related:

Annualized rate of CAEs requiring a burst of systemic corticosteroid (injection, or 
if oral, at least a doubling from the current OCS dose for at least 3 days); an 
asthma-specific hospital admission; or an asthma-specific emergency department 
visit during the treatment period (weeks 0 to 24)

Proportion of patients discontinuing OCS at weeks 20 to 24, while maintaining 
asthma control
2.3.3.
Other Prespecified Efficacy Endpoints
The other efficacy endpoints are as follows:

Time to first CAE

Other clinic lung functions including the following:

Pre-bronchodilator FEV1: change from DoR/baseline to weeks 4, 8, 12, 16, 20, 
and 24 or early withdrawal

Post-bronchodilator FEV1: change from DoR/baseline to weeks 4, 12, 20, and 24 
or early withdrawal

Ambulatory lung function: change in morning (AM) and evening (PM) peak 
expiratory flow (PEF) from run-in baseline at each week through week 24 or early 
withdrawal

Asthma Quality of Life (AQLQ) + 12 score: change from DoR/baseline to weeks 4, 8, 
12, 16, 20, and 24 or early withdrawal

ACQ-6 score: change from DoR/baseline to weeks 4, 8, 12, 16, 20, and 24 or early 
withdrawal

Change in total inhalations of reliever bronchodilator medication (eg, SABA)
(number of inhalations per 24 hours: day+night) from run-in baseline at each week 
through week 24 or early withdrawal

Number of nighttime awakenings due to asthma over the 24-week treatment period

Change in total asthma symptom score from run-in baseline at each week through 
week 24 or early withdrawal


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
European Quality of Life 5-dimension health state utility index (EQ-5D) score: 
change from DoR/baseline to week 24 or early withdrawal

St. George’s Respiratory Questionnaire (SGRQ) score: change from DoR/baseline to 
weeks 12 and 24 or early withdrawal
2.3.4.
Target Biomarker Endpoint
The target biomarker endpoints are the blood eosinophil counts at DoR/baseline; weeks 4, 8, 12,
16, 20, and 24 or early withdrawal; and at the follow-up visit (approximately week 32).
2.3.5.
Immunogenicity Endpoints
The immunogenicity endpoints are the immunogenicity incidence and the impact of ADA on 
clinical outcomes. The drug-emergent ADA response will be identified by analyzing ADA test 
results for serum samples obtained before the administration of study drug at DoR/baseline; prior 
to study drug administration at weeks 4, 8, 12, and 24 or early withdrawal; and at the follow-up 
visit (approximately week 32). An additional sample will be obtained at the late follow-up visit 
(approximately week 48).
2.3.6.
Pharmacokinetic Endpoints
There are no specific endpoints related to PK. Measured concentrations will be used to 
characterize the PK of sc reslizumab in the studied population and to explore exposure-response 
relationships. Serum reslizumab concentrations will be determined from blood samples collected 
from each patient at DoR/baseline; and prior to study drug administration at weeks 4, 8 12, and 
24 or early withdrawal; and at the follow-up visit (approximately week 32). An additional PK 
sample will be obtained at the late follow-up visit (approximately week 48).
2.3.7.
Exploratory Endpoints
The exploratory endpoints are as follows:


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2.3.8.
Safety Endpoints
Safety endpoints will include the following:

occurrence of adverse events throughout the study, including the week 32 follow-up 
visit

clinical laboratory evaluations of serum chemistry at screening, DoR, and periodically 
throughout the study

clinical laboratory evaluations of hematology throughout the study

vital signs (pulse, body temperature, respiratory rate, and blood pressure) 
measurements throughout the study

ECG evaluation at screening and at week 24 or early withdrawal

physical examination findings, including body weight measurements, throughout the 
study

signs and/or symptoms of adrenal insufficiency (OCS withdrawal effects) throughout 
the study

concomitant medication usage throughout the study, including the week 32 follow-up 
visit


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3.
STUDY DESIGN
3.1.
General Design and Study Schema
This is a Phase 3, 24-week, double-blind, placebo-controlled, parallel-group study to evaluate the 
efficacy and safety of sc reslizumab treatment at a dosage of 110 mg every 4 weeks in patients 
12 years of age and older with OCS-dependent asthma and elevated blood eosinophils. The study 
will consist of a screening period of up to 2 weeks, followed by an optimization period of up to 
10 weeks, a run-in period of at least 2 weeks, a 24-week double-blind treatment period, an
8-week follow-up period, and an additional 16-week follow-up period to collect drug wash-out 
samples for immunogenicity assessments. 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. 
3.1.1.
Screening Period
Patients will begin screening up to 14 weeks before DoR. During the screening period, a signed 
and dated informed consent form (ICF) (and an assent form for children 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 (CBC) determined. If the patient’s 
eosinophil count is 300/μL or greater while on daily OCS and if the patient’s medication 
compliance and inhaler use technique are optimal, the patient will be eligible to continue. Note: a 
patient will meet inclusion criteria if an eosinophil count of 300/μL or greater becomes manifest 
during the OCS optimization period or at the week -2 visit (end of optimization period/beginning 
of run-in period). Patient medical history; pre-bronchodilator spirometry; 12-lead ECG; physical 
examination; urinalysis; vital signs measurements; beta human chorionic gonadotropin (βHCG) 
serum pregnancy test (for all females of childbearing potential); testing for human 
immunodeficiency virus (HIV), hepatitis B, and hepatitis C(HCV); and concomitant medication 
history will also be assessed at screening.
To be eligible to enroll in the study, a patient will have an airway FEV1 reversibility of at least 
12% to beta-agonist administration, a blood eosinophil count of at least 300/μL while on daily 
OCS or during the OCS optimization period or at the week -2 visit or a documented blood 
eosinophil level of at least 300/μL during the previous 12 months while on at least medium dose 
ICS, a current fluticasone propionate dosage of at least 880 μg daily or equivalent plus another 
controller, and will have met all the inclusion and none of the exclusion criteria.
3.1.2.
Optimization Period
Patients who meet screening eligibility requirements will enter the optimization period for up to 
10 weeks to determine the patient’s minimal effective OCS requirement. The patient’s previous 
OCS will be standardized to an equivalent dose and regimen of prednisone to facilitate 
optimization; the same formulation should be maintained through the end of treatment (EOT)


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visit. It is expected that the optimization period will be shorter than 10 weeks for those patients 
who are at or near their optimal corticosteroid dose at enrollment. The patient’s previous non-
OCS background asthma controller medications will be continued unchanged throughout the 
pre-randomization period and the entire study. At the beginning of the optimization period, an 
asthma symptom diary and electronic peak flow meter will be distributed where the patient will 
record asthma symptoms, number of reliever bronchodilator inhalations, nighttime awakenings 
due to asthma requiring rescue inhaler, and AM and PM PEF.
For optimization, the prednisone dose should be reduced at 1-week intervals, according to the 
algorithm shown in Table 1, for up to 10 weeks, or until there is a worsening of asthma signs and 
symptoms. Worsening of asthma signs and symptoms should be based on the following:

FEV1 <80% of the screening value AND/OR

The physician’s global assessment of asthma worsening based on trends in daily diary 
measures for the past 7 days compared with the week prior, as well as any physical 
examination signs
When either a lung function or a symptomatic deterioration occurs, the patient will be returned to 
the previously effective OCS level, which will then constitute the minimally effective dose for 
the purpose of run-in. If this previously effective dose is no longer effective, the investigator can 
determine the clinically appropriate minimally effective dose for the purpose of run-in.
Regarding the amount and rate of OCS reduction during dose optimization, in order to provoke a 
worsening of asthma signs and symptoms within the 10-week, monitored optimization period, 
OCS reduction should be attempted approximately every 1 week after evaluation in the clinic. 
The magnitude of OCS reduction will be based on the following Optimization Phase OCS Dose 
Reduction Algorithm (Table 1).


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Table 1:
Optimization Phase Prednisone Dose Reduction Algorithm
Time Course
Oral OCS Dose (mg/day)
Visit 2 starting dosea
40+b
35
30
25
20
15
10
7.5
5
1st reduction at Visit 2
35
30
25
20
15
10
7.5
5
2.5c
+ 1 week
30
25
20
15
10
7.5
5
2.5c
+ 1 week
25
20
15
10
7.5
5
2.5c
+ 1 week
20
15
10
7.5
5
2.5c
+ 1 week
15
10
7.5
5
2.5c
+ 1 week
10
7.5
5
2.5c
+ 1 week
7.5
5
2.5c
+ 1 week
5
2.5c
+ 1 week
2.5c
+ 1 week
a Starting doses that fall between values shown in this table should utilize the algorithm for the higher of the 2
doses.
b Patients who the investigator believes may be able to decrease OCS dose to 40 mg during the optimization period 
may be enrolled. OCS dose reduction during optimization for patients on >40 mg daily at that start of optimization 
should follow weekly reductions with magnitudes similar to those in the table (this may be discussed with medical 
monitor). Patients who require >40 mg OCS to maintain asthma control at the end of optimization will not be 
randomized.
c Patients must be using an average daily dose of ≥5 mg OCS after optimization. Patients who require <5 mg OCS 
to maintain asthma control will not be randomized.
OCS=oral corticosteroid
Regarding eosinophil counts during the optimization period, blood eosinophils ≥300/μL that 
become manifest during OCS reductions during optimization, will count toward the eosinophil 
inclusion criterion for this study.
3.1.3.
Run-In Period
Patients whose minimal effective OCS dose remains between ≥5 mg and ≤ 40 mg of prednisone
daily at the end of optimization may advance to run-in (for at least 2 weeks). During run-in, 
patients will continue to keep their daily asthma control diary and a PEF meter to perform daily 
self-monitoring of asthma symptoms while maintaining their minimally effective OCS dose and 
previous background asthma medications unchanged. The frequency of symptoms, use of 
inhaled reliever bronchodilator, nighttime awakenings due to asthma requiring rescue inhaler, 
and ambulatory lung function during the last 7 days of run-in will constitute the baseline level of 
control for analysis and the basis for OCS reduction algorithm to be used during the treatment 
period. 
3.1.4.
Treatment Period
Patients continuing to meet eligibility criteria on the day of randomization (day 1, week 0) will 
be randomly assigned in a 1:1 ratio to receive placebo or reslizumab 110 mg once every 4 weeks 


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through week 20, followed by an EOT visit at week 24. Patients will begin treatment on day 1 
after completing baseline assessments, and they will return to the research facility for outpatient 
visits every 4 weeks through week 24 (EOT visit) for safety, PK, PD, immunogenicity, and 
efficacy assessments as applicable. 
During the treatment period, the patient will continue his/her usual non-OCS background asthma 
medication without change; the OCS dose will be tapered per protocol. The treatment periods 
consist of the following:

Induction: The minimally effective dose of OCS will be maintained, unchanged, 
during the first 4 weeks of the treatment period to allow sufficient time for any 
potential treatment effect to become established.

OCS reduction: The minimally effective OCS dose will be reduced per protocol at 
scheduled clinic visits from the beginning of week 5 (ie, end of the induction period) 
through week 20, as long as all 5 criteria in Table 2 are met and there are no clinical 
manifestations of adrenal insufficiency. These 5 eligibility criteria assure that the 
patient's asthma control is not significantly worsened compared to baseline. The last 
possible dose reduction can occur at week 20. The algorithm for OCS reductions 
during the treatment period is given in Table 3.
If the OCS dose could not be decreased, it should be held constant, or may be 
increased to a previous level, at the investigator’s discretion, until dose reduction 
criteria are met.

Maintenance: OCS will be held stable from week 20 through EOT at week 24.
Table 2:
Eligibility Criteria for Scheduled Oral Corticosteroid Reductions During the 
Treatment Period (Must Meet All)
1
Forced expiratory volume in 1 second (FEV1) ≥80% of baselinea
2
AM PEF ≥80% of baseline mean AM PEF on at least 5 of the 7 days preceding the visit
3
Mean nighttime awakenings due to asthma requiring rescue inhaler over the preceding 7 days ≤ 
150% increase over the baseline period 
4
Reliever bronchodilator inhaler use does not exceed 150% of the baseline inhaler use per 24 hours 
on more than 2 of the preceding 7 days
5
No increase in OCS dose since the previous visit
b
a Baseline for clinic visit measures (FEV1) is the DoR value. Baseline for diary measures is the average over the 7 
days before DoR.
b If a dose increase results in a return to the previous dose, then it is acceptable to attempt dose decrease again at the 
investigator’s discretion.
AM=morning; DoR=date of randomization; FEV1=forced expiratory volume in 1 second; PEF=peak expiratory 
flow; OCS=oral corticosteroid.


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Table 3:
Oral Corticosteroid Decrements During the Treatment Period
Time Course
Oral OCS Dose (mg/day)
Optimized OCS dose
40
35
30
25
20
15
10
7.5
5
1st reduction
30
25
20
15
10
10
7.5
5
2.5
+ 4 weeks
20
15
10
10
7.5
7.5
5
2.5
0
+ 4 weeks
10
10
5
5
5
5
2.5
0
+ 4 weeks
5
5
2.5
2.5
2.5
2.5
0
+ 4 weeks
2.5
2.5
0
0
0
0
3.1.4.1.
Handling of Asthma Exacerbations During the Treatment Period
Patients should be treated with an OCS burst: 40 to 60 mg (or at least double the current dose) of 
OCS tapered over a 7- to 10-day period to a new maintenance dose of 2.5 mg above the pre-burst 
dose. It is understood that im or iv corticosteroid may also be administered as part of the 
treatment of the asthma exacerbation. If a second OCS burst (doubling of current dose) is 
required, the patient should be maintained on a fixed OCS dose without any tapering attempts for 
the remainder of the double-blind treatment phase and the follow-up period.
Patients who complete all scheduled visits will have final procedures and assessments performed 
at the EOT visit (visit 19). Patients who withdraw from the study before completing the 24-week
treatment period will have visit 19 (week 24 ±7 days or early termination) procedures and 
assessments performed at their final visit. Patients will return for a follow-up evaluation 8 weeks
(±7 days) after the EOT visit in this study for assessment of pre-bronchodilator spirometry, 
ACQ-6 score, PK samples, adverse events, blood eosinophils, CAEs and related health care 
utilizations, and blood for ADA.
The assessments and procedures performed during each study visit are detailed in Table 5 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 his/her 
withdrawal from the study (see Section 4.5).
The study schema is presented in Figure 1. 


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Figure 1:
Overall Study Schema
Note: An additional, late follow-up for immunogenicity 
(ie, approximately week 48).
AE=adverse event; DoR=day of randomization; EOT=e
OCS=oral corticosteroid; PK=pharmacokinetic; V=visit
Placebo-
52
and PK testing will be performed 28 weeks (±2 weeks) after the last dose 
nd of treatment;
F/u=follow
t; wk=week.
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w up; IP=investigational product; 


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3.2.
Justification for Study Design
The rationale for the design of the study is summarized in Table 4.
Table 4:
Rationale for Protocol
Area
Rationale
Study population
Representative of the OCS dependent asthma population with 
elevated blood eosinophils
Investigational product dosage regimen 
and duration of treatment
Sc dose and regimen based on BREATH iv program Study 
3081
Choice of comparison drug(s) (placebo, 
active)
Placebo control is essential to establish efficacy and safety
Number of subjects (including number 
per treatment group)
Based on historical OCS reduction studies
Treatment blinding (ie, rationale for 
blinded or open-label design)
Double-blinding and randomized treatment allocation to 
prevent bias efficacy study
Primary analysis (measure, variable, time 
point, statistical test)
Reduction OCS dose is the primary objective
Inclusion of ancillary studies: PK, PD, 
PGx, immunogenicity
PK and target blood eosinophil PD are important to 
interpretation of efficacy results
 
 
Immunogenicity assessments are essential to evaluate the 
safety and efficacy of reslizumab
Key safety measures
Standard measures consistent with iv reslizumab studies in
eosinophilic esophagitis and eosinophilic asthma
iv=intravenous; OCS=oral corticosteroid; PD=pharmacodynamic; PGx=pharmacogenomic; PK=pharmacokinetic; 
sc=subcutaneous.
3.3.
Primary and Secondary Measures and Time Points
A more detailed description of the efficacy measures is provided in Section 6.
3.3.1.
Primary Efficacy Measure and Time Points
The primary efficacy variable and endpoint for this study is the categorized percent reduction in 
the daily OCS during weeks 20 to 24 compared with the dose at the end of the optimization 
phase. Refer to Section 6.1 for additional details regarding the categorization of the reduction in 
OCS dose.


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3.3.2.
Secondary Efficacy Measures and Time Points
The secondary efficacy measures and time points include the following:

≥50% reduction in OCS dose, while maintaining asthma control, at weeks 20 to 24 
relative to OCS dose at DoR/baseline

Reduction to ≤5 mg daily dose at weeks 20 to 24, while maintaining asthma control

OCS dose at weeks 20 to 24 relative to DoR/baseline

Less than 5 mg decrement in OCS dose (ie, the minimal and non-responders) at 
weeks 20 to 24, while maintaining asthma control

Clinical asthma exacerbation related:

Annualized rate of CAEs requiring a burst of systemic corticosteroid (injection, or 
if oral, at least a doubling from the current OCS dose for at least 3 days); an 
asthma-specific hospital admission; or an asthma-specific emergency department 
visit during the treatment period (weeks 0 to 24)

OCS discontinuations at weeks 20 to 24, while maintaining asthma control
These measures will be evaluated at the time points in Table 5.
3.3.3.
Other Prespecified Efficacy Measures and Time Points
The other efficacy measures and time points include the following:

Time to first CAE

Other clinic lung functions, including the following:

Spirometry, including pre- and post-bronchodilator FEV1

Ambulatory lung function including AM and PM PEF based on the PEF meter

AQLQ + 12

ACQ-6

Total reliever bronchodilator inhalation use (number of inhalations per 24 hours: day 
and night) based on the daily asthma control diary

Nighttime awakenings due to asthma requiring rescue inhaler based on the daily 
asthma control diary

Asthma symptoms based on the daily asthma control diary

EQ-5D

SGRQ
These measures will be evaluated at the time points in Table 5.


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3.4.
Target Biomarker Measures and Time Points
Blood eosinophils will be determined from blood samples collected at the time points indicated 
in Table 5.
3.5.
Immunogenicity Measures and Time Points
Serum ADAs will be determined from blood samples collected from each patient at the time 
points indicated in Table 5.
3.6.
Pharmacokinetic Measures and Time Points
Serum reslizumab concentration will be determined from blood samples collected from each 
patient at the time points indicated in Table 5. A description of the PK measures is provided in 
Section 8.1.
3.7.
Exploratory Measures and Time Points
The exploratory measures for this study include the following and will be evaluated at the time 
points indicated in Table 5.
3.8.
Safety Measures and Time Points
The following safety measures will be implemented throughout the study and evaluated at the 
time points in Table 5:

Inquiries about adverse events

Clinical laboratory evaluations of serum chemistry

Clinical laboratory evaluations of hematology

Vital signs (pulse, body temperature, respiratory rate, and blood pressure) 
assessments

ECGs

Physical examinations


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
Monitoring and evaluation of any signs and/or symptoms of adrenal insufficiency 
(OCS withdrawal effects)

Inquiries about concomitant medication usage
A description of the safety measures is provided in Section 6.15.
3.9.
Randomization and Blinding
This is a randomized, double-blind, placebo-controlled study. In order to achieve balance 
between treatment groups with regard to average daily OCS use/requirement and age, 
randomization will be stratified by optimized, average daily OCS dose of >10 mg or ≤10 mg and 
age (12 to <18 years of age or ≥18 years of age) at baseline. Within each stratum, patients will be 
randomly assigned to receive treatment with sc reslizumab at a dosage of 110 mg every 4 weeks
or a matching placebo in a 1:1 ratio. This system is used to ensure a balance across treatment 
groups.
The randomization list and treatment will be assigned to the relevant treatment groups through a 
qualified 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 CRO under the oversight of Teva’s Clinical 
Supply Chain.
The sponsor’s 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 (Global Bioassays and Technology), who, 
in order to facilitate PK and ADA sample analysis, will not be blinded. Eosinophils and 
monocytes will be redacted from the post-baseline differential cell count reports to avoid the 
possibility of removing the blind.
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 randomization 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.
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 


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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 randomly-assigned 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 afterward, 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), the Global Patient Safety and 
Pharmacovigilance department 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, Teva medical monitor, and study personnel) and the patient 
will not be withdrawn from the study.
In order to maintain the blinding in this study, each patient will receive either one 1.0-mL sc 
injection containing 110 mg of reslizumab or one 1.0-mL injection containing sterile placebo 
solution on each dosing day. Both reslizumab and placebo will be provided as clear solutions.
3.11.
Drugs Used in the Study
A description of administration procedures is given in Section 5.1.
Additional details may also be found in the current version of the IB for reslizumab. 
3.11.1.
Investigational Product
Reslizumab 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. Both reslizumab and placebo will be provided as clear solutions.


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Reslizumab will be administered sc in a dosage of 110 mg (1.0 mL) every 4 weeks, depending 
on treatment assignment. 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 containing 
 sodium acetate, with 
 
sucrose, 
 polysorbate 80, pH 5.5 buffer, presented as 1.0-mL per syringe. The needle 
shields of the prefilled syringes contain natural rubber latex.
Placebo will be administered as a sc injection. Each patient will receive a placebo dose of 1.0 mL
injected sc, depending on treatment assignment.
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), should not be frozen, and should be protected from light. Reslizumab and placebo will 
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 of the contents of the shipment, and 
drug return instructions and any applicable forms.
Each investigator is responsible for ensuring that deliveries of study drug and other study 
materials from the sponsor are correctly received and recorded, handled and stored safely and 
properly in accordance with the 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
The study is expected to last up to 62 weeks and will consist of a screening period of up to 
2 weeks, an optimization period of up to 10 weeks, a run-in period of at least 2 weeks on the 
optimized OCS dose, followed by a 24-week double-blind treatment period, an 8-week follow-up 
period. It is expected that the optimization period will be shorter than 10 weeks for those patients 
who are at or near their optimal corticosteroid dose at enrollment.
An additional, late follow-up for immunogenicity testing will be performed 28 weeks after the 
last dose of study drug. See Section 12.4 for the definition of the end of the study. 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.


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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, serious adverse events and adverse events of special interest 
will be reviewed by the sponsor (see Section 7.1.6) 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, 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 reaction, 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 timings are summarized in Table 5. 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 6.15 (safety assessments), 
and Section 8 (PK and other assessments).


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Table 5:
Study Procedures and Assessments
Procedures and 
assessments
Pretreatment
V12
Start 
run-in
Double-blind treatment period (visit/week)
Follow-up
Late 
follow-up
V1
V2-V11
V13a
V14a
V15a
V16a
V17a
V18a
V19a
V20
V21
Start of 
screening 
period
Standardize 
and optimize 
maintenance 
OCSabc
Week −14d
Between 
weeks −12 
and −3
W −2
DoR
W4±7d
W8±7d
W12±7d
W16±7d
W20±7d
W24±7d/
EOT/
early termination
W32/EOT 
+ 8w ±7d
W48/EOT 
+ 24w 
±14d
Informed assent/consent
X
Medical history
X
Medication history
X
Inclusion and/or exclusion 
criteria
X
Xe
X
X
Randomization criteria
X
Reversibility testingf
X
Pregnancy testingg
X
X
X
X
X
X
X
X
X
Blood for HIV, hepatitis B, 
and hepatitis C
X
CBC with differentialh
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry testsi
X
X
Xj
Xj
X
Xj
Xj
X
Urinalysis
X
Full physical examinationk
X
Brief physical examinationk
X
X
X
X
X
X
X
X
X
Vital signs measurementk
X
X
X
X
X
X
X
X
X
X
Heightl and weight
X
X
X


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Table 5:
Study Procedures and Assessments
Procedures and 
assessments
Pretreatment
V12
Start 
run-in
Double-blind treatment period (visit/week)
Follow-up
Late 
follow-up
V1
V2-V11
V13a
V14a
V15a
V16a
V17a
V18a
V19a
V20
V21
Start of 
screening 
period
Standardize 
and optimize 
maintenance 
OCSabc
Week −14d
Between 
weeks −12 
and −3
W −2
DoR
W4±7d
W8±7d
W12±7d
W16±7d
W20±7d
W24±7d/
EOT/
early termination
W32/EOT 
+ 8w ±7d
W48/EOT 
+ 24w 
±14d
ECGk
X
X
Provide and collect PEF 
meter
X
X
Provide/collect electronic 
asthma control diary; 
reinforce diary and PEF 
compliance
X
X
X
X
X
X
X
X
X
OCS reduction attempts
X
X
X
X
X
X
Pre-bronchodilator 
spirometrym
X
Xn
X
X
X
X
X
X
X
X
Post-bronchodilator 
spirometryo
X
X
X
X
X
X
PK samplesp
X
X
X
X
X
X
X
X
X
Blood for ADAq
X
X
X
X
X
X
X
IP administration
X
X
X
X
X
X
Injection site evaluation
X
X
X
X
X
X


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Table 5:
Study Procedures and Assessments
Procedures and 
assessments
Pretreatment
V12
Start 
run-in
Double-blind treatment period (visit/week)
Follow-up
Late 
follow-up
V1
V2-V11
V13a
V14a
V15a
V16a
V17a
V18a
V19a
V20
V21
Start of 
screening 
period
Standardize 
and optimize 
maintenance 
OCSabc
Week −14d
Between 
weeks −12 
and −3
W −2
DoR
W4±7d
W8±7d
W12±7d
W16±7d
W20±7d
W24±7d/
EOT/
early termination
W32/EOT 
+ 8w ±7d
W48/EOT 
+ 24w 
±14d
AQLQ+12 
X
X
X
X
X
X
X
ACQ-6
X
X
X
X
X
X
X
X
EQ-5D
X
X
St. George’s Respiratory 
questionnaire
X
X
X
Assess CAEs and related 
HCUr
X
X
X
X
X
X
X
Phadiatop allergy test
X
OCS withdrawal effects 
inquirys
X
X
X
X
X
X
X
X
Adverse event inquiryt
X
X
X
X
X
X
X
X
X
X
Concomitant medication 
inquiry
X
X
X
X
X
X
X
X
X
X
X
a The site will contact IWRS at every optimization and treatment visit.
b The patient’s previous OCS should be switched to an equivalent, standardized prednisone formulation. Optimization may occur once OCS standardization is complete.
c Attempts at OCS reduction should be made at 1-week intervals, for up to 10 weeks or until there is a worsening of asthma signs and symptoms, to help determine the patient’s 
lowest effective OCS dose. This period may be shortened if the lowest effective dose is achieved sooner. Eosinophil counts during the optimization period or at the week -2 visit 
may be considered in order to meet the eosinophil inclusion criteria for this study. Patients requiring an average daily dose of between ≥5 mg and ≤40 mg may proceed to run-in 
and maintained without change during run-in.
d The screening period (between V1 and V2) can be less than 2 weeks if all of the screening inclusion criteria are met sooner. 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 and reversibility testing.


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e Verify that essential screening inclusion criteria for asthma are met before entering optimization.
f Reversibility testing is most conveniently performed at the same visit as the screening, pre-bronchodilator spirometry. All patients must undergo reversibility testing, even if they 
are submitting historical reversibility or methacholine provocation results to support inclusion criterion e. Reversibility testing may be repeated once, within the 2-week 
screening period.
g βHCG serum pregnancy tests will be performed at screening; urine pregnancy testing will be performed every 4 weeks thereafter until week 24 or early withdrawal (female 
patients who are not 2 years postmenopausal or surgically sterile) and at the early follow-up visit (V20).
h The patient must have had a blood eosinophil count ≥300/μL in the 12 months before ICF or ≥300/μL during screening or during OCS optimization or at the week -2 visit. A 
CBC with differential need not be repeated at every visit during the optimization period and should be done at the investigator's discretion if the eosinophil criteria were not met 
at screening.
i 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 7.1.7.3.2.
j CPK measurement only. CPK will be collected with PK sample.
k Physical examination, vital signs, and ECG should be obtained before spirometry procedures and IP administration.
l For adults, height will be measured at screening only. For patients <18 years of age, height will be measured at screening, DoR, and EOT. Use of a stadiometer is preferable, if 
available, or use a cloth tape securely attached to the wall that will allow reproducible results. Height should be measured in centimeters, without shoes.
m Pre-bronchodilator spirometry assessments should only be performed after withholding short-acting bronchodilators (ie, inhaled short-acting beta-agonists and/or short acting 
anticholinergics) for at least 6 hours and long-acting bronchodilators (ie, inhaled LABAs 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.
n Optional at visits 2-11.
o For post-bronchodilatory spirometry, short-acting beta-agonists, 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 a metered dose inhaler as tolerated. Post-bronchodilator spirometry should be completed a minimum of 15 
minutes after dosing of short-acting beta-agonist.
p Blood samples for PK and ADA analysis will be drawn before administration of study drug.
q If possible, a blood sample for measurement of serum reslizumab concentrations will be obtained from patients experiencing an adverse event leading to withdrawal, a serious 
adverse event, an observation of any severe hypersensitivity reaction (eg, anaphylaxis), or an exacerbation of asthma symptoms.
r 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. Procedures and assessments to be performed if an unscheduled visit occurs are described in Protocol Section 3.16.5.
s Based on investigator's assessment.
t 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).
ACQ-6=6-item Asthma Control Questionnaire; ADA=anti-drug antibody; AQLQ=Asthma Quality of Life Questionnaire; βHCG=beta human chorionic gonadotropin; 
CAE=clinical asthma exacerbation; CBC=complete blood count; CPK=creatine phosphokinase; CRF = case report form; DoR=date of randomization; ECG=electrocardiogram; 
eDiary = electronic diary; EOT=end of treatment; EQ-5D=European Quality of Life 5-dimension health state utility index; FEV1=forced expiratory volume in 1 second; 
 HCU=health care utilizations; HIV=human immunodeficiency virus; ICF=Informed Consent Form; IP=Investigational Product; LABA=long-acting 
beta-agonist; OCS=oral corticosteroid; PEF=peak expiratory flow; PK=pharmacokinetic; 
 ULN = upper limit of normal V=visit; W=week.


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3.16.1.
Procedures for Screening and Enrollment (Visit 1)
A signed and dated ICF will be obtained from all patients 18 years of age or older before any 
study-specific screening procedures are performed (see Section 12.1). For patients 12 through 
<18 years of age, a signed and dated ICF will be obtained from a 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 within a specified 
timeframe before informed consent may be used for the study. Parents/legal guardians 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 
third patient screened at center 5 would be given the number of 01005003).
A patient who is screened but not randomized, for example, because entry criteria were not met, 
may be considered for screening once more, for example, if 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 date of 
Screen Failure and the re-screening must be >30 days.
The following procedures will be performed at the screening visit (visit 1):

Obtain written informed consent before any other study-related procedures are 
performed

Review medical history

Review prior and concomitant medication 

Review inclusion/exclusion criteria

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 
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 a metered 


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dose inhaler, as tolerated. Post-bronchodilator spirometry should be completed a 
minimum of 15 minutes after dosing of SABA.

Perform serum pregnancy testing (female patients who are not 2 years 
postmenopausal or surgically sterile only)

Perform clinical laboratory tests (chemistry, hematology, and urinalysis); only 
patients with an eosinophil counts of 300 eosinophils/μL or greater at screening while 
on chronic OCS, or those with a documented level of at least 300 eosinophils/μL 
during the previous 12 months will be eligible to continue in the study
○
Note: a patient will meet inclusion criteria if an eosinophil count of 300/μL or 
greater becomes manifest during the OCS optimization period or at the 
week -2 visit (end of optimization period/beginning of run-in period).

Perform full physical examination

Perform vital signs assessments (includes systolic and diastolic blood pressure, pulse, 
body temperature, and respiratory rate)

Measure height and weight

Perform ECG

Perform pre bronchodilator spirometry

Collect blood for HIV, hepatitis B, and hepatitis C testing

Inform patients of study restrictions and compliance requirements
3.16.2.
Procedures Before Study Drug Treatment
3.16.2.1.
Procedures During the Optimization Period (Weeks −12 through −3
[Visits 2 through 11])

Verify that essential screening inclusion criteria for asthma are met before entering 
optimization

Perform hematology tests (CBC with differential) if the inclusion criterion of an 
eosinophil count of 300/μL or greater was not met at screening

Perform brief physical examination

Perform vital signs assessments

Provide and collect PEF meter

Provide/collect electronic asthma control diary; reinforce diary and PEF compliance

Attempt OCS reduction

Concomitant medication inquiry

Adverse event inquiry


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3.16.2.2.
Procedures During the Run-In Period (Week −2 [Visit 12])

Review inclusion/exclusion criteria

Perform hematology tests (CBC with differential) if the inclusion criterion of an 
eosinophil count of 300/μL or greater was not met at prior visits

Perform brief physical examination

Perform vital signs assessments

Provide/collect electronic asthma control diary; reinforce diary and PEF compliance

Assess any OCS withdrawal effects (based on investigator’s assessment)

Perform concomitant medication inquiry

Perform adverse event inquiry
For a minimum of 2 weeks after visit 12, patients will continue on their usual asthma 
medications and their optimized OCS dose and complete daily self-monitoring of symptoms 
using an asthma control diary and PEF meter. 
3.16.2.3.
Procedures at Baseline/Day of Randomization (Week 0 [Visit 13])
Patients who complete the run-in period will continue to visit 13, when baseline evaluations will 
be conducted.
The baseline visit (visit 13) will not take place more than 14 weeks after the screening visit. The 
following procedures will be performed at visit 13 before reslizumab or placebo administration:

Review inclusion/exclusion criteria

Review randomization 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 assessments (includes systolic and diastolic blood pressure, pulse, 
body temperature, and respiratory rate)

Measure height and weight

Complete asthma-specific tests

Collect and review electronic asthma control diary and reinforce diary and PEF 
compliance. 

Pre-bronchodilator spirometry, including FEV1, % predicted FEV1, FVC, and 
FEF25%-75%

Post-bronchodilator spirometry, including FEV1, % predicted FEV1, FVC, and 
FEF25%-75%


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
Complete the AQLQ+12

Complete ACQ-6

Collect blood for asthma biomarker analysis

Collect blood for serum reslizumab concentration determination (PK assessment)

Collect blood sample for immunogenicity (ie, ADA) assessment



Complete EQ-5D


Complete SGRQ

Assess CAEs and related health care utilizations

Collect blood for Phadiatop allergy test (Vidal et al 2005)

Assess any OCS withdrawal effects (based on investigator’s assessment)

Record any concomitant medications
A patient who is not randomly assigned to treatment on the basis of the 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 rescreening if there is a change in the patient’s medical 
background, a modification of study entry criteria, or other relevant change. A patient may be 
rescreened for this reason 1 time only. The duration between the first visit during the screening 
period and the rescreening must be >30 days. Patients may be screened again if they did not meet 
spirometry/reversibility criteria initially.
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 2 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 on day 
1:

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.


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3.16.3.
Procedures During Study Drug Treatment
3.16.3.1.
Double-Blind Treatment Period (Weeks 1 Through 24 [Visits 13 Through 19])
Study drug will be administered at approximately the same time in the morning on the days
indicated in Table 5. (Note: Patients must be observed for a minimum of 1 hour after study drug 
administration.)
3.16.3.1.1. Weeks 4, 8, 12, 16, 20, and 24 (Visits 14 Through 19)
During the study drug treatment period, patients will return to the study center once every 
4 weeks (±7 days) thereafter (relative to DoR/baseline) for administration of study drug and 
assessments until the end of the treatment period (week 24 or early withdrawal).
The following procedures/assessments will be performed before administration of study drug
unless otherwise indicated:

Perform urine pregnancy testing at weeks 4, 8, 12, 16, 20, and 24 or early withdrawal

Perform hematology tests (CBC with differential) at weeks 4, 8, 12, 16, 20, and 24 or 
early withdrawal

Perform serum chemistry tests (weeks 12 and 24 or early withdrawal) (a sample for 
CPK measurement only will also be collected on weeks 4, 8, 16, and 20).

Perform brief physical examination at weeks 4, 8, 12, 16, 20, and 24 or early 
withdrawal

Perform vital signs measurements (includes systolic and diastolic blood pressure, 
pulse, body temperature, and respiratory rate) at weeks 4, 8, 12, 16, 20, and 24 or 
early withdrawal

Measure height and weight (week 24 or early withdrawal) for patients 12 to <18 years 
of age

Measure weight (week 24 or early withdrawal) for adult patients

Perform ECG (week 24 or early withdrawal)

Perform adverse event inquiry

Complete asthma-specific tests

Provide and collect PEF meter (week 24 or early withdrawal)

Provide/collect electronic asthma control diary; reinforce diary and PEF 
compliance (weeks 4, 8, 12, 16, 20, and 24 or early withdrawal)

OCS reduction attempts (weeks 4, 8, 12, 16, and 20)

Pre-bronchodilator spirometry (weeks 4, 8, 12, 16, 20, and 24 or early 
withdrawal)

Post-bronchodilator spirometry (weeks 4, 12, 20, and 24 or early withdrawal)


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
AQLQ +12 (weeks 4, 8, 12, 16, 20, and 24 or early withdrawal) (may be 
completed after study drug administration during the 1-hour observation period)

ACQ-6 (weeks 4, 8, 12, 16, 20, and 24 or early withdrawal) (may be completed 
after study drug administration during the 1-hour observation period)

Collect blood for asthma biomarker analysis (week 24 or early withdrawal)

Assess CAEs and related health care utilizations

Collect blood for serum reslizumab concentration determination (PK assessment)
(weeks 4, 8, 12, 16, 20, and 24 or early withdrawal)

Collect blood sample for immunogenicity assessment (weeks 4, 8, 12, and 24 or early 
withdrawal)



Complete EQ-5D (week 24 or early withdrawal) (may be completed after study drug 
administration during the 1-hour observation period)


Complete SGRQ (weeks 12 and 24 or early withdrawal) (may be completed after 
study drug administration during the 1-hour observation period)

Record any concomitant medications

Investigational product (IP) administration (weeks 4, 8, 12, 16, and 20)

Assess any OCS withdrawal effects (based on investigator’s assessment)
Additionally, 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 24 weeks of 
double-blind treatment will be considered to have completed the treatment period. Patients who
complete the follow-up visit (approximately week 32) will be considered as having completed 
the study. See Section 12.4 for the definition of the end of the study.


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Patients who discontinue the study drug prematurely must be encouraged to continue to attend 
the regular scheduled visits and complete the prescribed safety and efficacy evaluations through 
the EOT/early withdrawal visit and the follow-up visit, if at all possible (see Section 4.5).
Patients who both discontinue the study drug and also withdraw from the study should have final 
evaluations performed on the last day they receive the study drug or as soon as possible 
thereafter. Patients should also return for the follow-up visit and procedures if at all possible (see
Section 4.5).
Procedures for patients who withdraw prematurely from the study are described in Section 4.5.
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 and Section 7.3, 
respectively. 
The following procedures/assessments will be performed at the follow-up visit (EOT + 8 weeks 
±7 days [visit 20]):

Hematology tests (CBC with differential)

Collect blood for serum reslizumab concentration determination (PK assessment)

Collect blood sample for immunogenicity assessment

Concomitant medication inquiry

Adverse event inquiry

Perform urine pregnancy test
The following procedures/assessments will be performed at the late follow-up visit 
(EOT + 24 weeks ±14 days [visit 21]):

Collect blood for serum reslizumab concentration determination (PK assessment)

Collect blood sample for immunogenicity assessment
3.16.5.
Unscheduled Visits
An unscheduled visit may be performed at any time during the study at the subject’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 within the patient’s source notes.
Procedures performed during unscheduled visits include the following:

Perform concomitant medication inquiry

Perform vital signs measurements

Perform adverse event inquiry


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
Perform evaluation of any signs and/or symptoms of adrenal insufficiency (OCS 
withdrawal effects)

Perform study compliance review
Other procedures may be performed at the discretion of the investigator.


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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 the study only if they meet all of the following criteria:
a.
The patient is male or female, 12 years of age and older, with a previous diagnosis of 
asthma. Patients 12 to <18 years of age are excluded from participating in South 
Korea, the Netherlands, and Argentina, and patients 66 years of age and older are 
excluded from participating in South Korea.
b. Written informed consent is obtained. During the screening period, a signed and dated 
informed consent form (ICF) (and an assent form for children 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.
c.
The patient continues to require an average daily maintenance dose of OCS for 
asthma of between 5 and 40 mg of prednisone or equivalent during the 3 months 
before screening. Patients on an OCS dose of >40 mg at screening who the 
investigator believes may be able to decrease OCS dose to ≤40 mg during the 
optimization period may also be enrolled. Note: every-other-day dosing that is within 
this daily average (ie, 10 to 80 mg) is allowed.
d. The patient has a documented blood eosinophil level of at least 300/L during the 
previous 12 months while on at least medium total daily dose of ICS based on Global 
Initiative for Asthma 2016 clinical comparability table (Appendix A), or ≥300/L at 
screening while on chronic OCS or that becomes manifest during the OCS 
optimization period or at the week -2 visit (end of optimization period/beginning of 
run-in period).
e.
The patient has required at least 880 μg of inhaled fluticasone propionate or 
equivalent daily PLUS another controller(s) (eg, LABA, long-acting anti-muscarinic 
antagonist, leukotriene inhibitor, or theophylline) or documented intolerance to 
another controller for at least 6 months before the screening visit. For a fixed-dose 
ICS/LABA preparation, the highest labeled dose in that region will satisfy this 
criterion. For patients 12 through <18 years of age, the ICS dose must correspond to 
at least a medium total daily ICS dose. Note: the dose and regimen of asthma 
controllers and any allergen immunotherapy should have been stable during the 
30 days before signing the Informed Assent Form/ICF.
f.
The patient has FEV1 reversibility of at least 12% after administration of inhaled 
reliever medication according to the standard American Thoracic Society (ATS) or 
European Respiratory Society (ERS) protocol. Given the refractory nature of the 
disease in this population and the influence of high background controller 
medications on reversibility testing, documented FEV1 reversibility of 12% or a


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provocation concentration producing a 20% fall in FEV1 for methacholine of 
≤8 mg/mL within 24 months of the screening visit, and performed according to the 
standard ATS/ERS procedures, would fulfill this criterion. Patients may be screened 
again if they did not meet spirometry/reversibility criteria initially. The duration 
between the date of Screen Failure and the re-screening must be >30 days.
g. 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. 
h. The patient must be willing and able to comply with study restrictions, willing and 
able to perform requisite procedures and 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. 
i.
Except for the OCS, which will be adjusted per protocol, the patient must maintain 
his/her usual asthma controller regimen without change throughout the screening, 
optimization, run-in, and treatment periods.
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 and 
interpretation of efficacy results or would 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 [also known as Churg-Strauss syndrome], or allergic 
bronchopulmonary aspergillosis).
c.
The patient has a known hypereosinophilic syndrome.
d. The patient has a history of any malignancy within 5 years of the screening visit, 
except for treated and cured nonmelanoma skin cancers.
e.
The patient is pregnant or intends to become pregnant during the study or within 
5 months from last dose of study drug or is lactating. 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.
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.


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h. The patient is currently using any systemic immunosuppressive or 
immunomodulatory biologic agents (eg, anti-immunoglobulin E mAb or other mAb
[eg, mepolizumab] or soluble receptor) or nonbiologic (eg, methotrexate, 
cyclosporine), except maintenance OCS for the treatment of asthma. Previous use of 
such agents that occurred >5 half-lives from the screening visit may be allowed, if 
approved by the medical monitor.
i.
The patient participated in a clinical study 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 immunodeficiency disorder including HIV.
m. The patient has current suspected drug and/or alcohol abuse.
n. The patient has had an active helminthic parasitic infection or was treated for one 
within 6 months of screening. 
o. The patient has a history of allergic reactions 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 OCS-dependent asthma phenotype with 
elevated eosinophils and that is likely to benefit from a targeted therapy such as reslizumab, 
while ensuring that enrolled patients are of sufficient health quality to ensure that participation in 
this study will not put them at unnecessary risk.
4.4.
Randomization criteria
After completion of the optimization/run-in period, patients may continue in the study if they 
meet all of the following criteria:
a.
The patient must be using an average daily dose of no less than 5 mg of prednisone 
after OCS optimization. A patient requiring less than 5 mg of prednisone to maintain 
control should not be randomized.
b. The patient must be using an average daily dose of no more than 40 mg of prednisone 
after OCS optimization. A patient requiring more than 40 mg of prednisone to 
maintain control should not be randomized.
c.
The patient should not have had an asthma exacerbation during the run-in period, 
defined as requiring a burst of systemic corticosteroid for an asthma worsening 
(injection, or if oral, at least a doubling from the current OCS dose for at least 
3 days); an asthma-specific hospital admission; or an asthma-specific emergency 
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d. The patient must have completed at least 4 days of diary entries (or any combination 
of 4 morning and 4 evening recordings) during the last 7 days of the run-in period.
4.5.
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 
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 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. If possible, a blood sample for 
measurement of serum reslizumab concentrations will be obtained from patients experiencing an 
adverse event leading to withdrawal, a serious adverse event, an observation of any severe 
hypersensitivity reaction (eg, anaphylaxis), or an exacerbation of asthma symptoms.
4.5.1.
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 will continue to 
receive study provided OCS (prednisone) treatment for the remainder of their participation in the 
study. 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 specified in the protocol for the early withdrawal visit (see Table 5). 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 24 (visit 19). The OCS dose and safety assessments at week 24 (visit 19) 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, 
OCS dose, and survival status at week 24. A safety follow-up visit (visit 20) should be conducted 
8 weeks after visit 19.


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4.5.2.
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, every effort should be made to complete and report the observations 
outlined in Section 4.5.1 (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, OCS dose, 
and survival status at the end of the 24-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 maintenance OCS dose of 
>10 mg or ≤10 mg and age (12 to <18 years of age or 18 years of age or older) at baseline, using 
IRT, which uses computerized central randomization. Study drug will be administered by 
qualified study personnel as sc injections in the upper arm(s) once every 4 weeks for a total of 
6 doses.
The pre-filled syringe has a staked 27G 0.5-inch 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. The sites where injections are given should be at least 1 inch away 
from each other. 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 3.11.1. 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 
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 at screening 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. Systemic corticosteroids and other medications 
will each be recorded in separate CRFs. The sponsor will encode all therapy and medication 
according to the World Health Organization (WHO) drug dictionary (WHO Drug).
Excluding OCS, which will be adjusted per protocol, the patient’s baseline asthma therapy 
regimen (including, but not limited to, ICS, leukotriene antagonists, 5-lipoxygenase inhibitors, 
cromolyn) must be stable for 30 days before screening and continue without dosage changes 
throughout the study. 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 during this study unless the patient’s safety is at risk. Changes in 
background maintenance therapy must be discussed with the medical monitor.


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The following medications will not be allowed during this study:

Patients should refrain from using reliever inhalers for 6 hours before any study visit 
that includes spirometry or airway reversibility testing, including the screening visit.

If a patient is taking LABAs, these should be withheld for 12 hours before any study 
visit that includes spirometry or airway reversibility testing, including the screening 
visit.

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

Inhaled nicotine (including electronic cigarettes)
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. A check of study drug 
compliance will be performed during each visit after the initial dispensation of study drug, and 
study drug accountability records will be completed. Compliance for OCS will be checked using 
pill counting at each study visit. 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
Blood draws will be separated by at least 2 weeks. The estimated total blood volume withdrawn 
over the entire study (including screening) is approximately 125 mL. To further reduce the 
volume of blood withdrawn, pediatric tubes will be used when possible.


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6.
ASSESSMENT OF EFFICACY AND IMMUNOGENICITY
6.1.
Primary Efficacy Measure and Justification
Percent reduction in the daily OCS dose will be categorized as follows:

90% to 100%

75% to <90%

50% to <75%

>0% to <50%

No decrease in OCS, loss of baseline asthma control during weeks 20 through 24, or 
discontinuation from study drug
Loss of baseline asthma control will be defined as FEV1 less than 80% of baseline at the week 24 
visit, clinically significant worsening in ACQ-6 score (change in score of 0.5) at the week 24 
visit compared with baseline, and/or CAE (as defined in Section 6.7) during weeks 20 
through 24.
6.2.
Spirometry
Pre-bronchodilator FEV1, FVC, FEF25%-75%, and post-bronchodilator FEV1 will be measured 
using spirometry. The FEV1 is the volume of air that 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 a 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 ATS/ERS 2005 procedural guidelines. 
The National Health and Nutrition Survey III reference equations will be used.
6.3.
PEF monitoring
AM and PM ambulatory PEF will be measured using a PEF meter. PEF is the maximum speed of 
exhalation. AM and PM 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 (AQLQ[S]), which was 
developed to measure functional impairments experienced by adults ≥17 years of age. The 
AQLQ +12 is valid for patients 12 to 70 years of age 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 


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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-6 is a validated asthma assessment tool that has been widely used (Juniper et al 1999). 
There are 6 self-assessment questions. Each item on the ACQ-6 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 D.
6.7.
Asthma Exacerbations
The number of CAEs requiring a burst of systemic corticosteroid (oral, iv, or im) and the 
time-to-first CAE will be measured.
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 (injection, or if oral, at least a doubling from the
current OCS 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 [injection, or if oral at least a doubling from the current OCS 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 (injectable), or 
for those with a doubling of the OCS dose, the stop date is when the return to their baseline dose, 
or the last day of an asthma-specific hospitalization or emergency department visit, whichever is 
later. For patients receiving at least a doubling from their current dose of OCS for at least 3 days 
that did not return to baseline (dose before exacerbation), an asthma exacerbation stop date will 
be the day that they have been on a new stable dose for at least 10 days.


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If a patient experiences an asthma exacerbation, they should be treated with an OCS burst: 40 to 
60 mg (or at least double his/her current dose) tapered over a 7- to 10-day period to a new 
maintenance dose of 2.5 mg above the pre-burst dose. It is understood that im or iv corticosteroid 
may also be administered as part of the treatment of the asthma exacerbation. If a second OCS 
burst is required, the patient should be maintained on a fixed OCS dose for the remainder of the 
double-blind treatment phase.
If possible, a blood sample for measurement of serum reslizumab concentrations will be obtained 
from patients experiencing an exacerbation of asthma symptoms, a serious adverse event, an 
observation of any severe hypersensitivity reaction (eg, anaphylaxis), or an adverse event leading 
to withdrawal.
6.8.
European Quality of Life 5-Dimension Health State Utility Index
The EQ-5D is a standardized questionnaire that assesses overall state of health (Appendix E).
The EQ-5D consists of 2 parts. In the first part, patients rate their health state in 5 health 
domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression using a 
scale of 1 to 3 where 1=no problem, 2=some problems, and 3=major problems. The second part 
consists of a 100 mm visual analog scale on which patients rate their perceived health state 
(0=worst imaginable health state, 100=best imaginable health state).
6.9.
Inhaled Reliever Medication Use
The number of times asthma reliever therapy (number of inhalations) is used will be assessed by 
reviewing the electronic asthma control diary. Note: Inhaled reliever therapy used for exercise 
before treatment should not be recorded.
6.10.
Nighttime Awakenings Requiring Rescue Inhaler Use
Patients will record nighttime awakenings and the amount of rescue medication taken in their 
electronic asthma control diary. The number of nighttime awakenings requiring rescue inhaler
treatment will be determined based on the review of these recorded data.


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6.14.
St. George’s Respiratory Questionnaire
The St. George's Respiratory Questionnaire is a 50-item health status survey specific for chronic 
obstructive pulmonary disease and other respiratory diseases (Appendix G; Barr et al 2000).
6.15.
Target Biomarker Measures
Biomarker measures will include blood eosinophils and 
 


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7.
ASSESSMENT OF SAFETY
In this study, safety will be assessed by qualified study staff by evaluating the following:

Adverse events throughout the study

Clinical laboratory test results (serum chemistry at screening, DoR/baseline, week 12, 
and week 24 or early withdrawal; hematology throughout the study; urinalysis at 
screening)

Vital signs (pulse, respiratory rate, body temperature, and blood pressure) throughout 
the study

ECG at screening and week 24 or early withdrawal

Physical examination findings (including body weight and height measurements)
throughout the study

Signs and/or symptoms of adrenal insufficiency (OCS withdrawal effects) throughout 
the study

Concomitant medication usage throughout the study
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 ICF
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 7.1.6. 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


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
significant worsening (change in nature, severity, or frequency) of pre-existing 
conditions

drug interactions

laboratory or diagnostic test abnormalities that result in the withdrawal of the patient 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, 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.)

events associated to study procedure (eg, clinically significant adrenal insufficiency)
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 ICF through the end of the follow-up period. For this study, the follow-up period 
is defined as 8 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 7.1.6.3.1). The investigator does not need to actively monitor subjects for adverse 
events once the study has ended. Serious adverse events that occur to a patient after the end of 
the study should be reported to the sponsor if the investigator becomes aware of them, following 
the procedures described in Section 7.1.6.3.1.
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 


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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: 
No limitation of usual activities
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 which, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events, which, 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 test 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 
test drug. 

it does not reappear or worsen when the 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 test drug administration cannot be 
ruled out with certainty nor felt with 
a high degree of certainty to be 
related to the study drug.
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 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 drug, yet drug-relatedness 
clearly exists.

it follows a known pattern of response to the test 
drug.
7.1.5.
Relationship of an Adverse Event to OCS Reduction
The relationship of an adverse event to OCS reduction (such as symptoms of adrenal 
insufficiency) will be indicated (yes/no) on the CRF.


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7.1.6.
Serious Adverse Events
7.1.6.1.
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 
severe form, might have caused death

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.
7.1.6.2.
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 IB. The 
sponsor’s Pharmacovigilance Department will determine the expectedness for all serious adverse 
events.
7.1.6.3.
Reporting a Serious Adverse Event
7.1.6.3.1. Investigator Responsibility
To satisfy regulatory requirements, all serious adverse events (as described in Section 7.1.6.1) 
(including the protocol-defined follow-up period, described in Section 7.1.2), regardless of 


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judged relationship to treatment with the study drug, must be reported to the sponsor by the 
investigator 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 subjects for adverse events once the 
study has ended. Serious adverse events occurring to a patient after 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 contract research organization [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.
The following information should be provided to record the event accurately and completely:

study number

investigator and investigational center identification

patient number

patient initials

onset date and 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

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)


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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 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 IRB/EC is also 
informed of the event, in accordance with local regulations.
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 pharmacovigilance 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.
7.1.6.3.2. 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
7.1.7.
Specific Protocol-Defined Adverse Events
7.1.7.1.
Adrenal Insufficiency
Adrenal insufficiency will be treated as an adverse event.


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Patients who experience the clinical symptoms of adrenal insufficiency (fatigue, weakness, 
anorexia, lightheadedness, abdominal pain, nausea/vomiting, myalgia) will be instructed to come 
to the study center for vital signs and evaluation by a physician if possible. Patients with severe 
symptoms will be instructed to proceed to the emergency department.
Blood samples will be taken for:

cortisol level (before iv corticosteroids or oral corticosteroid dose increase if 
possible) 

calcium level

sodium, potassium, chloride, glucose, creatinine, carbon dioxide, and blood urea 
nitrogen (BUN) levels

CBC with differential
Patients determined to have mild symptoms of adrenal insufficiency may have their OCS dose 
increased back to the previously effective OCS level (at the investigator’s discretion).
Patients determined to have clinically significant adrenal insufficiency will be instructed to (at 
minimum) double or triple their corticosteroid dose for ≥2 days.
Then, based on resolution of symptoms: 

If they recently (≤7 days) had a dose reduction, they will be instructed to return their 
corticosteroid dose to the previously effective OCS level.

If they have not had a recent dose reduction and another factor precipitated the 
adrenal insufficiency (eg, infection), they should be treated for the inciting factor 
before OCS dose reduction.
7.1.7.2.
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 7.1.6.1. 
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 7.1.6.3). A list of potential opportunistic 
infections is found in Appendix I .
7.1.7.3.
Specific Adverse Event Case Report Form Capturing
7.1.7.3.1. Anaphylaxis/Hypersensitivity Reactions Case Report Form
Information about all suspected anaphylaxis events will be recorded on the Suspected 
Anaphylaxis/Hypersensitivity Reactions CRF, including the investigator's assessment if the 
event followed the definition of anaphylaxis based on the diagnostic criteria as outlined by 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. 


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7.1.7.3.2. Creatine Phosphokinase/Muscular Adverse Events CRF
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× the 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 clinical project physician (CPP)/clinical leader 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 that, 
in the opinion of the investigator, is not severe enough to warrant discontinuation but requires the 
use of a prohibited medication, thereby requiring discontinuation of the patient. In such a case, 
the reason for discontinuation would be need to take a prohibited medication, not the adverse 
event.
If possible, a blood sample for measurement of serum reslizumab concentrations will be obtained 
from patients experiencing an adverse event leading to withdrawal, a serious adverse event, an 


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observation of any severe hypersensitivity reaction (eg, anaphylaxis), or an exacerbation of 
asthma symptoms.
Withdrawal from the study due to worsening of asthma or a CAE will be considered a 
withdrawal due to lack of effect, not a withdrawal due to an adverse event.
A patient 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 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 7.1.6.3). 
Any patient becoming pregnant during the study will be withdrawn. All patients who become 
pregnant 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 during the study and any complication of pregnancy that the 
investigator becomes aware of after termination from the study 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 
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
For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event.
7.3.
Clinical Laboratory Tests
All clinical laboratory test results outside the reference range will be interpreted by the 
investigator as belonging to 1 of the following categories:

abnormal but not a clinically significant worsening

abnormal and a clinically significant worsening
A laboratory test result that has significantly worsened (according to medical judgment) from the 
baseline result will be recorded on the source documentation, transcribed onto the CRF as an 
adverse event, and monitored as described in Section 7.1.2. An adverse 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.
In addition, potentially clinically significant values will be predefined by the sponsor for selected 
laboratory parameters (see Section 9.7.2) and will be detailed in the statistical analysis plan.
Clinical laboratory tests (serum chemistry and hematology) will be performed at the time points
detailed in Table 5. 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:

sodium

potassium

chloride

bicarbonate or carbon dioxide

glucose

BUN

creatinine

calcium

CPK

alanine aminotransferase 

aspartate aminotransferase

alkaline phosphatase

total protein

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
total bilirubin

direct bilirubin

7.3.2.
Hematology
The following hematology tests will be performed:

hemoglobin

hematocrit

platelet count

absolute neutrophil count

WBC count and differential count

polymorphonuclear leukocytes (neutrophils)

lymphocytes

eosinophils (blinded; absolute values)

monocytes (blinded)

basophils

7.3.3.
Other Clinical Laboratory Tests
Other clinical laboratory tests will be performed to ensure the safety of the patients but will not 
be used to assess the safety of the study drug.
7.3.3.1.
Urinalysis
Urinalysis will be performed at screening and will include testing for the following:

protein

glucose

ketones

blood (hemoglobin)

pH

specific gravity

microscopic

bacteria

red blood cells

WBCs


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
casts

crystals
7.3.3.2.
Hepatitis B, Hepatitis C, and HIV
At screening, patients will have tests for hepatitis B, hepatitis C, and HIV.
7.3.3.3.
Human Chorionic Gonadotrophin Tests
Women of childbearing potential will have a serum βHCG test at screening (visit 1). Human 
chorionic gonadotropin urine tests will be performed every 4 weeks thereafter until week 24 or 
early withdrawal, and at the early follow-up visit (visit 20). 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 (pulse, blood pressure, body temperature, and respiratory rate) will be measured at 
time points specified in Table 5 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 and week 24. 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 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 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 screening value will be considered an adverse 


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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 5. 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 CPP/medical monitor according to 
the safety monitoring plan (eg, scheduled safety reviews for reslizumab) 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/PHARMACODYNAMICS, AND 
IMMUNOGENICITY
8.1.
Pharmacokinetic Variables
Serum reslizumab concentration will be measured at time points indicated in Table 5 using an 
appropriate validated method. 
8.1.1.
Specimen Sampling and Handling
Blood samples (3 mL) for the measurement of serum reslizumab concentration will be collected
from all patients via venipuncture or indwelling catheter before each study drug administration at 
DoR/baseline and at weeks 4, 8, 12, 16, 20, and 24. Blood samples will also be collected at the 
week-32 follow-up visit and at the week-48 follow-up visit. If possible, a blood sample for
measurement of serum reslizumab concentrations will also be obtained from patients 
experiencing a serious adverse event, 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, randomization number, period, and nominal visit. Blood samples will be left 
standing upright at room temperature (20°C to 25°C) to clot for approximately 30 to 60 minutes. 
Samples should then be centrifuged at a minimum of 1500g for approximately 10 minutes at 4°C 
until clot and serum are well separated. If a 4°C centrifuge is not available, samples may be 
centrifuged at ambient temperature at 1500g 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 2 opaque, labeled, cryotubes (Aliquots A 
and B), immediately frozen in an upright position at a temperature within the range of –60°C to –
90°C, and stored under these conditions until they are shipped to the bioanalytical facility. 
Storage at –15°C to–25°C is acceptable for a period of up to 60 days if a freezer with a 
temperature of –65°C or lower is not available. The listed temperatures must be maintained. 
Labels for samples should include study number, randomization number, period, nominal visit, 
set (A or B), and indication that they are PK samples.
The actual date and time of the start and end of each study drug administration and the date and 
time of collection of each PK sample will be recorded in the source and will be transcribed to 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 they are shipped to Teva or its designee for analysis.
Samples will be stored in an upright position at a temperature within the range of –60°C to–80°C 
until assayed. The central laboratory will be notified before the shipment of the samples and will 
then be sent the shipping information when the samples are shipped. An electronic file 
containing sample demographics will be e-mailed to the bioanalytical laboratory and the Teva 


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Global Bioassays and Technology representative responsible for the bioanalysis for each 
shipment. 
Set A samples will be transported, frozen with sufficient dry ice for 4 days, by next-day courier 
to the central laboratory.
Set B samples will be sent to the same laboratory as that for set A on a subsequent day by 
next-day courier (unless shipment to another facility is requested by the sponsor). Instructions as 
to the disposition of the B samples will be provided by the sponsor.
Sample shipments should be sent no later in the week than Wednesday morning for next-day 
delivery. Samples are not to arrive on the weekend.
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. Blood samples from placebo-treated patients will not be analyzed.
8.2.
Pharmacodynamic Variables
Pharmacodynamic measures will include blood eosinophils and 
 
measured at the time points indicated in Table 5.
8.2.1.
Blood Eosinophil Counts
Blood samples (2 mL) will be collected via venipuncture or an indwelling catheter at the time 
points detailed in Table 5.
Details regarding the collection, handling, and shipment of samples for measurement are 
provided in the investigator laboratory manual and its associated specimen collection summary.
The results of the differential will be blinded in the post-baseline differential cell count reports to 
avoid the possibility removing the blind.
8.2.2.
Exploratory Biomarker Analysis
 
 
8.3.
Immunogenicity Testing
8.3.1.
Blood Sampling and Handling
Blood samples (5 mL) for the assessment of ADA response will be taken before dosing at the 
time points indicated in Table 5. Unscheduled blood samples for ADA 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 


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study number, randomization number, period, and nominal visit. Blood samples will be left 
standing upright at room temperature (20°C to 25°C) to clot for approximately 30 to 60 minutes. 
Samples should then be centrifuged at a minimum of 1500g for approximately 10 minutes at 4°C 
until clot and serum are well separated. Samples may be centrifuged at ambient temperature at 
1500g for 10 minutes as long as measures are taken as appropriate to maintain ambient 
temperature during centrifugation.
Separated serum will be transferred, in approximately equal portions, into 2 labeled cryovial 
tubes (primary Aliquot A and back-up Aliquot B) and stored in an ultralow freezer at –65°C or 
lower until they are shipped to a central or bioanalytical laboratory with temperature monitoring. 
Sample labels should include randomization number, period, study number, nominal visit, and 
indication that it is an ADA sample aliquot (A or B). Storage at –15°C to –20°C should not
exceed 1 month if a freezer with a temperature of –65°C or lower is not available. The listed 
temperatures must be maintained. The actual times and dates of sampling will be recorded on the 
CRF.
8.3.2.
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 they are shipped to 
the sponsor or its designee for analysis. Samples will be stored in an upright position at –65°C or 
lower 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. 
Set B samples will be sent to the same laboratory as that for set A on a later day by next-day 
courier (unless shipment to another facility is requested by the sponsor). 
Sample shipments should be sent no later in the week than Wednesday morning for next-day 
delivery. Samples are not to arrive on the weekend.
Additional details regarding the collection, handling, and shipment of samples for measurement 
of ADAs are provided in the investigator laboratory manual and its associated specimen 
collection summary.
The serum samples from reslizumab-treated patients will be analyzed using a validated method
for the detection of ADAs. The bioanalytical team will not be blinded for this analysis. Blood 
samples from placebo-treated patients will not be analyzed.


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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 and endpoint for this study is the percent reduction in the daily 
OCS dose during weeks 20 to 24 as compared with the dose at the end of the optimization phase.
The study will be considered positive if the measure meets statistical significance at the 
respective predefined significance level. A statistically significant effect of reslizumab over 
placebo, as measured by the primary efficacy variable, is required to establish the efficacy of 
reslizumab treatment.
The sample size was calculated based on the following assumptions:

Categorical reduction in OCS dose after 24 weeks of treatment will have the 
following distribution for the placebo group (based on Bel et al 2014): 

10.9% percent of subjects will have 90% to 100% reduction

7.9% percent of subjects will have 75% to <90% reduction

14.8% percent of subjects will have 50% to <75% reduction

10.8% percent of subjects will have 0% to <50% reduction

55.6% percent of subjects will have no reduction, loss of asthma control, or 
discontinuation from study drug

The overall odds ratio between reslizumab and placebo based on proportional odds 
model will be 2.63

Alpha level of 0.05
Based on the above assumptions, a sample size of 76 subjects per group will provide 90% power 
to detect a significant effect of reslizumab over placebo on the probability for a higher 
categorical reduction of OCS dose.
9.2.
Analysis Sets
9.2.1.
Intent-to-Treat Analysis Set
The intent-to-treat (ITT) analysis set will include all randomly assigned 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 randomly assigned, regardless of which 
treatment they actually received.


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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 randomly assigned. 
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
Sensitivity analyses for missing data will be detailed in the statistical analysis plan.
For most analyses, 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 randomly assigned, patients randomly 
assigned to treatment in the study, patients randomly assigned but not treated, patients in the
safety analysis set, patients in the per-protocol analysis set, patients who complete the treatment 
period (week 24), patients who complete the study (see Section 3.16.4 for definition of study 
completion), and patients who 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 the study drug but continue to attend study visits will be tabulated.
9.4.2.
Demographic and Baseline Characteristics 
Patient demographic and baseline characteristics, including medical history, comorbidities, prior 
and concomitant 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 (SE), 
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.


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9.5.
Efficacy Analysis
9.5.1.
Primary Endpoint
The primary efficacy endpoint for this study is the categorical reduction in the daily OCS dose 
during weeks 20 to 24.
Percent reduction in the daily OCS dose will be categorized as follows:

90% to 100%

75% to <90%

50% to <75%

>0% to <50%

No decrease in OCS, loss of baseline asthma control during weeks 20 through 24, or 
discontinuation from study drug
Loss of baseline asthma control will be defined as FEV1 less than 80% of baseline at the week 24 
visit, clinically significant worsening in ACQ-6 score (change in score of 0.5) at the week 24 
visit compared with baseline, and/or CAE during weeks 20 through 24.
9.5.2.
Secondary Endpoints
The secondary efficacy endpoints for this study are the following:

Proportion of patients achieving ≥50% reduction in OCS dose at weeks 20 to 24 
relative to the OCS dose at DoR/baseline, while maintaining asthma control

Proportion of patients achieving dose reduction to ≤5 mg daily dose at weeks 20 to 
24, while maintaining asthma control

Percent change from DoR/baseline in OCS dose at weeks 20 to 24

Proportion of patients achieving less than 5 mg decrement in OCS dose (ie, the 
minimal and non-responders) compared with the OCS dose at DoR/baseline at weeks 
20 to 24, while maintaining asthma control

Clinical asthma exacerbation-related:

Annualized rate of CAEs requiring a burst of systemic corticosteroid (injection, or 
if oral, at least a doubling from the current OCS dose for at least 3 days); an 
asthma-specific hospital admission; or an asthma-specific emergency department 
visit during the treatment period (weeks 0 to 24)

Proportion of patients discontinuing OCS at weeks 20 to 24, while maintaining 
asthma control
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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9.5.3.
Other Secondary Efficacy Endpoints:
Other efficacy endpoints for this study are the following:

Time to first CAE

Other clinic lung functions including the following:

Pre-bronchodilator FEV1: change from DoR/baseline to weeks 4, 8, 12, 16, 20, 
and 24 or early withdrawal

Post-bronchodilator FEV1: change from DoR/baseline to weeks 4, 12, 20, and 24 
or early withdrawal

Ambulatory lung function: change in AM and PM PEF from run-in baseline at each 
week through week 24 or early withdrawal

AQLQ + 12 score: change from DoR/baseline to weeks 4, 8, 12, 16, 20, and 24 or 
early withdrawal

ACQ-6: change from DoR/baseline to weeks 4, 8, 12, 16, 20, and 24 or early 
withdrawal

Change in total inhalations of reliever bronchodilator medication (eg, SABA)
(number of inhalations per 24 hours: day+night) from run-in baseline at each week 
through week 24 or early withdrawal

Number of nighttime awakenings due to asthma over the 24-week treatment period

Change in total asthma symptom scores from run-in baseline at each week through 
week 24 or early withdrawal

EQ-5D score: change from DoR/baseline to week 24 or early withdrawal

SGRQ score: change from DoR/baseline to weeks 12 and 24 or early withdrawal
9.5.4.
Exploratory Endpoints
Exploratory endpoints for this study are the following:


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9.5.5.
Target Biomarker Endpoint
The target biomarker endpoints are the blood eosinophil counts at DoR/baseline; weeks 4, 8, 12,
16, 20, 24 or early withdrawal; and at the follow-up visit (approximately week 32).
9.5.6.
Planned Method of Analysis
The ITT analysis set (see Section 9.2.1) will be used for all efficacy analyses unless otherwise 
noted. Summaries will be presented by treatment group. The per-protocol analysis set will be 
used as sensitivity analysis for the primary analysis.
9.5.6.1.
Primary Efficacy Analysis
The primary endpoint is the categorical reduction in OCS dose during weeks 20 to 24, compared 
with DoR/baseline dose, without loss of asthma control. Five categories of reduction will be 
defined: 90% to 100% reduction, 75% to <90% reduction, 50% to <75% reduction, >0% to 
<50% reduction, and no decrease in OCS dose/loss of asthma control/discontinuation from study 
drug. This categorical endpoint will be analyzed using proportional odds model. The model will 
include the treatment group and randomization stratification factors as model factors and the 
OCS baseline dose and duration of historical OCS use (ie, before screening) as covariates. The 
overall odds ratio between reslizumab and placebo and its 95% confidence interval will be 
estimated.
For the primary analysis, patients who discontinue the study drug early will be considered as 
nonresponders and will be categorized in the lowest category of response.
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 his/her withdrawal from the 
study (see Section 4.5).
9.5.6.2.
Sensitivity Analysis
Sensitivity analysis will include data collected after early discontinuation from study drug. In this 
analysis, patients will be categorized according to the percent dose reduction at 24 weeks 
regardless of whether they withdrew early from treatment or complete treatment. For patients 
who withdraw early, and for whom the sponsor fails to retrieve data after withdrawal despite all 
attempts to contact the patients, multiple imputation will be performed to determine the 
categorization according to the percent dose reduction at 24 weeks. Multiple imputations will use 
the post withdrawal data observed for patients who withdraw 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.
Other sensitivity analyses will include the following:

Repeating the primary analysis on the PP analysis set

“Tipping point” multiple imputation analysis to assess deviations from missing at 
random (MAR); details regarding this analysis will be provided in the SAP


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Additional sensitivity analyses may be included and will be detailed in the statistical analysis 
plan.
9.5.6.3.
Secondary Efficacy Analysis
All efficacy variables will be summarized by treatment group. For continuous variables, the 
summary statistics will include n, mean, SD, SE, median, minimum, and maximum. For 
categorical variables, patient counts and percentages will be provided.
The proportion of patients achieving ≥50% reduction in OCS dose at weeks 20 to 24 while 
maintaining asthma control, proportion of patients achieving dose reduction to ≤5 mg daily dose 
at weeks 20 to 24 while maintaining asthma control, proportion of patients achieving less than 5 
mg decrement in OCS dose (ie, the minimal and non-responders) at weeks 20 to 24 while 
maintaining asthma control, and proportion of patients discontinuing OCS at weeks 20 to 24 will 
be analyzed using a logistic regression model. The model will include the treatment group and 
randomization stratification factors as model factors and the OCS baseline dose and duration of 
historical OCS use (ie, before screening) as covariates. 
For the secondary analysis, patients who discontinue the study drug early will be considered as 
nonresponders and will be categorized in the lowest category of response
Analysis of the mean percentage change from baseline in OCS dose at weeks 20 to 24 will use an 
analysis of covariance model with treatment group and stratification factors as model factors and 
the OCS baseline dose and duration of historical OCS use (ie, before screening) as covariates. 
The frequency of CAEs will use the negative binomial (NB) regression model. The primary NB 
model will include the treatment group and randomization stratification factors 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.
Additional covariates or factors may be added to the statistical models. These will be detailed in 
the statistical analysis plan.
9.5.6.4.
Other Efficacy Analysis
Statistical modeling to be used for other efficacy endpoints will be described and detailed in the 
statistical analysis plan.
9.5.6.5.
Exploratory Efficacy Analysis
Statistical modeling to be used for exploratory efficacy endpoints will be described and 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 2-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 either until all comparisons of interest are interpreted inferentially or until 


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the point at which the resulting 2-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 3.8 and Table 5. The overall safety of 
reslizumab treatment will be assessed throughout the study by evaluating adverse events and the 
following additional safety variables.

Clinical laboratory evaluations of serum chemistry at screening, DoR, week 12, and 
week 24 or early withdrawal

Clinical laboratory evaluations of hematology throughout the study

Vital signs assessments (pulse, body temperature, respiratory rate, and blood 
pressure) throughout the study 

ECGs at screening and week 24 or early withdrawal

Physical examinations (including body weight measurements) throughout the study

Signs and/or symptoms of adrenal insufficiency (OCS withdrawal effects) throughout 
the study

Inquiries about concomitant medication usage throughout the study
9.7.2.
Safety Analysis
Safety data will be summarized using descriptive statistics by time point and/or treatment group, 
as appropriate. 
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 starting 
after first study drug administration (overall and by severity), adverse events determined by the 
investigator to be related to study treatment (ie, reasonable possibility; see Section 7.1.4, with 
missing relationship will be counted as related) (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. Patient listings of adverse events, serious adverse events, and adverse events leading to 
discontinuation will be presented and will include all adverse events reported (including before 
first study drug administration).


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Changes in laboratory, ECG, and vital signs measurement data will be summarized descriptively. 
All values will be compared with prespecified boundaries to identify potentially clinically 
significant changes or values, and such values will be listed.
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, SE, median, minimum, and 
maximum) will be provided for actual values and changes from baseline 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.
9.8.
Pharmacokinetic Analysis
Reslizumab concentration data will be summarized by time point and/or treatment group, as 
appropriate. 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 PPK and PK/PD analysis and reported in a separate report.
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.
Pharmacodynamic Analysis
Blood eosinophil counts will be summarized by treatment group and time point.
9.11.
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.
9.12.
Planned Interim Analysis
No interim analysis is planned for this study.
9.13.
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 complete statistical 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 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 affect 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 study.
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 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. 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 ICF 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 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 will contact each 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, to include 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 (SDV) 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. Each 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

missing or extra units (eg, primary container is received at the site with more or less 
than the designated number of units inside)


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
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 
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.


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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 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 and 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 ICF 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 assure 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 (eg, initials and 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 (approximately 
week 24). LSLV late follow up, for immunogenicity testing only, will be performed after the 
treatment period (approximately week 48). 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 ASSURANCE, 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 21 CFR 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 any 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
according to the data source. 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. 
With regard to data are processed from other sources (eg, central laboratory, bioanalytical 
laboratory, central image center, eDiary data), 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 screening 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 assurance, 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 assurance, will be described in a data-management 
plan.
CRFs 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 


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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.
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

CRFs 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 


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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, 
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 subject 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 of 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
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modification, and validation of the St. George’s Respiratory Questionnaire. Clin Ther 
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Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al; SIRIUS 
Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl 
J Med 2014;371(13):1189-97. 
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.
Castro M, Zangrilli J, Wechsler ME, Bateman ED, Brusselle GG, Bardin P, et al. Reslizumab for 
inadequately controlled asthma with elevated blood eosinophil counts: results from tow 
multicentre, parallel, double-blind, randomised, placebo-controlled, phase 3 trials. The Lancet 
2015. Published online.
Expert Panel Report 3 (EPR-3): Guidelines for the Diagnosis and Management of Asthma —
Summary Report 2007. National Asthma Education and Prevention Program.
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. Available at: http://www.ginasthma.org. Accessed 11 March 2015.
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.
 
International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. Available 
at: http://www.icmje.org/recommendations/. Accessed 02 July 2014.
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-


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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.
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.
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;47(4):373-80; PMID: 16546624]. J Allergy Clin
Immunol 2006;117(2):391-7.
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.
Stanbury RM and Graham EM, Systemic corticosteroid therapy — side effects and their 
management. Br J Opthalmol 1998; 82(704):704-8.
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.
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, Solari PG, Zazzali JL, Chen W. Real-time asthma outreach reduces 
excessive short-acting β2-agonist use: a randomized study. J Allergy Clin Immunol Pract 
2014;2(4):445-56.


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17.
SUMMARY OF CHANGES TO PROTOCOL
17.1.
Amendment 02 Dated 18 JULY 2016
The revisions listed below have been made to the protocol Study C38072-AS-30027 and are 
considered substantial by the Teva Authorized Representative.
Table 6:
Changes to the Protocol
Original text with changes shown
New wording
Reason/Justification 
for change
Clinical Study Personnel Contact Information
For Centers in Latin America
For Centers in Latin America
The contact physician 
for Latin America 
was updated and the 
operation lead was 
updated.
Clinical Study Protocol Synopsis
During the optimization period, the patient’s 
minimal effective OCS requirement will be 
determined. The patient’s previous OCS will be 
standardized to an equivalent dose and regimen 
of prednisone to the nearest 2.5 mg daily for 
once daily regimens or 5 mg for every other
day regimens. The patient’s previous non-OCS 
background asthma controller medications will 
be continued unchanged throughout the pre-
randomization period and the entire study. At 
the beginning of the optimization period, an 
asthma symptom diary and electronic peak 
flow meter will be distributed where the patient 
will record asthma symptoms, number of 
reliever bronchodilator inhalations, nighttime 
awakenings due to asthma requiring rescue
inhaler, and AM and PM PEF. For 
During the optimization period, the 
patient’s minimal effective OCS 
requirement will be determined. The 
patient’s previous OCS will be 
standardized to an equivalent dose and 
regimen of prednisone to the nearest 
2.5 mg daily. The patient’s previous non-
OCS background asthma controller 
medications will be continued unchanged 
throughout the pre-randomization period 
and the entire study. At the beginning of 
the optimization period, an asthma 
symptom diary and electronic peak flow 
meter will be distributed where the patient 
will record asthma symptoms, number of 
reliever bronchodilator inhalations, 
nighttime awakenings due to asthma 
Minor wording 
adjustment and 
language was added 
for clarity.


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Original text with changes shown
New wording
Reason/Justification 
for change
optimization, the OCS dose should be reduced 
at 1-week intervals, for up to 10 weeks or until 
there is a worsening of asthma signs and 
symptoms (minimum 1 day in optimization). 
When either a lung function or symptomatic 
deterioration occurs, the patient will be 
returned to the previously effective OCS level, 
which will then constitute the minimally 
effective dose for the purpose of run-in. If this 
previously effective dose is no longer effective, 
the investigator can determine the clinically 
appropriate, minimally effective dose for the 
purpose of run-in. Note: Patient may enter 
run-in (V12) on the same day as 
optimization ended if the patient is on the 
minimally effective prednisone dose (did not 
require a prednisone burst at end-
optimization).
requiring rescue inhaler, and AM and 
PM PEF. For optimization, the OCS dose 
should be reduced at 1-week intervals, for 
up to 10 weeks or until there is a 
worsening of asthma signs and symptoms 
(minimum 1 day in optimization). When 
either a lung function or symptomatic 
deterioration occurs, the patient will be 
returned to the previously effective OCS 
level, which will then constitute the 
minimally effective dose for the purpose of 
run-in. If this previously effective dose is 
no longer effective, the investigator can 
determine the clinically appropriate, 
minimally effective dose for the purpose of 
run-in. Note: Patient may enter run-in 
(V12) on the same day as optimization 
ended if the patient is on the minimally 
effective prednisone dose (did not require 
a prednisone burst at end-optimization).
Section 1.3.2: Clinical Studies
Additional Safety Issues Considerations
Additional Safety Considerations
Section renamed for 
clarity and 
inclusiveness.
Additional Safety Issues 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.
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.
Language was added 
to clarify that the 
number of reported 
events includes 
patients who received 
placebo in the overall 
clinical program.
Additional Safety Issues Considerations
Malignancy risk
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.
Additional Safety Considerations
Malignancy risk
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.
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 
Additional safety 
consideration for 
infections added for 
clarity.


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Original text with changes shown
New wording
Reason/Justification 
for change
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.
Section 3: Study Design
Section 3.1: General Design and Study Schema (Other sections affected by this change: Section 3.13) 
3.1 General Design and Study Schema
This is a Phase 3, 24-week, double-blind, 
placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of sc 
reslizumab treatment at a dosage of 110 mg 
reslizumab treatment at a fixed dose of 110 mg,
administered sc once every 4 weeks in patients 
12 years of age and older with OCS-dependent 
asthma and elevated blood eosinophils. The 
study will consist of a screening period of up to 
2 weeks, followed by an optimization period of 
up to 10 weeks, a run-in period of at least 2 
weeks, a 24-week double-blind treatment 
period, an 8-week follow-up period, and an 
additional 16-week follow-up period to collect 
drug wash-out samples for immunogenicity 
assessments. 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.
3.1 General Design and Study Schema
This is a Phase 3, 24-week, double-blind, 
placebo-controlled, parallel-group study to 
evaluate the efficacy and safety of sc 
reslizumab treatment at a dosage of 110 
mg every 4 weeks in patients 12 years of 
age and older with OCS-dependent asthma 
and elevated blood eosinophils. The study 
will consist of a screening period of up to 2 
weeks, followed by an optimization period 
of up to 10 weeks, a run-in period of at 
least 2 weeks, a 24-week double-blind 
treatment period, an 8-week follow-up 
period, and an additional 16-week follow-
up period to collect drug wash-out samples 
for immunogenicity assessments. 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.
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.
Section 3.1.3: Run-in Period (Other sections affected by this change: synopsis)
Patients whose minimal effective OCS dose 
remains between ≥5 mg and ≤ 40 mg of 
prednisone daily at the end of optimization 
may advance to run-in (for at least 2 weeks).
Patients whose minimal effective OCS 
dose remains between ≥5 mg and ≤ 40 mg 
of prednisone daily at the end of 
optimization may advance to run-in (for at 
least 2 weeks).
Clarification of OCS 
medication in run-in 
period.


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Section 3.1.4: Treatment Period (Other sections affected by this change: Section 6.7)
OCS Reduction: The minimally effective OCS 
dose will be reduced per protocol at scheduled 
clinic visits from the beginning of week 5 (ie, 
end of the induction period) through week 20, 
as long as all 5 criteria in Table 2 are met and 
there are no clinical manifestations of adrenal 
insufficiency. These 5 eligibility criteria 
assure that the patient's asthma control is 
not significantly worsened compared to 
baseline. The last possible dose reduction can 
occur at week 20. The algorithm for OCS 
reductions during the treatment period is given 
in Table 3.
OCS Reduction: The minimally effective 
OCS dose will be reduced per protocol at 
scheduled clinic visits from the beginning 
of week 5 (ie, end of the induction period) 
through week 20, as long as all 5 criteria in 
Table 2 are met and there are no clinical 
manifestations of adrenal insufficiency. 
These 5 eligibility criteria assure that the 
patient's asthma control is not significantly 
worsened compared to baseline. The last 
possible dose reduction can occur at week 
20. The algorithm for OCS reductions 
during the treatment period is given in 
Table 3.
Clarification of 
eligibility criteria 
with respect to 
asthma control.
3.1.4.1. Handling of Asthma Exacerbations 
During the Treatment Period
Patients should be treated with an OCS burst: 
40 to 60 mg (or at least double the current 
dose) of OCS tapered over a 7- to 10-day 
period to a new maintenance dose of 2.5 mg 
above the pre-burst dose for once daily 
regimens or 5 mg above the pre burst dose for 
every other day regimens.
3.1.4.1. Handling of Asthma 
Exacerbations During the Treatment 
Period
Patients should be treated with an OCS 
burst: 40 to 60 mg (or at least double the 
current dose) of OCS tapered over a 7- to 
10-day period to a new maintenance dose 
of 2.5 mg above the pre-burst dose.
Language 
simplification made 
for clarity.
Section 3.11: Drugs Used in the Study (Other sections affected by this change: Section 5.1)
Section 3.11.1 Investigational Product
Reslizumab 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. Both reslizumab 
and placebo will be provided as clear solutions
Section 3.11.1 Investigational Product
Reslizumab 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. Both reslizumab and placebo will be 
provided as clear solutions
Information 
regarding the natural 
rubber component of 
the prefilled syringe 
was added for 
transparency.
Section 3.11.2 Placebo
Placebo will be provided as a sterile solution 
containing 
 sodium acetate, with 
 
sucrose, 
 polysorbate 80, pH 5.5 buffer, 
presented as 1.0-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 containing 
 sodium acetate, 
with 
 sucrose, 
 polysorbate 80, 
pH 5.5 buffer, presented as 1.0-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.


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Section 3.13: Duration of Patient Participation and Justification
An additional, late follow-up for 
immunogenicity testing will be performed 28 
weeks after the last dose of study drug. See 
Section 12.4 for the definition of the end of the 
study. 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.
An additional, late follow-up for 
immunogenicity testing will be performed 
28 weeks after the last dose of study drug.
See Section 12.4 for the definition of the 
end of the study. 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.
Section 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. 
…
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 reaction, 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. 
…
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 reaction, 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.
Section 3.16: Study Procedures; Table 5: Study Procedures and Assessments (Other sections affected by this 
change: Section 3.16.3.1.1)
V2-V11: Standardize and optimize 
maintenance OCS: Between weeks -12 and 4-3
V2-V11: Standardize and optimize 
maintenance OCS: Between weeks -12 and 
-3
Correction to upper 
time limit for this 
time period.
Addition of CPK assessments at Week 4, 8, 
16, and 20
Addition of CPK assessments at Week 4, 
8, 16, and 20.
Clarification added 
based on request by 
Health Authorities.
Addition of Injection site evaluation at Visit 
13-18
Injection site evaluation addition at Visit 
13-18 (Day of Randomization to Week 
20).
Row added aligning 
with IP visits for 
clarification of 
evaluation.
--
--
Minor adjustments to 
order of evaluations 
to align sequentially 
with timing
i.  CPK is collected with serum chemistry tests 
at scheduled visits. If potentially clinically 
significant CPK (≥3.1x ULN) is reported, 
i.  CPK is collected with serum chemistry 
tests at scheduled visits. If a potentially 
clinically significant CPK level (≥3.1x 
Footnote modified 
for clarity.


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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 7.1.7.3.2.
ULN) is reported, initiate the CPK/myalgia 
CRF and clinical monitoring as 
outlined in Protocol Section 7.1.7.3.2.
--  
j.  CPK measurement only. CPK will be 
collected with PK sample.
New footnote added 
to support the 
additional CPK 
collection.
3.16.2.3 Procedures at Baseline/Day of Randomization (Week 0 [Visit 13])
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 2 
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 on day 1:

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.
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 2 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 on day 1:

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.


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3.16.3.1.1 Weeks 4, 8, 12, 16, 20, and 24 (Visits 14 Through 19)
Perform serum chemistry tests (weeks 12 and 
24 or early withdrawal) (a sample for CPK 
measurement only will also be collected on 
weeks 4, 8, 16, and 20).
Perform serum chemistry tests (weeks 12 
and 24 or early withdrawal) (a sample for 
CPK measurement only will also be 
collected on weeks 4, 8, 16, and 20).
Edited to align with 
modification to 
schedule of 
assessments.
Additionally, 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.
Additionally, 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
Section 4.1: Selection and Withdrawal of Patients (Other sections affected by these changes: Study Synopsis)
4.1 Patient Inclusion Criteria
c. The patient continues to require an average 
daily maintenance dose of OCS or 
equivalent for asthma of between 5 and 40 
mg of prednisone or equivalent during 
the 3 months before screening. Patients on 
an OCS dose of >40 mg at screening who 
the investigator believes may be able to 
decrease OCS dose to ≤40 mg during the 
optimization period may also be enrolled. 
Note: every-other-day dosing that is within 
this daily average (ie, 10 to 80 mg) is 
allowed.
4.1 Patient Inclusion Criteria
c. The patient continues to require an 
average daily maintenance dose of 
OCS for asthma of between 5 and 40 
mg of prednisone or equivalent during 
the 3 months before screening. 
Patients on an OCS dose of >40 mg at 
screening who the investigator 
believes may be able to decrease OCS 
dose to ≤40 mg during the 
optimization period may also be 
enrolled. Note: every-other-day dosing 
that is within this daily average (ie, 10 
to 80 mg) is allowed.
The inclusion 
criterion was revised 
for clarity at the 
request of the Health 
Authority.
d.  The patient has a documented blood 
eosinophil level of at least 300/L during 
the previous 12 months while on at least 
d.  The patient has a documented blood 
eosinophil level of at least 300/L
during the previous 12 months while on 
GINA Guidance 
version updated.


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medium total daily dose of ICS based on 
Global Initiative for Asthma 20152016
clinical comparability table (Appendix A), 
or ≥300/L at screening while on chronic 
OCS or that becomes manifest during the 
OCS optimization period or at the week -2 
visit (end of optimization 
period/beginning of run-in period)
at least medium total daily dose of ICS 
based on Global Initiative for Asthma 
2016 clinical comparability table 
(Appendix A), or ≥300/L at screening 
while on chronic OCS or that becomes 
manifest during the OCS optimization 
period or at the week -2 visit (end of 
optimization period/beginning of run-in 
period)
f. The patient has FEV1 reversibility of at 
least 12% after administration of inhaled 
reliever medication according to the 
standard American Thoracic Society 
(ATS) or European Respiratory Society 
(ERS) protocol. Given the refractory 
nature of the disease in this population 
and the influence of high background 
controller medications on reversibility 
testing, documented FEV1 reversibility of 
12% or a provocation concentration 
producing a 20% fall in FEV1 for 
methacholine of ≤8 mg/mL within 24 
months of the screening visit, and 
performed according to the standard 
ATS/ERS procedures, would fulfill this 
criterion. Patients may be screened 
again if they did not meet 
spirometry/reversibility criteria 
initially. The duration between the date 
of Screen Failure and the re-screening 
must be >30 days.
f. The patient has FEV1 reversibility of 
at least 12% after administration of 
inhaled reliever medication according 
to the standard American Thoracic 
Society (ATS) or European 
Respiratory Society (ERS) protocol. 
Given the refractory nature of the 
disease in this population and the 
influence of high background 
controller medications on 
reversibility testing, documented 
FEV1 reversibility of 12% or a 
provocation concentration producing 
a 20% fall in FEV1 for methacholine 
of ≤8 mg/mL within 24 months of the 
screening visit, and performed 
according to the standard ATS/ERS 
procedures, would fulfill this 
criterion. Patients may be screened 
again if they did not meet 
spirometry/reversibility criteria 
initially. The duration between the 
date of Screen Failure and the re-
screening must be >30 days.
Criterion revised for 
clarity and alignment 
with case report form 
instructions.
g.  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. 
g.  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. 
Criterion revised for 
clarity and alignment 
with case report 
form.


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m.  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
m.  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.
4.5  Criteria and Procedures for Discontinuation of Study Treatment and/or Study Withdrawal
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. If possible, a blood sample for 
measurement of serum reslizumab 
concentrations will be obtained from 
patients experiencing an adverse event 
leading to withdrawal, a serious adverse 
event, an observation of any severe 
hypersensitivity reaction (eg, anaphylaxis), 
or an exacerbation of asthma symptoms.
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. If possible, a blood sample for 
measurement of serum reslizumab 
concentrations will be obtained from 
patients experiencing an adverse event 
leading to withdrawal, a serious adverse 
event, an observation of any severe 
hypersensitivity reaction (eg, anaphylaxis), 
or an exacerbation of asthma symptoms.
Statement added per 
request of Health 
Authority.
5.3: Prior and Concomitant Therapy or Medication
Any prior or concomitant therapy, medication, 
or procedure a patient has had at screening up 
to the end of the study period 4 weeks before 
study drug administration and up to the end of 
the study period, including follow-up, will be 
recorded on the CRF.
Any prior or concomitant therapy, 
medication, or procedure a patient has had 
at screening up to the end of the study 
period, including follow-up, will be 
recorded on the CRF.
Clarification of text.


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5.5: Total Blood Volume
Blood draws will be separated by at least 2 
weeks. The estimated total blood volume 
withdrawn over the entire study (including 
screening) is approximately 120125 mL.
Blood draws will be separated by at least 2 
weeks. The estimated total blood volume 
withdrawn over the entire study (including 
screening) is approximately 125 mL.
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 
Section7.1.6. 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 (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, 
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 
Section7.1.6. 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…
Clarification of the 
reporting of the 
disease under study 
as an adverse event.


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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.
Section 7.1.6.1 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 for an 
elective procedure or for treatment of a 
pre existing condition that has not 
worsened during participation in the 
study will not be considered serious 
adverse events 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  
Section 7.1.6.1 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. 
Section 7.1.7: Specific Protocol-Defined Adverse Events (Other sections affected by this change: Appendix I)
Section 7.1.7.2: 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 
7.1.6.1. The process for reporting a protocol-
defined adverse event for expedited reporting is 
the same as that for reporting a serious adverse 
Section 7.1.7.2: 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 7.1.6.1. The process for 
reporting a protocol-defined adverse event 
A list of opportunistic 
infections was 
provided to increase 
investigators’ 
awareness of the 
potential for 
opportunistic 
infection during 
reslizumab treatment.


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event (see Section 7.1.6.3). A list of potential 
opportunistic infections is found in Appendix 
I.
for expedited reporting is the same as that 
for reporting a serious adverse event (see 
Section 7.1.6.3). A list of potential 
opportunistic infections is found in 
Appendix I.
7.1.7.3.1. Anaphylaxis/Hypersensitivity 
Reactions Case Report Form
Information about all suspected systemic 
reactions anaphylaxis events will be recorded 
on the Suspected Anaphylaxis/Hypersensitivity 
Reactions CRF, including the investigator's 
assessment if the event followed the definition 
of anaphylaxis based on the diagnostic criteria 
as outlined by the 2006 Joint NIAID/FAAN 
Second Symposium on Anaphylaxis (Sampson 
et al 2006) (Appendix G 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.
7.1.7.3.1. Anaphylaxis/Hypersensitivity 
Reactions Case Report Form
Information about all suspected 
anaphylaxis events will be recorded on the 
Suspected Anaphylaxis/Hypersensitivity 
Reactions CRF, including the 
investigator's assessment if the event 
followed the definition of anaphylaxis 
based on the diagnostic criteria as outlined 
by 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.
The appendix 
referencing the 
diagnosis of 
anaphylaxis reactions 
was corrected.
7.1.7.3.2.  Creatine Phosphokinase/Muscular Adverse Events CRF
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 
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 
Requested edits from
Health Authority and 
for overall clarity.


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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.
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 (potentially rhabdomyolysis), study 
drug discontinuation should occur at least 
until CPK normalization or longer based 
on investigator clinical assessment.
9.11  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.
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.
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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Appendix I
Appendix I. Opportunistic Infections
Appendix I. Opportunistic Infections
Appendix added per 
Health Authority 
request.
17.2.
Amendment 01 Dated 27 January 2016
The revisions listed below have been made to the protocol Study C38072-AS-30027 and are 
considered substantial by the Teva Authorized Representative.
Table 7:
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:
The back-up Medical 
Monitor for North 
America was 
changed.
The name of the 
 
 was 
corrected.
 
 
The operational lead 
was changed for this 
study.


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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.
The word “iv” was 
removed, as the 
2195 subjects 
included 45 subjects 
who received sc 
reslizumab in 
Study 1107.
Serious adverse events and death cases from the 
ongoing open-label study (Study 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.
Serious Adverse Events
The incidence of serious adverse events was 
similar in the reslizumab 3.0 mg/kg treatment 
group (6%) compared towith 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 
(2%) patients in reslizumab 3.0 mg/kg group 
and 24 (3%) patients in the placebo group and 
24 (2%) patients in the reslizumab 3.0 mg/kg 
group. 
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 or of
reslizumab. MildSmall decreases in the mean 
values of total white blood cell (WBC) counts 
waswere also observed in some studies and has
have been assessed as reflecting the decrease in 
the eosinophil count in hypereosinophilic 
patientscomponent of the differential cell 
counts. The mean values of eosinophil and 
WBC white blood cell counts returned to 
baseline values at the end of study follow-up 
visit (4 months after the last dose of 
reslizumab).
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
…
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 or 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 the 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).
Subheaders were 
added for easier 
identification of 
contents.
The presentation of 
SAE data was made 
consistent with the 
presentation 
elsewhere in the 
document.


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As expected with administration of a mAb, 
hypersensitivity/anaphylactic reactions were 
Adverse Drug Reactions
Anaphylaxis related to reslizumab infusion 
has been reported and areis considered an
adverse drug reactions (ADRs). 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 
Three infusion-related anaphylaxis reactions, 
reported as anaphylaxis, occurred during or 
shortly after related to reslizumab infusion in 
the BREATH studies and were characterized; 
all variously by skin or mucosal involvement, 
dyspnea, wheezing, gastrointestinal 
symptoms, and chills. The 3 events were 
treated at the study site, and the patients were 
withdrawndiscontinued from the study. 
Myalgia (without evidence for muscle 
injury), which was reported at a slightly 
higher incidence in the reslizumab 3.0 mg/kg 
group (1%) than in the placebo group (0.5%)
and anaphylaxis areis considered an ADRs 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 
plan occurred in the eosinophilic 
esophagitis studies and were deemed 
related to known food allergies by the 
investigator 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 
incidence in the reslizumab 3.0 mg/kg 
group (1%) than in the placebo group 
(0.5%) and is considered an ADR of 
reslizumab.
The text was updated 
based on the most 
recent data.


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Additional Safety Issues
Malignancy risk
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 
mMalignancies in the reslizumab-treated 
patients were of diverse tissues origin (1 colon, 
1 anal, 3 melanoma, 2 prostate, 3 breast, 2 lung, 
1 plasmacytoma, 1 lymphoma, 1 lung 
metastasis of a previous resected colon cancer, 
ovarian adenocarcinoma, borderline ovarian 
tumor, and 5 nonmelanoma 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%) patients (; 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%) 
patients in the placebo group; a. All 
malignancies in the reslizumab-treated patients 
were diagnosed within less than 6 months from 
first reslizumab dosing, with the exception of
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 nonmelanoma 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 risk
As of February 2015, there were 
27 treatment-emergent adverse events 
reported by 24 patients related to 
malignancy for the entire clinical program. 
The 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 nonmelanoma 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 nonmelanoma 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.
The text was updated 
based on the most 
recent data.


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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 in 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 withled 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.
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 or 
reslizumab. Mild decrease in the mean value of 
total white blood cell (WBC) counts was also 
observed in some studies and has been assessed 
as reflecting the decrease in the eosinophil 
count in hypereosinophilic patients. The mean 
values of eosinophil and WBC counts returned 
to baseline values at the end of study follow up 
visit (4 months after the last dose of 
reslizumab).
Pregnancy
The safety of reslizumab in pregnant 
women or in the 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 physiological jaundice. One pregnancy 
case was lost to follow-up, and the 
outcome is unknown.
The text was updated 
based on the most 
recent data.


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Immunogenicity
Immunogenicity analysis showed that
Anti-drug antibodyADA 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) ranged from 3.3% 
to 11.8% of patients in the different studies. In 
general, the ADA responses were low in titer 
and often transient, and were neithernot
associated with an effect on reslizumab 
concentration, or eosinophil count, nor 
associated with specific clinical manifestations,
(including hypersensitivity reactions).
Immunogenicity
Anti-drug antibody 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). 
The text was updated 
based on the most 
recent data.
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 
ADRs 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 ADRs of iv reslizumab.
There are limited safety data regarding sc 
administration of reslizumab.
The text was updated 
based on the most 
recent data.


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Reason/Justification 
for change
Section 1.4.3: Overall Risk and Benefit Assessment for This Study:
The majority of adverse events in reslizumab-
treated patients waswere mild to moderate in 
severity,; was considered to be unrelated to 
study drug treatment, as determined by the 
investigator,; and, (as expected) was 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”. 3Three of anaphylaxis 
reactions related to reslizumab infusions that
were reported during the BREATH asthma 
program.; Nnone of these 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; 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.
The additions further 
clarified the text.
Section 1.7: Population to be Studied and Justification (Other sections affected by this change: Clinical Study 
Protocol Synopsis and Section 4.1):
Patients 12 to <18 years of age are excluded 
from participating in South Korea, the 
Netherlands, and Argentina, and patients 66 
years of age and older are excluded from 
participating in South Korea.
Patients 12 to <18 years of age are 
excluded from participating in South 
Korea, the Netherlands, and Argentina, 
and patients 66 years of age and older are 
excluded from participating in South 
Korea.
Exclusion of 
pediatric patients is a 
local exclusion for 
the Netherlands
Section 2.3.3: Other Prespecified Efficacy Endpoints (Other sections affected by this change: Clinical Study 
Protocol Synopsis and Section 9.5.3):
Change in total inhalations of reliever
bronchodilator medication (eg, SABA) use
(number of inhalations per 24 hours: 
day+night) from run-in baseline at each week 
through week 24 or early withdrawal
Change in total inhalations of reliever 
bronchodilator medication (eg, SABA) 
(number of inhalations per 24 hours: 
day+night) from run-in baseline at each 
week through week 24 or early withdrawal
This change 
accommodates 
inhaled rescue
medications other 
than SABA.


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Change in Number of nighttime awakenings
due to asthma requiring rescue inhaler from 
run in baseline at each week through week 24 
or early withdrawalover the 24-week 
treatment period
Number of nighttime awakenings due to 
asthma over the 24-week treatment period
This text was updated 
to make this endpoint 
more general.
Section 2.3.6: Pharmacokinetic Endpoints (Other sections affected by this change: Clinical Study Protocol 
Synopsis and Section 2.3.5):
Serum reslizumab concentrations will be 
determined from blood samples collected from 
each patient at DoR/baseline; and prior to 
study drug administration at weeks 4, 8 12, 
and 24 or early withdrawal; and at the follow-
up visit (approximately week 32).
Serum reslizumab concentrations will be 
determined from blood samples collected 
from each patient at DoR/baseline; and 
prior to study drug administration at weeks 
4, 8 12, and 24 or early withdrawal; and at 
the follow-up visit (approximately week 
32).
This addition clarified 
that the sample 
collection was to be 
done prior to study 
drug administration at 
certain visits.
Section 3.1.1: Screening Period (Other sections affected by this change: Clinical Study Protocol Synopsis and 
Section 4.1)
To be eligible to enroll in the study, a patient 
will have an airway FEV1 reversibility of at 
least 12% and an absolute change of at least 
200 mL to beta-agonist administration, a blood 
eosinophil count of at least 300/μL while on 
daily OCS or during the OCS optimization 
period or at the week -2 visit or a documented 
blood eosinophil level of at least 300/μL during 
the previous 12 months while on at least 
medium dose ICS (eg, ≥440 μg/day of 
fluticasone propionate or equivalent daily), a 
current fluticasone propionate dosage of at least 
880 μg daily or equivalent plus another 
controller, and will have met all the inclusion 
and none of the exclusion criteria.
To be eligible to enroll in the study, a 
patient will have an airway FEV1
reversibility of at least 12% to beta-agonist 
administration, a blood eosinophil count of 
at least 300/μL while on daily OCS or 
during the OCS optimization period or at 
the week -2 visit or a documented blood 
eosinophil level of at least 300/μL during 
the previous 12 months while on at least 
medium dose ICS, a current fluticasone 
propionate dosage of at least 880 μg daily 
or equivalent plus another controller, and 
will have met all the inclusion and none of 
the exclusion criteria.
This deletion was 
made for severe 
asthma patients on 
high GINA step 
therapy (i.e., ICS plus 
another controller (s) 
including OCS ), it 
may be overly 
difficult to achieve 
both criteria..
Section 3.1.2: Optimization Period (Other sections affected by this change: Clinical Study Protocol Synopsis, 
Sections 2.3.3, 3.1.3, 3.1.4 [Table 2], 3.3.3, 4.1, 5.3, 6.9, and 9.5.3):
At the beginning of the optimization period, an 
asthma symptom diary and electronic peak flow 
meter will be distributed where the patient will 
record asthma symptoms, number of reliever 
bronchodilator inhalations, of SABA, 
nighttime awakenings due to asthma requiring 
rescue inhaler, and AM and PM PEF.
At the beginning of the optimization 
period, an asthma symptom diary and 
electronic peak flow meter will be 
distributed where the patient will record 
asthma symptoms, number of reliever 
bronchodilator inhalations, nighttime 
awakenings due to asthma requiring rescue 
inhaler, and AM and PM PEF.
Added 
“bronchodilator” to 
“reliever 
inhalations,” or 
removed “SABA” to 
create more 
generalized wording.
Section 3.1.4: Treatment Period; Table 3: Oral Corticosteroid Decrements During the Treatment Period:
<< Edits made in Table 3 >>
“0” (oral OCS dose mg/day) was added to 
the table.
These additions were 
made for 
clarification.
Section 3.1.4.1: Handling of Asthma Exacerbations During the Treatment Period (Other sections affected by 
this change: Section 3.16.4 and 9.5.6.1):


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Reason/Justification 
for change
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 his/her 
withdrawal from the study (see Section 4.5).
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 
his/her withdrawal from the study (see 
Section 4.5).
Section link added 
for clarification.
Section 3.3.3: Other Prespecified Efficacy Measures and Time Points (Other sections affected by this change: 
Clinical Study Protocol Synopsis):
Total reliever bronchodilator inhalation
SABA use (number of inhalations per 24 
hours: day and night) based on the daily
asthma control diary 
Nighttime awakenings due to asthma 
requiring rescue inhaler based on the daily
asthma control diary
Asthma symptoms based on the daily asthma 
control diary
Total reliever bronchodilator inhalation 
use (number of inhalations per 24 hours: 
day and night) based on the daily asthma 
control diary
Nighttime awakenings due to asthma 
requiring rescue inhaler based on the 
daily asthma control diary
Asthma symptoms based on the daily 
asthma control diary
This change clarified 
that the asthma 
control diary will 
measure asthma 
symptoms, reliever 
bronchodilator 
inhalation use, and 
nighttime awakenings 
due to asthma on a 
daily basis.
Section 3.9: Randomization and Blinding (Other sections affected by this change: Clinical Study Protocol 
Synopsis):
The randomization list and treatment will be 
assigned to the relevant treatment groups 
through a qualified service providerCRO, 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.”
In addition, tThe sponsor’s 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 (Global 
Bioassays and Technology), who, in order to 
facilitate PK and ADA sample analysis, will 
not be blinded. A third party vendor involved 
in PK and/or ADA data analysis may also be 
unblinded prior to database lock. Eosinophils 
and monocytes will be redacted from the post-
baseline differential cell count reports to avoid 
the possibility of removing the blind.
The sponsor’s 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 
(Global Bioassays and Technology), who, 
in order to facilitate PK and ADA sample 
analysis, will not be blinded. Eosinophils 
and monocytes will be redacted from the 
post-baseline differential cell count reports 
to avoid the possibility of removing the 
blind.
Removed from 
Section 3.9 and 
updated in 3.10.


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Section 3.10.2: Blinding/Unblinding:
The individuals responsible for PK and ADA 
sample analysis will know which patients 
received the study drug and which patients 
received placebo. 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 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 Teva statistician, 
service providerCRO 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 and 
PK/ADA data analysis 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 the 
Teva standard operating procedure (SOP) 
GBP_RD_703. The form will be signed at 
the study initiation stage by 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 updates were 
made to add clarity to 
the text.
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 3.14: Stopping Rules and Discontinuation Criteria:
T Other than pregnancy, there are no formal 
rules for early withdrawal from this study.
Other than pregnancy, there are no formal 
rules for early withdrawal from this study.
These updates were 
made to add clarity to 
the text.
Section 3.16: Study Procedures; Table 5: Study Procedures and Assessments: (Other sections affected by this 
change: Section 7.3.3.3):
X was added for pregnancy testing at V20
Additional day for pregnancy testing (V20)
This change creates 
consistency with text.


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Additional days for pre-bronchodilator 
spirometry at V2-11
“X” was added for pre-bronchodilator 
spirometry at V2-V11.
This change creates 
consistency with text.
g βHCG serum pregnancy tests will be 
performed at screening; urine pregnancy testing 
will be performed every 4 weeks thereafter 
until week 24 or early withdrawal (female 
patients who are not 2 years postmenopausal or 
surgically sterile) and at the early follow-up 
visit (V20).
g βHCG serum pregnancy tests will be 
performed at screening; urine pregnancy 
testing will be performed every 4 weeks 
thereafter until week 24 or early 
withdrawal (female patients who are not 2 
years postmenopausal or surgically sterile)
and at the early follow-up visit (V20).
Footnote g was 
clarified to indicate 
that pregnancy 
testing will also be 
performed at visit 20.
Serum chemistry testsi
i 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 testsi
i 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 i was added 
for the serum 
chemistry tests 
assessment.
m Optional at visits 2-11.
m Optional at visits 2-11.
Footnote m was 
added for 
pre-bronchodilator 
spirometry 
assessment, V2-V11 
time point.
Post-bronchodilator spirometryn
n For post-bronchodilatory spirometry, 
short-acting beta-agonists, 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 a metered dose inhaler as tolerated. Post-
bronchodilator spirometry should be 
completed a minimum of 15 minutes after 
dosing of short-acting beta-agonist.
Post-bronchodilator spirometryn
n For post-bronchodilatory spirometry, 
short-acting beta-agonists, 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 a metered dose inhaler as 
tolerated. Post-bronchodilator spirometry 
should be completed a minimum of 
15 minutes after dosing of short-acting 
beta-agonist.
Footnote n was added 
for the 
post-bronchodilator 
spirometry 
assessment.
Blood for ADAp
p If possible, a blood sample for 
measurement of serum reslizumab 
concentrations will be obtained from 
patients experiencing an adverse event 
leading to withdrawal, a serious adverse 
event, an observation of any severe 
hypersensitivity reaction (eg, anaphylaxis), 
or an exacerbation of asthma symptoms.
Blood for ADAp
p If possible, a blood sample for 
measurement of serum reslizumab 
concentrations will be obtained from 
patients experiencing an adverse event 
leading to withdrawal, a serious adverse 
event, an observation of any severe 
hypersensitivity reaction (eg, anaphylaxis), 
or an exacerbation of asthma symptoms.
Footnote p was added 
for the blood for 
ADA assessment.


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Adverse event inquiryr
r 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 inquiryr
r 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 r was added 
for the adverse event 
inquiry assessment.
Section 3.16.1: Procedures for Screening and Enrollment (Visit 1):
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 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 a 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 
screening period, and up to 4 puffs of SABA 
therapy are permitted for each airway 
reversibility test
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 
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 a 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 
in Table 5 Study 
Procedures and 
Assessments.


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Section 3.16.3.1: Double-Blind Treatment Period (Weeks 1 Through 24 [Visits 13 Through 19]):
Study drug will be administered at 
approximately 0800 (±2 hours)the same time 
in the morning on the days indicated in Table 
5.
Study drug will be administered at 
approximately the same time in the 
morning on the days indicated in Table 5.
As this is an anti-
inflammatory drug 
with a long half-life, 
the exact hour is not 
critical.
Section 3.16.3.1.1: Weeks 4, 8, 12, 16, 20, and 24 (Visits 14 Through 19):
Section 3.16.3.1.1: Weeks 4, 8, 12, 16, 20, and 
24 (Visits 14, 15, 16, 17, 18, Through 19)
Section 3.16.3.1.1: Weeks 4, 8, 12, 16, 20, 
and 24 (Visits 14 Through 19)
Change was made for 
consistency with the 
other section 
headings.
The following procedures/assessments will be 
performed beforeprior to administration of 
study drug unless otherwise indicated:
…

Perform adverse event inquiry

Complete asthma-specific tests

…

AQLQ+12 at (weeks 4, 8, 12, 16, 20, 
and 24 or early withdrawal) (may be 
completed after study drug 
administration during the 1-hour 
observation period)

ACQ-6 at (weeks 4, 8, 12, 16, 20, and 
24 or early withdrawal) (may be 
completed after study drug 
administration during the 1-hour 
observation period)

…

Complete EQ-5D (week 24 or early 
withdrawal) (may be completed after 
study drug administration during the 1-
hour observation period)

 
 

Complete SGRQ (weeks 12 and 24 or early 
withdrawal) (may be completed after 
study drug administration during the 1-
hour observation period)
The following procedures/assessments will 
be performed before administration of 
study drug unless otherwise indicated:
…
Perform adverse event inquiry
Complete asthma-specific tests

…

AQLQ+12 (weeks 4, 8, 12, 16, 20, 
and 24 or early withdrawal) (may be 
completed after study drug 
administration during the 1-hour 
observation period)

ACQ-6 (weeks 4, 8, 12, 16, 20, and 
24 or early withdrawal) (may be 
completed after study drug 
administration during the 1-hour 
observation period)

…

Complete EQ-5D (week 24 or early 
withdrawal) (may be completed after 
study drug administration during the 
1-hour observation period)

 
 
Complete SGRQ (weeks 12 and 24 or 
early withdrawal) (may be completed 
after study drug administration during 
the 1-hour observation period)
This change was 
made to ensure 
consistency with 
Table 5 Study 
Procedures and 
Assessments.
Clarification around 
timing of 
questionnaires was 
also added.


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Reason/Justification 
for change
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 Aadverse 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 7.1.7.
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
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 7.1.7.
Remind the patients that they will receive a 
post-injection symptom inquiry via the 
eDiary.
These updates were 
made to capture 
events during study 
drug administration.
Section 3.16.4: Procedures After Study Drug Treatment:
•
Perform urine pregnancy test
•
Perform urine pregnancy test
These updates were 
made to capture 
events after study 
drug administration.
Section 4.1: Patient Inclusion Criteria (Other sections affected by this change: Clinical Study Protocol 
Synopsis):
d. The patient has a documented blood 
eosinophil level of at least 300/L during the 
previous 12 months while on at least medium 
total daily dose of ICS (based on Global 
Initiative for Asthma 2015 clinical 
comparability table (Appendix A) eg, ≥440 
μg/day of fluticasone propionate or equivalent 
daily), or ≥300/L at screening while on 
chronic OCS or that becomes manifest during 
the OCS optimization period or at the week -2 
visit (end of optimization period/beginning of 
run-in period).
d.  The patient has a documented blood 
eosinophil level of at least 300/L during 
the previous 12 months while on at least 
medium total daily dose of ICS based on 
Global Initiative for Asthma 2015 clinical 
comparability table (Appendix A), or 
≥300/L at screening while on chronic 
OCS or that becomes manifest during the 
OCS optimization period or at the week -2 
visit (end of optimization period/beginning 
of run-in period).
This update was 
added 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.


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e. The patient has required at least 880 μg of 
inhaled fluticasone propionate or equivalent 
daily PLUS another controller(s) (eg, long-
acting beta-agonist [LABA], long-acting anti-
muscarinic antagonist, leukotriene inhibitor, or 
theophylline), or documented intolerance to 
another controller, for at least 6 months before 
the screening visit. For a fixed-dose ICS/LABA 
preparation, the highest labeled dose in that 
region will satisfy this criterion. For patients 12 
through <18 years of age, the ICS dose must 
≥440 μg/day of fluticasone propionate or 
equivalent correspond to at least a medium 
total daily dose. Note: the dose and regimen of 
asthma controllers and any allergen 
immunotherapy should have been stable during 
the 30 days before signing the Informed Assent 
Form/Informed Consent Form (ICF).
The patient has required at least 880 μg of 
inhaled fluticasone propionate or 
equivalent daily PLUS another 
controller(s) (eg, long-acting beta-agonist 
[LABA], long-acting anti-muscarinic 
antagonist, leukotriene inhibitor, or 
theophylline), or documented intolerance 
to another controller, for at least 6 months 
before the screening visit. For a fixed-dose 
ICS/LABA preparation, the highest labeled 
dose in that region will satisfy this 
criterion. For patients 12 through <18
years of age, the ICS dose must correspond 
to at least a medium total daily ICS dose. 
Note: the dose and regimen of asthma 
controllers and any allergen 
immunotherapy should have been stable 
during the 30 days before signing the 
Informed Assent Form/Informed Consent 
Form (ICF).
This update was 
added 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.
Section 4.2: Patient Exclusion Criteria (Other sections affected by this change: Clinical Study Protocol 
Synopsis):
e. The patient is pregnant or intends to become 
pregnant during the study or within 5 months 
from last dose of study drug or is lactating. 
Any woman becoming pregnant during the 
study will be withdrawn from the study.
e. The patient is pregnant or intends to 
become pregnant during the study or 
within 5 months from last dose of study 
drug or is lactating. Any woman becoming 
pregnant during the study will be 
withdrawn from the study.
Clarification added.


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Section 4.5: Criteria and Procedures for Discontinuation of Study Treatment and/or Study Withdrawal:
4.5. Withdrawal 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), each patient is free topatients 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. 
EachThe 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, 
3.16.4, 5.4, and 7.1.8.
Should a patient decide to withdraw 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 should be given as to why the 
patient is withdrawing or being withdrawn from 
the study.
The reason for and date of discontinuation from 
the study drug and the reasons for and date of 
withdrawal from the study must be recorded on 
the source documentation and transcribed onto 
the CRF. If a patient withdraws consent, every 
attempt will be made to determine the reasons. 
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(s) must be recorded on the 
source documentation and transcribed onto the 
CRF.
4.5. 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 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 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.
These edits clarified 
the procedures for 
discontinuation or 
withdrawal from the 
study.


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4.5.1
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 
will continue to receive study provided OCS 
(prednisone) treatment for the remainder of 
their participation in the study. 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
termination withdrawal visit (see Table 5).
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 24 (visit 
19). The OCS dose and safety assessments at 
week 24 (visit 19) 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, OCS dose, and survival 
status at week 24. A safety follow-up visit 
(visit 20) should be conducted 8 weeks after 
visit 19.
4.5.1
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 will continue to receive study 
provided OCS (prednisone) treatment for 
the remainder of their participation in the 
study. 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 
specified in the protocol for the early 
withdrawal visit (see Table 5). 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 
24 (visit 19). The OCS dose and safety 
assessments at week 24 (visit 19) 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, OCS 
dose, and survival status at week 24. A 
safety follow-up visit (visit 20) should be 
conducted 8 weeks after visit 19.
This section was 
inserted to clarify 
discontinuation of 
study treatment.


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4.5.2
Complete Withdrawal from Study
Patients whoIf 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 
(±7 days) after the early termination visit. All 
protocol specified evaluations should be 
performed at the follow up visit 8 weeks (±7 
days) after the early termination visit (see Table 
5).(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 4.5.1
(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, OCS dose, and survival status at the 
end of the 24-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 possible, a blood sample for measurement of 
serum reslizumab concentrations will be 
obtained from patients experiencing an adverse 
event leading to withdrawal, a serious adverse 
event, or an exacerbation of asthma symptoms.
If the final visit is conducted more than 28 days 
after the final dose of study drug, all safety 
evaluations will be performed, but efficacy 
evaluations will not be made (see Section 
3.16.4).
4.5.2
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, every effort should be made to 
complete and report the observations 
outlined in Section 4.5.1 (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, OCS dose, and survival 
status at the end of the 24-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).
This section was 
inserted to clarify 
complete withdrawal 
from the study.


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Section 5.3: Prior and Concomitant Therapy or Medication:
Systemic corticosteroids and other 
medications will each be recorded in 
separate CRFs. The sponsor will encode all 
therapy and medication according to the World 
Health Organization drug dictionary (WHO 
Drug).
Systemic corticosteroids and other 
medications will each be recorded in 
separate CRFs. The sponsor will encode all 
therapy and medication according to the 
World Health Organization drug dictionary 
(WHO Drug).
Clarification added.
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 6.2: 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 a 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 ATS/ERS 
2005 procedural guidelines.
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 a 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 ATS/ERS 2005 procedural guidelines.
The doses of various 
beta-agonists for 
spirometry were 
clarified by this 
addition. 
Year of guidance was 
specified for clarity.
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 7.1.6.3.1: Investigator Responsibility (Other sections affected by this change: Sections 3.16 [Table 5], 
6.7, 7.1.8, and 8.1.1):
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.
The text was updated 
to reflect a new 
reason why blood 
samples for serum 
reslizumab 
concentrations will 
be obtained from 
patients.
Section 7.1.6.3.1: Investigator Responsibility (Other sections affected by this change: Section 1.4.3):
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.


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Section 7.1.7: Specific Protocol-Defined Adverse Events:
7.1.7 Specific Protocol-Defined Adverse 
Events for Expedited Reporting
7.1.7.1 Adrenal Insufficiency
7.1.7 
Specific Protocol-Defined 
Adverse Events
7.1.7.1 Adrenal Insufficiency
Headings were 
updated to clarify 
subsections.
7.1.7.2. Protocol-Defined Adverse Events 
for Expedited Reporting to Teva
Additionally, fFor 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. Hypersensitivity reactions 
will be monitored using the diagnostic criteria 
for anaphylaxis as outlined by the 2006 Joint 
NIAID/FAAN Second Symposium on 
Anaphylaxis (Sampson et al 2006) 
(Appendix G). The process for reporting a 
protocol defined adverse event is the same as 
that for reporting a serious adverse event (see 
Section 7.1.6.3).Protocol defined adverse 
events for expedited reporting can be either 
serious or nonserious according to the criteria 
outlined in Section 7.1.6.1. 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 7.1.6.3).
7.1.7.2. 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, and parasitic helminth 
infection. Protocol defined adverse events 
for expedited reporting can be either 
serious or nonserious according to the 
criteria outlined in Section 7.1.6.1. 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 7.1.6.3).
Additional text added 
to clarify where all 
anaphylaxis are to be 
recorded.
7.1.7.3. Specific Adverse Event Case Report 
Form Capturing
7.1.7.3.1. Anaphylaxis/Hypersensitivity 
Reactions Case Report Form
Information about all suspected systemic 
reactions will be recorded on the Suspected 
Anaphylaxis/Hypersensitivity Reactions 
CRF, including the investigator's assessment 
if the event followed the definition of 
anaphylaxis based on the diagnostic criteria 
as outlined by the 2006 Joint NIAID/FAAN 
Second Symposium on Anaphylaxis 
(Sampson et al 2006) (Appendix G). 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.
7.1.7.3. Specific Adverse Event Case 
Report Form Capturing
7.1.7.3.1. Anaphylaxis/Hypersensitivity 
Reactions Case Report Form
Information about all suspected systemic 
reactions will be recorded on the 
Suspected Anaphylaxis/Hypersensitivity 
Reactions CRF, including the 
investigator's assessment if the event 
followed the definition of anaphylaxis 
based on the diagnostic criteria as outlined 
by the 2006 Joint NIAID/FAAN Second 
Symposium on Anaphylaxis (Sampson et 
al 2006) (Appendix G). 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.
Headings were 
updated to clarify 
subsections.
Additional text added 
to clarify capturing of 
CRFs.


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Section 7.1.7.3.2: Creatine Phosphokinase/Muscular Adverse Events CRF:
7.1.7.3.2. Creatine Phosphokinase/Muscular 
Adverse Events CRF
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 ×
the 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”).
7.1.7.3.2. Creatine 
Phosphokinase/Muscular Adverse 
Events CRF
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× the 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 7.3.3.1: 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 7.3.3.3: Human Chorionic Gonadotropin Tests:
Women of childbearing potential will have a 
blood serum βHCG test at screening (visit 1).
Human chorionic gonadotropin urine tests 
will be performed every 4 weeks thereafter 
until week 24 or early withdrawal, and at the 
early follow-up visit (visit 20)and will be 
followed by urine tests monthly during the 
treatment period). Any patient who becomes 
pregnant during the study will be withdrawn. 
Procedures for reporting the pregnancy are 
provided in Section 7.2.
Women of childbearing potential will have 
a serum βHCG test at screening (visit 1). 
Human chorionic gonadotropin urine tests 
will be performed every 4 weeks thereafter 
until week 24 or early withdrawal, and at 
the early follow-up visit (visit 20). Any 
patient who becomes pregnant during the 
study will be withdrawn. Procedures for 
reporting the pregnancy are provided in 
Section 7.2.
The collection of 
pregnancy test results 
were clarified. 


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Section 7.4: Vital Signs:
Vital signs (pulse, blood pressure, body 
temperature, and respiratory rate) will be 
measured at time points specified in Table 5
and beforeprior to 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

height
Vital signs (pulse, blood pressure, body 
temperature, and respiratory rate) will be 
measured at time points specified in Table 
5 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
Height was removed 
from the list of vital 
signs assessed, as it is 
not assessed at the 
same time as the 
other measurements.
Section 9.2.2: Safety Analysis Set:
The safety populationanalysis set will include 
all randomly assigned patients who receive at 
least 1 dose of study drug.
The safety analysis set will include all 
patients who receive at least 1 dose of 
study drug.
The description of the 
safety analysis set 
was updated based on 
feedback from the 
FDA.
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 
on the treatment actually received, regardless of 
the treatment to which they were randomly 
assigned. Major violations will be defined in 
the statistical analysis plan.
Additional analysis sets may be detailed in the 
statistical analysis plan.
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.
The deletion adds 
clarity to the per-
protocol analysis set.


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Section 9.5.6.2: Sensitivity Analysis:
Other Ssensitivity analyses will include the 
following:
Analysis including data collected after early 
withdrawal from treatment. In this analysis, 
patients will be categorized according to the 
percent dose reduction at 24 weeks 
regardless of whether they withdrew early 
from treatment or completed treatment. For 
those patients from which the sponsor fails 
to retrieve data despite all attempts, 
multiple imputations method will be used.
Repeating the primary analysis on the PP 
analysis set
“Tipping point” multiple imputation 
analysis to assess deviations from missing at 
random (MAR); details regarding this 
analysis will be provided in the SAP
Additional sensitivity analyses may be 
included and will be detailed in the statistical 
analysis plan.
Other sensitivity analyses will include the 
following:
Repeating the primary analysis on the 
PP analysis set
“Tipping point” multiple imputation 
analysis to assess deviations from 
missing at random (MAR); details 
regarding this analysis will be provided 
in the SAP
Additional sensitivity analyses may be 
included and will be detailed in the 
statistical analysis plan.
Revised so as to be 
updated in the 
statistical analysis 
plan.
Section 9.5.6.3: Secondary Efficacy Analysis (Other sections affected by this change: Clinical Study Protocol 
Synopsis):
Additional covariates or factors may be added 
to the logistic regressionstatistical models. 
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.
Revised so as to be 
updated in the 
statistical analysis 
plan.


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Section 9.7.2: Safety Analysis:
Summaries will be presented for all adverse 
events starting during or after first study drug 
administration (overall and by severity), 
adverse events determined by the investigator 
to be related to study treatment (ie, reasonable 
possibility; see Section 7.1.4, with missing 
relationship will be counted as related) (overall 
and by severity), serious adverse events, 
adverse events causing withdrawal from the 
studydiscontinuation from study treatment, 
adverse events with onset date after EOT 
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. Patient 
listings of adverse events, serious adverse 
events, and adverse events leading to 
withdrawaldiscontinuation will be presented 
and will include all adverse events reported 
(including before first study drug 
administration).
Summaries will be presented for all 
adverse events starting after first study 
drug administration (overall and by 
severity), adverse events determined by the 
investigator to be related to study 
treatment (ie, reasonable possibility; see 
Section 7.1.4, with missing relationship 
will be counted as related) (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. Patient 
listings of adverse events, serious adverse 
events, and adverse events leading to 
discontinuation will be presented and will 
include all adverse events reported 
(including before first study drug 
administration).
This text was 
clarified.
Section 9.11: Immunogenicity Analysis (Other sections affected by this change: Clinical Study Protocol 
Synopsis):
ADA 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 11.1.2: Protocol Violations:
11.1.2 Protocol DeviationsViolations
11.1.2 Protocol Violations
Section title changed 
to match template.
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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Appendices A, B, C, D, E, and F:
(Sample provided in this appendix is for 
reference only.)
(Sample provided in this appendix is for 
reference only.)
Clarification added.


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APPENDIX A. GLOBAL INITIATIVE FOR ASTHMA ICS
EQUIVALENCY TABLE
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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Source: 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;47:76-83.


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APPENDIX C. ASTHMA CONTROL QUESTIONNAIRE
(Sample provided in this appendix is for reference only.)
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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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 D. ASTHMA CONTROL DIARY
(Sample provided in this appendix is for reference only.)
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 1 short period during the day
2=Symptoms for 2 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


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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:
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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APPENDIXE. EUROPEAN QUALITY OF LIFE 5-DIMENSION HEALTH 
STATE UTILITY INDEX
(Sample provided in this appendix is for reference only.)


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


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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;47(4):373-80; 
PMID: 16546624]. J Allergy Clin Immunol 2006;117(2):391-7.


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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

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
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 Amendment 01
A Phase 3, 24-Week Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and
Safety Study of Reslizumab Subcutaneous Dosing (110 mg Every 4 Weeks) in Patients 
With Oral Corticosteroid Dependent Asthma and Elevated Blood Eosinophils
Study Number C38072-AS-30027
NCT02501629
Date: 08 March 2017


Statistical Analysis Plan with Amendment 01
Study C38072-AS-30027
1
 
TEVA BRANDED PHARMACEUTICAL PRODUCTS R&D, INC. 
STATISTICAL ANALYSIS PLAN
A Phase 3, 24-Week Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and 
Safety Study of Reslizumab Subcutaneous Dosing (110 mg Every 4 Weeks) in Patients With 
Oral Corticosteroid Dependent Asthma and Elevated Blood Eosinophils
Study C38072-AS-30027 Phase 3
Date: 08-March-2017
Version: Amendment 01
Prepared by:


Statistical Analysis Plan with Amendment 01
Study C38072-AS-30027
2
TABLE OF CONTENTS
TITLE PAGE...................................................................................................................................1
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS..................................................8
INTRODUCTION .........................................................................................................................11
1.
STUDY OBJECTIVES ..............................................................................................12
1.1.
Primary Objective.......................................................................................................12
1.2.
Secondary Objective...................................................................................................12
1.3.
Other Efficacy Objective ............................................................................................12
1.4.
Target Biomarker Objective .......................................................................................12
1.5.
Immunogenicity Objective .........................................................................................12
1.6.
Pharmacokinetic Objective.........................................................................................12
1.7.
Exploratory Objective.................................................................................................12
1.8.
Safety Objective..........................................................................................................13
2.
STUDY DESIGN .......................................................................................................14
2.1.
General Design and Study Schema.............................................................................14
2.1.1.
Screening Period.........................................................................................................14
2.1.2.
Optimization Period....................................................................................................14
2.1.3.
Run-In Period..............................................................................................................16
2.1.4.
Treatment Period ........................................................................................................16
2.1.4.1.
Handling of Asthma Exacerbations During the Treatment Period.............................18
2.2.
Primary and Secondary Measures and Endpoints ......................................................23
2.2.1.
Primary Efficacy Endpoint .........................................................................................23
2.2.2.
Secondary Efficacy Endpoints....................................................................................23
2.2.3.
Other Efficacy Endpoints ...........................................................................................23
2.2.4.
Target Biomarker Endpoint........................................................................................24
2.2.5.
Immunogenicity Endpoint ..........................................................................................24
2.2.6.
Pharmacokinetic Endpoint..........................................................................................24
2.2.7.
Exploratory Endpoints................................................................................................25
2.2.8.
Safety Endpoints.........................................................................................................25
2.3.
Sample Size and Power Considerations .....................................................................26
2.4.
Randomization and Blinding......................................................................................26
2.5.
Sequence of Planned Analyses ...................................................................................27


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2.5.1.
Interim Analyses.........................................................................................................27
2.5.2.
Final Analyses and Reporting.....................................................................................27
3.
POPULATIONS/ANALYSIS SETS..........................................................................28
3.1.
Intent to Treat Analysis Set ........................................................................................28
3.1.1.
ITT Analysis Set (Patients 12-70 Years)....................................................................28
3.2.
Safety Analysis Set.....................................................................................................28
3.3.
Per-Protocol Analysis Set...........................................................................................29
3.3.1.
Major Protocol Violations ..........................................................................................29
3.4.
Subgroup Analysis Sets ..............................................................................................30
3.4.1.
Age Strata ...................................................................................................................30
3.4.2.
OCS Strata ..................................................................................................................30
3.4.3.
Other Subgroups .........................................................................................................30
4.
GENERAL ISSUES FOR DATA ANALYSIS..........................................................31
4.1.
General........................................................................................................................31
4.2.
Specification of Baseline Values................................................................................31
4.2.1.
Oral Corticosteroid Dose ............................................................................................31
4.2.2.
Diary ...........................................................................................................................31
4.2.3.
Lung Function.............................................................................................................31
4.2.4.
Patient Reported Outcomes ........................................................................................31
4.2.5.
Biomarkers..................................................................................................................31
4.2.6.
Safety..........................................................................................................................31
4.3.
Multiple Comparisons and Multiplicity......................................................................31
4.4.
Handling Withdrawals and Missing Data...................................................................32
4.5.
Study Days and Visit Windows..................................................................................32
5.
STUDY POPULATION.............................................................................................34
5.1.
General........................................................................................................................34
5.2.
Patient Disposition......................................................................................................34
5.3.
Demographics and Baseline Characteristics...............................................................34
5.4.
Medical History ..........................................................................................................34
5.5.
Prior Medications........................................................................................................35
5.6.
Electrocardiography....................................................................................................35
5.7.
Physical Examinations................................................................................................35
5.8.
Protocol Violations.....................................................................................................35


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5.9.
Childbearing Potential ................................................................................................35
6.
EFFICACY ANALYSIS ............................................................................................36
6.1.
General........................................................................................................................36
6.2.
Primary Efficacy Variable(s) and Analysis ................................................................36
6.2.1.
Variable Definition.....................................................................................................36
6.2.2.
Primary Analysis ........................................................................................................36
6.2.3.
Sensitivity Analyses for the Primary Variable ...........................................................37
6.2.4.
Subgroup Analyses for the Primary Variable.............................................................38
6.3.
Secondary Efficacy Variable(s) and Analysis ............................................................38
6.3.1.
Secondary Variables ...................................................................................................38
6.3.2.
OCS Dose ...................................................................................................................39
6.3.2.1.
Variable Definition.....................................................................................................39
6.3.2.2.
Analysis ......................................................................................................................41
6.3.3.
Clinical Asthma Exacerbations...................................................................................43
6.3.3.1.
Variable Definition.....................................................................................................43
6.3.3.2.
Analysis ......................................................................................................................43
6.4.
Other (and Exploratory) Efficacy Variable(s) and Analysis ......................................44
6.4.1.
Other (and Exploratory) Efficacy Variable(s) ............................................................44
6.4.2.
Time to First Clinical Asthma Exacerbation ..............................................................45
6.4.2.1.
Variable Definition.....................................................................................................45
6.4.2.2.
Analysis ......................................................................................................................45
6.4.3.
Pulmonary Function Tests..........................................................................................46
6.4.3.1.
Variable Definition.....................................................................................................46
6.4.3.2.
Analysis ......................................................................................................................46
6.4.4.
AQLQ +12..................................................................................................................47
6.4.4.1.
Variable Definition.....................................................................................................47
6.4.4.2.
Analysis ......................................................................................................................48
6.4.5.
ACQ-6.........................................................................................................................48
6.4.5.1.
Variable Definition.....................................................................................................48
6.4.5.2.
Analysis ......................................................................................................................49
6.4.6.
SGRQ..........................................................................................................................49
6.4.6.1.
Variable Definition.....................................................................................................49
6.4.6.2.
Analysis ......................................................................................................................50


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6.4.7.
EQ-5D.........................................................................................................................50
6.4.7.1.
Variable Definition.....................................................................................................50
6.4.7.2.
Analysis ......................................................................................................................51
6.4.8.
..51
6.4.8.1.
..51
6.4.8.2.
..51
6.4.9.
Asthma Control Diary.................................................................................................52
6.4.9.1.
Variable Definition.....................................................................................................52
6.4.9.2.
Analysis ......................................................................................................................52
7.
SAFETY ANALYSIS ................................................................................................54
7.1.
General........................................................................................................................54
7.2.
Study Drug Administration.........................................................................................54
7.3.
Adverse Events ...........................................................................................................54
7.3.1.
Adverse Events of Special Interest.............................................................................55
7.3.1.1.
Administration Site Reactions....................................................................................55
7.3.1.2.
Anaphylaxis and Hypersensitivity..............................................................................55
7.3.1.3.
Malignancies...............................................................................................................55
7.3.1.4.
Helminth infections ....................................................................................................55
7.3.1.5.
Muscle Disorders........................................................................................................56
7.3.1.6.
Opportunistic Infections .............................................................................................56
7.3.1.7.
OCS Use and OCS Withdrawal..................................................................................59
7.3.2.
Adverse Events by Subgroup......................................................................................59
7.4.
Deaths .........................................................................................................................60
7.5.
Clinical Laboratory Tests ...........................................................................................60
7.6.
Vital Signs ..................................................................................................................63
7.7.
Electrocardiography....................................................................................................63
7.8.
Physical Examinations................................................................................................64
7.9.
Other Safety Measures and Variables.........................................................................64
7.9.1.
Concomitant Therapy or Medication..........................................................................64
8.
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSIS..............................65
8.1.
Pharmacokinetic Analysis ..........................................................................................65
8.2.
Pharmacodynamic Analysis........................................................................................65
8.2.1.
Target Biomarker (Blood Eosinophil Counts)............................................................65


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8.2.2.
..65
8.3.
..65
8.4.
Immunogenicity..........................................................................................................66
9.
STATISTICAL SOFTWARE ....................................................................................67
10.
CHANGES TO PROTOCOL SPECIFIED ANALYSES ..........................................68
11.
REFERENCES ...........................................................................................................76
APPENDIX A.
IMPUTATION AND ANALYSIS STEPS FOR SENSITIVITY 
ANALYSIS OF THE PRIMARY VARIABLE .........................................................77
APPENDIX B.
TIPPING POINT ANALYSIS ..........................................................................79
APPENDIX C.
SGRQ – ITEM WEIGHTS FOR PROGRAMMING........................................81


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LIST OF TABLES
Table 1:
Optimization Phase Prednisone Dose Reduction Algorithm......................................16
Table 2:
Eligibility Criteria for Scheduled Oral Corticosteroid Reductions During the 
Treatment Period (Must Meet All) .............................................................................17
Table 3:
Oral Corticosteroid Decrements During the Treatment Period..................................18
Table 4:
Study Procedures and Assessments............................................................................19
Table 5:
Major Protocol Violations ..........................................................................................29
Table 6:
Definition of Analysis Days for Diary Data...............................................................33
Table 7:
Conversion of ICS to Fluticasone-Equivalent Doses .................................................35
Table 8:
Definition of Analysis Days for OCS Dose................................................................40
Table 9:
Conversion of Corticosteroid to Prednisone-Equivalent Doses .................................42
Table 10:
List of Search Terms for Opportunistic Infections.....................................................56
Table 11:
Criteria for Potentially Clinically Significant Laboratory Values..............................61
Table 12:
Criteria for Potentially Clinically Significant Vital Signs..........................................63
Table 13:
Changes to the Protocol Specified Analyses ..............................................................68
Table 14:
Key Changes to the Statistical Analysis Plan, Amendment 01 ..................................69


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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
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
EQ-5D
European Quality of Life 5-Dimension
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
GLM
Generalized Linear Model


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HLGT
High Level Group Term
HLT
High Level Term
ICF
Informed Consent Form 
ICH
International Conference on Harmonization
ICS
Inhaled Corticosteroid
im
Intramuscular
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
OR
Odds Ratio
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


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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 01
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11
INTRODUCTION
This Statistical Analysis Plan (SAP) describes the planned analysis and reporting for TEVA 
Branded Pharmaceuticals Products R&D, Inc. study C38072-AS-30027 (A Phase 3, 24-Week 
Double-Blind, Placebo-Controlled, Parallel-Group, Efficacy and Safety Study of Reslizumab 
Subcutaneous Dosing (110 mg Every 4 Weeks) in Patients With Oral Corticosteroid Dependent 
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-30027 Amendment 02, issued 18 July 2016

Case report form (CRF) for Study C38072-AS-30027

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 01
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1.
STUDY OBJECTIVES
1.1.
Primary Objective
The primary objective of the study is to determine the ability of reslizumab (110 mg) 
administered sc once every 4 weeks to produce a corticosteroid-sparing effect (as demonstrated 
by percent reduction in daily OCS use) in patients with OCS-dependent asthma and elevated 
blood eosinophils, without loss of asthma control.
1.2.
Secondary Objective
The secondary objective of this study is to evaluate the clinical benefits of reslizumab in the 
context of OCS reduction.
1.3.
Other Efficacy Objective
Another efficacy objective of this study is to evaluate the effect of reslizumab on standard 
asthma control measures during tapering of OCS in patients with OCS-dependent asthma.
1.4.
Target Biomarker Objective
The target biomarker objective is to evaluate the effect of sc dosing of reslizumab on blood 
eosinophil counts.
1.5.
Immunogenicity Objective
The immunogenicity objective is to evaluate the potential of sc dosing of reslizumab to raise 
ADAs.
1.6.
Pharmacokinetic Objective
The PK objective is to characterize the PK of sc reslizumab in the study population.
1.7.
Exploratory Objective
The exploratory objectives are:


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1.8.
Safety Objective
The safety objective is to evaluate the safety of chronic sc dosing of reslizumab and tapering of 
OCS as assessed by the following:

Occurrence of adverse events

Clinical laboratory evaluations of serum chemistry and hematology

Vital signs (pulse, respiratory rate, and blood pressure) measurements

ECG findings

Physical examination findings, including body weight measurements

Signs and/or symptoms of adrenal insufficiency (OCS withdrawal effects)

Concomitant medication usage


Statistical Analysis Plan with Amendment 01
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2.
STUDY DESIGN
2.1.
General Design and Study Schema
This is a Phase 3, 24-week, double-blind, placebo-controlled, parallel-group study to evaluate the 
efficacy and safety of sc reslizumab treatment at a dosage of 110 mg every 4 weeks in patients 
12 years of age and older with OCS-dependent asthma and elevated blood eosinophils. The study 
will consist of a screening period of up to 2 weeks, followed by an optimization period of up to 
10 weeks, a run-in period of at least 2 weeks, a 24-week double-blind treatment period, an 
8-week follow-up period, and an additional 16-week follow-up period to collect drug wash-out 
samples for immunogenicity assessments.
2.1.1.
Screening Period
Patients will begin screening up to 14 weeks before day of randomization. During the screening 
period, a signed and dated informed consent form (ICF) (and an assent form for children 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 (CBC) determined. If 
the patient’s eosinophil count is 300/μL or greater while on daily OCS and if the patient’s 
medication compliance and inhaler use technique are optimal, the patient will be eligible to 
continue. A patient will meet inclusion criteria if an eosinophil count of 300/μL or greater 
becomes manifest during the OCS optimization period or at the week -2 visit (end of 
optimization period/beginning of run-in period). Patient medical history; pre-bronchodilator 
spirometry; 12-lead ECG; physical examination; urinalysis; vital signs measurements; beta 
human chorionic gonadotropin serum pregnancy test (for all females of childbearing potential); 
testing for human immunodeficiency virus, hepatitis B, and hepatitis C; and concomitant 
medication history will also be assessed at screening.
To be eligible to enroll in the study, a patient will have an airway FEV1 reversibility of at least 
12% to beta-agonist administration, a blood eosinophil count of at least 300/μL while on daily 
OCS or during the OCS optimization period or at the week -2 visit or a documented blood 
eosinophil level of at least 300/μL during the previous 12 months while on at least medium dose 
ICS, a current fluticasone propionate dosage of at least 880 μg daily or equivalent plus another 
controller, and will have met all the inclusion and none of the exclusion criteria.
2.1.2.
Optimization Period
Patients who meet screening eligibility requirements will enter the optimization period for up to 
10 weeks to determine the patient’s minimal effective OCS requirement. The patient’s previous 
OCS will be standardized to an equivalent dose and regimen of prednisone to facilitate 
optimization; the same formulation should be maintained through the end of treatment (EOT) 
visit. It is expected that the optimization period will be shorter than 10 weeks for those patients 
who are at or near their optimal corticosteroid dose at enrollment. The patient’s previous non-


Statistical Analysis Plan with Amendment 01
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OCS background asthma controller medications will be continued unchanged throughout the 
pre-randomization period and the entire study. At the beginning of the optimization period, an 
asthma symptom diary and electronic peak flow meter will be distributed where the patient will 
record asthma symptoms, number of reliever bronchodilator inhalations, nighttime awakenings 
due to asthma requiring rescue inhaler, and AM and PM PEF.
For optimization, the prednisone dose should be reduced at 1-week intervals, according to the 
algorithm shown in Table 1, for up to 10 weeks, or until there is a worsening of asthma signs and 
symptoms. Worsening of asthma signs and symptoms should be based on the following:

FEV1 <80% of the screening value AND/OR

The physician’s global assessment of asthma worsening based on trends in daily diary 
measures for the past 7 days compared with the week prior, as well as any physical 
examination signs
When either a lung function or a symptomatic deterioration occurs, the patient will be returned to 
the previously effective OCS level, which will then constitute the minimally effective dose for 
the purpose of run-in. If this previously effective dose is no longer effective, the investigator can 
determine the clinically appropriate minimally effective dose for the purpose of run-in.
Regarding the amount and rate of OCS reduction during dose optimization, in order to provoke a 
worsening of asthma signs and symptoms within the 10-week monitored optimization period, 
OCS reduction should be attempted approximately every 1 week after evaluation in the clinic.
The magnitude of OCS reduction will be based on the following Optimization Phase OCS Dose 
Reduction Algorithm (Table 1).


Statistical Analysis Plan with Amendment 01
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Table 1:
Optimization Phase Prednisone Dose Reduction Algorithm
Time Course
Oral OCS Dose (mg/day)
Visit 2 starting dosea
40+b
35
30
25
20
15
10
7.5
5
1st reduction at Visit 2
35
30
25
20
15
10
7.5
5
2.5c
+ 1 week
30
25
20
15
10
7.5
5
2.5c
+ 1 week
25
20
15
10
7.5
5
2.5c
+ 1 week
20
15
10
7.5
5
2.5c
+ 1 week
15
10
7.5
5
2.5c
+ 1 week
10
7.5
5
2.5c
+ 1 week
7.5
5
2.5c
+ 1 week
5
2.5c
+ 1 week
2.5c
+ 1 week
a Starting doses that fall between values shown in this table should utilize the algorithm for the higher of the 2 
doses.
b Patients who the investigator believes may be able to decrease OCS dose to 40 mg during the optimization period 
may be enrolled. OCS dose reduction during optimization for patients on >40 mg daily at that start of optimization 
should follow weekly reductions with magnitudes similar to those in the table (this may be discussed with medical 
monitor). Patients who require >40 mg OCS to maintain asthma control at the end of optimization will not be 
randomized.
c Patients must be using an average daily dose of ≥5 mg OCS after optimization. Patients who require <5 mg OCS 
to maintain asthma control will not be randomized.
OCS=oral corticosteroid
Regarding eosinophil counts during the optimization period, blood eosinophils ≥300/μL that 
become manifest during OCS reductions during optimization, will count toward the eosinophil 
inclusion criterion for this study.
2.1.3.
Run-In Period
Patients whose minimal effective OCS dose remains between ≥5 mg and ≤40 mg of prednisone 
daily at the end of optimization may advance to run-in (for at least 2 weeks). During run-in, 
patients will continue to keep their daily asthma control diary and a PEF meter to perform daily 
self-monitoring of asthma symptoms while maintaining their minimally effective OCS dose and 
previous background asthma medications unchanged. The frequency of symptoms, use of 
inhaled reliever bronchodilator, nighttime awakenings due to asthma requiring rescue inhaler, 
and ambulatory lung function during the last 7 days of run-in will constitute the baseline level of 
control for analysis and the basis for OCS reduction algorithm to be used during the treatment 
period.
2.1.4.
Treatment Period
Patients continuing to meet eligibility criteria on the day of randomization (day 1, week 0) will 
be randomly assigned in a 1:1 ratio to receive placebo or reslizumab 110 mg once every 4 weeks 


Statistical Analysis Plan with Amendment 01
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through week 20, followed by an EOT visit at week 24. Patients will begin treatment on day 1 
after completing baseline assessments, and they will return to the research facility for outpatient 
visits every 4 weeks through week 24 (EOT visit) for safety, PK, PD, immunogenicity, and 
efficacy assessments as applicable.
During the treatment period, the patient will continue his/her usual non-OCS background asthma 
medication without change; the OCS dose will be tapered per protocol. The treatment period 
consists of the following:

Induction: The minimally effective dose of OCS will be maintained, unchanged, 
during the first 4 weeks of the treatment period to allow sufficient time for any 
potential treatment effect to become established.

OCS reduction: The minimally effective OCS dose will be reduced per protocol at 
scheduled clinic visits from the beginning of week 5 (ie, end of the induction period)
through week 20, as long as all 5 criteria in Table 2 are met and there are no clinical 
manifestations of adrenal insufficiency. These 5 eligibility criteria assure that the 
patient’s asthma control is not significantly worsened compared to baseline. The last
possible dose reduction can occur at week 20. The algorithm for OCS reductions 
during the treatment period is given in Table 3. If the OCS dose could not be 
decreased, it should be held constant or may be increased to a previous level, at the 
investigator’s discretion, until dose reduction criteria are met.

Maintenance: OCS dose will be held stable from week 20 through EOT at week 24.
Table 2:
Eligibility Criteria for Scheduled Oral Corticosteroid Reductions During the 
Treatment Period (Must Meet All)
1.
Forced expiratory volume in 1 second (FEV1) ≥80% of baselinea
2.
AM PEF ≥80% of baseline mean AM PEF on at least 5 of the 7 days preceding the visit
3.
Mean nighttime awakenings due to asthma requiring rescue inhaler over the preceding 7 
days ≤150% increase over the baseline period 
4.
Reliever bronchodilator inhaler use does not exceed 150% of the baseline inhaler use per 
24 hours on more than 2 of the preceding 7 days 
5.
No increase in OCS dose since the previous visit
b
a Baseline for clinic visit measures (FEV1) is the DoR value. Baseline for diary measures is the average over the 7 
days prior to DoR.
b If a dose increase results in a return to the previous dose, then it is acceptable to attempt dose decrease again at the 
investigator’s discretion.
AM=morning; DoR=date of randomization; FEV1=forced expiratory volume in 1 second; PEF=peak expiratory 
flow; OCS=oral corticosteroid.


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Table 3:
Oral Corticosteroid Decrements During the Treatment Period
Time Course
Oral OCS Dose (mg/day)
Optimized OCS dose
40
35
30
25
20
15
10
7.5
5
1st reduction
30
25
20
15
10
10
7.5
5
2.5
+ 4 weeks
20
15
10
10
7.5
7.5
5
2.5
0
+ 4 weeks
10
10
5
5
5
5
2.5
0
+ 4 weeks
5
5
2.5
2.5
2.5
2.5
0
+ 4 weeks
2.5
2.5
0
0
0
0
2.1.4.1.
Handling of Asthma Exacerbations During the Treatment Period
Patients should be treated with an OCS burst: 40 to 60 mg (or at least double the current dose) of 
OCS tapered over a 7- to 10-day period to a new maintenance dose of 2.5 mg above the pre-burst 
dose. It is understood that im or iv corticosteroid may also be administered as part of the 
treatment of the asthma exacerbation. If a second OCS burst (doubling of current dose) is 
required, the patient should be maintained on a fixed OCS dose without any tapering attempts for 
the remainder of the double-blind treatment phase and the follow-up period.
Patients who complete all scheduled visits will have final procedures and assessments performed 
at the EOT visit (visit 19). Patients who withdraw from the study before completing the 24-week 
treatment period will have visit 19 (week 24 ± 7 days or early termination) procedures and 
assessments performed at their final visit. Patients will return for a follow-up evaluation 8 weeks 
(±7 days) after the EOT visit in this study for assessment of pre-bronchodilator spirometry, 
ACQ-6 score, PK samples, adverse events, blood eosinophils, CAEs and related health care 
utilizations, and blood for ADA.
The assessments and procedures performed during each study visit are detailed in Table 4. 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 his/her withdrawal from the study.


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Table 4:
Study Procedures and Assessments
Procedures and 
assessments
Pretreatment
V12
Start 
run-in
Double-blind treatment period (visit/week)
Follow-up
Late 
follow-up
V1
V2-V11
V13a
V14a
V15a
V16a
V17a
V18a
V19a
V20
V21
Start of 
screening 
period
Standardize 
and optimize 
maintenance 
OCSabc
Week −14d
Between 
weeks −12 
and −3
W −2
DoR
W4±7d
W8±7d
W12±7d
W16±7d
W20±7d
W24±7d/
EOT/
early termination
W32/EOT 
+ 8w ±7d
W48/EOT 
+ 24w 
±14d
Informed assent/consent
X
Medical history
X
Medication history
X
Inclusion and/or exclusion 
criteria
X
Xe
X
X
Randomization criteria
X
Reversibility testingf
X
Pregnancy testingg
X
X
X
X
X
X
X
X
X
Blood for HIV, hepatitis B, 
and hepatitis C
X
CBC with differentialh
X
X
X
X
X
X
X
X
X
X
X
Serum chemistry testsi
X
X
Xj
Xj
X
Xj
Xj
X
Urinalysis
X
Full physical examinationk
X
Brief physical examinationk
X
X
X
X
X
X
X
X
X
Vital signs measurementk
X
X
X
X
X
X
X
X
X
X
Heightl and weight
X
X
X


Statistical Analysis Plan with Amendment 01
Study C38072-AS-30027
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Procedures and 
assessments
Pretreatment
V12
Start 
run-in
Double-blind treatment period (visit/week)
Follow-up
Late 
follow-up
V1
V2-V11
V13a
V14a
V15a
V16a
V17a
V18a
V19a
V20
V21
Start of 
screening 
period
Standardize 
and optimize 
maintenance 
OCSabc
Week −14d
Between 
weeks −12 
and −3
W −2
DoR
W4±7d
W8±7d
W12±7d
W16±7d
W20±7d
W24±7d/
EOT/
early termination
W32/EOT 
+ 8w ±7d
W48/EOT 
+ 24w 
±14d
ECGk
X
X
Provide and collect PEF 
meter
X
X
Provide/collect electronic 
asthma control diary; 
reinforce diary and PEF 
compliance
X
X
X
X
X
X
X
X
X
OCS reduction attempts
X
X
X
X
X
X
Pre-bronchodilator 
spirometrym
X
Xn
X
X
X
X
X
X
X
X
Post-bronchodilator 
spirometryo
X
X
X
X
X
X
PK samplesp
X
X
X
X
X
X
X
X
X
Blood for ADAq
X
X
X
X
X
X
X
IP administration
X
X
X
X
X
X
Injection site evaluation
X
X
X
X
X
X
AQLQ+12 
X
X
X
X
X
X
X


Statistical Analysis Plan with Amendment 01
Study C38072-AS-30027
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Procedures and 
assessments
Pretreatment
V12
Start 
run-in
Double-blind treatment period (visit/week)
Follow-up
Late 
follow-up
V1
V2-V11
V13a
V14a
V15a
V16a
V17a
V18a
V19a
V20
V21
Start of 
screening 
period
Standardize 
and optimize 
maintenance 
OCSabc
Week −14d
Between 
weeks −12 
and −3
W −2
DoR
W4±7d
W8±7d
W12±7d
W16±7d
W20±7d
W24±7d/
EOT/
early termination
W32/EOT 
+ 8w ±7d
W48/EOT 
+ 24w 
±14d
ACQ-6
X
X
X
X
X
X
X
X
EQ-5D
X
X
St. George’s Respiratory 
questionnaire
X
X
X
Assess CAEs and related 
HCUr
X
X
X
X
X
X
X
Phadiatop allergy test
X
OCS withdrawal effects 
inquirys
X
X
X
X
X
X
X
X
Adverse event inquiryt
X
X
X
X
X
X
X
X
X
X
Concomitant medication 
inquiry
X
X
X
X
X
X
X
X
X
X
X
a The site will contact IWRS at every optimization and treatment visit.
b The patient’s previous OCS should be switched to an equivalent, standardized prednisone formulation. Optimization may occur once OCS standardization is complete.
c Attempts at OCS reduction should be made at 1-week intervals, for up to 10 weeks or until there is a worsening of asthma signs and symptoms, to help determine the patient’s 
lowest effective OCS dose. This period may be shortened if the lowest effective dose is achieved sooner. Eosinophil counts during the optimization period or at the week -2 visit 
may be considered in order to meet the eosinophil inclusion criteria for this study. Patients requiring an average daily dose of between ≥5 mg and ≤40 mg may proceed to run-in 
and maintained without change during run-in.
d The screening period (between V1 and V2) can be less than 2 weeks if all of the screening inclusion criteria are met sooner. 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 and reversibility testing.
e Verify that essential screening inclusion criteria for asthma are met before entering optimization.
f Reversibility testing is most conveniently performed at the same visit as the screening, pre-bronchodilator spirometry. All patients must undergo reversibility testing, even if they 
are submitting historical reversibility or methacholine provocation results to support inclusion criterion e. Reversibility testing may be repeated once, within the 2-week 
screening period.


Statistical Analysis Plan with Amendment 01
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g βHCG serum pregnancy tests will be performed at screening; urine pregnancy testing will be performed every 4 weeks thereafter until week 24 or early withdrawal (female 
patients who are not 2 years postmenopausal or surgically sterile) and at the early follow-up visit (V20).
h The patient must have had a blood eosinophil count ≥300/μL in the 12 months before ICF or ≥300/μL during screening or during OCS optimization or at the week -2 visit. A 
CBC with differential need not be repeated at every visit during the optimization period and should be done at the investigator's discretion if the eosinophil criteria were not met 
at screening.
i 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 7.1.7.3.2.
j CPK measurement only. CPK will be collected with PK sample.
k Physical examination, vital signs, and ECG should be obtained before spirometry procedures and IP administration.
l For adults, height will be measured at screening only. For patients <18 years of age, height will be measured at screening, DoR, and EOT. Use of a stadiometer is preferable, if 
available, or use a cloth tape securely attached to the wall that will allow reproducible results. Height should be measured in centimeters, without shoes.
m Pre-bronchodilator spirometry assessments should only be performed after withholding short-acting bronchodilators (ie, inhaled short-acting beta-agonists and/or short acting 
anticholinergics) for at least 6 hours and long-acting bronchodilators (ie, inhaled LABAs 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.
n Optional at visits 2-11.
o For post-bronchodilatory spirometry, short-acting beta-agonists, 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 a metered dose inhaler as tolerated. Post-bronchodilator spirometry should be completed a minimum of 15 
minutes after dosing of short-acting beta-agonist.
p Blood samples for PK and ADA analysis will be drawn before administration of study drug.
q If possible, a blood sample for measurement of serum reslizumab concentrations will be obtained from patients experiencing an adverse event leading to withdrawal, a serious 
adverse event, an observation of any severe hypersensitivity reaction (eg, anaphylaxis), or an exacerbation of asthma symptoms.
r 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. Procedures and assessments to be performed if an unscheduled visit occurs are described in Protocol Section 3.16.5.
s Based on investigator's assessment.
t 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).
ACQ-6=6-item Asthma Control Questionnaire; ADA=anti-drug antibody; AQLQ=Asthma Quality of Life Questionnaire; βHCG=beta human chorionic gonadotropin; 
CAE=clinical asthma exacerbation; CBC=complete blood count; CPK=creatine phosphokinase; CRF = case report form; DoR=date of randomization; ECG=electrocardiogram; 
eDiary = electronic diary; EOT=end of treatment; EQ-5D=European Quality of Life 5-dimension health state utility index; FEV1=forced expiratory volume in 1 second; 
 HCU=health care utilizations; HIV=human immunodeficiency virus; ICF=Informed Consent Form; IP=Investigational Product; LABA=long-acting 
beta-agonist; OCS=oral corticosteroid; PEF=peak expiratory flow; PK=pharmacokinetic; 
 ULN = upper limit of normal V=visit; W=wee


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2.2.
Primary and Secondary Measures and Endpoints
2.2.1.
Primary Efficacy Endpoint
The primary efficacy variable and endpoint for this study is the categorized percent reduction in 
the daily OCS dose during weeks 20 to 24 as compared with the dose at the end of the 
optimization phase. Percent reduction will be categorized as follows:

90% to 100%

75% to <90%

50% to <75%

>0% to <50%

No decrease in OCS, or loss of baseline asthma control during weeks 20 through 24, 
or discontinuation from study drug
Loss of baseline asthma control will be defined as FEV1 value of less than 80% of baseline at the 
week 24 visit, or clinically significant worsening in ACQ-6 score (change in score of 0.5) at the 
week 24 visit compared with baseline, and/or CAE during weeks 20 through 24 (CAE defined in 
Section 6.3.3.1).
2.2.2.
Secondary Efficacy Endpoints
The secondary efficacy endpoints for this study are as follows:

Proportion of patients achieving ≥50% reduction in OCS dose at weeks 20 to 24 
relative to the OCS dose at the date of randomization (DoR)/baseline, while 
maintaining asthma control

Proportion of patients achieving dose reduction to ≤5 mg daily dose at weeks 20 to 
24, while maintaining asthma control

Percent change from DoR/baseline in OCS dose at weeks 20 to 24

Proportion of patients achieving less than 5 mg decrement in OCS dose (ie, the 
minimal and non-responders) at weeks 20 to 24 compared with the OCS dose at 
DoR/baseline, while maintaining asthma control

Clinical asthma exacerbation related:

Annualized rate of CAEs requiring a burst of systemic corticosteroid (injection, or 
if oral, at least a doubling from the current OCS dose for at least 3 days); an 
asthma-specific hospital admission; or an asthma-specific emergency department 
visit during the treatment period (weeks 0 to 24)

Proportion of patients discontinuing OCS at weeks 20 to 24, while maintaining 
asthma control
2.2.3.
Other Efficacy Endpoints
The other efficacy endpoints are as follows:


Statistical Analysis Plan with Amendment 01
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
Time to first clinical asthma exacerbation 

Other clinic lung functions including the following:

Pre-bronchodilator FEV1: change from DoR/baseline to weeks 4, 8, 12, 16, 20, 
and 24 or early withdrawal

Post-bronchodilator FEV1: change from DoR/baseline to weeks 4, 12, 20, and 24 
or early withdrawal

Ambulatory lung function: change in morning (AM) and evening (PM) peak 
expiratory flow (PEF) from run-in baseline at each week through week 24 or early 
withdrawal

Asthma Quality of Life (AQLQ) + 12 score: change from DoR/baseline to weeks 4, 8, 
12, 16, 20, and 24 or early withdrawal

ACQ-6 score: change from DoR/baseline to weeks 4, 8, 12, 16, 20, and 24 or early 
withdrawal

Change in total inhalations of reliever bronchodilator medication (eg, SABA) 
(number of inhalations per 24 hours: day+night) from run-in baseline at each week 
through week 24 or early withdrawal

Number of nighttime awakenings due to asthma over the 24-week treatment period

Change in total asthma symptom score from run-in baseline at each week through 
week 24 or early withdrawal

European Quality of Life 5-dimension health state utility index (EQ-5D) score: 
change from DoR/baseline to week 24 or early withdrawal

St. George’s Respiratory Questionnaire (SGRQ) score: change from DoR/baseline to 
weeks 12 and 24 or early withdrawal
2.2.4.
Target Biomarker Endpoint
The target biomarker endpoints are the blood eosinophil counts at DoR/baseline; weeks 4, 8, 12, 
16, 20, and 24 or early withdrawal; and at the follow-up visit (approximately week 32).
2.2.5.
Immunogenicity Endpoint
The immunogenicity endpoints are the immunogenicity incidence and the impact of ADA on 
clinical outcomes. The drug-emergent ADA response will be identified by analyzing ADA test 
results for serum samples obtained before the administration of study drug at DoR/baseline; prior 
to study drug administration at weeks 4, 8, 12, and 24 or early withdrawal; and at the follow-up 
visit (approximately week 32). An additional sample will be obtained at the late follow-up visit 
(approximately week 48).
2.2.6.
Pharmacokinetic Endpoint
There are no specific endpoints related to PK. Measured concentrations will be used to 
characterize the PK of sc reslizumab in the studied population and to explore exposure-response 
relationships. Serum reslizumab concentrations will be determined from blood samples collected 


Statistical Analysis Plan with Amendment 01
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from each patient at DoR/baseline; and prior to study drug administration at weeks 4, 8 12, and 
24 or early withdrawal; and at the follow-up visit (approximately week 32). An additional PK 
sample will be obtained at the late follow-up visit (approximately week 48).
2.2.7.
Exploratory Endpoints
The exploratory endpoints are as follows:
2.2.8.
Safety Endpoints
Safety endpoints will include the following:

Occurrence of adverse events throughout the study, including the week 32 follow-up 
visit

Clinical laboratory evaluations of serum chemistry at screening, DoR, and 
periodically throughout the study

Clinical laboratory evaluations of hematology throughout the study

Vital signs (pulse, body temperature, respiratory rate, and blood pressure) 
measurements throughout the study

ECG evaluation at screening and at week 24 or early withdrawal

Physical examination findings, including body weight measurements, throughout the 
study

Signs and/or symptoms of adrenal insufficiency (OCS withdrawal effects) throughout 
the study

Concomitant medication usage throughout the study, including the week 32 follow-up 
visit


Statistical Analysis Plan with Amendment 01
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2.3.
Sample Size and Power Considerations
The primary efficacy variable and endpoint for this study is the percent reduction in the daily 
OCS dose during weeks 20 to 24 as compared with the dose at the end of the optimization phase.
The study will be considered positive if the measure meets statistical significance at the 
respective predefined significance level. A statistically significant effect of reslizumab over 
placebo, as measured by the primary efficacy variable, is required to establish the efficacy of 
reslizumab treatment.
The sample size was calculated based on the following assumptions:

Categorical reduction in OCS dose after 24 weeks of treatment will have the 
following distribution for the placebo group (based on Bel et al 2014):

10.9% percent of subjects will have 90% to 100% reduction

7.9% percent of subjects will have 75% to <90% reduction

14.8% percent of subjects will have 50% to <75% reduction

10.8% percent of subjects will have 0% to <50% reduction

55.6% percent of subjects will have no reduction, loss of asthma control, or 
discontinuation from study drug

The overall odds ratio between reslizumab and placebo based on proportional odds 
model will be 2.63

Alpha level of 0.05
Based on the above assumptions, a sample size of 76 subjects per group will provide 90% power 
to detect a significant effect of reslizumab over placebo on the probability for a higher 
categorical reduction of OCS dose.
2.4.
Randomization and Blinding
This is a randomized, double-blind, placebo-controlled study. In order to achieve balance 
between treatment groups with regard to average daily OCS use/requirement and age, 
randomization will be stratified by optimized, average daily OCS dose (>10 mg or ≤10 mg) and 
age at baseline (12 to <18 years or ≥18 years). Within each stratum, patients will be randomly 
assigned to receive treatment with sc reslizumab at a dosage of 110 mg every 4 weeks or a 
matching placebo in a 1:1 ratio. This system is used to ensure a balance across treatment groups.
The randomization list and treatment will be assigned to the relevant treatment groups through a 
qualified 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 CRO under the oversight of Teva’s Clinical 
Supply Chain.
The sponsor’s 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 (Global Bioassays and Technology), who will not 
be blinded in order to facilitate PK and ADA sample analysis. Eosinophils and monocytes will


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be redacted from the post-baseline differential cell count reports to avoid the possibility of 
removing the blind.
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.


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3.
POPULATIONS/ANALYSIS SETS
3.1.
Intent to Treat Analysis Set
The intent to treat (ITT) analysis set will include all randomized patients. 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 24) 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 all efficacy endpoints, the on-treatment approach will be utilized as the main approach to 
analysis. However, it should be noted that all patients will be included in the analysis of the 
primary and secondary endpoints related to OCS dose reduction by incorporating missing data 
(due to dropout) as nonresponders. The analytic approach including all data collected from 
patients will additionally be conducted as sensitivity analyses for the primary endpoint.
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 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. 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.
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 24) 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.


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3.3.
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. 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 5 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 5:
Major Protocol Violations
Violation
Approach to identifying protocol violations
Patient was not on a daily maintenance 
dose of OCS prior to screening
Inclusion criteria (c); disposition CRF
Medication CRF
Protocol violation CRF
Patient does not have a documented blood 
eosinophil ≥300/μL
Inclusion criteria (d); disposition CRF
Laboratory data (for eosinophils obtained during the 
screening and optimization periods)
Subject status CRF (for historical eosinophils)
Protocol violation CRF
Patient was not on ICS (at least 880 μg of 
inhaled fluticasone propionate or equivalent) 
plus another controller at baseline (eg, LABA, 
LAMA, LTRA, or theophylline).
For patients 12 through <18 years, ICS dose 
must correspond to at least a medium total 
daily ICS dose.
Inclusion criteria (e); disposition CRF
Medication CRF
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.
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


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3.4.
Subgroup Analysis Sets
3.4.1.
Age Strata
Selected efficacy endpoints including OCS dose (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.
OCS Strata
Selected efficacy endpoints including OCS dose (primary), pre-bronchodilator FEV1, AQLQ+12, 
ACQ-6, and blood eosinophils will be analyzed separately for patients taking an optimized
baseline dose of OCS ≤10 mg and >10 mg. OCS strata will be defined based on the optimized 
baseline dose of OCS recorded in the clinical database.
3.4.3.
Other Subgroups
Selected efficacy endpoints including OCS dose (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)

Duration of OCS use (<5, ≥5 years)

ADA status (Positive, Negative) – for reslizumab-treated patients only


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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.
Oral Corticosteroid Dose
The baseline value is the prescribed optimized OCS dose following the optimization period and 
will be defined as the OCS dose reported on the day of first dose of study drug.
4.2.2.
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 6
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.
4.2.3.
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.
4.2.4.
Patient Reported Outcomes
The baseline value for patient reported variables (eg, ACQ-6, AQLQ +12, SGRQ, EQ-5D) will 
be the last observed value prior to the first dose of study drug.
4.2.5.
Biomarkers
The baseline value for blood eosinophil levels will be the maximum value of the observed 
assessments from the screening visit to Week -2 (inclusive).
4.2.6.
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 


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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 6.3.1.
No multiplicity adjustments will be made for other efficacy and exploratory analyses.
4.4.
Handling Withdrawals and Missing Data
Analysis of the primary and secondary variables related to categorical OCS dose reduction will 
incorporate missing data as nonresponders, as described in Section 6.2.2 and Section 6.3.2. The 
primary variable will also be assessed including multiple imputations for missing data as a 
sensitivity analysis, as described in Section 6.2.3 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 
24) 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 24) 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.


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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 6. Weekly average data will be generated using 7-day 
window intervals derived based on these analysis days.
Table 6:
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
…
..
PM
..
AM
Day 167
167
PM
168
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.


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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 in the safety analysis set, patients 
in the PP analysis set, patients who completed treatment (all 24 weeks while on study treatment), 
patients who completed the planned treatment phase (remained active in the study for the full 24 
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 32, for patients not participating in the LTE study) or 
up to and including end of treatment (Week 24, 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 optimized OCS dose) 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 
system organ class (SOC) and preferred term (PT). Patients are only counted once in each SOC 
and once in each PT.


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Asthma- and allergy-specific medical history, duration of oral corticosteroid use for asthma, and 
will be collected and reported.
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 7:
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.
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
6.2.1.
Variable Definition
The primary efficacy variable for this study is the categorized percent reduction in the daily OCS
dose during weeks 20 to 24 as compared with the OCS dose at the end of the optimization phase.
The week 20 to 24 maintenance dose and corresponding values for absolute and percent change 
(reduction) from baseline will be calculated as follows:

Baseline dose = the prescribed optimized OCS dose following the OCS optimization 
period (Table 8)

Maintenance dose = mean of all daily OCS doses during the maintenance period 
extending from Week 20 to Week 24 (Table 8)

Absolute reduction = maintenance dose – baseline dose

Percent reduction = 100 x (absolute reduction / baseline dose)
For both the primary and secondary efficacy analyses, OCS dose will refer to the total daily dose 
of oral prednisone prescribed for asthma (as per CRF), unless otherwise noted.
The 5 categories for the primary analysis of percent reduction during weeks 20 to 24 are:

90% to 100% reduction

75% to <90% reduction

50% to <75% reduction

>0% to <50% reduction

No decrease in OCS, or loss of baseline asthma control during weeks 20 through 24, 
or discontinuation from study drug
Loss of baseline asthma control will be defined as FEV1 value of <80% of baseline at the week 
24 visit, or clinically significant worsening in ACQ-6 score (increase ≥0.5) at the week 24 visit 
compared with baseline, and/or clinical asthma exacerbation during weeks 20 through 24 (CAE
defined in Section 6.3.3.1).
6.2.2.
Primary Analysis
The primary endpoint is the 5-level categorical percent reduction in OCS dose during weeks 20 
to 24, compared to the optimized dose at baseline. The primary analysis will incorporate data 
from all randomized patients. Patients who are unable to maintain asthma control or who 


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withdraw treatment prematurely will be analyzed as part of the lowest category of response. The
primary endpoint will be analyzed using a proportional odds model including factors for 
treatment group and the randomization strata (age and OCS dose, as defined in Section 2.4); 
baseline OCS dose and duration of OCS use prior to study entry will also be included as 
covariates. Age and OCS dose will be based on data recorded in the clinical database.
The proportional odds ratio (reslizumab/placebo) will be estimated from this model, representing 
the ratio of the odds of a patient outcome being in a higher OCS dose reduction category for 
reslizumab compared to placebo. The estimated odds ratio, 95% CI, and p-value will be reported.
A frequency distribution bar graph will be provided for the number of patients in each of the 5 
categories by treatment group.
The following sample Statistical Analysis Software (SAS®) code pertains to the primary efficacy 
analysis of categorical dose reduction; ‘treatment’ is the randomized group (‘0’=placebo) and 
‘out_cat5’ is the 5-level response category (1=worst category, …, 5=best category):
     proc genmod data=<<>> order=internal descending;
class treatment (param=ref ref=’0’) strata1 strata2;
model out_cat5 = treatment strata1 strata2 ocsbase ocsdur
                                         / dist=mult link=cumlogit aggregate=treatment type3;
estimate “odds ratio” treatment 1 -1 / exp;
ods output parameterestimates=<<>>;
     run;
Note that multicollinearity occurs when there is a high degree of correlation among two or more 
of the independent variables included within a linear model; it can lead to unstable and unreliable 
estimates of the regression coefficients. It is recognized that, in the model described above for 
the primary endpoint (and for the models described subsequently in Section 6.3.2.2 for the 
related secondary endpoints), the categorical variable for OCS dose randomization strata is 
expected to be correlated to the continuous variable for OCS dose at baseline. The presence of 
collinearity between these variables will tend to make the estimates for each of these coefficients 
unstable, as well as increase the standard errors of their estimated coefficients. However, since 
the variable of interest in these models is the effect of treatment, and OCS dose at baseline has
been included in the model as a control variable, estimation of the regression coefficient for 
treatment should be unaffected by the presence of this collinearity and the performance of OCS 
dose as a control variable in the model should not be impaired.
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 control variables (age and OCS dose) 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).

Per-protocol: analysis of the primary endpoint, based on the PP analysis set.

Additional analysis including data collected after early withdrawal from treatment.


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
If a patient elects to withdraw from treatment (or is discontinued from treatment 
by the investigator), every attempt will be made to continue the assessments 
subsequent to his/her withdrawal from the study. If the patients agrees to remain 
in the study, they will continue to receive study prednisone treatment for the 
remainder of their participation in the study.

In this analysis, patients will be categorized according to the percent dose 
reduction at 24 weeks regardless of whether they withdrew early from treatment 
or completed treatment. For patients who withdraw early and for whom the 
sponsor fails to retrieve data after withdrawal despite all attempts to contact the 
patients, multiple imputation will be performed to determine the categorization 
according to the percent dose reduction at 24 weeks. The multiple imputations 
will use 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 will be detailed in Appendix A.

“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.
Subgroup Analyses 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 analysis described for the primary endpoint 
(Section 6.2.2). An interaction p-value will be derived from a separate proportional odds 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.
6.3.
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 24) visit for patients who 
completed treatment and from the first dose of study drug to the last dose of study drug (+4 
weeks) for patient 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 for this study are as follows:

Proportion of patients achieving ≥50% reduction in OCS dose at weeks 20 to 24 
relative to the OCS dose at the date of randomization (DoR)/baseline, while 
maintaining asthma control


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
Proportion of patients achieving dose reduction to ≤5 mg daily dose at weeks 20 to 
24, while maintaining asthma control

Percent change from DoR/baseline in OCS dose at weeks 20 to 24

Proportion of patients achieving less than 5 mg decrement in OCS dose (ie, the 
minimal and non-responders) at weeks 20 to 24 compared with the OCS dose at 
DoR/baseline, while maintaining asthma control

Annualized rate of clinical asthma exacerbations requiring a burst of systemic 
corticosteroid (injection, or if oral, at least a doubling from the current OCS dose for 
at least 3 days); an asthma-specific hospital admission; or an asthma-specific 
emergency department visit during the treatment period (weeks 0 to 24)

Proportion of patients discontinuing OCS at weeks 20 to 24, while maintaining 
asthma control
Testing of the secondary variables will be performed using the sequential testing procedure in the 
order specified above, as described in Section 4.3.
6.3.2.
OCS Dose
Note: All analyses related to OCS dose will be discussed within this section; this will include the 
planned analyses related to the list of secondary variables (in Section 6.3.1), as well as additional 
planned analyses related to OCS dose that have not otherwise been specified. The analysis of 
OCS dose as a continuous variable will be discussed separately from the analysis of OCS dose as 
a categorical variable.
6.3.2.1.
Variable Definition
6.3.2.1.1. Continuous Variable
The post-baseline values for OCS dose and corresponding values for absolute and percent 
change from baseline will be calculated as follows:

Baseline dose = the prescribed optimized OCS dose following the OCS optimization 
period (Table 8)

Post-baseline dose = mean of all daily OCS doses during each defined analysis
period (Table 8)

Absolute reduction = post-baseline dose – baseline dose

Percent reduction = 100 x (absolute reduction / baseline dose)


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Table 8:
Definition of Analysis Days for OCS Dose
Analysis period
Start day
Stop day
Baseline Dose
Day of first dose of study drug
N/A
Baseline to Week 4
Day of first dose of study drug + 1 day
Day of W4 Visit
Week 4 to Week 8
Day of W4 Visit + 1 day
Day of W8 Visit
Week 8 to Week 12
Day of W8 Visit + 1 day
Day of W12 Visit
Week 12 to Week 16
Day of W12 Visit + 1 day
Day of W16 Visit
Week 16 to Week 20
Day of W16 Visit + 1 day
Day of W20 Visit
Week 20 to Week 24 
(Maintenance Dose)
Day of W20 Visit + 1 day
Day of W24 Visit
DoR=Day of Randomization
6.3.2.1.2. Categorical Variable
The proportion of patients achieving a 50% or greater reduction in OCS dose at weeks 20 to 24
will be based on the percent reduction from baseline to weeks 20 to 24. The categories for this 
analysis are:

50-100% reduction

<50% reduction, or loss of baseline asthma control during weeks 20 through 24, or 
discontinuation from study drug
The proportion of patients who achieve a reduction of their OCS dose to less than or equal to 5
mg at weeks 20 to 24 will be based on the observed post-baseline value during weeks 20 to 24.
The categories for this analysis are:

≤5 mg

>5 mg, or loss of baseline asthma control during weeks 20 through 24, or 
discontinuation from study drug
The proportion of patients who achieve a total reduction (discontinuation) of their OCS dose at 
weeks 20 to 24 will be based on the observed post-baseline value during weeks 20 to 24. The 
categories for this analysis are:

=0 mg

>0 mg, or loss of baseline asthma control during weeks 20 through 24, or 
discontinuation from study drug
Note: Total reduction implies no OCS use during the entire period (weeks 20 to 24).
The proportion of patients achieving less than a 5 mg reduction in OCS dose at weeks 20 to 24 
will be based on the absolute reduction from baseline to weeks 20 to 24. The categories for this 
analysis are:

≥5 mg reduction


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
<5 mg reduction, or loss of baseline asthma control during weeks 20 through 24, or 
discontinuation from study drug
6.3.2.2.
Analysis
6.3.2.2.1. Continuous Variable
Summary statistics for OCS dose and change from baseline (percent and absolute) 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 (12 to <18 years and ≥18 years), OCS dose at baseline (>10 
mg and ≤10 mg); baseline OCS dose and duration of OCS use prior to study entry as covariates, 
and patient as a random effect (see Section 6.4.3.2 for sample SAS® code for the MMRM 
model). Age and OCS dose at baseline 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.
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. A line graph 
presenting the LS mean change from baseline over time (at each visit) will be provided for OCS 
dose by treatment group.
6.3.2.2.2. Categorical Variable
Each of the categorical secondary endpoints will be analyzed using a binary logistic regression 
model, incorporating the same covariates as the primary endpoint. The estimated odds ratio, 
95% CI, and p-value will be presented. Patients who are unable to maintain asthma control or 
who withdraw treatment prematurely will be counted as nonresponders and analyzed as part of 
the lowest category of response. A frequency distribution bar graph will be provided for the 
number of patients in each of the categories by treatment group.
The following sample SAS® code pertains to the secondary efficacy analysis of categorical dose 
reduction; ‘treatment’ is the randomized group (‘0’=placebo) and ‘out_cat2’ is the 2-level 
response category (1=worst category, 2=best category):
     proc logistic data=<<>>;
class treatment (param=ref ref=’0’) strata1 strata2; 
model out_cat2 (desc) = treatment strata1 strata2 ocsbase ocsdur / expb;
contrast “odds ratio” treatment 1 -1 / estimate;
ods output contrastestimate=<<>>;
     run;


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6.3.2.2.3. Other Sensitivity Analyses
Change from baseline to weeks 20 to 24 will additionally be analyzed using a non-parametric 
(Wilcoxon rank-sum) test in which the patient’s rank is analyzed rather than the actual observed 
percent reduction. For patients who withdraw early or do not maintain asthma control between 
weeks 20 to 24, a rank corresponding to a value less than the smallest observed reduction among 
all patients will be imputed. The median and 95% CI will be calculated with the use of the 
Hodges-Lehmann estimate. The p-value will be based on the Wilcoxon rank-sum test.
To further assess corticosteroid burden, the total number of days corticosteroids are taken for 
exacerbations (defined in Section 6.3.3.1) and the total cumulative dose of corticosteroids taken 
during the entire study will be summarized separately by treatment group. Corticosteroids taken 
for exacerbations will be based on medication use, as per the CAE CRF. Cumulative dose will be
the sum of the corticosteroid doses (prescribed for either asthma or CAE, as per the medication 
CRF) multiplied by the duration of corticosteroid treatment, taking dose frequency into account.

If 5mg is prescribed once daily for 10 days, the cumulative dose is 5*10 = 50. 

If 5mg is prescribed once every other day for 10 days, the cumulative dose is 5*5=25.
The analyses of corticosteroid burden will include all oral, iv, and im corticosteroid preparations.
Non-prednisone treatments will be converted to a prednisone equivalent dose using the 
conversion factors in Table 9. The list of medications will be reviewed and updated, if necessary, 
prior to unblinding. The final table will be documented in the minutes from the final Statistical 
Data Review meeting.
Table 9:
Conversion of Corticosteroid to Prednisone-Equivalent Doses
Medication Type
Medication
Conversion Factor
Short-acting:
Cortisone
0.2
Hydrocortisone
0.25
Intermediate-acting:
Methylprednisolone
1.25
Meprednisone
1.25
Prednisolone
1
Prednisone
1
Triamcinolone
1.25
Long-acting:
Betamethasone
8.33
Dexamethasone
6.67
Analysis of the total cumulative dose of corticosteroids will be performed using an ANCOVA 
model with fixed effects for treatment, age group, OCS dose group, and baseline OCS dose as a 
covariate. Similarly, analysis of the total number of days corticosteroids taken for exacerbations
will be performed using an ANOVA model with fixed effects for treatment, age group, and OCS 
dose group.


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6.3.3.
Clinical Asthma Exacerbations
6.3.3.1.
Variable Definition
A clinical asthma exacerbation (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 (injection, or if oral, at least a doubling from the 
current OCS 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 [injection, or if oral at least a doubling from the current OCS 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 (injectable), or 
for those with a doubling of the OCS dose, the stop date is when the return to their baseline dose
(dose prior to exacerbation), or the last day of an asthma-specific hospitalization or emergency 
department visit, whichever is later. For patients receiving at least a doubling from their current 
dose of OCS for at least 3 days that did not return to baseline (dose prior to exacerbation), the 
CAE stop date will be the day that they have been on a new stable dose for at least 10 days.
6.3.3.2.
Analysis
The annualized rate of CAEs will be analyzed using the generalized linear model (GLM) for data 
from the negative binomial distributions, commonly referred to as the negative binomial (NB) 
regression model. The NB model will include factors for treatment group, randomization strata
(age and OCS dose as defined in Section 2.4), number of exacerbations in the previous year, 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 OCS dose will be 
based on data recorded in the clinical database.
The ratio of CAE rate between the treatment groups and its 95% CI will be estimated from the 
NB model. Treatment effect will be evaluated using the likelihood based chi-square test. The 
analysis of clinical asthma exacerbations will be on-treatment, excluding exacerbations observed 
after stopping study 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 24) 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. Analyses will only be performed if a 
sufficient number of patients have exacerbations for the model to converge satisfactorily.


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The following sample SAS® code pertains to the 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;
6.4.
Other (and Exploratory) 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 24) 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.
 
 
 
 
6.4.1.
Other (and Exploratory) Efficacy Variable(s)
The other (and exploratory) efficacy endpoints are:

Time to first clinical asthma exacerbation 

Other clinic lung functions including the following:

Pre-bronchodilator FEV1: change from DoR/baseline to weeks 4, 8, 12, 16, 20, 24 
or early withdrawal; 
 

Post-bronchodilator FEV1: change from DoR/baseline to weeks 4, 12, 20, 24 or 
early withdrawal; 
 

Ambulatory lung function: change in morning (AM) and evening (PM) peak 
expiratory flow (PEF) from run-in baseline at each week through week 24 or early 
withdrawal


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
Asthma Quality of Life (AQLQ) + 12 score: change from DoR/baseline to weeks 4, 8, 
12, 16, 20, and 24 or early withdrawal

ACQ-6 score: change from DoR/baseline to weeks 4, 8, 12, 16, 20, 24 or early 
withdrawal; 

Change in total inhalations of reliever bronchodilator medication (number of 
inhalations per 24 hours: day+night) from run-in baseline at each week through week 
24 or early withdrawal

Number of nighttime awakenings due to asthma over the 24-week treatment period

Change in total asthma symptom score from run-in baseline at each week through 
week 24 or early withdrawal

European Quality of Life 5-dimension health state utility index (EQ-5D) score: 
change from DoR/baseline to week 24 or early withdrawal

St. George’s Respiratory Questionnaire (SGRQ) score: change from DoR/baseline to 
weeks 12 and 24 or early withdrawal

 
6.4.2.
Time to First Clinical Asthma Exacerbation
6.4.2.1.
Variable Definition
Refer to Section 6.3.3.1 for the definition of a clinical asthma exacerbation.
6.4.2.2.
Analysis
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.
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 24) 
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 this time frame will be censored at 
either the date of the end of treatment (week 24) 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;


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     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.
6.4.3.
Pulmonary Function Tests
6.4.3.1.
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 4, 8, 12, 16, 20, 24, and 32 (follow-up) and post-bronchodilator assessments (FEV1) are 
measured at weeks 4, 12, 20, 24, and 32 (follow-up).
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).
6.4.3.2.
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), OCS dose at baseline
(>10 mg and ≤10 mg), and sex, height and baseline value as covariates, and patient as a random 
effect. Age and OCS dose at baseline 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;


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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, FVC, FEF25%-75% by treatment group.
Pre-bronchodilator FEV1 at Week 24 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 24.
6.4.4.
AQLQ +12
6.4.4.1.
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.
The AQLQ +12 is a 32-item instrument administered as a self assessment at weeks 4, 8, 12, 16, 
20, and 24. 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


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
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
6.4.4.1.1. 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.
6.4.4.2.
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 6.4.3.2 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 24 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 24.
6.4.5.
ACQ-6
6.4.5.1.
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 4, 8, 12, 16, 20, 24, and 32 (follow-up), the patient answers each of the 6 questions, 
identifying the response that best describes how the patient has been during the past week.
6.4.5.1.1. 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.


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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.
6.4.5.2.
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 6.4.3.2 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 24 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 24.
6.4.6.
SGRQ
6.4.6.1.
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 12 and 24.
The questions in the SGRQ are divided into 3 domains:

Symptoms: Questions 1-8

Activity: Questions 11, 15

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.


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6.4.6.1.1. 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.
6.4.6.2.
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 6.4.3.2 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 24.
6.4.7.
EQ-5D
6.4.7.1.
Variable Definition
The EQ-5D consists of the descriptive system and the visual analogue scale (VAS). The 
descriptive system is comprised of 5 health domains (mobility, self care, usual activities, 
pain/discomfort, anxiety/depression) and each domain has 3 levels of response (1=no problems, 
2=some problems, 3=major problems). For the VAS component, the response is indicated on the 


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visual analogue scale provided and the value corresponding to the scale is recorded in the 
designated box (0=worst imaginable health state, 100=best imaginable health state). The EQ-5D 
is administered as a self assessment at week 24.
6.4.7.1.1. Missing data handling and total score calculation
For the descriptive system, there should be only one response recorded for each domain. If 
multiple responses are indicated for a single domain, the response will be treated as missing.
A unique health state is defined by a 5-digit code, combining levels across each of the 5 
domains. For example, 11111 would indicate no problem in any domain and 33333 would 
indicate major problems in all domains.
6.4.7.2.
Analysis
For the descriptive system, the number and percentage of patients at each of the levels 1-3 will 
be summarized descriptively for each domain.
For the VAS component, summary statistics of actual values and change from baseline to Week 
24 will be provided by treatment group. Analysis of the change from baseline to Week 24 will be 
performed using an analysis of covariance (ANCOVA) model with fixed effects for treatment, 
age group, OCS dose at baseline, and baseline value as covariate.


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6.4.9.
Asthma Control Diary
6.4.9.1.
Variable Definition
6.4.9.1.1. 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.
6.4.9.1.2. 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.
6.4.9.1.3. 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.
6.4.9.1.4. 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.
6.4.9.2.
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, AM/PM reliever use, 
AM/PM PEF, and nighttime awakenings. 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).
PEF measurements collected in the morning and in the evening will be summarized separately.
Asthma symptoms collected in the morning and in the evening will be summed to derive a total 


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daily symptom score. Total reliever use will be derived as the sum of the morning and evening 
counts.
A weekly average of the daily diary measures (AM/PM PEF, total asthma symptom score, and 
total reliever use) will be derived (see Table 6 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.
Nighttime awakenings will be derived and analyzed as a percentage over the treatment period, 
derived as:
Awakening-free nights (%) = 100 x (total number of awakening-free nights / total 
number of days during the treatment period)
The treatment period is defined in Section 6.4. Note that missing data will be treated as non-
responders in this analysis (eg, if response for nighttime awakenings is missing for a given day, 
then the day will not be counted as an awakening-free night).
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 6.4.3.2 with the exception of inclusion of sex and height in the model.
Analysis of the percentage of awakening-free nights will be performed using an analysis of 
variance (ANOVA) model with fixed effects for treatment, age group, and OCS dose at baseline.
A line graph presenting the LS mean change from baseline over time (at each week) will be 
provided for morning PEF, evening PEF, total asthma symptom score, and total reliever use by 
treatment group.


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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 24) 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 24) 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 10. 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 10:
List of Search 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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Term
Code
Level
FDA term (if applicable)
If LLT- under which PT 
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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Term
Code
Level
FDA term (if applicable)
If LLT- under which PT 
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


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Term
Code
Level
FDA term (if applicable)
If LLT- under which PT 
Nocardiosis
10029444
PT
Nocardiosis
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
7.3.1.7.
OCS Use and OCS Withdrawal
Adverse events associated with oral corticosteroid use and oral corticosteroid withdrawal 
(investigator-assessed) will be recorded on the Adverse Event CRF and summarized separately.
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


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
Patients with at least one AE related to OCS withdrawal

Patients with at least one AE related to OCS use
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.
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 andat 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 11; 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 11:
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 mol/L
Increase >0
177 mol/L
Increase >0
  Uric acid:
Men
625 mol/L
Increase >0
625 mol/L
Increase >0
Women
506 mol/L
Increase >0
506 mol/L
Increase >0
  Bilirubin (total)
34.2 mol/L
Increase >0
34.2 mol/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 11:
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
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 12 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 12:
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 24 will be summarized using patient counts.
Summary statistics for ECG variables will be presented at week 24. Actual values and changes 
from baseline to week 24 will be summarized.


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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 24

QTc interval >450 msec

QTc interval >500 msec

Change from baseline to week 24

QTc interval increase >30 msec

QTc interval increase >60 msec

Combined absolute value and change from baseline to week 24

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.
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).
Oral corticosteroid medications will be summarized separately.


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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; and prior to study 
drug administration at weeks 4, 8, 12, 24 or early withdrawal; and at the follow up visit 
(approximately week 32). An additional PK sample will be taken at the late follow-up visit
(approximately week 48).
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 4, 8, 12, 
16, 20, 24 or early withdrawal; and at the follow-up visit (approximately week 32).
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.


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8.4.
Immunogenicity
Samples for immunogenicity assessment for development of anti-drug antibodies will be 
obtained before the administration of study drug at baseline/DoR; weeks 4, 8, 12, 24 or early 
withdrawal; and at the follow-up visit (approximately week 32). An additional sample will be 
obtained at the late follow-up visit (approximately week 48). These data may be presented in a 
CSR addendum.
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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10.
CHANGES TO PROTOCOL SPECIFIED ANALYSES
Table 13 presents changes to the analyses specified in the CSP, Amendment 02.
Table 13:
Changes to the Protocol Specified Analyses
Protocol 
Section
Protocol Description
Change/Rationale
9.5.6.3
The NB model will include the 
treatment group and randomization 
stratification factors as model factors 
and an offset variable.
The number of exacerbations in the previous year 
has been added as a covariate in the NB model. 
This variable has been shown to be influential in 
previous studies of reslizumab iv.
Table 14 summarizes the key changes that have been implemented since the original approved 
SAP. Only substantive changes have been included; editorial and/or administrative changes are 
generally not listed.


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Table 14:
Key Changes to the Statistical Analysis Plan, Amendment 01
SAP
Section
SAP Description
Change
Rationale
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 24) 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 all efficacy endpoints, the on-treatment 
approach will be utilized as the main 
approach to analysis. However, it should be 
noted that all patients will be included in 
the analysis of the primary and secondary 
Clarification


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SAP
Section
SAP Description
Change
Rationale
endpoints related to OCS dose reduction by 
incorporating missing data (due to dropout) 
as nonresponders. The analytic approach 
including all data collected from patients 
will additionally be conducted as sensitivity 
analyses for the primary endpoint.
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 24) 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 
OCS dose (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 
OCS dose (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 
Inclusion of 2 additional efficacy endpoints 
and clarification regarding definition of age 
strata


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Rationale
the age recorded in the clinical database.
3.4.2
Selected efficacy endpoints including 
OCS dose (primary), pre-bronchodilator 
FEV1, and blood eosinophils will be 
analyzed separately for patients taking 
an optimized baseline dose of OCS ≤10 
mg and >10 mg.
Selected efficacy endpoints including 
OCS dose (primary), pre-bronchodilator 
FEV1, AQLQ+12, ACQ-6, and blood 
eosinophils will be analyzed separately for 
patients taking an optimized baseline dose 
of OCS ≤10 mg and >10 mg. OCS strata 
will be defined based on the optimized 
baseline dose of OCS recorded in the 
clinical database.
Inclusion of 2 additional efficacy endpoints 
and clarification regarding definition of OCS
strata
3.4.3
Selected efficacy endpoints including 
OCS dose (primary), pre-bronchodilator 
FEV1, and blood eosinophils will also 
be examined for the following 
demographic subgroups:
Selected efficacy endpoints including 
OCS dose (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.
4.2.1
6.3.2.1.1 
(Table 8)
The baseline value is the prescribed 
optimized OCS dose following the 
optimization period and will be defined 
as the OCS dose reported on the day of 
randomization.
Start day for “Baseline Dose” equal to 
DoR
Start day for “Baseline to Week 4” equal 
to DoR + 1 day
The baseline value is the prescribed 
optimized OCS dose following the 
optimization period and will be defined as 
the OCS dose reported on the day of first 
dose of study drug.
Start day for “Baseline Dose” equal to Day 
of first dose of study drug
Start day for “Baseline to Week 4” equal to
Day of first dose of study drug + 1 day
Reference start date changed from day of 
randomization to day of first dose of study 
drug administration
4.5, 
6.3, 
6.3.3.2, 
6.4, 
6.4.2.2, 
6.4.9.2
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 24) visit. For
patients who prematurely discontinue 
treatment, the treatment period will be 
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 24) visit. For 
patients who prematurely discontinue 
treatment, the treatment period will be 
Reference start date changed from day of 
randomization to day of first dose of study 
drug administration


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defined from the day of randomization to 
the last dose of study drug + 4 weeks.
defined from the first dose of study drug to 
the last dose of study drug + 4 weeks.
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 
32, for patients not participating in the LTE 
study) or up to and including end of 
treatment (Week 24, 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
6.2.1
Percent reduction in OCS dose will 
be calculated as:

100 x ( (baseline dose –
maintenance dose) / 
baseline dose )
In this calculation, the maintenance 
dose is defined as the mean of all 
daily OCS doses during the 
maintenance period extending from 
The week 20 to 24 maintenance dose and 
corresponding values for absolute and 
percent change (reduction) from baseline 
will be calculated as follows:

Baseline dose = the 
prescribed optimized OCS 
dose following the OCS 
optimization period (Table 
8)
Clarification


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the Week 20 visit to the Week 24 
visit, and baseline dose is the 
prescribed optimized OCS dose 
following the OCS optimization run-
in period.

Maintenance dose = mean 
of all daily OCS doses 
during the maintenance 
period extending from Week 
20 to Week 24 (Table 8)

Absolute reduction = 
maintenance dose – baseline
dose

Percent reduction = 100 x 
(absolute reduction / baseline 
dose)
6.2.2, 
6.3.2.2.1, 
6.3.3.2, 
6.4.3.2
<<null>>
Age and OCS dose will be based on data 
recorded in the clinical database.
Clarification
6.2.3
<<null>>
The primary analysis with control variables 
(age and OCS dose) 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
If a patient elects to withdraw from 
treatment (or is discontinued from 
treatment by the investigator), every 
attempt will be made to continue the 
assessments subsequent to his/her 
withdrawal from the study. If the 
patients agrees to remain in the study, 
they will continue to receive study 
If a patient elects to withdraw from 
treatment (or is discontinued from treatment 
by the investigator), every attempt will be 
made to continue the assessments 
subsequent to his/her withdrawal from the 
study. If the patients agrees to remain in the 
study, they will continue to receive study 
prednisone treatment for the remainder of 
Correction


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prednisone treatment according to the 
OCS dose reduction algorithm for the 
remainder of their participation in the 
study.
their participation in the study.
6.2.4
An interaction p-value will be derived 
from a separate proportional odds model
including terms for treatment, subgroup, 
and treatment by subgroup interaction.
An interaction p-value will be derived from 
a separate proportional odds model 
including additional terms for subgroup and 
treatment by subgroup interaction.
Clarification
6.4.2.2
<<null>>
The hazard ratio (95% CI) and p-value will 
be estimated using a Cox proportional 
hazards regression model adjusting for the 
stratification factors.
New analysis added
6.4.3.2
<<null>>
The proportion of patients achieving an 
increase of ≥100 mL in FEV1 from baseline 
to each scheduled visit will be summarized. 
A 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 24.
New analysis added
6.4.4.2
<<null>>
AQLQ +12 at Week 24 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
6.4.5.2
<<null>>
ACQ-6 at Week 24 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 
New analysis added


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SAP
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be presented graphically using forest plots.
7.3.1.6
<<null>>
Opportunistic Infections
New section added
7.5
Table 11
Table 11
PCS (potentially clinically significant) 
criteria for CPK changed to Grades 3-4
8.2.2


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11.
REFERENCES
Bel EH, Wenzel SE, Thompson PJ, Prazma CM, Keene ON, Yancey SW, et al; SIRIUS 
Investigators. Oral glucocorticoid-sparing effect of mepolizumab in eosinophilic asthma. N Engl 
J Med 2014;371(13):1189-97.
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 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 
SENSITIVITY ANALYSIS OF THE PRIMARY 
VARIABLE
The following represents an outline of the planned methodology for the multiple imputation 
procedure for the sensitivity analysis of the primary OCS response 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 (49476) that will be used in the 
analysis after unblinding.
data 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 24 weeks of treatment
2. ET1; patients who withdrew early from treatment but remained in the study contributing 
post-treatment follow-up data through week 24
3. ET2; patients who withdrew early from treatment but elected not to remain in the study 
through week 24
Step 3: Imputation of missing data. 
Missing values for OCS dose (continuous) at week 24 and at visits in which earlier OCS doses 
were missing will be imputed. The missing OCS dose will be imputed based on measurements 
observed at previous visits and treatment group, assuming data are missing at random (MAR).
The resulting observations at week 24 will be categorized as per the primary endpoint.
If the pattern of missing data is monotonic, the MONOTONE method in PROC MI will be used 
for imputation with a linear regression technique.
proc mi data=&indata out=&outdata nimpute=10 seed=&seed;
  class treatment;
  monotone regression (week4=treatment base /details); 
  monotone regression (week8=treatment base week4 /details); 
  monotone regression (week12=treatment base week4 week8 /details); 
  monotone regression (week16=treatment base week4 week8 week12 /details); 
  monotone regression (week20=treatment base week4 week8 week12 week16/details); 
  monotone regression (week24=treatment base week4 week8 week12 week16 week20/details); 
  var treatment base week4 week8 week12 week16 week20 week24;
run;


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If the pattern of missing data is not monotonic, the MCMC MONOTONE method can be 
selected to transform the missing data pattern to a monotonic missing data structure by filling in 
missing values for earlier visits that have lower rates of missing data (ie, MCMC MONOTONE 
as a preliminary step, to be followed by application of the MONOTONE method in PROC MI).
proc mi data=&indata out=&outdata nimpute=10 seed=&seed;
  mcmc impute=monotone NBIter=2000 NIter=10000; 
  var base week4 week8 week12 week16 week20 week24;
  by treatment;
run;
proc mi data=&outdata out=&outdata2 nimpute=1 seed=&seed;
  class treatment;
  monotone regression (week4=treatment base /details); 
  monotone regression (week8=treatment base week4 /details); 
  monotone regression (week12=treatment base week4 week8 /details); 
  monotone regression (week16=treatment base week4 week8 week12 /details); 
  monotone regression (week20=treatment base week4 week8 week12 week16/details); 
  monotone regression (week24=treatment base week4 week8 week12 week16 week20/details); 
  var treatment base week4 week8 week12 week16 week20 week24;
  by _imputation_;
run;
After this step, 10 datasets with complete data have been created.
Step 4: Re-run the primary analysis model.
Percent change from baseline and the corresponding 5-level response variable will be computed
based on the imputed dose values at week 24. The proportional odds model will be fitted to the 
complete set of data for each of the 10 imputed datasets using the same covariates that were used 
for the primary analysis.
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 odds ratio.


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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 primary response variable (OCS dose). 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.
Imputations will be performed for the missing OCS dose at week 24 and the resulting 
observations will be categorized as per the primary endpoint. OCS dose 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 OCS dose in the control group will be 
imputed assuming that missing data are MAR. For the treatment group, the OCS dose will be 
imputed in the same manner, but then a constant shift (>0) will be added to the imputed values to 
allow for MNAR. In the treatment group, this shift will be progressively increased and the 
process repeated until the treatment effect is no longer significant at the 5% level. The value of 
the shift 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. Missing values will be imputed assuming MAR in both treatment groups using the 
multiple imputation 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 shift parameter will be used to 
adjust imputed values for OCS dose, by adding the shift parameter to the imputed values.
The following pseudo-code is provided to demonstrate this concept, where OUTMI is the 
output dataset(s) from Step 1, COMPLETER identifies the patients who discontinued 
treatment early with incomplete follow-up, week24 is the OCS dose at week 24, and δ is 
the shift parameter.
data outmi;
   set outmi;
   if armcd='RESLIZUMAB' and COMPLETER='N' then week24=week24+δ;
run;
After this step, 10 datasets with complete data have been created.


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3. The proportional odds 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 
outline described in Appendix A (Step 4).
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 shift parameter resulting in 
estimates of the odds ratio and p-values for each shift parameter.
The odds ratio and associated p-value will be summarized corresponding to each selected shift
value until the tipping point is achieved.


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APPENDIX C. SGRQ – ITEM WEIGHTS FOR PROGRAMMING


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