Clinical trial NCT02937168
Conditions: Asthma
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2017-05-08; Completion date: 2017-05-24
Enrollment: 5 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is an exploratory study with the following primary objectives: 1) to establish that PET/CT of the lung can reliably distinguish healthy, non-asthmatic participants from participants with severe asthma and an eosinophilic phenotype and 2) to examine the utility of PET/CT for demonstrating that reslizumab produces a reduction in lung inflammation in participants with severe asthma and an eosinophilic phenotype .

Detailed description:

Arms: arm 1: Healthy participants will have 2 PET/CT scan in Part 1: within 7 days of eligibility being confirmed, and 7 days after the first PET/CT scan. Participants will receive Fluorodeoxyglucose F-18 (FDG) as part of the PET/CT procedures and will provide sputum/blood samples. arm 2: Reslizumab 3.0 milligrams/kilogram (mg/kg) will be administered by intravenous (IV) infusion, over 20 to 50 minutes, at Baseline (Day 1) of Part 2. PET/CT scan will be done on Weeks 2, 4 and 6. Participants will receive FDG as part of the PET/CT procedures and will provide sputum/blood samples. arm 3: Matching placebo will be administered by IV infusion at Baseline (Day 1) of Part 2. PET/CT scan will be done on Weeks 2, 4 and 6. Participants will receive FDG as part of the PET/CT procedures and will provide sputum/blood samples.
Interventions: intervention 1: Reslizumab intervention 2: Fludeoxyglucose F 18 (FDG) intervention 3: Placebo
Intervention descriptions: intervention 1: Reslizumab will be administered as per the dose and schedule specified in the arm. intervention 2: FDG will be administered by IV infusion prior to each PET/CT scan. intervention 3: Placebo matching to reslizumab will be administered as per the schedule specified in the arm.

Protocol documents:
Prot_000.pdf: 
Clinical Study Protocol 
Distribution of Eosinophils in Asthma after Reslizumab (DEAR). A 7-week, Placebo-
Controlled, Double-Blinded, Parallel-Group, Imaging Study Using Positron Emission 
Tomography/Computed Tomography (PET/CT) to Characterize the Effect of Intravenous 
Reslizumab on Airway Inflammation in Patients with Eosinophilic Asthma 
Study Number C38072-AS-40105 (or CEP38072-AS-40105) 
NCT02937168 
Protocol Approval Date: 24 June 2016 


 
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Clinical Study Protocol 
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Clinical Study Protocol 
Study Number CEP38072-AS-40105 
Distribution of Eosinophils in Asthma after Reslizumab (DEAR). A 7-week, Placebo-
Controlled, Double-Blinded, Parallel-Group, Imaging Study Using Positron Emission 
Tomography/Computed Tomography (PET/CT) to Characterize the Effect of Intravenous 
Reslizumab on Airway Inflammation in Patients with Eosinophilic Asthma 
Phase 4 
BLA number: 761033 
Protocol Approval Date: 24 June 2016 
 
 
 
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); national country 
regulations; and the sponsor’s Standard Operating Procedures (SOPs). 
This document contains confidential and proprietary information (including confidential commercial information 
pursuant to 21CFR§20.61) and is a confidential communication of Teva Pharmaceuticals. The recipient agrees that 
no information contained herein may be published or disclosed without written approval from the sponsor. 
© 2016 Teva Branded Pharmaceutical Products R&D, Inc. All rights reserved. 


 
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INVESTIGATOR AGREEMENT 
 


 
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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS 
Sponsor’s Authorized Representative 
 
Sponsor’s Medical Expert 
 
 
Contract Research Organization 
MedQualis 
1240 Avenue Beaumont #208 
Mont-Royal, QC  
H3P 3E5 
 
Sponsor’s Representative of Global Patient Safety and Pharmacovigilance 
  
 
Clinical Laboratory and Biomarker Evaluation 
 
 
 
Electrocardiography 
 
 
Bioanalytical Immunogenicity Evaluation 
Teva Pharmaceuticals 
Global Bioassays and Technology 
618 Brandywine Parkway 
West Chester, PA 19380 
Radiology Center 
 
 
 


 
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CLINICAL STUDY PERSONNEL CONTACT INFORMATION 
For medical issues, contact the physician listed below: 
 
Teva Pharmaceuticals 
 
 
 
 
For operational issues, contact the operational lead listed below: 
 
 Teva R&D 
 
 
 
For protocol issues, contact the study leader listed below: 
 
 
 
 
 
For serious adverse events: 
Send by email to the local safety officer (LSO). The email address will be provided in the serious 
adverse event report form. In the event of difficulty transmitting the form, contact the sponsor’s 
study personnel identified above for further instruction. 


 
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CLINICAL STUDY PROTOCOL SYNOPSIS 
Study CEP38072-AS-40105 
Title of Study: Distribution of Eosinophils in Asthma after Reslizumab (DEAR). A 7-week, Placebo-Controlled, 
Double-Blinded, Parallel-Group, Imaging Study Using Positron Emission Tomography/Computed Tomography 
(PET/CT) to Characterize the Effect of Intravenous Reslizumab on Airway Inflammation in Patients with 
Eosinophilic Asthma 
Sponsor: Teva Global Medical Affairs 
Biologic License Application (BLA) Number: 761033 
Name of Active Ingredient: Reslizumab (CEP-38072) 
Name of Investigational Product: Reslizumab (CEP-38072) 
Phase of the Study: 4 
Number of Investigational Centers Planned: 1 clinical center 
 and 1 radiology center 
 
Countries Planned: United States 
Planned Study Period: Approximately 4th quarter 2016 to 4th quarter 2018  
Number of Patients Planned: This study is exploratory in nature; therefore, no formal hypothesis testing is 
planned. Based on clinical and practical considerations, 5 healthy subjects and 10 eosinophilic asthma patients 
(5 patients treated with reslizumab, 5 patients treated with placebo) is considered adequate for: 
• 
a validation of the ability of positron emission tomography (PET)/ computed tomography (CT) to 
differentiate patients with eosinophilic asthma from healthy controls (HCs) 
• 
an evaluation of the effect of reslizumab versus placebo on inflammation of the lungs. 
Study Population: Males and females, from the ages of 18 through 50 years. Five HCs and 10 patients with asthma 
and current blood eosinophil levels of at least 400/µL, using ≥440 mcg of fluticasone-equivalent and an allowed 2nd 
asthma controller (eg, long-acting β-agonist [LABA]) will be recruited. 
Enrollment will include a minimum of 2 and a maximum of 3 female healthy control subjects and a minimum of 
4 and a maximum of 6 female patients with eosinophilic asthma. 
Primary Objective: There are 2 related primary objectives of this study: 
• 
To establish that PET/CT imaging of the lung can reliably distinguish healthy, non-asthmatic 
volunteers and patients with severe asthma with an eosinophilic phenotype (initial validation). 
• 
If the utility of PET/CT scanning is established as per objective 1: to show that reslizumab produces a 
reduction in signal intensity (reduction in lung inflammation) in patients with severe asthma with an 
eosinophilic phenotype. 
Secondary Objectives: The secondary objectives of this study are:  
• 
to demonstrate a correlation between the benefit observed on imaging (PET/CT) with: 
− 
reductions blood eosinophil counts 
− 
improvement in clinic visit lung function 
− 
reductions in fractional exhaled nitric oxide (FeNO) 


 
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− 
improvements in Asthma Quality of Life questionnaire (AQLQ) scores 
Exploratory Objectives: The exploratory and other objectives of the study are:  
• 
to demonstrate a correlation between changes in the lung PET/CT signal produced by reslizumab and 
serum biological markers of asthmatic inflammation 
• 
to demonstrate a correlation between changes in the lung PET/CT signal produced by reslizumab and 
other lung function variables including forced vital capacity (FVC), peak expiratory flow rate (PEFR) 
and forced expiratory flow at the 25% point to the 75% point of forced vital capacity (FEF25%-75%) 
• 
to demonstrate that reslizumab produces greater reductions in inflammation of whole body lymph 
nodes and bone marrow than placebo as seen on PET/CT 
• 
for those patients that can produce sputum, to demonstrate an association between changes in sputum 
eosinophil numbers produced by reslizumab and the lung PET/CT signal produced by reslizumab 
Study Endpoints: 
This study is designed in 2 parts. Part 1 is a validation step which will include 2 measures, (1) the intrapatient 
reproducibility in the global lung glycolysis (GLG) measure, and (2) the signal window representing difference in 
the measure of GLG for individual patients with severe asthma with an eosinophilic phenotype and the mean GLG 
of the healthy controls group. The limit for step 1 above (reproducibility within patients) will be set at ≤10% of 
sequential GLG measures. The limit for step 2 above (the signal window) will be set at ≥5%. These limits have been 
provided by subject matter experts. 
Primary Endpoint: The primary efficacy endpoint is the change from baseline to week 4 in GLG (ΔGLG). 
The supportive primary efficacy endpoint is the change from baseline to week 4 in lung parenchyma (LP) 
standardized uptake value (SUV) mean. 
Secondary Endpoints: The secondary efficacy endpoints are: 
• 
the change from baseline to week 4 in blood eosinophil counts 
• 
the change from baseline to week 4 in forced expiratory volume in 1 second (FEV1) 
• 
the change from baseline to week 4 in FeNO 
• 
the change from baseline to week 4 in AQLQ 
Exploratory Endpoints: The exploratory endpoints of this study are changes in: 
• 
biological markers of inflammation and asthma (blood):  
− 
immunoglobulin E (IgE) 
− 
dipeptidyl peptidase 4 (DPP4) 
− 
25-hydroxy vitamin D 
− 
eotaxin-1, -2, and -3 
− 
thymus and activation regulated chemokine (TARC) 
− 
monocyte chemoattractant protein-1 (MCP-1) and MCP-4 
− 
group 2 innate lymphoid cells (ILC2) 


 
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• 
lung function variables: 
− 
FVC 
− 
PEFR 
− 
FEF25%-75% 
• 
the global uptake of fludeoxyglucose (FDG) in the lymph nodes and bone marrow as measured by the 
PET/CT imaging parameters indicated for the primary efficacy variable 
• 
sputum eosinophils for those patients that can produce sputum 
Safety Endpoints: The safety endpoints are: 
• 
occurrence of adverse events throughout the study 
• 
vital signs (pulse, respiratory rate, and blood pressure) throughout the study 
• 
clinical laboratory evaluations throughout the study  
• 
physical examination findings throughout the study 
• 
use of concomitant medication throughout the study 
General Design and Methods: All subjects who participate in this study will consent at 
 prior to 
undergoing any study procedures. After consent is obtained, all participants will undergo all tests and procedures 
required for eligibility, including sputum and blood eosinophil level assessments. Patients with asthma (does not 
apply to HC subjects) must have a screening blood eosinophil count of ≥400 cells/μL to be included. A maximum of 
3 blood eosinophil assessments will be conducted. If the 1st assessment yields a blood eosinophil level below 400 
cells/µL patients with asthma may return for a 2nd assessment of blood eosinophil level after 7 days. A 3rd and final 
assessment will be performed 7 days after the 2nd assessment, if necessary (eg, if the blood eosinophil level remains 
<400 cells/μL at the 2nd assessment). 
The patient must maintain their usual asthma controller regimen without change throughout the screening and study 
periods. A patient who experiences an asthma exacerbation during this time that requires additional medication, 
beyond increased short-acting β-agonist (SABA) use, will be considered to have failed screening and cannot 
undergo randomization. A patient may be rescreened for this reason 1 time only. If a patient experiences an asthma 
exacerbation requiring treatment with systemic steroids, they will only be allowed to be rescreened 6 weeks after 
completion of treatment. All patients that have to be rescreened must be stable on other asthma medications for 
30 days prior to rescreening. 
The DEAR study is designed in 2 parts. Part 1 is a validation of the PET/CT signal as a surrogate of lung 
inflammation. In this part, the sponsor wishes to determine (1) the intrapatient reproducibility in the GLG measure, 
and (2) the difference in the GLG measure between individual patients with severe asthma with an eosinophilic 
phenotype (1-by-1) and the entire HC group. Limits for both the reproducibility within patients and difference 
among the 2 groups have been provided by subject matter experts. 
Part 2 will be a 7-week double-blind evaluation of patients with severe asthma with an eosinophilic phenotype that 
have been randomized to receive a single dose of either placebo or reslizumab at 3 mg/kg. 
Part 1 
Within 7 days (±3 days) of eligibility being confirmed, participants will have a PET/CT scan. Participants will return 
to the 
 7 days (±3) after the first PET/CT scan (taken during visit 2) for a second PET/CT 


 
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scan. Healthy control subjects (n=5) may also have a second sputum induction and blood sample collection at 
 with 1 day of the 2nd PET/CT scan, if feasible (preferred but not required). Healthy subjects will 
be considered complete at this time. Only after all 5 HCs have completed the study will patients with asthma be 
screened. 
If the relative difference in GLG (based on the average of the 2 measurements) between healthy and asthma patients 
will be ≥5%, then the asthma patients will be randomized. 
A 10% variability (measured as relative difference between first measurement and second measurement) between 
PET/CT scans as measured by GLG within each group will be considered as the maximum allowed variability. The 
part 1 criteria have been set at these levels to observe a difference between the healthy subjects and patients with 
asthma and to ensure intra-group reproducibility; the criteria are based on the investigators’ prior experience. If 
these exploratory criteria are not met (eg, 8 or more patients do not meet the criteria to enter Part 2 [inclusion criteria 
k and l]), then the study will be reevaluated. 
Part 2 
If eligible (eg, if inter- and intra-group GLG variability criteria are met), patients will be randomized. This may 
occur at any time after confirmation of eligibility and up to the time of dosing. Patients will return to 
 
 for baseline clinical, serological, and biochemical measures according to standard procedures. Once these 
are completed, patients will receive either placebo or reslizumab and will receive the infusion at 
. 
Any new serious adverse events, reslizumab-related adverse events, and new concomitant medications will be 
reported. 
All planned PET/CT scans (weeks 2, 4, and 6) should be scheduled at the time of randomization. Within 2 weeks 
(±3 days) of the infusion, patients will return to 
 for clinical tests and procedures. Within 3 days 
of this visit, patients will undergo a PET/CT scan at the 
. Patients repeat the clinical tests 
and procedures at weeks 4 and 6 post-infusion. Each visit at 
 will be followed by a PET/CT scan 
at the 
 as described above. 
Method of Randomization and Blinding: After the 2 baseline PET/CT scans and successful completion of all 
requirements (Part 1), patients will be randomly assigned 1:1 in a double-blind fashion to receive either placebo or 
intravenous (iv) 3.0 mg/kg reslizumab. 
In order to maintain the blind, each patient will be assigned a unique identifier number and all reference to the 
patient will be by using this identifier. 
Study Drug Dose, Mode of Administration, and Administration Rate:  
Investigational Product: Reslizumab will be provided as a sterile solution for infusion presented as 100 mg 
(10 mL) per vial, formulated at 10 mg/mL in 20 mM sodium acetate, 7% sucrose, pH 5.5 buffer. Reslizumab will be 
administered by iv infusion, over 20 to 50 minutes, at the baseline visit. 
Reference Treatment: 
Placebo: Placebo will be provided as a sterile solution of 20 mM sodium acetate, 7% sucrose, pH 5.5 buffer. 
Matching placebo will be administered by iv infusion at the baseline visit. 
Comparator: None 
Other: Fludeoxyglucose F 18 (FDG) injection will be provided as a ready to use isotonic, sterile, pyrogen free, 
clear, colorless citrate buffered solution. Each mL will contain between 0.740 to 7.40 gigabecquerel (20.0 to 
200 millicurie [mCi]) of 2-deoxy-2-[18F]fluoro-D glucose at the end of synthesis (EOS), 4.5 mg of sodium 
chloride and 7.2 mg of citrate ions. The pH of the solution will be between 5.5 and 7.5. The solution will be 


 
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packaged in a multiple-dose glass vial and will not contain any preservative. Fludeoxyglucose F 18 will be 
administered by iv infusion. 
Duration of Patient Participation: This study will consist of Part 1, a 21-day PET/CT screening period, and Part 2 
(only patients with asthma), a 6-week double blind treatment/assessment period followed by a 7-day follow up 
period. 
Inclusion Criteria: Healthy subjects and patients may be enrolled in this study only if they meet all of the following 
criteria 
a. 
Male or female, 18 through 50 years of age. 
b. Females that are either surgically sterile, are 2 years postmenopausal, or have a negative pregnancy test 
beta-human chorionic gonadotropin (β-HCG) at screening (serum) and all PET/CT imaging visits 
(urine). 
c. 
Females of childbearing potential (not surgically sterile or 2 years postmenopausal), have to use a 
medically accepted method of contraception and have to agree to continue to use of this method for the 
duration of the study and for 5 months after study drug administratin. Acceptable methods of 
contraception include barrier method with spermicide, abstinence, intrauterine device (IUD), or 
steroidal contraceptive (oral, transdermal, implanted, and injected). Note: partner sterility alone is not 
acceptable for inclusion in the study. 
d. Subjects and patients with less that 10-pack year history of smoking. 
Patients may be included in the study only if they also meet all of the following, additional criteria: 
e. 
Male or female, 18 through 50 years of age, with a previous diagnosis of asthma. 
f. 
Patients taking inhaled fluticasone at a dosage of at least 440 mcg daily, or equivalent. 
g. The patient’s baseline asthma therapy regimen (including, but not limited to, inhaled corticosteroids, 
leukotriene receptor antagonists, 5-lipoxygenase inhibitors, or cromolyn) must be stable for 30 days 
prior to screening and judged by their treating physician to be able to continue without dosage changes 
throughout the study.  
h. Patients with a blood eosinophil level of at least 400/µL at screening. Patients with a blood eosinophil 
level below 400/μL will be given 2 additional screening opportunities to determine blood eosinophil 
levels. 
i. 
Patients with airway reversibility of at least 12% to β-agonist administration. 
j. 
Patients with an Asthma Control Questionnaire (ACQ) score of at least 1.5 at either screening or 
baseline visits. 
Patients may be included in Part 2 of the study only if they also meet the following, additional criteria: 
k. the intrapatient reproducibility, taken as sequential GLG measures on visits 2 and 3, differs by only 
≤10% 
l. 
the intragroup variability (signal window), taken as a difference in the 2 subcriteria (below) to be ≥5%: 
○ 
the mean GLG of healthy controls determined by taking the mean of the average GLG for 
visits 2 and 3 for each HC. 
○ 
the mean GLG of each single patient with severe asthma with an eosinophilic phenotype, 
taken as sequential GLG measures on visits 2 and 3. 


 
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Exclusion Criteria: Healthy subjects and patients will be excluded from participating in this study if they meet any 
of the following criteria: 
a. 
Patients requiring treatment with oral, intramuscular, or iv corticosteroids within 6 weeks of the Part 1 
baseline visit. 
b. Patients with any other confounding underlying lung disorder including but not limited to: 
bronchiectasis, chronic obstructive pulmonary disorder, smoking ≥10 pack year history, pulmonary 
fibrosis, emphysema, cystic fibrosis, and lung cancer. 
c. 
Patients with a blood glucose level at screening or baseline greater than or equal to 150 mg/dL. 
d. Patients diagnosed with diabetes mellitus. 
e. 
Patients with pulmonary conditions and blood eosinophilia other than eosinophilic asthma including, 
but not limited to: Churg-Strauss syndrome, allergic bronchopulmonary aspergillosis and 
hypereosinophilic syndrome. 
f. 
Patients with clinically meaningful comorbidity that can interfere with the study schedule or 
procedures, or compromise the patient’s safety. 
g. Patients that are current smokers (ie, have smoked within the last 12 months prior to screening). 
h. Patients using systemic immunosuppressive, immunomodulating, or other biologic agents (including, 
but not limited to, anti-IgE monoclonal antibody [mAb], methotrexate, cyclosporin, interferon-α, or 
anti–tumor necrosis factor mAb) within 6 months prior to screening. 
i. 
Patients who have previously received an anti-human interleukin-5 (anti-hIL-5) mAb (eg, reslizumab, 
mepolizumab [Nucala®]) or anti IL-5 receptor mAb (eg, benralizumab). 
j. 
Patients who had concurrent infection or disease that may preclude assessment of active asthma. 
k. Patients with a history of concurrent immunodeficiency (human immunodeficiency virus or acquired 
immunodeficiency syndrome or congenital immunodeficiency). 
l. 
Patients that had an active parasitic infection within 6 months prior to screening. 
m. Patients with a history of exposure to water-borne parasites within 6 weeks prior to screening or during 
the screening period or a history of diarrheal illness of undetermined etiology within 3 months prior to 
screening or during the screening period. 
n. Any patient who had an infection requiring the following: 
− 
an admission to the hospital for at least 24 hours within 4 weeks prior to screening or during the 
screening period 
− 
treatment with iv antibiotics within 4 weeks prior to screening or during the screening period 
− 
treatment with oral antibiotics within 4 weeks prior to screening or during the screening period 
o. Patients with any disorder that may interfere with drug absorption, distribution, metabolism, or 
excretion (including gastrointestinal surgery). 
p. Female subjects who are pregnant or breast-feeding or considering becoming pregnant during the study 
or within 5 months after reslizumab dosing. 
q. Known hypersensitivity to study drug or to FDG/contrast agents 


 
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r. 
Treatment with metformin. 
s. 
Compromised renal function 
Measures and Time Points: 
A ≤10% variability between PET/CT scans as measured by global lung glycolysis (GLG) within each group 
will be considered as the maximum allowed variability. 
A ≥5% difference in GLG (ΔGLG) between HC subjects and patients with eosinophilic asthma will be selected 
as minimal difference that validates the ability PET/CT to differentiate these 2 populations. If a 5% difference 
cannot be achieved, the study will be evaluated as patients with asthma complete Part 1 and are considered for 
eligibility to enter Part 2. 
Primary Efficacy Measure and Time Points: GLG will be measured at 2 baseline visits and at weeks 2, 4, 
and 6 (all ±3 days) post randomization.. 
Secondary Efficacy Measures and Time Points: The secondary efficacy measures and time points for this 
study are as follows: 
• 
blood eosinophil counts from baseline to weeks 2, 4, and 6 (all ±3 days) 
• 
FEV1 from baseline to weeks 2, 4, and 6 (all ±3 days) 
• 
FeNO measurements from baseline to weeks 2, 4, and 6 (all ±3 days) 
• 
AQLQ scores from baseline to weeks 2, 4, and 6 (all ±3 days) 
Exploratory Efficacy Measures and Time Points: The exploratory efficacy measures and time points are:  
• 
biological markers of inflammation and asthma:  
− 
IgE 
− 
DPP4 
− 
25-hydroxy vitamin D 
− 
eotaxin-1, -2, and -3 
− 
TARC 
− 
MCP-1 and MCP-4 
− 
ILC2 
• 
lung function variables: 
− 
FVC 
− 
PEFR 
− 
FEF25%-75% 
• 
the global uptake of FDG in the lymph nodes and bone marrow as measured by the PET/CT imaging 
parameters indicated for the primary efficacy variable 
• 
for those patients that can produce sputum, to demonstrate a correlation between reductions in 
inflammation by reslizumab with a reduction in sputum eosinophils 
All variables will be measured at 2 baseline visits and at weeks 2, 4, and 6 post-randomization. 


 
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Safety Measures and Time Points: The safety measures and timepoints are: 
• 
occurrence of adverse events throughout the study 
• 
vital signs (pulse, respiratory rate, and blood pressure) throughout the study 
• 
clinical laboratory evaluations throughout the study  
• 
physical examination findings throughout the study 
• 
use of concomitant medication throughout the study 
Patient safety will be assessed by standard asthma management and physician practice. If a patient experiences 
an asthma exacerbation during Part 1, they will be treated with oral corticosteroids (OCS) for a period of 
2 weeks, followed by a 6-week period without OCS to ensure asthma control. Stable patients will then re-enter 
the study at the time point of the exacerbation. 
Immunogenicity Measures and Time Points: Blood samples for assessment of anti-drug antibodies (ADA) 
will be collected at baseline (pre-study drug administration) and at weeks 2 and 6. 
Allowed and Prohibited Medications before and during the Study: Patients currently taking, or who have 
previously taken, anti-IL-5/anti-IL-5 receptor medications may not participate in this study. Oral corticosteroids 
must have been stopped 6 weeks prior to screening. Immunosuppressive agents and biological drugs, including 
anti-IgE medications, must have been stopped at least 6 months prior to screening. Asthma therapies, including 
inhaled corticosteroids (with a LABA or long-acting muscarinic antagonist), leukotriene antagonists, 5-lipoxygenase 
inhibitors, and/or cromolyn must be stable for 30 days prior to screening and must remain stable throughout the 
study. 
Statistical Considerations: 
Sample Size Rationale: This study is exploratory in nature; therefore, no formal hypothesis testing is planned. 
Based on clinical and practical considerations, 5 healthy subjects and 10 eosinophilic asthma patients (5 patients 
treated with reslizumab, 5 patients treated with placebo) is considered adequate for: 
• 
a validation of the ability of PET/CT to differentiate patients with eosinophilic asthma from HCs 
• 
an evaluation of the effect of reslizumab versus placebo on inflammation of the lungs. 
The below are only for Part 2: 
Analysis of Primary Endpoint: The primary efficacy endpoint is the change from baseline to week 4 in GLG 
(ΔGLG). 
The supportive primary efficacy endpoint is the change from baseline to week 4 in LP SUVmean. 
All imaging variables will be measured at 2 baseline visits and at weeks 2, 4, and 6 post randomization. 
Change in GLG from baseline to each of the postbaseline visits will be summarized using descriptive statistics 
(number [n], mean, standard deviation, median, minimum, and maximum) by treatment group. The difference in 
means between reslizumab and placebo will be summarized and reported. The same methods will be used to analyze 
the supportive-to-primary endpoint. 
Analysis of Secondary Endpoints: The secondary efficacy endpoints are: 
• 
Change from baseline to weeks 2, 4, and 6 in blood eosinophil count 
• 
Change from baseline to weeks 2, 4, and 6 in FEV1 


 
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• 
Change from baseline to weeks 2, 4, and 6 in FeNO measurements 
• 
Change from baseline to weeks 2, 4, and 6 in AQLQ scores 
The same methods as described for the primary efficacy analysis will be used to analyze the secondary endpoints. 
In addition, correlation between each of the secondary endpoints and change from baseline to week 4 in GLG will 
be calculated. Spearman’s Rho correlation will be used for this analysis. No inferential statistics will be used for 
secondary endpoints and analyses. Additional details about secondary endpoints analyses may be detailed in the 
statistical analysis plan. 
Multiple Comparisons and Multiplicity: No multiple comparisons will be made. 
Analysis of Exploratory Endpoints: Analysis of the exploratory endpoints will be detailed in the statistical 
analysis plan (to be finalized and signed before unblinding). 
Safety Analyses: The safety analysis set will include all patients who received at least 1 dose of reslizumab/placebo 
in this study. Safety will be summarized using descriptive statistics.  


 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
INVESTIGATOR AGREEMENT...................................................................................................2 
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............3 
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................4 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................5 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................23 
1. 
BACKGROUND INFORMATION ...........................................................................26 
1.1. 
Introduction .................................................................................................................26 
1.1.1. 
Asthma ........................................................................................................................26 
1.1.2. 
Molecular Imaging in Asthma ....................................................................................26 
1.2. 
Name and Description of Investigational Product ......................................................27 
1.3. 
Findings from Nonclinical and Clinical Studies .........................................................27 
1.3.1. 
Nonclinical Studies .....................................................................................................27 
1.3.2. 
Clinical Studies ...........................................................................................................28 
1.3.2.1. 
Clinical Pharmacology Studies ...................................................................................28 
1.3.2.2. 
Clinical Safety and Efficacy Studies ..........................................................................28 
1.4. 
Known and Potential Benefits and Risks to Patients ..................................................31 
1.4.1. 
Benefits and Risks of Reslizumab ..............................................................................31 
1.4.1.1. 
Benefits of Reslizumab ...............................................................................................31 
1.4.1.2. 
Risks of Reslizumab ...................................................................................................31 
1.4.2. 
Risks of Computerized Tomography/Positron Emission Tomography Scans ...........31 
1.4.2.1. 
Risks of Fludeoxyglucose F 18 Injection ...................................................................31 
1.4.2.2. 
Risks of Computerized Tomography/Positron Emission Tomography Scans ...........31 
1.4.3. 
Overall Benefit and Risk Assessment for This Study ................................................32 
1.5. 
Selection of Drugs and Doses .....................................................................................32 
1.5.1. 
Justification for Dose of Active Drug .........................................................................32 
1.5.2. 
Justification for Use of Placebo ..................................................................................32 
1.6. 
Compliance Statement ................................................................................................32 
1.7. 
Study Population and Justification .............................................................................33 
1.8. 
Location and Study Duration ......................................................................................33 
2. 
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2.1. 
Purpose of the Study ...................................................................................................34 
2.2. 
Study Objectives .........................................................................................................34 
2.2.1. 
Primary Objective .......................................................................................................34 
2.2.2. 
Secondary Objectives .................................................................................................34 
2.2.3. 
Exploratory Objectives ...............................................................................................34 
2.3. 
Study Endpoints ..........................................................................................................35 
2.3.1. 
Primary Efficacy Endpoint .........................................................................................35 
2.3.2. 
Secondary Efficacy Endpoints ....................................................................................35 
2.3.3. 
Exploratory Endpoints ................................................................................................35 
2.3.4. 
Safety Endpoints .........................................................................................................35 
3. 
STUDY DESIGN .......................................................................................................37 
3.1. 
General Design and Study Schematic Diagram ..........................................................37 
3.2. 
Justification for Study Design ....................................................................................41 
3.3. 
Primary and Secondary Efficacy Measures and Time Points .....................................43 
3.3.1. 
Primary Efficacy Measure and Time Points ...............................................................43 
3.3.2. 
Secondary Efficacy Measures and Time Points .........................................................43 
3.4. 
Safety Measures and Time Points ...............................................................................43 
3.5. 
Pharmacokinetic Measures and Time Points ..............................................................44 
3.6. 
Exploratory Efficacy Measures and Time Points .......................................................44 
3.7. 
Randomization and Blinding ......................................................................................44 
3.8. 
Maintenance of Randomization and Blinding ............................................................45 
3.8.1. 
Maintenance of Randomization ..................................................................................45 
3.8.2. 
Blinding/Unblinding ...................................................................................................45 
3.8.3. 
Data Monitoring Committee .......................................................................................46 
3.9. 
Drugs Used in the Study .............................................................................................46 
3.9.1. 
Investigational Product ...............................................................................................46 
3.9.2. 
Placebo ........................................................................................................................46 
3.9.3. 
Fludeoxyglucose F 18 .................................................................................................46 
3.10. 
Drug Supply and Accountability ................................................................................46 
3.10.1. 
Drug Storage and Security ..........................................................................................46 
3.10.1.1. 
Reslizumab and Placebo .............................................................................................46 
3.10.1.2. 
Fludeoxyglucose F 18 .................................................................................................47 
3.10.2. 
Drug Accountability ...................................................................................................47 


 
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3.11. 
Duration of Patient Participation and Justification .....................................................47 
3.12. 
Stopping Rules and Discontinuation Criteria .............................................................47 
3.13. 
Source Data Recorded on the Case Report Form .......................................................48 
3.14. 
Study Procedures and Assessments ............................................................................48 
3.14.1. 
Procedures for Screening and Enrollment (Visit 1) ....................................................52 
3.14.2. 
Procedures Before Study Drug Treatment (Part 1 Baseline [Visit 2, Day 1]) ............53 
3.14.2.1. 
Week 1 (Visit 3) ..........................................................................................................53 
3.14.3. 
Procedures During Study Drug Treatment .................................................................53 
3.14.3.1. 
Part 2 (Week 1 [Visit 4]) ............................................................................................53 
3.14.3.2. 
Weeks 2, 4, and 6 (Visits 5, 6, and 7) .........................................................................54 
3.14.4. 
Procedures After Study Drug Treatment ....................................................................55 
3.14.4.1. 
Telephone Follow-Up (Visit 8, Up To 7 Days After Visit 7) .....................................55 
3.14.5. 
Unscheduled Visits .....................................................................................................55 
4. 
SELECTION AND WITHDRAWAL OF PATIENTS ..............................................56 
4.1. 
Patient Inclusion Criteria ............................................................................................56 
4.2. 
Patient Exclusion Criteria ...........................................................................................57 
4.3. 
Justification for Key Inclusion and Exclusion Criteria...............................................58 
4.4. 
Withdrawal Criteria and Procedures ...........................................................................58 
5. 
TREATMENT OF PATIENTS ..................................................................................59 
5.1. 
Drugs Administered During the Study .......................................................................59 
5.1.1. 
Reslizumab .................................................................................................................59 
5.1.2. 
Fludeoxyglucose F 18 .................................................................................................59 
5.2. 
Restrictions .................................................................................................................59 
5.3. 
Prior and Concomitant Medication or Treatment .......................................................59 
5.4. 
Procedures for Monitoring Patient Compliance .........................................................60 
5.5. 
Total Blood Volume ...................................................................................................60 
6. 
ASSESSMENT OF EFFICACY ................................................................................61 
6.1. 
Primary Efficacy Measure and Justification ...............................................................61 
6.1.1. 
Positron Emission Tomography/Computerized Tomography Scans ..........................61 
6.1.2. 
Image Analysis ...........................................................................................................61 
6.1.3. 
Calculations ................................................................................................................62 
6.2. 
Spirometry ..................................................................................................................63 
6.3. 
Asthma Control Questionnaire ...................................................................................63 


 
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6.4. 
Asthma Quality of Life Questionnaire for Patients 12 years and Older .....................63 
7. 
ASSESSMENT OF SAFETY .....................................................................................64 
7.1. 
Adverse Events ...........................................................................................................64 
7.1.1. 
Definition of an Adverse Event ..................................................................................64 
7.1.2. 
Recording and Reporting of Adverse Events .............................................................65 
7.1.3. 
Severity of an Adverse Event .....................................................................................66 
7.1.4. 
Relationship of an Adverse Event to the Study Drug .................................................66 
7.1.5. 
Serious Adverse Events ..............................................................................................66 
7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................66 
7.1.5.2. 
Expectedness ...............................................................................................................67 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................67 
7.1.6. 
Protocol-Defined Adverse Events for Expedited Reporting to Teva .........................69 
7.1.7. 
Specific Adverse Event Case Report Form Capturing ...............................................69 
7.1.7.1. 
Anaphylaxis/Hypersensitivity Reactions Case Report Form .....................................69 
7.1.7.2. 
Creatine Phosphokinase/Muscular Adverse Events Case Report Form .....................70 
7.1.8. 
Withdrawal Due to an Adverse Event ........................................................................70 
7.1.9. 
Overdose of Study Drug .............................................................................................70 
7.1.10. 
Protocol Deviations Because of an Adverse Event ....................................................70 
7.2. 
Pregnancy ...................................................................................................................71 
7.3. 
Medication Error and Special Situations ....................................................................71 
7.4. 
Clinical Laboratory Tests ...........................................................................................72 
7.4.1. 
Serum Chemistry, Hematology, and Urinalysis .........................................................72 
7.4.2. 
Other Clinical Laboratory Tests .................................................................................73 
7.4.2.1. 
Human Chorionic Gonadotropin Tests .......................................................................73 
7.5. 
Vital Signs ..................................................................................................................73 
7.6. 
Electrocardiography ....................................................................................................74 
7.7. 
Physical Examinations ................................................................................................74 
7.8. 
Concomitant Medication or Treatment .......................................................................74 
7.9. 
Methods and Time Points of Assessing, Recording, and Analyzing Safety 
Data .............................................................................................................................74 
8. 
ASSESSMENT OF BIOMARKERS AND IMMUNOGENICITY ...........................75 
8.1. 
Assessment of Exploratory Biomarkers .....................................................................75 
8.1.1. 
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8.1.1.1. 
Background .................................................................................................................75 
8.1.1.2. 
Specimen Sampling and Handling ..............................................................................76 
8.1.2. 
Dipeptidyl Peptidase-4 ................................................................................................76 
8.1.2.1. 
Background .................................................................................................................76 
8.1.2.2. 
Specimen Sampling and Handling ..............................................................................76 
8.1.3. 
25-Hydroxy Vitamin D ...............................................................................................76 
8.1.3.1. 
Background .................................................................................................................76 
8.1.3.2. 
Specimen Sampling and Handling ..............................................................................77 
8.1.4. 
Eotaxin-1, -2, and -3 ...................................................................................................77 
8.1.4.1. 
Background .................................................................................................................77 
8.1.4.2. 
Specimen Sampling and Handling ..............................................................................78 
8.1.5. 
Thymus and Activation Regulated Chemokine ..........................................................78 
8.1.5.1. 
Background .................................................................................................................78 
8.1.5.2. 
Specimen Sampling and Handling ..............................................................................78 
8.1.6. 
Monocyte Chemoattractant Protein-1 and -4 ..............................................................78 
8.1.6.1. 
Background .................................................................................................................78 
8.1.6.2. 
Specimen Sampling and Handling ..............................................................................79 
8.1.7. 
Type 2 Innate Lymphoid Cells ...................................................................................79 
8.1.7.1. 
Background .................................................................................................................79 
8.1.7.2. 
Specimen Sampling and Handling ..............................................................................79 
8.1.8. 
Shipment and Analysis of Samples ............................................................................79 
8.2. 
Immunogenicity Testing .............................................................................................80 
8.2.1. 
Blood Sampling and Handling....................................................................................80 
8.2.2. 
Shipment and Analysis of Samples ............................................................................80 
9. 
STATISTICS ..............................................................................................................81 
9.1. 
Sample Size and Power Considerations .....................................................................81 
9.2. 
Analysis Sets ...............................................................................................................81 
9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................81 
9.2.2. 
Safety Analysis Set .....................................................................................................81 
9.2.3. 
Full Analysis Set .........................................................................................................81 
9.2.4. 
Enrolled Analysis Set .................................................................................................81 
9.3. 
Data Handling Conventions ........................................................................................82 
9.3.1. 
Handling Withdrawals and Missing Data ...................................................................82 


 
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9.4. 
Study Population .........................................................................................................82 
9.4.1. 
Patient Disposition ......................................................................................................82 
9.4.2. 
Demographic and Baseline Characteristics ................................................................82 
9.5. 
Efficacy Analysis ........................................................................................................82 
9.5.1. 
Primary Endpoint ........................................................................................................82 
9.5.2. 
Secondary Endpoints ..................................................................................................82 
9.5.3. 
Exploratory Endpoints ................................................................................................83 
9.5.4. 
Planned Method of Analysis .......................................................................................83 
9.5.4.1. 
Primary Efficacy Analysis ..........................................................................................83 
9.5.4.2. 
Supportive to Primary Efficacy Endpoint Analysis ....................................................83 
9.5.4.3. 
Secondary Efficacy Analysis ......................................................................................83 
9.5.4.4. 
Exploratory Efficacy Analysis ....................................................................................84 
9.6. 
Multiple Comparisons and Multiplicity......................................................................84 
9.7. 
Safety Endpoints and Analysis ...................................................................................84 
9.7.1. 
Safety Endpoints .........................................................................................................84 
9.7.2. 
Safety Analysis ...........................................................................................................84 
9.8. 
Tolerability Variables and Analysis ...........................................................................84 
9.9. 
Biomarker Analysis ....................................................................................................85 
9.10. 
Immunogenicity Analysis ...........................................................................................85 
9.11. 
Planned Interim Analysis ............................................................................................85 
9.12. 
Reporting Deviations from the Statistical Plan ..........................................................85 
10. 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ...............................86 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................87 
11.1. 
Protocol Amendments and Protocol Deviations and Violations ................................87 
11.1.1. 
Protocol Amendments ................................................................................................87 
11.1.2. 
Protocol Violations .....................................................................................................87 
11.2. 
Information to Study Personnel ..................................................................................87 
11.3. 
Study Monitoring ........................................................................................................88 
11.4. 
Clinical Product Complaints .......................................................................................88 
11.4.1. 
Product Quality Related Complaint Information Needed from the 
Investigational Center .................................................................................................89 
11.4.2. 
Handling of Study Drug at the Investigational Center ...............................................89 


 
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11.4.3. 
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint ...................................................................................................................90 
11.4.4. 
Documenting a Product Complaint ............................................................................90 
11.5. 
Audit and Inspection ...................................................................................................90 
12. 
ETHICS ......................................................................................................................91 
12.1. 
Informed Consent .......................................................................................................91 
12.2. 
Competent Authorities and Independent Ethics Committees/Institutional 
Review Boards ............................................................................................................91 
12.3. 
Confidentiality Regarding Study Patients ..................................................................91 
12.4. 
Declaration of the End of Clinical Study ....................................................................91 
12.5. 
Registration of the Clinical Study...............................................................................92 
13. 
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING ...................................................................................................................93 
13.1. 
Data Collection ...........................................................................................................93 
13.2. 
Data Quality Control ...................................................................................................93 
13.3. 
Archiving of Case Report Forms and Source Documents ..........................................94 
13.3.1. 
Sponsor Responsibilities .............................................................................................94 
13.3.2. 
Investigator Responsibilities .......................................................................................94 
14. 
FINANCING AND INSURANCE .............................................................................96 
15. 
REPORTING AND PUBLICATION OF RESULTS ................................................97 
16. 
REFERENCES ...........................................................................................................98 
APPENDIX A. ASTHMA CONTROL QUESTIONNAIRE ...................................................104 
APPENDIX B. ASTHMA QUALITY OF LIFE QUESTIONNAIRE .....................................106 
APPENDIX C. CLINICAL CRITERIA FOR DIAGNOSING ANAPHYLAXIS ...................112 


 
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LIST OF TABLES 
Table 1: 
Rationale for Protocol .................................................................................................42 
Table 2: 
Study Procedures and Assessments ............................................................................49 
Table 3: 
Blood Volumes ...........................................................................................................60 
Table 4: 
Clinical Laboratory Tests ...........................................................................................73 
 


 
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LIST OF FIGURES 
Figure 1: 
Health Control Subjects-Study Flow ..........................................................................39 
Figure 2: 
Patients with Asthma-Study Flow: Part 1 ...................................................................40 
Figure 3: 
Patients with Asthma-Study Flow: Part 2 ...................................................................41 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table of Abbreviations 
Abbreviation 
Term 
ACQ 
Asthma Control Questionnaire 
ADA 
anti-drug antibodies 
ADR 
adverse drug reaction 
anit-hIL-5 
anti-human interleukin-5 
AQLQ 
Asthma Quality of Life Questionnaire 
ASUI 
Asthma Symptom Utility Index 
BAL 
bronchoalveolar lavage 
BP 
blood pressure 
CDMS 
clinical data management system 
CFR 
Code of Federal Regulations (US) 
CPK 
creatine phosphokinase 
CPP 
clinical project physician 
CRC 
Clinical Research Center 
CRF 
case report form (refers to any media used to collect study data [ie, paper or 
electronic]) 
CRO 
contract research organization 
CSR 
clinical study report 
CT 
computed tomography 
DPP4 
dipeptidyl peptidase 4 
ECG 
electrocardiogram 
EOS 
end of synthesis 
EU 
European Union 
FDA 
United States Food and Drug Administration 
FDG 
fludeoxyglucose 
FEF25%-75% 
forced expiratory flow at the 25% point to the 75% point of forced vital capacity 
FeNO 
fractional exhaled nitric oxide 
FEV1 
forced expiratory volume in 1 second 
FVC 
forced vital capacity 
GCP 
Good Clinical Practice 


 
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Abbreviation 
Term 
GLG 
global lung glycolysis 
ΔGLG 
change from baseline in global lung glycolysis 
HC 
healthy control 
ICH 
International Conference on Harmonisation 
ICS 
inhaled corticosteroids 
IEC 
Independent Ethics Committee 
IgE 
immunoglobulin E 
IL-5 
Interleukin-5 
ILC 
innate lymphoid cell 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IUD 
intrauterine device 
iv 
intravenous 
LABA 
long-acting β-agonist 
LP 
lung parenchyma 
LSO 
local safety officer 
LV 
lung volume 
mAb 
monoclonal antibody 
mCi 
millicurie 
MCP 
monocyte chemoattractant protein 
mrem 
millirem 
n 
number 
OCS 
oral corticosteroids 
PEFR 
peak expiratory flow rate 
PET 
positron emission tomography 
PI 
Prescribing Information 
PK 
pharmacokinetic 
RR 
respiratory rate 
RSI 
reference safety information 
ROI 
region of interest 
SABA 
short-acting β-agonist 
sc 
subcutaneous 


 
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Abbreviation 
Term 
SOP 
Standard Operating Procedure 
sLG 
sectional lung glycolysis 
sLV 
sectional lung volume 
SpO2 
blood oxygen saturation 
SUSAR 
suspected unexpected serious adverse reaction 
SUV 
standardized uptake value 
sSUV 
sectional mean standardized uptake value 
TARC 
thymus and activation regulated chemokine 
ULN 
upper limit of normal 
US(A) 
United States (of America) 
VDBP 
vitamin D-binding protein 


 
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1. 
BACKGROUND INFORMATION 
1.1. 
Introduction 
1.1.1. 
Asthma 
Asthma is a common, chronic lung disorder characterized by inflammation and narrowing of the 
airways. Symptoms of asthma include cough, breathlessness, and wheezing. The most recent 
estimates suggest that as many as 334 million people in the world have asthma (Global Asthma 
Network 2014). 
Asthma is a heterogeneous syndrome with distinct phenotypes and variable severity. Certain 
patients are prone to experiencing asthma exacerbations defined as an acute or sub-acute 
worsening in symptoms and lung function from the patient’s usual status (Global Initiative for 
Asthma [GINA] 2015) in patients who are unable to achieve control despite chronic use of 
inhaled corticosteroids (ICS) and other asthma medications. These patients are considered at 
high risk because of the morbidity and potential mortality associated with exacerbations. During 
acute asthma exacerbations, patients often require additional therapy, such as a course of 
systemic corticosteroids, which have substantial adverse effects (Walsh et al 2001, Wardlaw et al 
2000). 
Interleukin-5 (IL-5) is the prototypic maturation and survival factor for eosinophilic 
granulocytes, which has been strongly implicated in asthma pathogenesis (Wardlaw et al 2000). 
Eosinophils are major effector cells involved in initiation and propagation of diverse 
inflammatory responses. A high blood eosinophil count is a risk factor for increased future 
asthma exacerbations and excessive short-acting beta-agonist (SABA) use after adjustment of 
potential confounders in adults with persistent asthma, which suggests a higher disease burden in 
patients with asthma and high blood eosinophil counts (Tran et al 2014, Zeiger et al 2014). 
Therapies directed against IL-5 or its receptor (mepolizumab [Nucala®], reslizumab, and 
benralizumab) work by reducing eosinophil counts in the circulation and in the airway and have 
been shown to reduce asthma exacerbations, improve Asthma Control Questionnaire [ACQ] 
scores, and/or improve 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). 
1.1.2. 
Molecular Imaging in Asthma 
Molecular imaging has been broadly defined as the use of imaging methods that ‘‘directly or 
indirectly monitor and record the spatiotemporal distribution of molecular or cellular processes 
for biochemical, biologic, diagnostic, or therapeutic applications’’ (Thakur and Lentle 2008). 
This study proposes the use of positron emission tomography/computed tomography (PET/CT) 
to investigate the inflammatory response in patients with eosinophilic asthma after anti-IL5 
therapy.  
Molecular imaging with PET/CT requires coupling a positron emitting radioisotope with a short 
half-life, such as 18F, 11C, or 15O, to a molecule that functions within a known metabolic 


 
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pathway. The most commonly used molecule in PET/CT imaging is 18F-fluorodeoxyglucose 
(18F-FDG), a radiolabeled glucose analog. When injected intravenously, FDG is transported into 
metabolically active cells and phosphorylated by the enzyme hexokinase in the same manner as 
glucose. However, the FDG-6-phosphate is not metabolized further and becomes trapped 
intracellularly, resulting in an increase in signal from the metabolically active cells. 
FDG-PET/CT is most commonly used in oncologic imaging because of its ability to depict the 
increased glucose metabolism present in most malignant neoplasms. However, FDG-PET/CT has 
also shown promise as an imaging biomarker of lung inflammation. The accumulated evidence 
suggests that primed and activated neutrophils are the primary (although perhaps not the only) 
source of increased FDG signal in the lung (Chen and Schuster 2006). In animal models 
increased FDG uptake has been demonstrated in acute lung injury (Chen and Schuster 2004, 
Musch et al 2007) and after inhalation of cigarette smoke (Schroeder et al 2007). In human 
subjects increases in FDG uptake have been found in several conditions characterized by 
inflammation, such as respiratory tract infections, including pneumonia (Jones et al 1997), cystic 
fibrosis (Chen et al 2006), sarcoidosis (Brudin et al 1994, Xiu et al 2005), and chronic 
obstructive pulmonary disease (Jones et al 2003). 
The ability to quantify a component of the inflammatory response with FDG-PET/CT suggests 
that it might also be useful for learning more about the pathogenesis of asthma, phenotypic 
differences, and responses to anti-inflammatory therapies. 
1.2. 
Name and Description of Investigational Product 
Reslizumab (CEP-38072) is a humanized anti-human interleukin-5 (anti-hIL-5) monoclonal 
antibody (mAb) of the immunoglobulin G4/κ isotype being developed for administration by the 
intravenous (iv) and subcutaneous routes. CINQAIR® (reslizumab iv 3 mg/kg) was recently 
approved by the United States Food and Drug Administration (FDA) for the add-on maintenance 
treatment of patients with severe asthma aged 18 years and older with an eosinophilic phenotype. 
A more detailed description of the product is given in Section 3.9. 
1.3. 
Findings from Nonclinical and Clinical Studies 
1.3.1. 
Nonclinical Studies 
A correlation between IL-5–induced eosinophilia and pulmonary hyper-reactivity was originally 
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, 
accumulate lung damage, or demonstrated any increased airway hyper-responsiveness. 
Otherwise, IL-5 gene knockout mice developed normally and had normal antibody and cytotoxic 
T-cell responses. 
In vitro, reslizumab bound with high affinity to IL-5 from several species (mouse, rat, and 
monkey); in vivo, reslizumab showed biological activity in all species mentioned above plus 
guinea pig and rabbit. Reslizumab inhibited eosinophilia in lungs or skin and reduced airway 
hyper-responsiveness after antigenic challenge in sensitized animals. Inhibition of pulmonary 
eosinophilia was observed for up to 8 weeks post-dose in mice and for up to 6 months in 


 
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monkeys. Reslizumab’s effects on eosinophilia in mice were additive with the effects of 
prednisolone. 
In single-dose iv toxicity studies with reslizumab, no adverse effects were observed at the 
maximum doses administered (500 mg/kg in mice and rats; 100 mg/kg in monkeys). In repeat 
dose studies, reslizumab was well tolerated by mice and monkeys given 2 iv doses of 1, 5, or 
25 mg/kg reslizumab 14 days apart; the no-observed-effect level was 5 mg/kg in male mice and 
at least 25 mg/kg in female mice and monkeys. The 6-month studies in mice and monkeys with 
once-monthly dosing showed no toxicity and a no-observed-effect level of at least 25 mg/kg. The 
no-observed-effect level for evidence of reslizumab-related binding to nervous system tissues of 
monkeys was also at least 25 mg/kg. Reslizumab was not genotoxic and did not affect 
reproductive parameters. In safety pharmacology studies, reslizumab had no effect on parameters 
related to organ function. 
Further details may be found in the current United States (US) Prescribing Information (PI) for 
CINQAIR (reslizumab) (CINQAIR 2016). 
1.3.2. 
Clinical Studies 
1.3.2.1. 
Clinical Pharmacology Studies 
The pharmacokinetics (PK), pharmacodynamics, 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. 
Systemic exposure to reslizumab increases in a dose-proportional manner over the range of 
0.03 to 3.0 mg/kg in patients with asthma and from 1.0 to 3.0 mg/kg in patients with nasal 
polyps. Serum concentration declines from peak in a biphasic manner with a mean elimination 
half-life of 24 days. The volume of distribution for reslizumab is low (approximately 4 to 6 L), 
suggesting minimal distribution of reslizumab into extravascular tissues. 
Further details may be found in the current PI (CINQAIR 2016). 
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 dose of reslizumab in 14 clinical studies. 
The Phase 3 BREATH program in adult and adolescent 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, 52-week Studies C38072/3082 and C38072/3083, and open label safety extension 
Study C38072/3085) and 0.3 mg/kg (Study C38072/3081 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 [ASUI]) were observed for patients with eosinophilic asthma defined by 
a screening blood eosinophil count of ≥400/μL (Studies C38072/3081, C38072/3082, and 
C38072/3083). In asthma patients without elevated blood eosinophils (Study C38072/3084), 
reslizumab produced non-significant improvements in lung function and other measures of 
efficacy. In contrast, patients with blood eosinophil levels ≥400/μL in this study demonstrated 


 
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significant improvements in lung function and other measures of efficacy following treatment 
with reslizumab. 
The safety of reslizumab was evaluated in adults and in children in clinical studies. 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. The safety profile of reslizumab, 3 mg/kg iv, in patients with 
asthma is reflected in the US PI (CINQAIR 2016). 
The following summary relates to integrated adverse events data of the 5 asthma 
placebo-controlled completed studies (ie, Studies Res-5-0010, C38072/3081, C38072/3082, 
C38072/3083, and C30872/3084) that include the 3 mg/kg iv dose and every 4 weeks dosing 
regimen (up to 52 weeks). Serious adverse events and deaths from the open-label 
Study C38072/3085 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).  
The incidence of all common adverse events (>2%) was the same or higher in the placebo group 
compared to the reslizumab group with the exception of oropharyngeal pain, which was slightly 
higher in the 3.0 mg/kg reslizumab-treated patients (2.6%) than in the placebo-treated patients 
(2.2%). 
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. Three serious adverse events of anaphylaxis events were assessed 
as related to reslizumab treatment. 
Deaths 
There were 4 deaths in the Phase 3 asthma clinical development program: 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 
Overall, laboratory test values were similar in patients treated with reslizumab and placebo, with 
the exception of creatine phosphokinase (CPK) elevation and the expected pharmacological 
effect of decreasing blood eosinophil counts. There were no clinically meaningful differences or 
potentially clinically important trends in vital signs, electrocardiogram (ECG) intervals, or 
overall ECG assessments. 
Adverse Drug Reactions 


 
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Anaphylaxis 
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/immunotherapy, and not to reslizumab. In the Phase 3 BREATH program, 3 
infusion-related reactions, reported as anaphylaxis, occurred during or shortly after reslizumab 
infusion and were characterized variously by dyspnea, decreased oxygen saturation,wheezing, 
vomiting, and skin and mucosal involvement, including urtcaria. The 3 events were treated at the 
study site, and patients were withdrawn from the study. 
Oropharyngeal pain 
Adverse reactions that occurred at greater than or equal to 2% incidence and more commonly 
than in the placebo group included 1 event: oropharyngeal pain (2.6% versus 2.2%). 
CPK elevations and muscle-related adverse reactions 
Elevated baseline CPK was more frequent in patients randomized to reslizumab (14%) versus 
placebo (9%). Transient CPK elevations in patients with normal baseline CPK values were 
observed more frequently with reslizumab (20%) versus placebo (18%) during routine laboratory 
assessments. CPK elevations >10x the upper limit of normal (ULN), regardless of baseline CPK 
value, were 0.8% in the CINQAIR group compared to 0.4% in the placebo group. CPK 
elevations >10xULN were asymptomatic and did not lead to treatment discontinuation. 
Myalgia was reported in 1% (10/1028) of patients in the reslizumab 3 mg/kg group compared to 
0.5% (4/730) of patients in the placebo group. On the day of infusion, musculoskeletal adverse 
reactions were reported in 2.2% and 1.5% of patients treated with reslizumab 3 mg/kg and 
placebo, respectively. These reactions included (but were not limited to) musculoskeletal chest 
pain, neck pain, muscle spasms, extremity pain, muscle fatigue, and musculoskeletal pain. 
Malignancy 
The impact of lowering eosinophils with an anti-IL-5 active substance, such as reslizumab on the 
development of malignancies is not known. In placebo-controlled iv clinical studies, 6 out of 
1028 patients (0.6%) receiving 3 mg/kg reslizumab had at least 1 malignant neoplasm reported 
compared to 2 out of 730 patients (0.3%) in the placebo group. The observed malignancies in 
reslizumab treated patients were diverse in nature and without clustering of any particular tissue 
type. The majority of malignancies were diagnosed within less than 6 months of exposure to 
reslizumab.  
Additional Safety Issues 
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 May 2015, there have been 
12 pregnancies during the entire clinical development of reslizumab, 4 of which occurred during 
the screening period of the study and 8 in patients receiving reslizumab. All patients were 
withdrawn from the study. Two of the 8 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 pregnancy outcome is unknown. 


 
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Immunogenicity 
Anti-drug antibody (ADA) responses were observed in 5% 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). Neutralizing antibodies and 
product-specific IgE antibodies were not evaluated. 
Further details may be found in the current PI (CINQAIR 2016). 
1.4. 
Known and Potential Benefits and Risks to Patients 
1.4.1. 
Benefits and Risks of Reslizumab 
Information regarding the risks and benefits of reslizumab to human patients may be found in the 
current PI (CINQAIR 2016). 
1.4.1.1. 
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). 
1.4.1.2. 
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). Severe systemic reactions (including 
anaphylaxis), myalgia, elevated CPK, malignancy and oropharyngeal pain are considered as 
ADRs of iv reslizumab. 
Additional information regarding the risks and benefits of reslizumab to human patients may be 
found in the current PI (CINQAIR 2016). 
1.4.2. 
Risks of Computerized Tomography/Positron Emission Tomography Scans 
1.4.2.1. 
Risks of Fludeoxyglucose F 18 Injection 
Use in patients with diabetes mellitus or hyperglycemia has not been well studied. It is 
recommended that patients be normoglycemic when undergoing positron emission tomography 
(PET) imaging with Fludeoxyglucose (FDG) F 18 injection. 
Additional information regarding the risks and benefits of FDG to human patients may be found 
in the current PI (FDG 2014). 
1.4.2.2. 
Risks of Computerized Tomography/Positron Emission Tomography Scans  
Potential risks from the study assessment procedures are low; FDG-PET/ computed tomography 
(CT) scans are associated with: 
1. small radiation dose from the radiolabeled glucose and low dose CT 


 
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2. incidental findings that will be communicated to the participants themselves and to their 
primary health care providers 
3. allergic reactions to the glucose tracer, which are rare and have not been reported within 
the past decade.  
To minimize radiation-absorbed dose to the bladder, adequate hydration should be encouraged to 
permit frequent voiding during the first few hours after intravenous administration of FDG 
injection. This may be achieved by having patients drink at least an 8 oz glass of water prior to 
drug administration. To help protect themselves and others in their environment, patients should 
take the following precautions for 12 hours after injection: whenever possible, a toilet should be 
used and should be flushed several times after each use and hands should be washed thoroughly 
after each voiding or fecal elimination. If blood, urine or feces soil clothing, the clothing should 
be washed separately. 
The exposure to radiation from this study is not significant and is within the acceptable range for 
research studies involving the use of radiotracers as outlined by the regulatory agencies. The 
radiation dose from FDG and the PET/CT scan is not necessary for medical care and will occur 
only as a result of subject participation in the study. At doses much higher than the subject will 
receive in this study, radiation is known to increase the risk of developing cancer after many 
years. At the doses of radiation subjects will receive in this study, it is very likely that they will 
see no effects at all. 
1.4.3. 
Overall Benefit and Risk Assessment for This Study 
This is a research study exploring the effect of a single dose of reslizumab iv 3 mg/kg on 
biomarkers of lung inflammation. Therefore, no direct benefit to the participant is expected. 
However, information obtained from this study may benefit patients in the future by establishing 
the validity of a non-invasive measure of lung inflammation for asthma research purposes and 
for clinical assessment of severe eosinophilic asthma. 
1.5. 
Selection of Drugs and Doses 
A detailed description of study drug administration is presented in Section 5.1. 
1.5.1. 
Justification for Dose of Active Drug 
The dose to be evaluated in this double blind study is 3.0 mg/kg administered every 4 weeks as 
per the US PI for CINQAIR (reslizumab). 
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 the patients 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) Harmonised Tripartide Guideline for Good Clinical Practice (GCP) E6 and 
any applicable national and local laws and regulations (eg, Title 21 Code of Federal Regulations 


 
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[21CFR] Parts 11, 50, 54, 56, 312, and 314, Directive 2001/20/EC of the European Parliament 
and of the Council on the approximation of the laws, regulations and administrative provisions of 
the Member States relating to the implementation of good clinical practice in the conduct of 
clinical trials on medicinal products for human use). Any episode of noncompliance will be 
documented. 
The investigator is responsible for performing the clinical 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 
clinical study in accordance with the protocol will be documented in separate clinical study 
agreements with the sponsor and other forms as required by national competent authorities in the 
country where each investigational center is located. 
The investigator is responsible for ensuring the privacy, health, and welfare of the patients during 
and after the clinical study; and must ensure that trained personnel are immediately available in 
the event of a medical emergency. The investigator and the involved clinical study personnel 
must be familiar with the background and requirements of the study; and with the properties of 
the study drug(s) as described in the Investigator’s Brochure or PI. 
The principal investigator has the overall responsibility for the conduct and administration of the 
clinical study and for contacts with study management, with the Independent Ethics 
Committee/Institutional Review Board (IEC/IRB), and with competent authorities. 
1.7. 
Study Population and Justification 
This study will include 5 healthy control (HC) subjects and 10 patients with asthma. Males and 
females, from the ages of 18 through 50 years with asthma and current blood eosinophil levels of 
at least 400/µL, using ≥440 mcg of fluticasone equivalent and an allowed 2nd asthma controller 
(eg, long-acting β-agonist [LABA]), will be recruited.  
Enrollment will include a minimum of 2 and a maximum of 3 female HC subjects and a 
minimum of 4 and a maximum of 6 female patients with eosinophilic asthma. 
1.8. 
Location and Study Duration 
This study is planned to be conducted in the US at 1 clinical investigational center 
 
 and 1 radiology center 
. It is expected to start in 4th 
quarter 2016 and have a duration of approximately 2 years. 


 
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2. 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES 
2.1. 
Purpose of the Study 
The purpose of the study is to demonstrate that reslizumab reduces lung inflammation in patients 
with eosinophilic asthma. 
2.2. 
Study Objectives 
2.2.1. 
Primary Objective 
There are 2 related primary objectives of this study: 
1. To establish that positron emission tomography (PET)/computerized tomography (CT) 
imaging of the lung can reliably distinguish healthy, non-asthmatic volunteers and 
patients with severe asthma with an eosinophilic phenotype (initial validation). 
2. If the utility of PET/CT scanning is established as per objective 1: to show that 
reslizumab produces a reduction in signal intensity (reduction in lung inflammation) in 
patients with severe asthma with an eosinophilic phenotype. 
2.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• to demonstrate a correlation between the benefit observed on imaging (PET/CT) with: 
− reductions blood eosinophil counts 
− improvement in clinic visit lung function 
− reductions in fractional exhaled nitric oxide (FeNO) 
− improvements in Asthma Quality of Life questionnaire (AQLQ) scores 
2.2.3. 
Exploratory Objectives 
Exploratory objectives are: 
• to demonstrate a correlation between changes in the lung PET/CT signal produced by 
reslizumab and serum biological markers of asthmatic inflammation 
• to demonstrate a correlation between changes in the lung PET/CT signal produced by 
reslizumab and other lung function variables including forced vital capacity (FVC), 
peak expiratory flow rate (PEFR) and forced expiratory flow at the 25% point to the 
75% point of forced vital capacity (FEF25%-75%) 
• to demonstrate that reslizumab produces greater reductions in inflammation of 
whole-body lymph nodes and bone marrow than placebo as seen on PET/CT 
• for those patients that can produce sputum, to demonstrate an association between 
changes in sputum eosinophil numbers produced by reslizumab and the lung PET/CT 
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2.3. 
Study Endpoints 
2.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the change from baseline to week 4 in global lung glycolysis 
(GLG) (GLGΔ). 
The supportive primary efficacy endpoint is the change from baseline to week 4 in lung 
parenchyma (LP) standardized uptake value (SUV) mean. 
2.3.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• the change from baseline to week 4 in blood eosinophil counts 
• the change from baseline to week 4 in FEV1 
• the change from baseline to week 4 in FeNO 
• the change from baseline to week 4 in AQLQ 
2.3.3. 
Exploratory Endpoints 
The exploratory endpoints of this study are: 
• biological markers of inflammation and asthma (blood):  
− immunoglobulin E (IgE) 
− dipeptidyl peptidase 4 (DPP4) 
− 25-hydroxy vitamin D 
− eotaxin-1, -2, and -3 
− thymus and activation regulated chemokine (TARC) 
− monocyte chemoattractant protein-1 (MCP-1) and MCP-4 
− group 2 innate lymphoid cells (ILC2) 
• lung function variables: 
− FVC 
− PEFR 
− 
FEF25%-75% 
• the global uptake of FDG in the lymph nodes and bone marrow as measured by the 
PET-CT imaging parameters indicated for the primary efficacy variable 
• sputum eosinophils for those patients that can produce sputum 
2.3.4. 
Safety Endpoints 
The safety endpoints are: 


 
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• occurrence of adverse events throughout the study 
• vital signs (pulse, respiratory rate, and blood pressure) throughout the study 
• clinical laboratory evaluations throughout the study  
• physical examination findings throughout the study 
• use of concomitant medication throughout the study 


 
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3. 
STUDY DESIGN 
3.1. 
General Design and Study Schematic Diagram 
This is a 7-week, single-center, randomized, double-blind, placebo-controlled, parallel-group 
study to evaluate the effect of reslizumab administered at 3.0 mg/kg in adult patients with 
eosinophilic asthma. The study will consist of a screening period (up to 21 days), a 6-week, 
double-blind treatment/assessment period, and a follow-up telephone contact (7±3 days after last 
visit). 
All subjects who participate in this study will consent at 
 prior to undergoing 
any study procedures. After consent is obtained, all participants will undergo all tests and 
procedures required for eligibility, including sputum and blood eosinophil level assessments. 
Patients with asthma (does not apply to HC subjects) must have a screening blood eosinophil 
count of ≥400 cells/μL to be included. A maximum of 3 screening blood eosinophil assessments 
will be conducted. If the 1st assessment yields a blood eosinophil level below 400 cells/µL 
patients with asthma may return for a 2nd assessment of blood eosinophil level after 7 days. A 3rd 
and final assessment will be performed 7 days after the 2nd assessment, if necessary (eg, if the 
blood eosinophil level remains <400 cells/μL at the 2nd assessment). 
The patient must maintain their usual asthma controller regimen without change throughout the 
screening and study periods. A patient who experiences an asthma exacerbation during this time 
that requires additional medication, beyond increased SABA use, will be considered to have 
failed screening and cannot undergo randomization. A patient may be rescreened for this reason 
1 time only. If a patient experiences an asthma exacerbation requiring treatment with systemic 
steroids, they will only be allowed to be rescreened 6 weeks after completion of treatment. All 
patients that have to be rescreened must be stable on other asthma medications for 30 days prior 
to rescreening. 
The DEAR study is designed in 2 parts. Part 1 is a validation step whereby the sponsor wishes to 
determine (1) the intrapatient reproducibility in the GLG measure, and (2) the difference in the 
GLG measure between individual patients with severe asthma with an eosinophilic phenotype 
(1-by-1) and the entire HC group. Limits for both the reproducibility within patients and 
difference among the 2 groups have been provided by subject matter experts. 
Part 2 will be a 7-week double-blind evaluation of patients with severe asthma with an 
eosinophilic phenotype that have been randomized to receive a single dose of either placebo or 
reslizumab at 3 mg/kg. 
Part 1 
Within 7 days (±3 days) of eligibility being confirmed, participants will have a PET/CT scan as 
per the PET/CT scan protocol described in Part 2 below. Participants will return to the 
 
 7 days (±3) after the first PET/CT scan (taken during visit 2) for a second 
PET/CT scan following the same procedures described above. HC subjects (n=5) may also have 
a second sputum induction and blood sample collection at 
 with 1 day of the 
2nd PET/CT scan, if feasible (preferred but not required). Healthy subjects will be considered 


 
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complete at this time. Only after all 5 HCs have completed the study will patients with asthma be 
screened. 
If the relative difference in GLG (based on the average of the 2 measurements) between healthy 
and asthma patients will be ≥5%, then the asthma patients will be randomized. 
A 10% variability (measured as relative difference between first measurement and second 
measurement) between PET/CT scans as measured by GLG within each group will be 
considered as the maximum allowed variability. The part 1 criteria have been set at these levels 
to observe a difference between the healthy subjects and patients with asthma and to ensure 
intra-group reproducibility; the criteria are based on the investigators’ prior experience. If these 
exploratory criteria are not met (eg, 8 or more patients do not meet the criteria to enter Part 2 
[inclusion criteria k and l]), then the study will be reevaluated. 
Part 2 
If eligible (eg, if inter- and intra-group GLG variability criteria are met), patients will be 
randomized. This may occur at any time after confirmation of eligibility and up to the time of 
dosing. Patients will return to 
 for baseline clinical, serological, and 
biochemical measures at the Clinical Research Center (CRC) according to standard procedures. 
Once these are completed, patients will receive either placebo or reslizumab and will receive the 
infusion at 
. Any new serious adverse events, reslizumab-related adverse 
events, and new concomitant medications will be reported. 
All planned PET/CT scans (weeks 2, 4, and 6) should be scheduled at the time of randomization. 
Within 2 weeks (±3 days) of the infusion, patients will return to 
 for clinical 
tests and procedures. Within 3 days of this visit, patients will undergo a PET/CT scan at the 
. Patients repeat the clinical tests and procedures at weeks 4 and 
6 post-infusion. Each visit at 
 will be followed by a PET/CT scan at the 
 as described above. 
PET/CT scan procedure 
A PET/CT scan consent will be signed before any PET/CT scan procedures are initiated. Patients 
will undergo a whole-body FDG 18 F-PET/CT scan using the standard protocol (Section 6.1.1). 
Image Analysis 
Axial, sagittal, and coronal PET reconstructions will be interpreted, with and without attenuation 
correction, using non-contrast CT images for anatomical correlation. The investigators plan to 
measure global and regional inflammation within the lung, lymph nodes and bone marrow by 
utilizing quantitative parameters based on both volume and SUV. Standardized uptake value is a 
well validated measure which normalizes FDG uptake by any particular object/tissue volume by 
the administered dose and either total body weight or total body surface area. Regions of interest 
(ROIs) will be drawn manually around the outer boundaries of the lung on every transverse slice 
passing through the lung on fused FDG PET/CT images from each subject. The trachea and main 
stem bronchi will be excluded from the ROIs to capture only the inflammation in the lung 
parenchyma. Lung sectional mean standardized uptake value (sSUV mean) and the area of the 
lung ROI will be recorded from each slice. Subsequently, the sectional lung volume (sLV) will 
be calculated from each slice by multiplying the lung ROI area (in centimeters squared) by 0.4 
(slice thickness 4 mm). The sectional lung glycolysis (sLG) will be determined by multiplying 


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sLV and lung sSUV mean from each slice. The lung volume (LV) will be calculated by adding 
all the sLV from slices passing through the lung, and the GLG will be determined by adding all 
the sLG from slices passing through the lung. Finally, the lung SUV mean will be calculated by 
dividing the GLG by the LV. Applying this methodology to different tissues or regions of the 
lungs will allow us to determine average and global SUV measures for the following tissues: 
whole lung parenchyma, right and left lung parenchyma, trachea, bronchi, and right and left 
bronchi. These regions will be delineated in the CT images by using the image segmentation 
techniques. These tissue volumes will be registered with the PET images as outlined below for 
the estimation of SUVs within these regions. Similar methodology will be applied to the lymph 
nodes and bone marrow. 
The assessments and procedures performed during each study visit are detailed in Table 2 and 
Section 3.14. 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 4.4). 
Schemas presenting the walk-through of the study are shown in Figure 1, Figure 2, and Figure 3. 
Figure 1: 
Health Control Subjects-Study Flow 
V1
(screening)
•
IC
•
Comp P/E
•
H + W
•
Vitals
•
Med Hx
•
Sm Hx
•
Prior meds
7-10 d
PET/CT #1
•
GLG
V3
7 d ± 3 d
PET/CT #2
•
GLG
•
AEs
•
Con meds 
•
♀β-HCG (u)
•
Glucose (u)
∆GLG
≤10% vs V2
∆GLG
>10% vs V2
Ø, Part 1 fail due to irreproducible PET signal
V2
[Bp1:d1]
•
IC-PET
•
I/E criteria
•
AEs
•
Con meds
•
♀β –HCG (u)
•
Glucose (u)
V3
Ø, Part 1 successful – begin recruitment of asthma pts
•
I/E criteria
•
Labs
•
Blood EOS
•
♀β-HCG (s)
•
Spirometry (only FEV1)
•
ECG
•
AEs
 
AE=adverse event; β-HCG=beta-human chorionic gonadotropin; Bp1=baseline Part 1; Comp=complete; 
Con=concomitant; CT=computerized tomography; d=day; ECG=electrocardiography; EOS=eosinophils; 
FEV1=forced expiratory volume in 1 second; GLG=global lung glycolysis; H=height; Hx=history; IC=informed 
consent; I/E=inclusion/exclusion; Labs=laboratory samples; Med=medical; meds=medications; P/E=physical exam; 
; PET=positron emission tomography; pts=patients; 
; 
s=serum; Sm=smoking; u=urine analysis; V=visit; W=weight 


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Figure 2: 
Patients with Asthma-Study Flow: Part 1 
 
ACQ=Asthma Control Questionnaire; ADA=anti-drug antibody; AE=adverse event; AQLQ=Asthma Quality of Life 
Questionnaire; β-HCG=beta-human chorionic gonadotropin; b/f=before; Bp1=baseline Part 1; Bp2=baseline Part 2; 
Br=brief; Comp=complete; Con=concomitant; CT=computerized tomography; d=day; ECG=electrocardiography; 
EOS=eosinophils; FeNO=fractional exhaled nitric oxide; FEV1=forced expiratory volume in 1 second; GLG=global 
lung glycolysis; H=height; h=hour; HC=healthy control subjects; Hx=history; IC=informed consent; 
I/E=inclusion/exclusion; inf=infusion; Labs=laboratory samples; Med=medical; meds=medications; P/E=physical 
exam; 
; PET=positron emission tomography; R=randomization; 
 
; s=serum; Sm=smoking; u=urine analysis; V=visit; W=weight 


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Figure 3: 
Patients with Asthma-Study Flow: Part 2 
 
ADA=anti-drug antibody; AE=adverse event; AQLQ=Asthma Quality of Life Questionnaire; β-HCG=beta-human 
chorionic gonadotropin; Br=brief; Comp=complete; Con=concomitant; CT=computerized tomography; d=day; 
EOS=eosinophils; FeNO=fractional exhaled nitric oxide; GLG=global lung glycolysis; Labs=laboratory samples; 
meds=medications; P/E=physical exam;
; PET=positron emission tomography; 
; u=urine analysis; V=visit; w2=week 2. 
3.2. 
Justification for Study Design 
The rationale for the design of the study is summarized in Table 1. 


 
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Table 1: 
Rationale for Protocol 
Area 
Rationale 
Conducting the study 
To date, there has been no report of direct visualization of whole lung 
inflammation in asthmatic patients treated with placebo versus an 
anti-IL-5 therapy. In addition, there has been no report on the rapidity 
by which an anti-IL-5 therapy can affect whole lung inflammation in 
asthmatic patients. 
Study population 
Patients with eosinophilic asthma and HCs, males and females that are 
between the ages of 18 and 50. Patient with asthma must have a 
current blood eosinophil levels of at least 400/µL on ≥440 μg of 
fluticasone-equivalent and a LABA or any allowed additional 
treatment to control asthma symptoms. 
Study design 
Single-center, placebo-controlled, double-blinded, parallel-group, 
imaging study as Part 1 (validation) and Part 2 (evaluation) 
Investigational product dosage 
regimen and duration of 
treatment 
Reslizumab (CEP-38072), 3.0 mg/kg, iv, 1 administration only 
Choice of comparison drug(s) 
(placebo, active, reference) 
Placebo 
Number of subjects (including 
number per treatment group) 
Fifteen in Part I (5 as HCs, including a minimum of 2 and a maximum 
of 3 females, and 10 patients with eosinophilic asthma, including a 
minimum of 4 and a maximum of 6 females). The latter group will 
advance to Part 2 with 5 patients randomized to placebo and 5 patients 
randomized to reslizumab. 
Key inclusion and exclusion 
criteria 
See above 
Treatment blinding (ie, rationale 
for blinded or open-label 
design) 
Each patient will be assigned a unique identifier number and all 
reference to the patient will be using this identifier. 
Double-blinding is important to ensure that the treatment effect of 
reslizumab is truly ascribed to the treatment. 
Primary analysis (measure, 
variable, time point, statistical 
test) 
The primary efficacy variable is the update of FDG in the whole lung 
between placebo- and reslizumab-treated patients as measured by 
ΔGLG. The supportive primary efficacy variable will be the ΔLP SUV 
mean. All measurements made at 2 baseline visits and at weeks 2, 4, 
and 6 post-randomization. 
The ΔGLG will be described using descriptive statistics. No statistical 
testing will be conducted. 
Inclusion of ancillary studies: 
PK, PD, immunogenicity 
A number of biomarkers will be evaluated to monitor whether they 
change as part of the response to treatment. Anti-drug antibodies will 
be evaluated for all patients. 


 
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Area 
Rationale 
Key safety measures 
Key safety measures include: 
• inquiries about adverse events 
• clinical laboratory evaluations 
• vital signs (pulse, respiratory rate, and blood 
pressure) 
• physical examination findings 
• inquiries about use of concomitant medication 
anti-hIL-5=anti-human interleukin-5; FDG=fludeoxyglucose; ΔGLG=change from baseline in global lung 
glycolysis; HC=healthy control; iv=intravenous; LABA=long-acting beta-agonist; LP=lung parenchyma; OCS=oral 
corticosteroids; PD=pharmacodynamic; PK=pharmacokinetics; SUV=standardized uptake value 
3.3. 
Primary and Secondary Efficacy Measures and Time Points 
A description of the efficacy measures is provided in Section 6. 
3.3.1. 
Primary Efficacy Measure and Time Points 
GLG will be measured at 2 baseline visits and at weeks 2, 4, and 6 (all ±3 days) 
post randomization. 
3.3.2. 
Secondary Efficacy Measures and Time Points 
The secondary efficacy measures and time points for this study are as follows:: 
− blood eosinophil counts from baseline to weeks 2, 4, and 6 (all ±3 days) 
− FEV1 from baseline to weeks 2, 4, and 6 (all ±3 days) 
− FeNO measurements from baseline to weeks 2, 4, and 6 (all ±3 days) 
− AQLQ scores from baseline to weeks 2, 4, and 6 (all ±3 days) 
3.4. 
Safety Measures and Time Points 
Patient safety will be assessed by standard asthma management and physician practice. If a 
patient experiences an asthma exacerbation during Part 1, they will be treated with 
oral corticosteroids (OCS) for a period of 2 weeks, followed by a 6-week observation period 
without OCS to ensure asthma control. Stable patients will then re-enter the study at the time 
point of the exacerbation. 
The following safety measures will be implemented during the study: 
• occurrence of adverse events throughout the study 
• vital signs (pulse, respiratory rate, and blood pressure) throughout the study 
• clinical laboratory evaluations throughout the study  
• physical examination findings throughout the study 


 
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• use of concomitant medication throughout the study 
A description of the safety measures is provided in Section 7. 
3.5. 
Pharmacokinetic Measures and Time Points 
Pharmacokinetics will not be assessed in this study. 
3.6. 
Exploratory Efficacy Measures and Time Points 
The exploratory efficacy measures and time points are:  
• biological markers of inflammation and asthma:  
− IgE 
− DPP4 
− 25-hydroxy vitamin D 
− eotaxin-1, -2, and -3 
− TARC 
− MCP-1 and MCP-4 
− ILC2 
• lung function variables: 
− FVC 
− PEFR 
− FEF25%-75% 
• the global uptake of FDG in the lymph nodes and bone marrow as measured by the 
PET/CT imaging parameters indicated for the primary efficacy variable 
• for those patients that can produce sputum, to demonstrate a correlation between 
reductions in inflammation by reslizumab with a reduction in sputum eosinophils 
All variables will be measured at 1 (biomarkers only) or 2 baseline visits and at weeks 2, 4, and 
6 post-randomization. 
3.7. 
Randomization and Blinding 
This is a randomized, double-blind, placebo-controlled study. After the 2 baseline PET/CT scans 
and successful completion of all requirements (Part 1), patients will be randomly assigned 1:1 in 
a double-blind fashion to receive either placebo or iv 3.0 mg/kg reslizumab. 
In order to maintain the blind, each patient will be assigned a unique identifier number and all 
reference to the patient will be by using this identifier. 
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list. The specifications for randomization will be under the responsibility and 


 
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oversight of Teva Global Statistics. The output of the randomization process will be a patient 
randomization list. 
The sponsor’s clinical personnel involved in the study will be blinded to the study drug identity 
until the database is locked for analysis and the treatment assignment is revealed, with the 
exception of the bioanalytical group who will not be blinded to facilitate ADA sample analysis 
and an un-blinded person who will be responsible for randomization assignment. Additionally, in 
order to maintain the study blind, blood and sputum eosinophil levels assessed after study drug 
administration will not available to investigators, their blinded staff, the sponsor, and blinded 
members of the clinical research organization. There will be un-blinded data management, 
un-blinded site staff, and an un-blinded CRA who will not sit on the study team and be 
responsible for un-blinded eosinophil data. 
3.8. 
Maintenance of Randomization and Blinding 
3.8.1. 
Maintenance of Randomization 
Patient randomization codes will be maintained in a secure location at the service provider 
contracted to generate the codes. At the time of analysis (after the end of study), after receiving 
unblinding request from Teva statistician, the service provider will provide the unblinded 
treatment assignment according to the processes defined in the relevant Standard Operating 
Procedure (SOP). 
3.8.2. 
Blinding/Unblinding 
For information about personnel who may be aware of treatment assignments, see Section 3.7. 
These individuals will not be involved in conduct of any study procedures or assessment of any 
adverse events. 
An envelope containing individual sealed envelopes that correspond to each study drug package 
will be provided to the investigational center. The envelopes will contain the randomization 
number and the name and dose (if applicable) of the study drug for each patient. In case of a 
serious adverse event, pregnancy, or in cases when knowledge of the study drug assignment is 
needed to make treatment decisions, the investigator may open the patient’s envelope and 
unblind the patient’s drug assignment as deemed necessary, mainly in emergency situations. If 
possible, the sponsor should be notified of the event before breaking of the code. If this is not 
possible, the sponsor should be notified immediately afterwards and the patient’s drug code 
assignment should not be revealed. All envelopes must be returned to the sponsor at the 
completion of the study. Breaking of the treatment code can always be performed by the 
investigational center 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 on 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 an adverse event defined as a suspected unexpected serious adverse 
reaction (SUSAR) (ie, reasonable possibility; see Section 7.1.4), Global Patient Safety and 
Pharmacovigilance may independently request that the treatment code be broken (on a 


 
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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 the 
investigator and for other personnel involved in the conduct of the study, and analysis and 
reporting of the data. 
3.8.3. 
Data Monitoring Committee 
A Data Monitoring Committee will not be used during this study. 
3.9. 
Drugs Used in the Study 
A description of administration procedures is given in Section 5.1. 
Additional details may be found also be found in the current US PI for reslizumab 
(CINQAIR 2016) and for FDG 18 (FDG 2014). 
3.9.1. 
Investigational Product 
Reslizumab will be provided as a sterile solution for infusion presented as 100 mg (10 mL) per 
vial, formulated at 10 mg/mL in 20 mM sodium acetate, 7% sucrose, pH 5.5 buffer. 
The contents of the label will be in accordance with all applicable local regulatory requirements. 
A more detailed description of administration procedures is given in Section 5.1. 
3.9.2. 
Placebo 
Placebo will be provided as a sterile solution of 20 mM sodium acetate, 7% sucrose, pH 5.5 
buffer. 
A more detailed description of administration procedures is given in Section 5.1. 
3.9.3. 
Fludeoxyglucose F 18 
Fludeoxyglucose F 18 injection will be provided as a ready to use isotonic, sterile, pyrogen free, 
clear, colorless citrate buffered solution. Each mL will contain between 0.740 to 
7.40 gigabecquerel (20.0 to 200 millicurie [mCi]) of 2-deoxy-2-[18F]fluoro-D glucose at the end 
of synthesis (EOS), 4.5 mg of sodium chloride and 7.2 mg of citrate ions. The pH of the solution 
will be between 5.5 and 7.5. The solution will be packaged in a multiple-dose glass vial and will 
not contain any preservative. 
A more detailed description of administration procedures is given in Section 5.1. 
3.10. 
Drug Supply and Accountability 
3.10.1. 
Drug Storage and Security 
3.10.1.1. Reslizumab and Placebo 
Reslizumab and matching placebo must be stored in a refrigerator at controlled temperature (2°C 
to 8°C) and should not be frozen and should be protected from light. Reslizumab and placebo 
supplies must be kept in a secure area (eg, locked refrigerator). The site should have a process 
for monitoring the storage temperature of unused study drug. 


 
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3.10.1.2. Fludeoxyglucose F 18 
Receipt, transfer, handling, possession, or use of FDG is subject to the radioactive material 
regulations and licensing requirements of the US Nuclear Regulatory Commission, Agreement 
States or Licensing States as appropriate. 
The FDG vial must be stored upright in a lead shielded container at 25°C (77°F); excursions 
permitted to 15°C to 30°C (59°F to 86°F). 
Store and dispose of FDG in accordance with the regulations and a general license, or its 
equivalent, of an Agreement State or a Licensing State. The expiration date and time are 
provided on the container label. Use FDG within 12 hours from the EOS time. 
3.10.2. 
Drug Accountability 
Each study drug shipment will include a packing slip listing the contents of the shipment, drug 
return instructions, and any applicable forms. 
The investigator is responsible for ensuring that deliveries of study drug and other study 
materials from the sponsor are correctly received, recorded, handled, and stored safely and 
properly in accordance with the CFR or national and 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 or designee. 
3.11. 
Duration of Patient Participation and Justification 
This study will consist of Part 1, a 21-day PET/CT screening period, and Part 2 (only patients 
with asthma), a 6 week double blind treatment/assessment period followed by a 7-day follow up 
period. See Section 12.4 for the definition of the end of study. 
3.12. 
Stopping Rules and Discontinuation Criteria 
Other than in the event a participant becomes pregnant, there are no formal rules for early 
termination of this study. During the conduct of the study, serious adverse events will be 
reviewed by Teva in an ongoing basis (see Section 7.1.5) as they are reported to Teva by the 
investigational center to identify safety concerns. 
The study may be terminated by the sponsor for reasons including, but not limited to, a safety 
concern. 
Termination of patient participation is required in Part 2 in the event of an asthma exacerbation. 
Should this happen, additional patients will be enrolled until 10 patients (including at least 4 
female patients) have completed all 3 post-reslizumab/placebo PET/CT scans. 
A patient may discontinue participation in the study at any time for any reason (eg, lack of 
efficacy, withdrawal of consent, and adverse event); every effort should be undertaken to find 
out the reason for discontinuation. The investigator or sponsor can withdraw a patient from the 


 
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study at any time for any reason (eg, protocol violation or deviation as defined in Section 11.1.2, 
noncompliance, or adverse event). 
3.13. 
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 to the CRF. Data may not be recorded directly on the CRF 
and considered as source data unless the sponsor provides written instructions specifying which 
data are permitted to be recorded directly to the CRF. 
If data are processed from other institutions or means (eg, clinical laboratory, central image 
center, or electronic diary data) the results will be sent to the investigational center, where they 
will be retained and transcribed to the CRF. All data from other institutions will be available to 
the investigator. 
The CRFs are filed in the sponsor’s central file. 
3.14. 
Study Procedures and Assessments 
Study procedures and assessments with their time points are summarized in Table 2. Detailed 
by-visit information is provided starting with Section 3.14.1. Detailed descriptions of each 
assessment are provided in Section 6 (efficacy assessments), Section 7 (safety assessments), and 
Section 8 (other assessments). 


 
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Table 2: 
Study Procedures and Assessments 
Study period 
Part 1 
Part 2 
Follow-up 
Visit number 
V1a 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Allowed time windows 
Up to -21 days 
0 days 
±3 day(s) 
Within 3 days 
of V3 
±3 day(s) 
±3 day(s) 
±3 day(s) 
Up to +7 days 
Procedures and assessments 
Screening 
 
Baseline 
(day 1) 
 
W1 
(day 8) 
 
Baseline 
(day 1) 
 
W2 
(day 15 
from V4) 
W4 
(day 29 from 
V4) 
W6 
(day 43 from 
V4)/early 
termination 
W7 
Informed consent 
X 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
 
Prior medication and treatment 
history 
X 
 
 
 
 
 
 
 
Complete physical examinationb 
X 
 
 
 
 
 
A 
 
Brief physical examinationb 
 
 
 
A 
A 
A 
 
 
Vital signs measurementbc 
X 
 
 
A 
A 
A 
A 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
Clinical chemistrybd 
X 
 
 
A 
 
 
A 
 
Urine/serum β HCG test for women 
of child bearing potentialbe 
X 
X 
X 
A 
A 
A 
A 
 
Hematology (eosinophils)f 
X 
 
 
A 
A 
A 
A 
 
Sputum sampling for eosinophilsg 
X 
 
 
A 
A 
A 
A 
 
Urinalysish 
X 
X 
X 
 
A 
A 
A 
 
PET/CT scan 
i 
 
X 
X 
 
A 
A 
A 
 
ACQ-6 for entry criterion 
A 
 
 
 
 
 
 
 
Electrocardiographyb 
X 
 
 
 
 
 
 
 
Spiromety 
X 
 
 
A 
A 
A 
A 
 


 
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Study period 
Part 1 
Part 2 
Follow-up 
Visit number 
V1a 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Allowed time windows 
Up to -21 days 
0 days 
±3 day(s) 
Within 3 days 
of V3 
±3 day(s) 
±3 day(s) 
±3 day(s) 
Up to +7 days 
Procedures and assessments 
Screening 
 
Baseline 
(day 1) 
 
W1 
(day 8) 
 
Baseline 
(day 1) 
 
W2 
(day 15 
from V4) 
W4 
(day 29 from 
V4) 
W6 
(day 43 from 
V4)/early 
termination 
W7 
ADAbj 
 
 
 
A 
A 
 
A 
 
Blood collection for biomarker 
analysisb 
 
 
 
A 
A 
A 
A 
 
AQLQ 
 
 
 
A 
A 
A 
A 
 
Randomization 
 
 
 
Ak 
 
 
 
 
Study drug infusion 
 
 
 
A 
 
 
 
 
Adverse event inquiry 
X 
X 
X 
A 
A 
A 
A 
A 
Concomitant medication inquiry 
X 
X 
X 
A 
A 
A 
A 
A 
a screening visit (visit 1) will take place up to 21 days before the V2 visit. It is understood that not all procedures can be completed on the same day. In 
particular, the patient may need to return to satisfy the medication hold for screening pre-bronchodilator FEV1. 
b Physical examination, vital signs, blood samples, and ECG should be obtained before spirometry procedures and IP administration. 
c Vital signs measurements will include blood pressure, pulse, respiratory rate, body temperature, and blood oxygen saturation (SpO2). Height and weight 
measurements are required only at screening visit. 
d The clinical chemistry will include a complete metabolic panel. 
e A serum β-HCG pregnancy test will be performed at V1 only, for all participating women of childbearing potential. Urine β-HCG tests will be performed, for 
all participating women of childbearing potential, at V2, V3, V5, V6, and V7, prior to performance of PET/CT scan. 
f Hematology will include a complete blood count with differential. The results of the differential blood tests performed after study drug administration will be 
blinded. If there is a medical need to review these results, the investigator will contact the medical monitor. 
g The results of the sputum eosinophil assessments performed after study drug administration will be blinded. If there is a medical need to review these results, 
the investigator will contact the medical monitor. 
h A complete urinalysis will be performed at the screening visit, visit 4, and visit 7; a urine dipstick test for glucose will be performed prior to each PET/CT scan. 
i Patients should be observed for 1 hour following completion of PET/CT scan. 
j Blood samples for ADA assessment will be collected at baseline (before study drug administration) and other scheduled time points, and upon observation of 
any severe hypersensitivity reaction (eg, anaphylaxis). 


 
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k Randomization can occur any time from determining that the patient qualifies for Part 2 up to study drug infusion. Patient qualification is based on meeting 
both of the following 2 steps: 1) ∆GLG ≤10% versus V2 [for reproducibility] and 2) ∆GLG≥5% versus HC [for signal] to study drug infusion. 
A=patients with asthma only; ACQ-6=6-item Asthma Control Questionnaire; ADA=anti-drug antibodies; AQLQ=Asthma Quality of Life Questionnaire; 
β-HCG= beta human chorionic gonadotropin; CBC=complete blood count; CT=computerized tomography; GLG=gloal lung glycolysis; HC=healthy control 
subjects only; IP=investigational product; PET=positron emission tomography; 
; V=visit; 
W=week; X=patients with asthma and healthy control subjects. 


 
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3.14.1. 
Procedures for Screening and Enrollment (Visit 1) 
A signed and dated informed consent form will be obtained before any screening procedures 
commence (see Section 12.1). Assessments conducted as part of routine medical care and 
performed during the screening period may be used in place of the protocol-specific assessments. 
In addition, disease-specific assessments performed within a specified time frame before 
informed consent may be used for the study. Patients 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 assigned number of the investigational center, and the last 
3 digits will be assigned at the investigational center (eg, if the number assigned to the country is 
01, the 3rd patient screened at 5th investigational center would be given the number of 01005003). 
The screening visit (visit 1) will take place not more than 3 weeks before the Part 1 baseline visit 
(visit 2). The following procedures will be performed at visit 1: 
• Obtain written informed consent before any study-related procedures are performed 
• Review inclusion and exclusion criteria 
• Review medical history 
• Review medication history 
• Review smoking history 
• Perform clinical laboratory tests (chemistry, hematology, and urinalysis). Patients 
with an eosinophil count <400/μL may be retested up to 2 additional times within the 
21-day screening period. Patients must have an eosinophil level ≥400/μL to complete 
screening. 
• Perform serum pregnancy test (for women of childbearing potential) 
• Perform complete physical examination including height and weight 
• Assess vital signs, including blood pressure (BP), pulse, respiratory rate (RR), body 
temperature, and blood oxygen saturation level (SpO2) 
• Perform ECG 
• Perform spirometry 
• Collect sputum sample 
• Complete ACQ-6 (patients only, not HC subjects) 
• Inquire about adverse events 
• Inquire about concomitant medication usage 
• Inform patients of study restrictions and compliance requirements 


 
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3.14.2. 
Procedures Before Study Drug Treatment (Part 1 Baseline [Visit 2, Day 1]) 
Patients who meet the inclusion and exclusion criteria and complete the assessments at visit 1 
will continue to visit 2 (up to 3 days after completing the screening procedures). 
The following procedures will be performed at visit 2: 
• Confirm patient meets inclusion and exclusion criteria 
• Ensure written informed consent is in place before any procedures at the 
 
 are performed 
• Perform urine pregnancy test (for women of child bearing potential) 
• Perform urine glucose test 
• Perform PET/CT scan 
• Observe for 1 hour after completion of PET/CT scan 
• Inquire about concomitant medication usage 
• Inquire about adverse events 
3.14.2.1. Week 1 (Visit 3) 
The following procedures/assessments will be performed at visit 3, day 8 (±3 days): 
• Perform urine pregnancy test (for women of child bearing potential) 
• Perform urine glucose test 
• Perform PET/CT scan 
• Observe for 1 hour after completion of PET/CT scan 
• Inquire about concomitant medication usage 
• Inquire about adverse events 
Healthy subjects are considered complete at this point and do not need to return for any follow 
up visits. 
3.14.3. 
Procedures During Study Drug Treatment 
3.14.3.1. Part 2 (Week 1 [Visit 4]) 
Randomization may occur at any time from determining that the patient qualifies for Part 2 up to 
study drug infusion. Patient qualification is based on meeting both of the following 2 steps: 
1) ∆GLG ≤10% versus V2 (for reproducibility) and 2) ∆GLG≥5% versus HC (for signal). 
Patients will be assigned a permanent, unique randomization number and a treatment number. 
These 2 assigned numbers will be entered in the CRF. 
On Part 2, day 1 (within 72 hours of the PET/CT scan), the following procedures will be 
performed: 
• Inquire about adverse events 


 
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• Inquire about concomitant medication usage 
• Perform brief physical examination 
• Assess vital signs (as described in Section 3.14.1) 
• Perform urine pregnancy test (for women of child bearing potential) 
• Perform clinical laboratory tests (chemistry, urinalysis, and hematology). 
• Collect sputum sample. 
• Administer the AQLQ+12 
• Collect blood sample for serum ADA assay 
• Collect blood sample for biomarkers analyses 
• Perform spirometry 
Once the above procedures have been performed, study drug infusion will occur. Any adverse 
events that occurred, or concomitant medications that were administered, during the visit will be 
recorded. 
Observe patients for 1 hour after completion of study drug infusion. 
3.14.3.2. Weeks 2, 4, and 6 (Visits 5, 6, and 7) 
The following procedures/assessments will be performed at weeks 2, 4, and 6 (visits 5, 6, and 7): 
The following procedures will be performed at the CRTC of the 
: 
• Perform urine pregnancy test (for women of child bearing potential) 
• Perform urine glucose test 
• Perform PET/CT scan 
• Observe for 1 hour after completion of PET/CT scan 
Up to 72 hours after the PET/CT scan, the following procedures will be performed: 
• Inquire about adverse events 
• Inquire about concomitant medication usage 
• Perform clinical laboratory tests (chemistry [week 6, visit 7 only], urinalysis [week 6, 
visit 7 only], and hematology). The results of the differential blood tests performed 
after study drug administration will be blinded. If there is a medical need to review 
these results, the investigator will contact the medical monitor. 
• Collect sputum sample. The results of the sputum eosinophil assessments performed 
after study drug administration will be blinded. If there is a medical need to review 
these results, the investigator will contact the medical monitor. 
• Perform physical examination: 
− brief exam at week 2 (visit 5) and week 4 (visit 6) 


 
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− complete exam at week 6 (visit 7) only 
• Assess vital signs, including BP, pulse, RR, body temperature, and SpO2 
• Administer the AQLQ+12 
• Obtain blood sample for serum ADA assay (weeks 2 and 6 [visits 5 and 7] only) 
• Obtain blood sample for biomarkers analyses 
• Perform spirometry 
3.14.4. 
Procedures After Study Drug Treatment 
Patients who participate in the study in compliance with the protocol for at least 6 weeks from 
the start of Part 2 will be considered to have completed the study. See Section 12.4 for the 
definition of the end of study. 
For patients who complete the study or withdraw prematurely, final evaluations will be 
performed at an end-of treatment visit or as soon as possible thereafter. Procedures for patients 
who withdraw prematurely from the study are described in Section 4.4. Patients should be treated 
with standard of care after termination of the study as appropriate. 
Patients with ongoing adverse events will be monitored as described in Section 7.1.2. Otherwise, 
visit 7 will be the last study visit. 
3.14.4.1. Telephone Follow-Up (Visit 8, Up To 7 Days After Visit 7) 
The following procedures/assessments will be completed at the follow-up contact (visit 8, 
week 7, up to 7 days after visit 7): 
• Inquire about adverse events. 
• Inquire about concomitant medication usage. 
3.14.5. 
Unscheduled Visits 
An unscheduled visit may be performed at any time during the study at the patient’s request and 
as deemed necessary by the investigator. The date and reason for the unscheduled visit will be 
recorded on the CRF as well as any other data obtained (eg, adverse events, concomitant 
medications and treatments, and results from procedures or tests). 
Procedures performed during unscheduled visits include the following: 
• concomitant medication inquiry 
• vital signs measurements 
• adverse event inquiry 
• review study compliance 
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 inclusion and exclusion criteria to allow patients to 
be enrolled are not granted by Teva (see Section 11.1.2). 
4.1. 
Patient Inclusion Criteria 
Healthy subjects and patients may be enrolled in this study only if they meet all of the following 
criteria: 
a. Male or female, 18 through 50 years of age. 
b. Females that are either surgically sterile, are 2 years postmenopausal, or have a 
negative pregnancy test beta-human chorionic gonadotropin at screening (serum) and 
all PET/CT imaging visits (urine). 
c. Females of childbearing potential (not surgically sterile or 2 years postmenopausal), 
have to use a medically accepted method of contraception and have to agree to 
continue to use of this method for the duration of the study and for 5 months after 
study drug administration. Acceptable methods of contraception include barrier 
method with spermicide, abstinence, intrauterine device (IUD), or steroidal 
contraceptive (oral, transdermal, implanted, and injected). Note: partner sterility alone 
is not acceptable for inclusion in the study. 
d. Subjects and patients with less that 10-pack year history of smoking. 
Patients may be included in the study only if they also meet all of the following, additional 
criteria: 
e. Male or female, 18 through 50 years of age, with a previous diagnosis of asthma. 
f. Patients taking inhaled fluticasone at a dosage of at least 440 mcg daily, or 
equivalent.  
g. The patient’s baseline asthma therapy regimen (including, but not limited to, inhaled 
corticosteroids, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, or 
cromolyn) must be stable for 30 days prior to screening and judged by their treating 
physician to be able to continue without dosage changes throughout the study.  
h. Patients with a blood eosinophil level of at least 400/µL at screening. Patients with a 
blood eosinophil level below 400/μL will be given 2 additional screening 
opportunities to determine blood eosinophil levels. 
i. Patients with airway reversibility of at least 12% to β-agonist administration. 
j. Patients with an ACQ score of at least 1.5 at either screening or baseline visits. 
Patients may be included in Part 2 of the study only if they also meet the following, additional 
criteria: 
k. the intrapatient reproducibility, taken as sequential GLG measures on visits 2 and 3 
(Table 2), differs by only ≤10% 


 
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l. the intragroup variability (signal window), taken as a difference in the 2 subcriteria 
(below) to be ≥5%: 
○ the mean GLG of healthy controls determined by taking the mean of the 
average GLG for visits 2 and 3 for each healthy control. 
○ the mean GLG of each single patient with severe asthma with an eosinophilic 
phenotype, taken as sequential GLG measures on visits 2 and 3 (Table 2). 
4.2. 
Patient Exclusion Criteria 
Healthy subjects and patients will be excluded from participating in this study if they meet any of 
the following criteria: 
a. Patients requiring treatment with oral, intramuscular, or iv corticosteroids within 
6 weeks of the Part 1 baseline visit. 
b. Patients with any other confounding underlying lung disorder including but not 
limited to: bronchiectasis, chronic obstructive pulmonary disorder, smoking ≥10 pack 
year history, pulmonary fibrosis, emphysema, cystic fibrosis, and lung cancer. 
c. Patients with a blood glucose level at screening or baseline greater than or equal to 
150 mg/dL. 
d. Patients diagnosed with diabetes mellitus. 
e. Patients with pulmonary conditions and blood eosinophilia other than eosinophilic 
asthma including, but not limited to: Churg-Strauss syndrome, allergic 
bronchopulmonary aspergillosis and hypereosinophilic syndrome. 
f. Patients with clinically meaningful comorbidity that can interfere with the study 
schedule or procedures, or compromise the patient’s safety. 
g. Patients that are current smokers (ie, have smoked within the last 12 months prior to 
screening). 
h. Patients using systemic immunosuppressive, immunomodulating, or other biologic 
agents (including, but not limited to, anti-IgE mAb, methotrexate, cyclosporin, 
interferon-α, or anti–tumor necrosis factor mAb) within 6 months prior to screening. 
i. Patients who have previously received an anti-hIL-5 mAb (eg, reslizumab, 
mepolizumab [Nucala]) or anti-IL-5 receptor mAb (eg, benralizumab). 
j. Patients who had concurrent infection or disease that may preclude assessment of 
active asthma. 
k. Patients with a history of concurrent immunodeficiency (human immunodeficiency 
virus or acquired immunodeficiency syndrome or congenital immunodeficiency). 
l. Patients that had an active parasitic infection within 6 months prior to screening. 
m. Patients with a history of exposure to water-borne parasites within 6 weeks prior to 
screening or during the screening period or a history of diarrheal illness of 
undetermined etiology within 3 months prior to screening or during the screening 
period 


 
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n. Any patient who had an infection requiring the following: 
− an admission to the hospital for at least 24 hours within 4 weeks prior to screening 
or during the screening period 
− treatment with iv antibiotics within 4 weeks prior to screening or during the 
screening period 
− treatment with oral antibiotics within 4 weeks prior to screening or during the 
screening period 
o. Patients with any disorder that may interfere with drug absorption, distribution, 
metabolism, or excretion (including gastrointestinal surgery). 
p. Female subjects who are pregnant or breast-feeding or considering becoming 
pregnant during the study or within 5 months after reslizumab dosing. 
q. Known hypersensitivity to study drug or to FDG/contrast agents. 
r. Treatment with metformin. 
s. Compromised renal function. 
4.3. 
Justification for Key Inclusion and Exclusion Criteria 
4.4. 
Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki, each patient is free to withdraw from the study at 
any time. The investigator also has the right to 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 3.8, 3.12, 3.14.4, 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 given as to why the patient is 
withdrawing or being withdrawn from the study. 
The reason for and date of withdrawal from the study must be recorded on the source 
documentation and transcribed to the CRF. 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 clinically 
significant abnormal laboratory test result, monitoring will be continued 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 specific event or test result must be recorded on the source 
documentation and transcribed to the CRF. 
All assessments should be performed according to the protocol. 
A patient who is has been identified as a potential participant but does not complete the 
screening period may be replaced with another eligible patient to ensure that at least 10 asthma 
patients (with at least 4 females) are evaluable for post-reslizumab PET/CT. 


 
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5. 
TREATMENT OF PATIENTS 
5.1. 
Drugs Administered During the Study 
5.1.1. 
Reslizumab 
At the Part 2 baseline visit, patients will be randomly assigned to treatment with reslizumab or to 
the placebo treatment group. Reslizumab (3.0 mg/kg) or matching placebo will be administered 
by iv infusion, over 20 to 50 minutes, at the baseline visit. Patients will be observed for 1 hour 
after administration of study drug/placebo. Additional administration information may be found 
in Section 2 of the US PI for reslizumab (CINQAIR 2016). 
Study drug will be administered by qualified study personnel who will ensure that the study drug 
is administered in accordance with the protocol. 
A more detailed description of the reslizumab drug product is provided in Section 3.9. 
5.1.2. 
Fludeoxyglucose F 18 
Prior to each PET/CT scan, FDG will be administered by iv infusion. 
Fludeoxyglucose F 18 will be administered by qualified study personnel who will ensure that the 
study drug is administered in accordance with the protocol. 
5.2. 
Restrictions 
Medications prohibited before or during the study are described in Section 5.3. Restrictions in 
regard to sexual activity and required laboratory values are provided in the inclusion and 
exclusion criteria. 
5.3. 
Prior and Concomitant Medication or Treatment 
Any prior or concomitant medication, treatment, or procedure a patient has had within 4 weeks 
before screening and up to the end of study period, including follow-up, will be recorded on the 
CRF. Generic or trade name, indication, and dosage will be recorded. The sponsor will encode 
all therapy and medication according to the World Health Organization drug dictionary. 
• 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. 
The following medications will not be allowed during this study: 
• Any immunosuppressive or immunomodulatory agents (biological and non 
biological), including, but not limited to systemic steroids, methotrexate, 
cyclosporine, and interferon (excluding maintenance allergen immunotherapy) 


 
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• All biologic therapies, including, but not limited to omalizumab (Xolair®), 
mepolizumab (Nucala), benralizumab, lebrikizumab, and anti-tumor necrosis factor 
monoclonal antibodies 
• All nonbiologic investigational drugs 
• Inhaled nicotine (including electronic cigarettes) 
The following medications are allowed as prior medications, with the restrictions as noted: 
• Treatment with systemic corticosteroids must have been stopped at least 6 weeks 
prior to the Part 1 baseline visit 
• Treatment with systemic immunosuppressive, immunomodulating, or other biologic 
agents (including, but not limited to, anti-IgE mAb, methotrexate, cyclosporin, 
interferon-α, or anti–tumor necrosis factor mAb) must have been stopped at least 
6 months prior to screening 
• Baseline asthma therapy regimen (including, but not limited to, inhaled 
corticosteroids, leukotriene receptor antagonists, 5-lipoxygenase inhibitors, or 
cromolyn) must be stable for 30 days prior to screening and judged by their treating 
physician to be able to continue without dosage changes throughout the study. 
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. If the investigator or the sponsor determines 
that the patient is not in compliance with the study protocol, the investigator and the sponsor 
should determine whether the patient should be withdrawn. The IEC/IRB should be notified. 
5.5. 
Total Blood Volume 
The total blood volume to be collected for each patient in this study is approximately 164.5 mL 
(Table 3). 
Table 3: 
Blood Volumes 
Type of samples 
Volume per sample (mL) 
Total number of samples 
Total volume (mL) 
Clinical laboratory 
15.5 
5a 
77.5 
Biomarkers 
18 
4  
72 
ADA 
5 
3 
15 
Total 
38.5 
12a 
164.5 
a A single clinical laboratory sample will be collected from the healthy control subjects, at the screening visit. 
ADA=anti-drug antibody. 


 
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6. 
ASSESSMENT OF EFFICACY 
6.1. 
Primary Efficacy Measure and Justification 
The primary efficacy measure for this study is the change in GLG as assessed by PET/CT. Part 1 
of the study will validate this measure by comparing this assessment between HC subjects and 
patients with eosinophilia asthma. In Part 2, only patients with eosinophilic asthma will be 
assessed for GLG at 2, 4, and 6 weeks, after randomization to placebo or treatment with a single 
dose of reslizumab. 
6.1.1. 
Positron Emission Tomography/Computerized Tomography Scans 
Patients must fast for 8 hours prior to the scan. Blood glucose level will be measured before the 
administration of FDG. Blood glucose level should not exceed 150 mg/dL at the time of 
injection. Whole-body, head-to-toe PET/CT image acquisition will begin about 120 minutes after 
iv administration of 7 mCi of the radioisotope fluorine-18 (18F)-FDG. PET/CT image acquisition 
will take 30 to 40 minutes. In total, patients will spend about 3 hours in the PET center per each 
imaging visit. Patients will be asked to return in 2 days for a repeat FDG-PET/CT scan to be 
used as technical replicates in Part 1. Because 18F has a half-life of 109 minutes and is effectively 
fully decayed within a few hours of administration, FDG will be re-administered during the 
follow up visits and PET/CT imaging will be performed following the same protocol described 
above. 
Each FDG-PET/CT scan will deliver about 800 millirem (mrem) of radiation to the patient. 
Because patients will undergo 5 PET/CT scans, it is estimated that patients will receive a total 
radiation of 4000 mrem, which is within yearly limits set by the 
 
 
To minimize radiation-absorbed dose to the bladder, adequate hydration should be encouraged to 
permit frequent voiding during the first few hours after iv administration of FDG injection. This 
may be achieved by having patients drink at least an 8 oz glass of water prior to drug 
administration. To help protect themselves and others in their environment, patients should take 
the following precautions for 12 hours after injection: whenever possible, a toilet should be used 
and should be flushed several times after each use and hands should be washed thoroughly after 
each voiding or fecal elimination. If blood, urine or feces soil clothing, the clothing should be 
washed separately. 
6.1.2. 
Image Analysis 
Axial, sagittal, and coronal PET reconstructions will be interpreted, with and without attenuation 
correction, using non-contrast CT images for anatomical correlation. The investigators plan to 
measure global and regional inflammation within the lung, lymph nodes and bone marrow by 
utilizing quantitative parameters based on both volume and SUV. SUV is a well validated 
measure which normalizes FDG uptake by any particular object/tissue volume by the 
administered dose and either total body weight or total body surface area. Regions of interest 
(ROIs) will be drawn manually around the outer boundaries of the lung on every transverse slice 
passing through the lung on fused FDG PET/CT images from each subject. The trachea and main 


 
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stem bronchi will be excluded from the ROIs to capture only the inflammation in the lung 
parenchyma. Lung sectional mean standardized uptake value (sSUV mean) and the area of the 
lung ROI will be recorded from each slice. Subsequently, the sLV will be calculated from each 
slice by multiplying the lung ROI area (in centimeters squared) by 0.4 (slice thickness 4 mm). 
The sLG will be determined by multiplying sLV and lung sSUV mean from each slice. The LV 
will be calculated by adding all the sLV from slices passing through the lung, and the GLG will 
be determined by adding all the sLG from slices passing through the lung. Finally, the lung SUV 
mean will be calculated by dividing the GLG by the LV. Applying this methodology to different 
tissues or regions of the lungs will allow us to determine average and global SUV measures for 
the following tissues: whole lung parenchyma, right and left lung parenchyma, trachea, bronchi, 
and right and left bronchi. These regions will be delineated in the CT images by using the image 
segmentation techniques. These tissue volumes will be registered with the PET images as 
outlined below for the estimation of SUVs within these regions. Similar methodology will be 
applied to the lymph nodes and bone marrow. 
6.1.3. 
Calculations 
The radiology center will determine the following: 
GLG is the total FDG uptake in the whole lung. 
An ROI is drawn around lung boundary in each axial slice. SUVmean and area of each ROI is 
recorded. Using the formula: area*slice thickness the volume of each slice is calculated. Then 
SUVmean of each slice is multiplied by the volume of the corresponding slice, which will 
represent the total FDG uptake in one slice. This number for each slice is summed together to 
provide GLG of that lung. 
GLG=
 
n=number of slices 
Intra-patient variability (reproducibility measure): 
Below is the calculation to determine the intra-patient variability between PET/CT scans as 
measured by GLG for HCs and patients with eosinophilic asthma. The accepted variability 
within each group is ≤10% and will be as follows: 
Relative difference of GLG=(GLG2-GLG1)/GLG1 
Relative difference of GLG=(GLG4-GLG3)/GLG3 
1= First time point (HCs) 
2= Second time point (HCs) 
3= First time point (patients with eosinophilic asthma) 
4= Second time point (patients with eosinophilic asthma) 


 
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Variability between HC group and individual patients with eosinophilic asthma: 
The planned method to assess whether the difference in GLG (ΔGLG) between HC subjects, as a 
group, and individual patients with eosinophilic asthma is ≥5% and will be as follows: 
For Females: 
Relative difference of GLG=(GLG6i-GLG5f)/GLG5f 
For Males: 
Relative difference of GLG=(GLG6i-GLG5m)/GLG5m 
5=average of 1 and 2 
6=average of 3 and 4 
GLG6i will be calculated for each individual patient using his/her two measurements, and if that 
amount is ≥5%, than the patient will be randomized. 
6.2. 
Spirometry 
Pre-bronchodilator FEV1, FVC, and FEF25%-75% and post-bronchodilator FEV1 will be measured 
using spirometry. The FEV1 is the volume of air which can be forcibly exhaled from the lungs in 
the first second, measured in liters. The FVC is the volume of air that can be forcibly blown out 
after full inspiration, measured in liters. The FEF25%-75% is the forced expiratory flow at 25% to 
75% forced vital capacity. For post-bronchodilatory spirometry, SABAs, such as salbutamol or 
albuterol, administered via a metered dose inhaler should be used. Four separate doses 
(eg, albuterol 360 μg or salbutamol 100 μg ex-valve) should be given by metered dose inhaler, as 
tolerated. Post-bronchodilator spirometry should be completed a minimum of 15 minutes after 
dosing of SABA. Spirometry will be done according to American Thoracic Society/European 
Respiratory Society 2005 procedural guidelines. The National Health and Nutrition Survey III 
reference equations will be used. 
6.3. 
Asthma Control Questionnaire 
The ACQ-6 is a validated asthma assessment tool that has been widely used (Juniper et al 1999). 
Six questions are self-assessments (completed by the patient). Each item on the ACQ-6 has a 
possible score ranging from 0 to 6, and the total score is the mean of all responses (Appendix A). 
6.4. 
Asthma Quality of Life Questionnaire for Patients 12 years and 
Older 
The AQLQ+12 is a modified version of the standardized AQLQ, which was developed to 
measure functional impairments experienced by adults ≥17 years of age. The AQLQ+12 is valid 
for patients aged 12 to 70 years and includes 32 questions in 4 domains (symptoms, activity 
limitation, emotional function, and environmental stimuli) (Juniper et al 1992, Wyrwich et al 
2011). Patients are asked to recall their experiences during the previous 2 weeks and score each 
of the questions on a 7-point scale where 7 = no impairment and 1 = severe impairment 
(Appendix B). 


 
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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, hematology, and urinalysis) 
throughout the study 
• Vital signs (pulse, respiratory rate, body temperature, blood pressure, and SpO2) 
throughout the study 
• Physical examination findings 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 informed 
consent form should be recorded and reported as an adverse event. 
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to the study drug. 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 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 


 
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the screening visit that preclude a patient from entering the study or receiving study 
treatment are not considered adverse events.) 
Worsening of the disease under study (ie, asthma) including asthma exacerbations requiring 
additional controller medication, will be collected as an efficacy assessment in this study. The 
aforementioned worsening of asthma should be recorded as an adverse event only if the 
presentation or outcome is more severe than would typically be expected from the normal course 
of the disease in a particular patient. 
7.1.2. 
Recording and Reporting of Adverse Events 
For adverse event recording, the study period is defined for each patient as that time period from 
signature of the Informed Consent Form through the end of the follow up period. For this study, 
the follow up period is defined as 1 week after visit 6 (week 6), approximately 7 weeks after the 
single dose of reslizumab. 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 to 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 be completed and the serious adverse event must be reported immediately (see 
Section 7.1.5.3.1). The investigator does not need to actively monitor patients for adverse events 
once the study has ended. Serious adverse events occurring in 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 7.1.5.3.1. 
At each contact with the patient, the investigator or designee must question the patient about 
adverse events by asking an open-ended question such as “Have you had any unusual symptoms 
or medical problems since the last visit? If yes, please describe”. 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, on the 
Serious Adverse Event Form. 
The clinical course of each adverse event will be monitored at suitable intervals until resolved, 
stabilized, or returned to baseline; or until the patient is referred for continued care to a 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 to the CRF. The approximate time of 
onset for each adverse event that starts within 24 hours of study drug administration will be also 
recorded. 
The relationship of each adverse event to study drug and study procedures, and the severity and 
seriousness of each adverse event, as judged by the investigator, must be recorded as described 
below. 


 
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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 that, after careful 
consideration, are clearly due to 
extraneous causes (disease, 
environment, etc) or to adverse 
events that, after careful medical 
consideration at the time they are 
evaluated, are judged to be unrelated 
to the study drug. 
The relationship of an adverse event may be considered 
“no reasonable possibility” if it is clearly due to 
extraneous causes or if at least 2 of the following apply: 
• 
It does not follow a reasonable temporal sequence 
from the administration of the study drug. 
• 
It could readily have been produced by the patient’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the patient. 
• 
It does not follow a known pattern of response to the 
study drug. 
• 
It does not reappear or worsen when the study drug is 
re-administered. 
Reasonable 
possibility 
(related) 
This category applies to adverse 
events for which, after careful 
medical consideration at the time 
they are evaluated, a connection with 
the study drug administration cannot 
be ruled out with certainty. 
The relationship of an adverse event may be considered 
“reasonable possibility” if at least 2 of the following 
apply: 
• 
It follows a reasonable temporal sequence from 
administration of the study drug. 
• 
It cannot be reasonably explained by the known 
characteristics of the patient’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the patient. 
• 
It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of the study drug, yet a drug 
relationship clearly exists. 
• 
It follows a known pattern of response to the study 
drug. 
7.1.5. 
Serious Adverse Events 
7.1.5.1. 
Definition of a Serious Adverse Event 
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions: 
• results in death 


 
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• is life-threatening adverse event (ie, the patient was at risk of death at the time of the 
event); it does not refer to an event which hypothetically might have caused death if it 
were more severe 
• requires inpatient hospitalization or prolongation of existing hospitalization, which 
means that hospital inpatient admission 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 the patient signed the informed consent form will 
not be considered serious adverse events, unless there was worsening of the 
preexisting condition during the patient’s participation in this study. 
• results in persistent or significant disability/incapacity (refers to a substantial 
disruption of one’s ability to conduct normal life functions) 
• is a congenital anomaly/birth defect 
• an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the patient and may require medical intervention 
to prevent one of the outcomes listed in this definition 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or the 
development of drug dependency or drug abuse. Note: Any suspected transmission of an 
infectious agent via a medicinal product is considered an important medical event. 
An adverse event that does not meet any of the criteria for seriousness listed above will be 
regarded as a nonserious adverse event. 
7.1.5.2. 
Expectedness 
A serious adverse event that is not included in the Adverse Reaction section of the relevant 
reference safety information (RSI) by its specificity, severity, outcome, or frequency is 
considered an unexpected adverse event. The RSI for this study is the US prescribing 
information for reslizumab and for FDG. 
7.1.5.3. 
Reporting a Serious Adverse Event 
7.1.5.3.1. Investigator Responsibility 
To satisfy regulatory requirements, all serious adverse events (as described in Section 7.1.5.1) 
that occur during the study period (including the protocol-defined follow-up period, described in 
Section 7.1.2), regardless of judged relationship to treatment with the study drug, must be 
reported to the sponsor by the investigator. The event must be reported within 24 hours of when 
the investigator learns about it. Completing the serious adverse event form and reporting the 
event must not be delayed, even if not all the information is available. The investigator does not 
need to actively monitor patients for adverse events once this study has ended. 
Serious adverse events occurring to a patient after the treatment of that patient has ended should 
be reported to the sponsor if the investigator becomes aware of them. 


 
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The serious adverse event form should be sent to the local safety officer (LSO) or (contact 
information is in the Clinical Study Personnel Contact Information section); the LSO will 
forward the report to the sponsor’s Global Patient Safety and Pharmacovigilance. 
The following information should be provided to record the event accurately and completely: 
• study number 
• investigator and investigational center identification 
• patient number 
• onset date and detailed description of adverse event 
• investigator’s assessment of the relationship of the adverse event to the study drug 
(no reasonable possibility, reasonable possibility) 
Additional information may include the following: 
• age and sex of patient 
• date of first dose of study drug 
• date and amount of last administered dose of study drug 
• action taken 
• outcome, if known 
• severity 
• explanation of assessment of relatedness 
• concomitant medication (including doses, routes of administration, 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) 
− autopsy findings (if available) 
The investigator must ensure that the IEC/IRB is also informed of the event, in accordance with 
national and local regulations. 
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. 
Additional information (follow-up) about any serious adverse event unavailable at the initial 
reporting should be forwarded by the investigator within 24 hours of when it becomes known to 
the same address as the initial report. 


 
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For all countries, the sponsor’s Global Patient Safety and Pharmacovigilance will distribute the 
Council for International Organizations of Medical Sciences form/Extensible Markup Language 
file to the LSO for submission to the competent authorities, IEC/IRBs, and investigators, 
according to regulations. The investigator is responsible for ensuring that the IEC/IRB is also 
informed of the event, in accordance with national and local regulations. 
Blinding will be maintained for all clinical study personnel. Therefore, in case of a SUSAR, only 
the LSO will receive 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). 
7.1.5.3.2. Sponsor Responsibility 
If a serious unexpected adverse event is believed to be related to the study drug or study 
procedures, the sponsor will take appropriate steps to notify the appropriate competent 
authorities (and IEC/IRB, as appropriate). 
In addition to notifying the investigators and competent authorities (and IEC/IRB, as 
appropriate), other measures may be required, including: 
• 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 all study participants of new findings 
• modifying listings of expected toxicities to include adverse events newly identified as 
related to reslizumab. 
7.1.6. 
Protocol-Defined Adverse Events for Expedited Reporting to Teva 
For the purposes of this protocol, the following are considered protocol-defined adverse events 
for expedited reporting to Teva: anaphylaxis, newly-diagnosed malignancy, and parasitic 
helminth and opportunistic infections. Protocol-defined adverse events for expedited reporting 
can be either serious or nonserious according to the criteria outlined in Section 7.1.5.1. The 
process for reporting a protocol-defined adverse event for expedited reporting is the same as that 
for reporting a serious adverse event (see Section 7.1.5.3). 
7.1.7. 
Specific Adverse Event Case Report Form Capturing 
7.1.7.1. 
Anaphylaxis/Hypersensitivity Reactions Case Report Form 
Information about all suspected anaphylaxis events will be recorded on the Suspected 
Anaphylaxis/Hypersensitivity Reactions CRF, which is based on the 2006 Joint NIAID/FAAN 
Second Symposium on Anaphylaxis (Sampson et al 2006, Appendix C). 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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Blood samples for ADA testing should be taken in any case where hypersensitivity is suspected 
to be related to study drug/placebo administration. 
7.1.7.2. 
Creatine Phosphokinase/Muscular Adverse Events Case Report Form 
Potentially clinically significant 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× ULN (Grade 3 based on the FDA “Guidance for Industry 
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventative 
Vaccine Clinical Trials”). 
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 Sponsor’s Authorized Representative as soon as possible of each 
patient who is being considered for withdrawal due to adverse events. Additional reports must be 
provided when requested. 
If a patient is withdrawn from study 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 that 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. 
7.1.9. 
Overdose of Study Drug 
Any dose of study drug (whether the investigational product, reference treatment, or 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 3.8. 
Any administration of medication that is not in accordance with the study protocol should be 
reported on the CRF, either as a violation or as a deviation, in the patient’s source documents, 
regardless of whether an adverse event occurs as a result. See Section 7.3 for additional 
information. 
7.1.10. 
Protocol Deviations Because of an Adverse Event 
If a patient experiences an adverse event or medical emergency, deviations from the protocol 
may be allowed on a case-by-case basis. To ensure patient safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 


 
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contact the physician identified in the Clinical Study Personnel Contact Information section of 
this protocol 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 
Any female patient becoming pregnant during the study will discontinue study medication. 
All pregnancies of women participating in the study that occur during the study, or within 
5 months after study medication infusion, are to be reported immediately to the individual 
identified in the Clinical Study Personnel Contact Information section of this protocol, and the 
investigator must provide the sponsor (LSO) with the completed pregnancy form. The process 
for reporting a pregnancy is the same as that for reporting a serious adverse event but using the 
pregnancy form (Section 7.1.5.3). 
All female patients who become pregnant will be monitored for the outcome of the pregnancy 
(including spontaneous, elective, or voluntary abortion). If the pregnancy continues to term, the 
outcome (health of the infant up to 8 weeks of age), including 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 withdrawal from the 
study will be reported as an adverse event or serious adverse event, as appropriate. 
If the pregnancy in the woman participating in the study does not continue to term, 1 of the 
following actions will be taken: 
• For a spontaneous abortion, report as a serious adverse event. 
• For an elective abortion due to developmental anomalies, report as a serious adverse 
event. 
• For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an adverse event. 
7.3. 
Medication Error and Special Situations 
Any administration of study medication that is not in accordance with the study protocol should 
be reported on the CRF either as a violation, if it meets the violation criteria specified in the 
protocol (Section 11.1.2), or as a deviation, in the patients source documents, regardless of 
whether an adverse event occurs as a result. All instances of incorrect medication administration 
should be categorized on the CRF as “Non-Compliance to investigational medicinal product 
(IMP)”. 
Types of medication errors and special situations: 
1. Medication error: Any unintentional error in the prescribing, dispensing, or 
administration of a medicinal product while in the control of the healthcare professional, 
patient, or consumer. 
2. Overdose: Administration of a quantity of a medicinal product given per administration 
or cumulatively which is above the maximum recommended dose according to the 
authorized product information. Clinical judgment should always be applied. 


 
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3. Misuse: Situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the authorized product information. 
4. Abuse: Persistent or sporadic, intentional excessive use of medicinal products which is 
accompanied by harmful physical or psychological effects. 
5. Off-label use: Situations where a medicinal product is intentionally used for a medical 
purpose not in accordance with the authorized product information. 
6. Occupational exposure: Exposure to a medicinal product, as a result of one’s professional 
or non-professional occupation. 
7.4. 
Clinical Laboratory Tests 
All clinical laboratory test results outside of the reference range will be judged by the 
investigator as belonging to one of the following categories: 
• abnormal and not clinically significant 
• abnormal and clinically significant 
A laboratory test result that has significantly worsened (according to investigator's medical 
judgment) from the baseline result will be recorded on the source documentation and should be 
repeated. An adverse investigational event includes a laboratory or diagnostic test abnormality 
(once confirmed by repeat testing) that results in the withdrawal of the patient from the study, the 
temporary or permanent cessation of treatment with study drug, or medical treatment or further 
diagnostic work-up. Any adverse clinical laboratory result should be monitored as described in 
Section 7.1.2. See Section 7.1.1 for a description of laboratory results that will be reported as 
adverse events. 
7.4.1. 
Serum Chemistry, Hematology, and Urinalysis 
Clinical laboratory tests (serum chemistry, hematology, and urinalysis) will be performed at the 
time points detailed in Table 2. Clinical laboratory tests will be performed using the local 
laboratory. Specific laboratory tests to be performed are provided in Table 4. 


 
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Table 4: 
Clinical Laboratory Tests 
Serum Chemistry 
Hematology 
Urinalysis 
calcium 
phosphate 
sodium 
potassium 
chloride 
creatinine 
glucose 
blood urea nitrogen (BUN) 
cholesterol (low density lipoprotein 
[LDL]/high density lipoprotein 
[HDL]/total)a 
triglyceridesa 
uric acid 
alanine aminotransferase (ALT) 
aspartate aminotransferase (AST) 
lactate dehydrogenase (LDH) 
gamma-glutamyl transpeptidase (GGT) 
alkaline phosphatase 
bicarbonate or carbon dioxide 
creatinine phosphokinase 
total protein 
albumin 
total bilirubin 
direct bilirubin 
indirect bilirubin 
hemoglobin 
hematocrit 
red blood cell (RBC) count 
RBC indices 
platelet count 
white blood cell (WBC) count, and 
differential count and percentage 
− absolute neutrophil count (ANC) 
− polymorphonuclear leukocytes 
(neutrophils) 
− lymphocytes 
− eosinophils 
− monocytes 
− basophils 
− atypical lymphocytes 
− other (to include band granulocytes) 
international normalized ratio (INR) 
protein 
glucose 
ketones 
blood (hemoglobin) 
pH 
specific gravity 
microscopic 
− bacteria 
− red blood cells (RBCs) 
− white blood cells (WBCs) 
 
a Assessed at the screening visit only 
7.4.2. 
Other Clinical Laboratory Tests 
At screening, patients will be tested for hepatitis B surface antigen, hepatitis C antibody, and 
human immunodeficiency virus. 
7.4.2.1. 
Human Chorionic Gonadotropin Tests 
Human chorionic gonadotropin tests in serum will be performed for all women at screening 
(visit 1) and, in urine, before study drug administration and before each PET/CT scan as 
specified in Table 2. Any female patient who becomes pregnant during the study will be 
withdrawn. Procedures for reporting the pregnancy are provided in Section 7.2. 
7.5. 
Vital Signs 
Vital signs (blood pressure, respiratory rate, body temperature, pulse, and SpO2) will be 
measured at the time points detailed in Table 2. All vital signs results outside of the reference 
ranges will be judged by the investigator as belonging to one of the following categories: 


 
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• abnormal and not clinically significant  
• abnormal and clinically significant 
Before blood pressure and pulse 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 clinically significant will be recorded on the source documentation, 
transcribed to the CRF as an adverse event, and monitored as described in Section 7.1.2. 
7.6. 
Electrocardiography 
A 12-lead ECG will be conducted at screening (visit 1). ECGs should be obtained before other 
assessments (eg, blood draw and pulmonary function testing). The ECG will be interpreted by 
the investigator (or qualified physician) as normal or abnormal. If the ECG is read as abnormal 
the investigator will specify the abnormality and indicate whether or not the abnormality is 
clinically significant (yes or no). Clinically significant abnormal ECG findings at screening 
should be recorded as part of the medical history. 
7.7. 
Physical Examinations 
Physical examinations, including height (to be obtained at the screening visit only) and weight, 
will be performed at the time points detailed in Table 2. The “full” physical examination should 
include the following organ systems: General appearance; Head, Eyes, Ears, Nose, and Throat; 
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; Head, Eyes, Ears, Nose, and Throat; Chest and Lung; and Heart. Any physical 
examination finding that is judged by the investigator as clinically significant will be considered 
an adverse event, recorded on the CRF, and monitored as described in Section 7.1.2. 
7.8. 
Concomitant Medication or Treatment 
Use of concomitant medication or treatment will be monitored throughout the study. Details of 
prohibited medications are found in Section 5.3. 
7.9. 
Methods and Time Points of Assessing, Recording, and Analyzing 
Safety Data 
All adverse events will be reviewed on a periodic basis by the medical monitor according to the 
safety monitoring plan (eg, scheduled safety reviews for reslizumab) as interim/preliminary 
safety databases become available. In addition, safety data will be evaluated periodically and ad 
hoc (if necessary) by the Teva Product Safety Group. 
Procedures for recording safety data are discussed in Section 13.1 and methods of analyses are 
discussed in Section 9.7.2. 


 
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8. 
ASSESSMENT OF BIOMARKERS AND IMMUNOGENICITY 
8.1. 
Assessment of Exploratory Biomarkers 
8.1.1. 
Immunoglobulin E 
8.1.1.1. 
Background 
Immunoglobulin (IgE) is synthesized by plasma cells as an immune reaction to parasites such as 
helminths (Erb 2007). IgE also has an essential role in type I hypersensitivity, which manifests 
various allergic diseases, such as allergic asthma, most types of sinusitis, allergic rhinitis, food 
allergies, and specific types of chronic urticaria and atopic dermatitis (Gould et al 2003). 
Immunoglobulin E also plays a pivotal role in responses to allergens, such as anaphylatic drugs, 
bee stings, and antigen preparations used in desensitization immunotherapy. 
It is well known that IgE, T-helper cell subset 2 (Th2)-derived cytokines, and eosinophils play a 
major role in the development of chronic airway inflammation, which is observed even in 
subjects with mild disease (Busse 2000, Holloway et al 2001, Novak and Bieber 2003, Pelaia et 
al 2012). Airway inflammation plays a central role in the pathogenesis of bronchial asthma and is 
associated with an increase in airway responsiveness to several trigger factors such as 
aeroallergens which induce bronchoconstriction in atopic asthma patients, acting sometimes in 
cooperation with other trigger factors such as viruses and air pollution (Martinez and 
Vercelli 2013). 
It is estimated that more than 50% of asthma has an allergic background and about 50% of 
patients with severe asthma have allergic-atopic asthma (Masoli et al 2004, Wenzel 2006), 
although many previously published data demonstrated that the severe phenotype is less frequent 
in atopic adult-onset asthma (Wenzel 2006, ENFUMOSA 2003, Moore et al 2007). 
The development of the first anti-IgE antibody has been a significant advance in the treatment of 
allergic asthma. In 2005, Humbert and colleagues examined the benefits of omalizumab 
(anti-IgE, Xolair®) as add-on therapy in patients with severe persistent asthma who are 
inadequately controlled despite best available therapy (Humbert et al 2005). The INNOVATE 
trial reported that the rate of clinically significant asthma exacerbations, after adjusting for an 
observed imbalance in asthma exacerbation history prior to randomization, was significantly 
reduced by 26.2% with omalizumab versus placebo. 
Overall, there are many therapeutic benefits of anti-IgE antibodies. These include serum IgE 
levels diminishing by greater than 95% compared to before treatment and consequently 
weakening early and late phase reactions (Fahy et al 1997, Milgrom et al 1999). The 2014 
Cochrane review (Normansell et al 2014) and other systematic reviews identify that omalizumab 
significantly reduces asthma exacerbations, and specifically that there was a reduction in the rate 
of exacerbations from 26% to 16% when comparing patients given a placebo to patients 
receiving omalizumab (Norman et al 2013, O’Byrne 2013).  
Despite all these advances, the effect of anti-IL5 therapy on the levels of IgE has never been 
studied. In this protocol, we wish to evaluate the quantity of IgE in peripheral blood and sputum 
and determine whether any changes occur following the administration of reslizumab. 


 
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8.1.1.2. 
Specimen Sampling and Handling 
Blood samples for assessment of IgE will be collected and processed using the procedures in 
place at the investigational center 
 
8.1.2. 
Dipeptidyl Peptidase-4 
8.1.2.1. 
Background 
The protein encoded by the dipeptidyl peptidase-4 (DPP4) gene is an antigenic enzyme 
expressed on the surface of most cell types and is associated with immune regulation, signal 
transduction and apoptosis (Chen 2006).  
The best known immunostimulatory activity of DPP4 is its contribution to T lymphocyte 
activation (Zhong et al 2013). Recently, it was reported that DPP4 has a proliferative effect on 
vascular smooth muscle cells (Ervinna et al 2013) and could be involved in airway remodeling 
by inducing the production of extracellular matrix proteins such as fibronectin (Shiobara et al 
2016).  
Although DPP4 has recently been demonstrated to be induced by IL-13 in normal human 
bronchial epithelial cells (Zhen et al 2007), the contribution of IL-5 is currently unknown and the 
effect of anti-IL-5 therapy on the expression of DPP4 has never been studied. In this protocol, we 
wish to evaluate levels of DPP4 in peripheral blood and sputum and determine whether any 
changes occur following the administration of reslizumab. 
8.1.2.2. 
Specimen Sampling and Handling 
Blood samples for assessment of DPP4 will be collected and processed using the procedures in 
place at the investigational center 
 
8.1.3. 
25-Hydroxy Vitamin D 
8.1.3.1. 
Background 
The relationship between low levels of vitamin D and declining lung function has been 
demonstrated in a number of clinical trials, observational studies and real-world evidence data 
(Poon et al 2013, Brumpton et al 2016).  
Black and Scragg evaluated data from the Third National Health and Nutrition Examinations 
Survey, which conducted a cross-sectional 6-year study on 14,091 participants. Eligible subjects 
had undergone spirometry and a measurement of serum 25-hydroxy vitamin D level. After 
adjustment for age, gender, height, body mass index, ethnicity, and smoking history, they 
observed a significant difference in mean FEV1 and mean FVC among participants with the 
highest quintile of serum 25-hydroxy vitamin D level (≥85.7 nmol/L) compared with the lowest 
quintile (≤40.4 nmol/L; p < 0.0001) (Black and Scragg 2005). 
The HUNT study reported on the association between low 25-hydroxyvitamin D levels and lung 
function decline in adults with asthma and whether this association was modified by smoking 
status or ICS use in a period spanning 11 years. Participants with low 25-hydroxyvitamin D (<50 
nmol/L) had more decline in the lung function measurements of FEV1 and FVC when compared 


 
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with those with high 25-hydroxyvitamin D (≥50 nmol/L). The associations were stronger in 
never smokers and non-ICS users (Brumpton et al 2016).  
Mechanistically, the beneficial effects of vitamin D on asthma can be proposed through several 
pathways. T-helper type 9 lymphocytes play an important role in the pathogenesis of asthma. 
Vitamin D can decrease inflammatory cytokines such as interleukin (IL)-9, IL-5, and IL-13 in 
these cells (Keating et al 2014). Steroid resistance is a major challenge in the treatment of asthma 
and vitamin D can overcome this resistance by generating IL-10-secreting regulatory T cells 
(Xystrakis et al 2006) and down-regulating the expression of fractalkine, a gene causing steroid 
resistance (Banerjee et al 2008). Even a combination of vitamin D and dexamethasone were 
more effective in decreasing the inflammatory cytokines than dexamethasone alone (Keating et 
al 2014, Chambers et al 2015). Interestingly, patients with glucocorticoid-resistant asthma were 
should to have significantly reduced levels of 25-hydroxyvitamin D and elevated levels of 
vitamin D-binding protein (VDBP) raising the possibility that serum VDBP may be a useful 
noninvasive biomarker to predict steroid resistance in asthma patients (Jiang et al 2016). 
As more evidence accumulates linking 25-hydroxyvitamin D to glucocorticoid resistance in 
asthma, little is known of the effects of an anti-IL5 therapy on the levels of 25-
hydroxyvitamin D. In this protocol, we wish to evaluate levels of vitamin D in peripheral blood 
and sputum and determine whether any changes occur following the administration of 
reslizumab. 
8.1.3.2. 
Specimen Sampling and Handling 
Blood samples for assessment of 25-hydroxy vitamin D will be collected and processed using the 
procedures in place at the investigational center 
 
8.1.4. 
Eotaxin-1, -2, and -3 
8.1.4.1. 
Background 
Eotaxin-1 (also known as CCL11) is a small cytokine belonging to the CC chemokine family. 
Eotaxin-1 selectively recruits eosinophils by inducing their chemotaxis, and, therefore, is 
implicated in allergic responses (Jose et al 1994; Ponath et al 1996; Garcia-Zepeda et al 1996a). 
Increased expression of eotaxin in bronchoalveolar lavage and airways of asthmatics contributes 
to the chemotaxis of eosinophils to the site of inflammation (Lamkhioued et al 1997). Eotaxin-2 
(CCL24) also belongs to the CC chemokine family and elevated levels of eotaxin-2 have been 
seen in patients with aspirin-exacerbated respiratory disease, such as asthma (Palikhe et al 2010). 
Lastly, eotaxin-3 (CCL26) is chemotactic for eosinophils and basophils and is expressed by 
several tissues including heart, lung and ovary, and in endothelial cells that have been stimulated 
with the cytokine IL-4 (Shinkai et al 1999; Guo et al 1999).  
Eosinophilia in lung tissue is driven by IL-5, which supports the development of eosinophils in 
the bone marrow, and by the recruitment of eosinophils to the lung mucosa and interstitium via 
production of eotactic chemokines such as eotaxins 1, 2 and 3 (CCL11, CCL24 and CCL26, 
respectively) (Lambrecht and Hamad 2015). In animal models, an iv injection of IL-5 in guinea 
pigs induces an acute increase in circulating eosinophils, and this amplifies tissue recruitment 
induced by locally administered eotaxin (Conroy and Williams 2001). 


 
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Although the role of the eotaxin family has been demonstrated as a chemotactic agent for 
eosinophils, the effect of anti-IL5 therapy on the expression of these eotaxins has never been 
studied. In this protocol, we wish to evaluate levels of eotaxins-1, -2, and -3 in peripheral blood 
and sputum and determine whether any changes occur following the administration of 
reslizumab. 
8.1.4.2. 
Specimen Sampling and Handling 
Blood samples for assessment of eotaxin-1, -2, and -3 will be collected and processed using the 
procedures in place at the investigational center 
 
8.1.5. 
Thymus and Activation Regulated Chemokine 
8.1.5.1. 
Background 
Thymus and activation regulated chemokine (TARC), also known as CCL17, is a small cytokine 
belonging to the CC chemokine family. TARC specifically binds and induces chemotaxis in 
T-cells, specifically Th2-type, and elicits its effects by interacting with the chemokine receptor 
CCR4 (Imai et al 1996, Imai et al 1997). It is expressed in dendritic cells and possibly in 
macrophages. 
In 2001, Kawasaki and colleagues demonstrated that TARC was constitutively expressed in the 
lung and was up-regulated in allergic inflammation. A specific antibody against TARC 
attenuated ovalbumin-induced airway eosinophilia and diminished the degree of airway 
hyperresponsiveness with a concomitant decrease in Th2 cytokine levels and eosinophil-
chemotactic chemokine expression in the lung (Kawasaki et al 2001).  
Despite these advances, the in vivo pathophysiological roles of TARC remain largely unknown 
and the effect of anti-IL-5 therapy on the expression of TARC has never been studied. In this 
protocol, we wish to evaluate levels of TARC in peripheral blood and sputum and determine 
whether any changes occur following the administration of reslizumab. 
8.1.5.2. 
Specimen Sampling and Handling 
Blood samples for assessment of TARC will be collected and processed using the procedures in 
place at the investigational center 
 
8.1.6. 
Monocyte Chemoattractant Protein-1 and -4 
8.1.6.1. 
Background 
Monocyte chemoattractant protein 1 (MCP-1) and 4 (MCP-4) are also known as CCL2 and 
CCL13, respectively, and belong to the CC chemokine family. Monocyte chemoattractant 
protein-1, RANTES, MCP-3, and eotaxin have been shown to be increased in the epithelium and 
bronchial mucosa in patients with asthma compared with normal control subjects (Sousa et al 
1994, Humbert et al 1997). Monocyte chemoattractant protein-1 is also increased in 
bronchoalveolar lavage (BAL) fluids from patients with asthma (Lamkhioued et al 1997, Rozyk 
et al 1997) and is released into the BAL fluid following endobronchial antigen challenge of 
patients with allergic asthma (Holgate et al 1997). 


 
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MCP-4 has been shown to be expressed in a limited number of human disease tissue. We have 
found that MCP-4 mRNA is expressed in the epithelium and submucosa of nasal biopsies 
obtained from patients with both allergic and nonallergic sinusitis and allergic rhinitis 
(Garcia-Zepeda et al 1996b, Mendez-Enriquez and Garcia-Zepada 2013, Kalayci et al 2004). 
MCP-4 is broadly active on immune cells implicated in the pathogenesis of asthma. The levels of 
MCP-4 protein in the BAL correlate with eosinophil influx. MCP-4 plays a role in the 
recruitment and activation of eosinophils in the airway of patients with asthma and thus the 
pathogenesis of this disease. 
Monocyte chemoattractant protein-1 and MCP-4 have demonstrated as a chemotactic agent for 
eosinophils, however the effect of anti-IL-5 therapy on the expression of these chemokines has 
never been studied. In this protocol, we wish to evaluate levels of MCP-1 and MCP-4 in 
peripheral blood and sputum and determine whether any changes occur following the 
administration of reslizumab. 
8.1.6.2. 
Specimen Sampling and Handling 
Blood samples for assessment of MCP-1 and MCP-4 will be collected and processed using the 
procedures in place at the investigational center 
 
8.1.7. 
Type 2 Innate Lymphoid Cells 
8.1.7.1. 
Background 
Type 2 innate lymphoid cells (ILC2s) are a relatively novel family of haematopoietic effector 
cells which, like traditional Th2 cells, produce Th2-associated cytokines, including high amounts 
of IL-5 and IL-13 and, to a lesser extent, IL-4 (Walker et al 2013, Spits et al 2013). Recent 
studies have demonstrated the presence of ILC2s in nasal polyps of chronic rhinosinusitis, which 
are characterized by large numbers of eosinophils (Mjösberg et al 2011) as well as in lung and 
peripheral blood of patients with asthma (Begin and Nadeau 2014).  
In a subset of patients with severe asthma, increased expression of epithelial-derived IL25, IL33 
and thymic stromal lymphopoietin drives activation of ILC2s which, in turn, contributes to 
refractory eosinophilia (Licona-Limon et al 2013, Halim et al 2012). In addition, ILC2s may 
influence the polarization and activation of Th2 cells by their ability absorb and display antigens 
via MHC II presentation (Scanlon and McKenzie 2015).  
The effect of anti-IL-5 therapy on the presence, distribution and/or activation of ILC2s in 
patients with eosinophilic asthma has never been studied. In this protocol, we wish to evaluate 
the number of ILC2 cells in peripheral blood and sputum by flow cytometry and determine 
whether any changes occur following the administration of reslizumab. 
8.1.7.2. 
Specimen Sampling and Handling 
Blood samples for assessment of ILC2s will be collected and processed using the procedures in 
place at the investigational center 
 
8.1.8. 
Shipment and Analysis of Samples 
Biomarker samples will be stored, shipped, and processed using the procedures in place at the 
investigational center 
 


 
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8.2. 
Immunogenicity Testing 
8.2.1. 
Blood Sampling and Handling 
Blood samples (5 mL) for assessment of ADA response will be taken before and after dosing at 
the time points indicated in Table 2. Unscheduled blood samples for anti-reslizumab antibody 
assessment will also be obtained from all patients experiencing a severe hypersensitivity reaction 
(eg, anaphylaxis). 
Samples will be collected into labeled serum separator tubes and inverted slowly at least 5 times 
to thoroughly mix the blood with the clotting activation agent. Labels for samples should include 
study number, patient number, period, and nominal collection time. Blood samples will be left 
standing upright at room temperature (20°C to 25°C) to clot for approximately 30-60 minutes. 
Samples should then be centrifuged at a minimum of 1500 g for approximately 10 minutes at 
4°C until clot and serum are well separated. Samples may be centrifuged at ambient temperature 
at 1500 g for 10 minutes as long as measures are taken as appropriate to prevent samples from 
heating significantly during centrifugation. 
Separated serum will be transferred, in approximately equal portions, into 2 labeled cryovial 
tubes (primary aliquot A and back-up aliquot B) and stored in an ultralow freezer at ≤-65°C until 
shipped to a central or bioanalytical laboratory with temperature monitoring. Sample labels 
should include patient number, study number, collection date, and indication that it is an ADA 
sample aliquot (A or B). Storage at -15 to -20°C is acceptable for a period of up to 1 month if a 
≤-65°C freezer is not available. The listed temperatures must be maintained. The actual times 
and dates of sampling will be recorded on the CRF. 
8.2.2. 
Shipment and Analysis of Samples 
Serum samples for immunogenicity assessment for all patients will be stored until shipped to the 
sponsor or its designee for analysis. Samples will be stored in an upright position at ≤–65ºC until 
assayed. The central laboratory will be notified before the shipment of the samples and will be 
sent the shipping information when the samples are shipped. Set A samples will be transported 
with a temperature data logger and frozen with sufficient dry ice by next-day courier to the 
central laboratory. 
Set B samples will either be sent to the same laboratory as that for set A on a later day by next-
day courier, or be retained at the investigational center until the study is completed (unless 
shipment to another facility is requested by the sponsor). 
Samples from reslizumab-treated patients will be analyzed using appropriate validated methods. 
Timing of the initiation of sample analysis will be determined by the Teva Pharmaceuticals 
bioanalytical department representative responsible for the bioanalysis. The bioanalytical team 
will not be blinded for this analysis. 
Additional details regarding the collection, handling, and shipment of samples for measurement 
of anti-drug antibodies are provided in the investigator laboratory manual and its associated 
specimen collection summary. 


 
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9. 
STATISTICS 
This section describes the statistical analysis as foreseen at the time of planning the study. 
Changes, additions, and further details about the analyses will be described in the statistical 
analysis plan. After finalization of the statistical analysis plan, any additional analyses or 
changes to analyses that may be required will be fully disclosed in the clinical study report 
(CSR). 
9.1. 
Sample Size and Power Considerations 
This study is exploratory in nature; therefore, no formal hypothesis testing is planned. Based on 
clinical and practical considerations, 5 healthy subjects and 10 eosinophilic asthma patients 
(5 patients treated with reslizumab, 5 patients treated with placebo) is considered adequate for: 
1. a validation of the ability of PET/CT to differentiate patients with eosinophilic asthma 
from HCs 
2. an evaluation of the effect of reslizumab versus placebo on inflammation of the lungs. 
9.2. 
Analysis Sets 
9.2.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all randomized patients. In this analysis set, 
treatment will be assigned according to the treatment to which patients were randomized, 
regardless of which treatment they actually received. 
9.2.2. 
Safety Analysis Set 
The safety analysis set will include all patients who receive at least 1 dose of study drug/placebo. 
In this analysis set, treatment will be assigned based on the treatment patients actually received, 
regardless of the treatment to which they were randomized. 
The safety analysis set will be used for safety analyses of Part 2 of the study. In addition, safety 
analyses may present safety data from both Part 1 and Part 2 of the study as deemed necessary. 
For these analyses, the combined safety analysis set and enrolled analysis set (See Section 9.2.4) 
will be used. 
9.2.3. 
Full Analysis Set 
The full analysis set will include all patients in the ITT analysis set who receive at least 1 dose of 
study drug and have at least 1 postbaseline efficacy assessment.  
9.2.4. 
Enrolled Analysis Set 
The enrolled analysis set will include all patients enrolled to Part 1 of the study, including 
healthy subjects and patients with eosinophilic asthma. 


 
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9.3. 
Data Handling Conventions 
For all variables, only the observed data from the patients will be used in the statistical analyses, 
ie, there is no plan to estimate missing data, unless otherwise specified. 
9.3.1. 
Handling Withdrawals and Missing Data 
Missing data will not be imputed, unless otherwise specified. 
9.4. 
Study Population 
Study population will be summarized for the ITT analysis set (see Section 9.2.1) as well as for 
the enrolled analysis set (see Section 9.2.4). Summaries will be presented by treatment group and 
for all patients. 
9.4.1. 
Patient Disposition 
Data from patients screened, patients screened but not randomized (and reason for not 
randomized), subjects/patients who are enrolled, patients who are randomized, patients 
randomized but not treated (and reason), patients in the ITT, safety, and full analysis sets, 
patients who complete the study, and patients who withdraw from the study will be summarized 
using descriptive statistics. Data from patients who withdraw from the study will also be 
summarized by reason for withdrawal using descriptive statistics. 
9.4.2. 
Demographic and Baseline Characteristics 
Patient and HC demographic and baseline characteristics, including medical history, prior 
medications and treatments, and ECG findings, will be summarized using descriptive statistics. 
For continuous variables, descriptive statistics (number [n], mean, standard deviation, median, 
minimum, and maximum) will be provided. For categorical variables, patient counts and 
percentages will be provided. Categories for missing data will be presented if necessary. 
9.5. 
Efficacy Analysis 
The efficacy endpoints for Part 2 of the study are discussed in Section 9.5.1 through 
Section 9.5.4.4. 
9.5.1. 
Primary Endpoint 
The primary efficacy endpoint is the change from baseline to week 4 in GLG (ΔGLG). 
The supportive primary efficacy endpoint is the change from baseline to week 4 in LP 
SUVmean. 
9.5.2. 
Secondary Endpoints 
The secondary efficacy endpoints are: 
• Change from baseline to weeks 2, 4, and 6 in blood eosinophil count 
• Change from baseline to weeks 2, 4, and 6 in FEV1 
• Change from baseline to weeks 2, 4, and 6 in FeNO measurements 


 
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• Change from baseline to weeks 2, 4, and 6 in AQLQ scores 
9.5.3. 
Exploratory Endpoints 
The exploratory endpoints are: 
• biological markers of inflammation and asthma: 
− IgE 
− DPP4 
− 25-hydroxy vitamin D 
− eotaxin-1, -2, and -3 
− TARC 
− MCP-1 and MCP-4 
− ILC2 
• the global uptake of FDG in the lymph nodes and bone marrow as measured by the 
PET-CT imaging parameters indicated for the primary efficacy variable. 
• sputum eosinophils for those patients that can produce sputum 
9.5.4. 
Planned Method of Analysis 
The ITT analysis set (see Section 9.2.1) will be used for summaries and the FAS will be used for 
all efficacy analyses. Summaries will be presented by treatment group. 
9.5.4.1. 
Primary Efficacy Analysis 
All imaging variables will be measured at 2 baseline visits and at weeks 2, 4, and 6 
post-randomization. 
Change in GLG from baseline to each of the postbaseline visits will be summarized using 
descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) by 
treatment group. The difference in means between reslizumab and placebo will be summarized 
and reported. 
No inferential statistics will be used for primary analysis and endpoint. 
9.5.4.2. 
Supportive to Primary Efficacy Endpoint Analysis 
The same methods as described in Section 9.5.4.1 will be used to describe the supportive 
endpoints to the primary endpoint. 
9.5.4.3. 
Secondary Efficacy Analysis 
The same methods as described in Section 9.5.4.1 will be used to analyze the secondary 
endpoints. 
In addition, correlation between each of the secondary endpoints and change from baseline to 
week 4 in GLG will be calculated. Spearman’s Rho correlation will be used for this analysis. No 


 
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inferential statistics will be used for secondary endpoints and analyses. Additional details about 
secondary endpoints analyses may be detailed in the statistical analysis plan. 
9.5.4.4. 
Exploratory Efficacy Analysis 
Analysis of the exploratory endpoints will be detailed in the statistical analysis plan (to be 
finalized and signed before unblinding). 
9.6. 
Multiple Comparisons and Multiplicity 
No adjustments will be made for the preplanned multiple comparisons/endpoints. 
9.7. 
Safety Endpoints and Analysis 
Safety analyses will be performed on the safety analysis set (Section 9.2.2). Safety analyses for 
the combined safety analysis set and enrolled analysis set, presenting safety data for Part 1 and 
Part 2 of the study may be presented as deemed necessary. 
9.7.1. 
Safety Endpoints 
Safety measures and time points are provided in Table 2. 
9.7.2. 
Safety Analysis 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. 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 (overall and by severity). 
Patient listings of serious adverse events and adverse events leading to withdrawal will be 
presented. 
Changes in laboratory and vital signs measurement data will be summarized descriptively. 
The use of concomitant medications will be summarized by therapeutic class using descriptive 
statistics. Concomitant medications will include all medications taken while the patient is treated 
with study drug. 
Newly occurring abnormalities in the physical examinations will be identified and listed. 
For continuous variables, descriptive statistics (n, mean, standard deviation, 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. Descriptive 
summaries of serious adverse events, patient withdrawals due to adverse events, and potentially 
clinically significant abnormal values (clinical laboratory or vital signs) based on predefined 
criteria will be provided as well. 
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 CSR. 
9.8. 
Tolerability Variables and Analysis 
Since this is a single-dose study, tolerability is not specifically defined. 


 
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9.9. 
Biomarker Analysis 
Biomarker results will be summarized using descriptive statistics. Analyses correlating efficacy 
variables and biomarkers will be explored as appropriate. 
9.10. 
Immunogenicity Analysis 
ADA information will be described for subjects who test positive. Samples from placebo-treated 
patients will not be analyzed. 
9.11. 
Planned Interim Analysis 
There will be no formal interim analysis. 
9.12. 
Reporting Deviations from the Statistical Plan 
Deviations from the statistical plan, along with the reasons for the deviations, will be described 
in protocol amendments, the statistical analysis plan, the CSR, or any combination of these, as 
appropriate, and in accordance with applicable national, local, and regional requirements and 
regulations. 


 
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10. 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS 
The medical experts, study monitors, auditors, IEC/IRB, and inspectors from competent 
authority (or their agents) will be given direct access to source data and documents (eg, medical 
charts/records, laboratory test results, printouts, videotapes) for source data verification, provided 
that patient confidentiality is maintained in accordance with national and 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 3.13). 
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 national and local 
competent authorities, as applicable, except when necessary to address immediate safety 
concerns to the patients or when the change involves only nonsubstantial logistics or 
administration. The principal investigator at each investigational center, the coordinating 
investigator (if applicable), and the sponsor will sign the protocol amendment. 
11.1.2. 
Protocol Violations 
Any deviation from the protocol that affects, to a significant degree, (a) the safety, physical, or 
mental integrity of the subjects of the study and/or (b) the scientific value of the study will be 
considered a protocol violation. Protocol violations may include non-adherence on the part of the 
patient, the investigator, or the sponsor to protocol-specific inclusion and exclusion criteria, 
primary objective variable criteria, or GCP guidelines; noncompliance to study drug 
administration; use of prohibited medications. Protocol violations will be identified and recorded 
by investigational center personnel in the CRF. All protocol violations will be reported to the 
responsible IEC/IRB, as required. 
When a protocol violation is reported, the sponsor will determine whether to discontinue the 
patient from the study or permit the patient to continue in the study, with documented approval 
from the medical expert. The decision will be based on ensuring the safety of the patient and 
preserving the integrity of the study. 
Changes in the inclusion and 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 
inclusion and exclusion criteria was entered in 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 violation will be recorded. 
11.2. 
Information to Study Personnel 
The investigator is responsible for giving information about the study to all personnel 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 personnel become involved). The investigator must 
ensure that all study personnel are qualified by education, experience, and training to perform 
their specific task. These study personnel members must be listed on the investigational center 
authorization form, which includes a clear description of each personnel 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 personnel, including the 
investigator, and for ensuring they comply with the protocol. Additional information will be 


 
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made available during the study when new personnel members become involved in the study and 
as otherwise agreed upon with either the investigator or the study monitor. 
11.3. 
Study Monitoring 
To ensure compliance with GCP guidelines, the study monitor or representative is responsible 
for ensuring that patients have signed the informed consent form and the study is conducted 
according to applicable SOPs, the protocol, and other written instructions and regulatory 
guidelines. 
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor 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 the investigator and visit the investigational center at regular 
intervals throughout the study. The study monitor will be permitted to check and verify the 
various records (CRFs and other pertinent source data records, including specific electronic 
source document [see Section 3.13]) relating to the study to verify adherence to the protocol and 
to ensure the completeness, consistency, and accuracy of the data being recorded. If electronic 
CRFs are used for the study, the study monitor will indicate verification by electronically 
applying source document verification flags to the CRF and will ensure that all required 
electronic signatures are being implemented accordingly. 
As part of the supervision of study progress, other sponsor personnel may, on request, 
accompany the study monitor on visits to the investigational center. The investigator and 
assisting personnel 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 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, 
chemical, micro-biological quality, or characteristics of clinical drug supplies or clinical device 
supplies used in a clinical research study sponsored by Teva. Examples of a product 
quality-related complaint include but are not limited to: 
• suspected contamination 
• questionable stability (eg, color change, flaking, crumbling, etc) 
• defective components 
• missing or extra units (eg, primary container is received at the investigational center 
with more or less than the designated number of units inside) 
• incorrect packaging, or incorrect or missing labeling/labels 
• unexpected or unanticipated taste or odor, or both 


 
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• device not working correctly or appears defective in some manner 
Each investigational center will be responsible for reporting a possible clinical product quality 
related complaint by completing the product quality complaint form provided by Teva and 
emailing it to 
 within 2 business days 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 Teva for investigative evaluation 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 Teva for investigative evaluation whenever possible. 
11.4.1. 
Product Quality Related Complaint Information Needed from the 
Investigational Center 
In the event that the product quality 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, lot number, 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 adverse event Yes/No 
• clinical supplies unblinded (for blinded studies) Yes/No 
• date and name (clinical study site) of person receiving the complaint 
Note: Reporting a product quality related complaint must not be delayed even if not all the 
required information can be obtained immediately. Known information must be reported 
immediately. The sponsor will collaborate with the investigator to subsequently obtain any 
outstanding information. 
11.4.2. 
Handling of 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 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 due to product complaint, the protocol 
should be followed for recording and reporting (Section 7.1.2 and Section 7.1.5.3, respectively). 
11.4.4. 
Documenting a Product Complaint 
The investigator will record in the source documentation a description of the product complaint, 
and 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, GCP guidelines, and applicable regulatory requirements. The sponsor’s Global 
Clinical Quality Assurance, independent of Global Clinical Development, is responsible for 
determining the need for (and timing of) an investigational center audit. 
The investigator must accept that competent authorities and sponsor representatives may conduct 
inspections and audits to verify compliance with GCP guidelines. 


 
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12. 
ETHICS 
Details of compliance with regulatory requirements and applicable laws are provided in 
Section 1.6. 
12.1. 
Informed Consent 
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 oral information about the study will be provided in a language as 
nontechnical as practical to be 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 documents. 
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 the informed 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 informed 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 participation in the study and free to withdraw from the study at any time without 
prejudice to future treatment. 
Patients will provide written informed consent prior to completing the PET/CT scans. 
12.2. 
Competent Authorities and Independent Ethics 
Committees/Institutional Review Boards 
Before this study starts, the protocol will be submitted to each IEC/IRB for review. As required, 
the study will not start before the IEC/IRB for the investigational center gives written approval 
or a favorable opinion. 
12.3. 
Confidentiality Regarding Study Patients 
The investigator must ensure that the privacy of the patients, including their identity and all 
personal medical information, will be maintained at all times. In CRFs and other documents or 
image material submitted to the sponsor, patients will be identified not by their names, but by an 
identification number. 
Personal medical information may be reviewed for the purpose of patient safety or for verifying 
data in the source and transcribed to the CRF. This review may be conducted by the study 
monitor, properly authorized persons on behalf of the sponsor, Global Quality Assurance, or 
competent authorities. Personal medical information will always be treated as confidential. 
12.4. 
Declaration of the End of Clinical Study 
The last visit (visit 7) is defined as end of treatment (approximately week 6). This will be 
considered the end of the trial for the purposes of end of trial notification 


 
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12.5. 
Registration of the Clinical Study 
In compliance with national and local regulations and in accordance with Teva standard 
procedures, this clinical study may be registered on clinical trials registry websites. 


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


 
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Data corrections in the CDMS will be made using the CDMS update function. The system 
requires a reason for each change and keeps a complete audit trail of the data values, dates, and 
times of modifications, and authorized electronic approvals of the changes. 
At the conclusion of the study, the CDMS and all other study data will be locked to further 
additions or corrections. Locking the study data represents the acknowledgement that all data 
have been captured and confirmed as accurate. 
13.3. 
Archiving of Case Report Forms and Source Documents 
13.3.1. 
Sponsor Responsibilities 
The sponsor will have final responsibility for the processing and quality control of the data. Data 
management oversight will be carried out as described in the sponsor’s SOPs for clinical studies. 
Day to day data management tasks for this study are delegated to a contract organization, and 
these functions may be carried out as described in the SOPs for clinical studies at that 
organization. These SOPs will be reviewed by the sponsor before the start of data management 
activities. The original CRFs will be archived by the sponsor. Investigational 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 national and local laws, including, but not limited to: 
• full case histories 
• signed informed consent forms 
• patient identification lists 
• case report forms for each patient on a per-visit basis 
• data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center, electronic diary) 
• safety reports 
• financial disclosure reports/forms 
• reports of receipt, use, and disposition of the study drug 
• copies of all correspondence with sponsor, the IEC/IRB, and any competent authority 
The investigator will retain all records related to the study and any additional records required, as 
indicated by the protocol and according to applicable laws and regulations, until the CRO or 
sponsor notifies the institution in writing that records may be destroyed. If, after 25 years from 
study completion, or earlier in the case of the investigational center closing or going out of 
business, the investigator reasonably determines that study record retention has become unduly 
burdensome, and sponsor has not provided written notification of destruction, then the 
investigator may submit a written request to sponsor at least 60 days before any planned 
disposition of study records. After receipt of such request, the sponsor may make arrangements 


 
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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 signed 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 applicable legal provisions. The policy coverage 
is subject to the full policy terms, conditions, extensions, and exclusions. Excluded from the 
insurance coverage 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 FDA 3454 form. 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 national, local, and regional requirements and regulations for 
registration and posting of results. 
The sponsor is responsible for the preparation of a CSR, in cooperation with the principal 
investigator. The final report is signed by the sponsor and, if applicable, by the principal 
investigator. 
When the sponsor generates reports from the data collected in this study for presentation to 
competent authorities, drafts may be circulated to the principal investigator for comments and 
suggestions. An endorsement of the final report will be sought from the principal 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 
“Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in 
Medical Journals” (www.ICMJE.org). Publication of the results will occur in a timely manner 
according to applicable regulations. Authorship will be based on meeting all the following 
4 criteria: 
• substantial contributions to the conception or design of the work; or the acquisition, 
analysis, or interpretation of data for the work 
• drafting the work or revising it critically for important intellectual content 
• final approval of the version to be published 
• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately 
investigated and resolved 
The publications committee established by the sponsor will oversee this process. Additional 
publications may follow. Policies regarding the publication of the study results are defined in the 
financial agreement. 
No patent applications based on the results of the study may be made by the investigator nor may 
assistance be given to any third party to make such an application without the written 
authorization of the sponsor. 


 
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16. 
REFERENCES 
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glucocorticoids differentially modulate chemokine expression in human airway smooth muscle 
cells. Br J Pharmacol 2008;155:84–92. 
Begin, P, Nadeau, KC. Epigenetic regulation of asthma and allergic disease. Allergy Asthma 
Clin Immunol 2014;10:27. 
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APPENDIX A. ASTHMA CONTROL QUESTIONNAIRE 
(Sample provided in this appendix is for reference only.) 


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


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APPENDIX B. ASTHMA QUALITY OF LIFE QUESTIONNAIRE 
(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. CLINICAL CRITERIA FOR DIAGNOSING 
ANAPHYLAXIS 
Anaphylaxis is highly likely when the following criteria are fulfilled: 
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) 
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. 

SAP_001.pdf: 
Statistical Analysis Plan 
Distribution of Eosinophils in Asthma after Reslizumab (DEAR). A 7-week, Placebo- 
Controlled, Double-Blinded, Parallel-Group, Imaging Study Using Positron Emission 
Tomography/Computed Tomography (PET/CT) to Characterize the Effect of Intravenous 
Reslizumab on Airway Inflammation in Patients with Eosinophilic Asthma 
Study Number C38072-AS-40105 (or CEP38072-AS-40105) 
NCT02937168 
Statistical Analysis Plan Approval Date: 30 May 2017 


Placebo-Controlled Study–Asthma with Eosinophilia 
Statistical Analysis Plan Version 1.0 
Study CEP38072-AS-40105 
1 
 
 
 
Statistical Analysis Plan 
Study CEP38072-AS-40105 
 Distribution of Eosinophils in Asthma after Reslizumab (DEAR). A 7-week, Placebo- 
Controlled, Double-Blinded, Parallel-Group, Imaging Study Using Positron Emission 
Tomography/Computed Tomography (PET/CT) to Characterize the Effect of Intravenous 
Reslizumab on Airway Inflammation in Patients with Eosinophilic Asthma 
Phase 4 
BLA number: 761033 
Approval Date: 30 May 2017 
Sponsor 
Teva Branded Pharmaceutical 
Products R&D, Inc. 
41 Moores Road 
Frazer, Pennsylvania 19355 
United States 
Prepared by: 
 
KEYRUS Biopharma 


 
Placebo-Controlled Study–Asthma with Eosinophilia 
Statistical Analysis Plan Version 1.0 
Study CEP38072-AS-40105 
2 
STATISTICAL ANALYSIS PLAN APPROVAL 
 
 


 
Placebo-Controlled Study–Asthma with Eosinophilia 
Statistical Analysis Plan Version 1.0 
Study CEP38072-AS-40105 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
STATISTICAL ANALYSIS PLAN APPROVAL ..........................................................................2 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................7 
INTRODUCTION ...........................................................................................................................8 
1. 
STUDY OBJECTIVES AND ENDPOINTS ................................................................9 
1.1. 
Primary and Secondary Study Objectives and Endpoints ............................................9 
1.1.1 
Primary Objectives and endpoints ................................................................................9 
1.1.2 
Secondary Objectives and endpoints ..........................................................................10 
1.2. 
Exploratory/ Safety Objectives and Endpoints ...........................................................10 
1.2.1. 
Exploratory Objectives and endpoints ........................................................................10 
1.2.2. 
Safety endpoints ..........................................................................................................11 
2. 
STUDY DESIGN .......................................................................................................12 
2.1. 
General Design ...........................................................................................................12 
2.2. 
Randomization and Blinding ......................................................................................17 
2.3. 
Data Monitoring Committee .......................................................................................17 
2.4. 
Sample Size and Power Considerations .....................................................................17 
2.5. 
Sequence of Planned Analyses ...................................................................................18 
2.5.1. 
Planned Interim Analyses ...........................................................................................18 
2.5.2. 
Final Analyses and Reporting .....................................................................................18 
3. 
ANALYSIS SETS ......................................................................................................19 
3.1.1. 
Intent-to-Treat Analysis Set ........................................................................................19 
3.1.2. 
Safety Analysis Set .....................................................................................................19 
3.1.3. 
Full Analysis Set .........................................................................................................19 
3.1.4. 
Enrolled Analysis Set .................................................................................................19 
4. 
GENERAL ISSUES FOR DATA ANALYSIS ..........................................................20 
4.1. 
General ........................................................................................................................20 
4.2. 
Specification of Baseline Values ................................................................................20 
4.3. 
Handling Withdrawals and Missing Data ...................................................................20 
4.4. 
Study Days and Visits .................................................................................................20 
5. 
STUDY POPULATION .............................................................................................21 
5.1. 
General ........................................................................................................................21 


 
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5.2. 
Patient Disposition ......................................................................................................21 
5.3. 
Demographics and Baseline Characteristics ...............................................................21 
5.4. 
Medical History ..........................................................................................................22 
5.5. 
Prior therapy and Medication .....................................................................................23 
5.6. 
Electrocardiography ....................................................................................................23 
5.7. 
Childbearing Potential and Methods of Contraception ..............................................23 
5.8. 
Study Protocol Violations ...........................................................................................24 
6. 
EFFICACY ANALYSIS ............................................................................................25 
6.1. 
General ........................................................................................................................25 
6.2. 
Primary Efficacy Endpoint and Analysis ...................................................................25 
6.2.1. 
Definition ....................................................................................................................25 
6.2.2. 
Primary Efficacy Analysis ..........................................................................................27 
6.2.3. 
Supportive Primary Efficacy Endpoint Analysis ........................................................27 
6.2.4. 
Sub-Group Analyses ...................................................................................................28 
6.3. 
Secondary Efficacy Endpoints and Analysis. .............................................................28 
6.3.1. 
Blood Eosinophil Count .............................................................................................28 
6.3.1.1. 
Definition ....................................................................................................................28 
6.3.1.2. 
Analysis ......................................................................................................................28 
6.3.2. 
Forced Expiratory Volume (FEV1) ............................................................................28 
6.3.2.1. 
Definition ....................................................................................................................28 
6.3.2.2. 
Analysis ......................................................................................................................28 
6.3.3. 
Fractional Exhaled Nitric Oxide (FeNO) Measurements ...........................................29 
6.3.3.1. 
Definition ....................................................................................................................29 
6.3.3.2. 
Analysis ......................................................................................................................29 
6.3.4. 
AQLQ score ................................................................................................................29 
6.3.4.1. 
Definition ....................................................................................................................29 
6.3.4.2. 
Analysis ......................................................................................................................29 
6.4. 
Exploratory Efficacy Endpoints Analysis ..................................................................29 
6.4.1. 
Biological Markers of Inflammation and Asthma: IgE, DPP4, 25-hydroxy  
vitamin D, eotaxin-1, -2, and -3, TARC, MCP-1 and MCP-4, ILC2 .........................30 
6.4.1.1. 
Definition ....................................................................................................................30 
6.4.1.2. 
Analysis ......................................................................................................................30 
6.4.2. 
Biological Lung Function Variables: FVC, PEFR, FEF25%-75% ............................30 


 
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6.4.2.1. 
Definition ....................................................................................................................30 
6.4.2.2. 
Analysis ......................................................................................................................30 
6.4.3. 
Upper-body Uptake of FDG in Lymph Nodes and Bone Marrow .............................31 
6.4.3.1. 
Definition ....................................................................................................................31 
6.4.3.2. 
Analysis ......................................................................................................................31 
6.4.4. 
Sputum Eosinophils ....................................................................................................31 
6.4.4.1. 
Definition ....................................................................................................................31 
6.4.4.2. 
Analysis ......................................................................................................................31 
7. 
MULTIPLE COMPARISONS AND MULTIPLICITY ............................................32 
8. 
SAFETY ANALYSIS ................................................................................................33 
8.1. 
General ........................................................................................................................33 
8.2. 
Adverse Events ...........................................................................................................33 
8.3. 
Death ...........................................................................................................................34 
8.4. 
Clinical Laboratory Tests ...........................................................................................34 
8.4.1. 
Other Clinical Laboratory Tests .................................................................................37 
8.5. 
Physical Examinations ................................................................................................37 
8.6. 
Vital Signs ..................................................................................................................38 
8.7. 
Electrocardiography ....................................................................................................39 
8.8. 
Concomitant Medications or Therapies ......................................................................39 
9. 
TOLERABILITY VARIABLES AND ANALYSIS..................................................40 
10. 
IMMUNOGENICITY ANALYSIS ............................................................................41 
11. 
STATISTICAL SOFTWARE ....................................................................................42 
12. 
REFERENCES ...........................................................................................................43 
 


 
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LIST OF TABLES 
Table 1. 
Study Procedures and Assessments 
Table 2: 
Clinical Laboratory Tests 
Table 3: 
Criteria for Potentially Clinically Significant Laboratory Values 
Table 4.  
Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Table 5.  
Criteria for Potentially Clinically Significant Vital Signs 
 
 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS  
 
Abbreviation 
Term 
AQLQ 
Asthma Quality of Life Questionnaire 
BMI 
Body mass index 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DPP4 
Dipeptidyl peptidase 4  
ECG 
Electrocardiogram/Electrocardiography 
FEF 
Forced Expiratory Flow 
FeNO 
Fractional exhaled Nitric Oxide 
FEV 
Forced Expiratory Volume 
FDG 
Fludeoxyglucose F 18 
FVC 
Forced Vital Capacity 
GLG 
Global Lung Glycolysis 
HC 
Healthy control 
IgE 
Immunoglobulin E 
ITT 
Intent-to-Treat 
LP 
Lung Parenchyma 
MedDRA 
Medical Dictionary for Regulatory Activities 
PCSA 
Potentially clinically significant abnormal  
PEFR 
Peak Expiratory Flow Rate 
PET/CT 
Positron Emission Tomography/Computed Tomography 
PP 
Per-Protocol 
R&D 
Research and Development 
SD 
Standard Deviation 
SE 
Standard Error 
SI 
Standard International 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
TARC 
Thymus and Activation Regulated Chemokine 


 
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INTRODUCTION 
This Statistical Analysis Plan describes the planned analysis and reporting for Teva Branded 
Pharmaceutical Products R&D, Inc study CEP38072-AS-40105, (Distribution of Eosinophils in 
Asthma after Reslizumab (DEAR). A 7-week, Placebo-Controlled, Double-Blinded, Parallel-
Group, Imaging Study Using Positron Emission Tomography/Computed Tomography (PET/CT) 
to Characterize the Effect of Intravenous Reslizumab on Airway Inflammation in Patients with 
Eosinophilic Asthma), and was written in accordance with SOP GBP_RD_702 (Statistical 
Analysis Plan). 
The reader of this Statistical Analysis Plan is encouraged to read the study protocol for details on 
the conduct of this study, the operational aspects and times of clinical assessments, and the timing 
for completing the participation of a patient in this study.  
The SAP is intended to be in agreement with the protocol, especially with regards to the primary 
and all secondary endpoints and their respective analyses. However, the SAP may contain more 
details regarding these particular points of interest, or other types of analyses (e.g. other 
endpoints).When differences exist in descriptions or explanations provided in the study protocol 
and this Statistical Analysis Plan, the Statistical Analysis Plan prevails; the differences will be 
explained in the Clinical Study Report. 
 


 
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1. 
STUDY OBJECTIVES AND ENDPOINTS 
1.1. 
Primary and Secondary Study Objectives and Endpoints 
1.1.1 Primary Objectives and endpoints 
This study is designed in two parts: Part 1 is validation of PET/CT scan and Part 2 is evaluation of 
the effect of reslizumab on inflammation in the lungs. There are 2 related primary objectives of 
this study: 
• To establish that positron emission tomography (PET)/computerized tomography (CT) 
imaging of the lung can reliably distinguish healthy control (HC), non-asthmatic subjects 
and patients with severe asthma with an eosinophilic phenotype (Part 1: initial validation 
of  PET/CT scan). 
• If the utility of PET/CT scanning is established as per objective 1 (Part 1): Part 2 objective 
is to show that reslizumab produces a reduction in signal intensity (reduction in lung 
inflammation) in patients with severe asthma with an eosinophilic phenotype (Part 2: 
evaluation of the effect of reslizumab vs placebo in reducing inflammation). 
 
For primary objective 1 (Part 1), a ≤10% variability between the first and second measurements of PET/CT 
scans as measured by global lung glycolysis (GLG) within each group [HCs (n=5) and patients with asthma 
(n=10)] will be considered as the maximum allowed variability. This criterion is a measure of intra-group 
reproducibility. At this point (i.e. establishing intra-group reproducibility), healthy subjects are considered 
completed. 
 
A ≥5% difference in GLG between HC subjects and patients with eosinophilic asthma, based on the average 
of the 2 measurements of PET/CT, will be selected as minimal difference that validates the ability PET/CT 
to differentiate these 2 populations of study participants. This criterion is a measure of inter-group 
reproducibility.  
 
Only after these intra- and inter-group variability criteria of Part 1 are met, the patients with asthma will 
be considered eligible to enter Part 2 of the study and randomly assigned in double-blind fashion to 
receive either placebo (n=5) or reslizumab (n=5). If these exploratory criteria (Part 1) are not met (8 or 
more asthma patients do not meet the criteria to enter Part 2 of the protocol), the study will be 
reevaluated. 
 
For primary objective 2 (Part 2), the primary efficacy endpoint is the change from baseline to week 4 in 
global lung glycolysis (GLG) (i.e., ΔGLG). 
 


 
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The supportive primary efficacy endpoint is the change from baseline to week 4 in lung parenchyma (LP) 
standardized uptake value (SUV) mean. 
 
1.1.2 Secondary Objectives and endpoints 
The secondary objectives of the study are to demonstrate a correlation between the benefit 
observed on imaging (PET/CT) with: 
•  reductions in blood eosinophil counts 
•  improvement in clinic visit lung function 
•  reductions in fractional exhaled nitric oxide (FeNO) 
•  improvements in Asthma Quality of Life questionnaire (AQLQ) scores. 
 
The secondary efficacy endpoints are: 
• the change from baseline to week 4 in blood eosinophil counts 
• the change from baseline to week 4 in FEV1 
• the change from baseline to week 4 in FeNO 
• the change from baseline to week 4 in AQLQ. 
1.2. 
Exploratory/ Safety Objectives and Endpoints 
1.2.1. Exploratory Objectives and endpoints 
Exploratory objectives are: 
• to demonstrate a correlation between changes in the lung PET/CT signal produced by 
reslizumab and serum biological markers of asthmatic inflammation 
• to demonstrate a correlation between changes in the lung PET/CT signal produced by 
reslizumab and other lung function variables including forced vital capacity (FVC), peak 
expiratory flow rate (PEFR) and forced expiratory flow at the 25% point to the 75% point 
of forced vital capacity (FEF25%-75%) 
• to demonstrate that reslizumab produces greater reductions in inflammation of upper-body 
lymph nodes and bone marrow than placebo as seen on PET/CT  
• for those patients that can produce sputum, to demonstrate an association between changes 
in sputum eosinophil numbers produced by reslizumab and the lung PET/CT signal 
produced by reslizumab. 
In this study, we wish to determine whether any changes in the levels/quantity of the following 
biomarkers occur following the administration of reslizumab: 
• biological markers of inflammation and asthma (blood): 
− IgE in peripheral blood  


 
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− DPP4 in peripheral blood  
− 25-hydroxy vitamin D in peripheral blood  
− eotaxin-1, -2, and -3 in peripheral blood  
− TARC in peripheral blood  
− MCP-1 and MCP-4 in peripheral blood  
− ILC2 in peripheral blood  
• lung function variables: 
− FVC 
− PEFR 
− FEF25%-75% 
• the uptake of FDG in the lymph nodes and bone marrow as measured by the PET-CT 
imaging parameters indicated for the primary efficacy variable. 
• sputum eosinophils for those patients that can produce sputum. 
Blood samples for assessment of these exploratory biomarkers will be collected and processed 
using the procedures in place at the investigational center 
. For more detailed 
descriptions, see section 8.1 of the protocol. 
1.2.2. Safety endpoints 
The safety endpoints are: 
• occurrence of adverse events throughout the study 
• vital signs (blood pressure, pulse, respiratory rate, body temperature, and blood oxygen 
saturation (SpO2)) throughout the study 
• clinical laboratory evaluations throughout the study 
• physical examination findings throughout the study 
• use of concomitant medication throughout the study. 
 
1.3  
Immunogenicity Objectives and Endpoints 
Blood samples for assessment of anti-drug antibodies (ADA) response in Part 2 will be collected 
from reslizumab-treated patients at scheduled visits at baseline (before dosing, V4) and after 
dosing at weeks 2 and 6 (visits 5 and 7) only. Unscheduled blood samples for anti-reslizumab 
antibody assessments will also be collected from reslizumab-treated patients with asthma upon 
experiencing a severe hypersensitivity reaction (e.g. anaphylaxis). 
 
 


 
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2. 
STUDY DESIGN 
2.1. 
General Design 
This is a 7-week, single-center, randomized, double-blind, placebo-controlled, parallel-group 
study using PET/CT to evaluate the effect of reslizumab administered at 3.0 mg/kg in adult patients 
with eosinophilic asthma. The study will consist of a screening period (up to 21 days), a 6-week, 
double-blind treatment/assessment period, and a follow-up telephone contact (7±3 days after last 
visit). 
All subjects who participate in this study will consent at the investigational center 
 
 prior to undergoing any study procedures. After consent is obtained, all participants 
will undergo all tests and procedures required for eligibility, including sputum and blood 
eosinophil level assessments. Patients with asthma (does not apply to HC subjects) must have a 
screening blood eosinophil count of ≥400 cells/μL to be included. A maximum of 3 screening 
blood eosinophil assessments will be conducted. If the first assessment yields a blood eosinophil 
level below 400 cells/μL patients with asthma may return for a second assessment of blood 
eosinophil level after 7 days. A third and final assessment will be performed 7 days after the second 
assessment, if necessary (e.g., if the blood eosinophil level remains <400 cells/μL at the second 
assessment). 
The patients must maintain their usual asthma controller regimen without change throughout the 
screening and study periods. A patient who experiences an asthma exacerbation during this time 
that requires additional medication, beyond increased SABA use, will be considered to have failed 
screening and cannot undergo randomization. A patient may be rescreened for this reason 1 time 
only. If a patient experiences an asthma exacerbation requiring treatment with systemic steroids, 
they will only be allowed to be rescreened 6 weeks after completion of treatment. All patients that 
have to be rescreened must be stable on other asthma medications for 30 days prior to rescreening. 
This study is designed in 2 parts. Part 1 is a validation step whereby the sponsor wishes to 
determine (1) the intra-patient reproducibility in the GLG measure, and (2) the difference in the 
GLG measure between individual patients with severe asthma with an eosinophilic phenotype (1-
by-1) and the entire HC group. Limits for both the reproducibility within patients and difference 
between the 2 groups have been provided by subject matter experts. Part 2 will be a 7-week double-
blind evaluation of patients with severe asthma with an eosinophilic phenotype that have been 
randomized to receive a single dose of either placebo or reslizumab at 3 mg/kg. 
Part 1 
Within 7 days (±3 days) of eligibility being confirmed, participants will have a PET/CT scan as 
per the PET/CT scan protocol described in Part 2 below. Participants will return to the 
 
 7 days (±3) after the first PET/CT scan (taken during visit 2) for a second PET/CT 
scan following the same procedures described above. HC subjects (n=5) may also have a second 
sputum induction and blood sample collection at 
 within 1 day of the second 
PET/CT scan, if feasible (preferred but not required). Healthy subjects will be considered complete 
at this time. Only after all 5 HCs have completed the study will patients with asthma be screened. 
If the relative difference in GLG (based on the average of the 2 measurements) between healthy 
subjects and asthma patients will be ≥5%, then the asthma patients will be randomized. A 10% 


 
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variability (measured as relative difference between first measurement and second measurement) 
between PET/CT scans as measured by GLG within each group will be considered as the 
maximum allowed variability. The Part 1 criteria have been set at these levels to observe a 
difference between the healthy subjects and patients with asthma and to ensure intra-group 
reproducibility. The criteria are based on the investigators’ prior experience. If these exploratory 
criteria are not met (i.e., 8 or more asthma patients do not meet the criteria to enter Part 2 [inclusion 
criteria k and l]), then the study will be reevaluated. 
Detailed by-visit information for Part 1 are provided in sections 3.14.1 and 3.14.2 of the protocol. 
Part 2 
If eligible (i.e., if inter- and intra-group GLG variability criteria are met), patients will be 
randomized. This may occur at any time after confirmation of eligibility and up to the time of 
dosing. Patients will return to 
 for baseline clinical, serological, and biochemical 
measures at the Clinical Research Center (CRC) according to standard procedures. Once these are 
completed, patients will randomly receive either placebo or reslizumab and will receive the 
infusion at 
. Any new serious adverse events, reslizumab-related adverse 
events, and new concomitant medications will be reported. 
All planned PET/CT scans (weeks 2, 4, and 6) should be scheduled at the time of randomization. 
Within 2 weeks (±3 days) of the infusion, patients will return to 
 for clinical 
tests and procedures. Within 3 days of this visit, patients will undergo a PET/CT scan at the 
. Patients repeat the clinical tests and procedures at weeks 4 and 6 post-
infusion. Each visit at 
 will be followed by a PET/CT scan at the 
 
 as described above.  
Schematic presentation of the study design for Part 1 and Part 2 is given in Figures 1, 2, and 3, 
section 3.1 of the protocol. 
The assessments and procedures performed during each study visit are detailed in Table 1 below 
and in Section 3.14 of the protocol. Detailed by-visit informations for Part 2 are provided in section 
3.14.3 of the protocol. Detailed description of each assessment is provided in section 6 (for 
efficacy), section 7 (for safety), and section 8 (other assessments) of the protocol. 
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 
Table 1 above and section 3.14 of the protocol). 
 


 
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Table 1. 
Study Procedures and Assessments 
Study period 
Pretreatment 
Phase 1 
Phase 2 
Follow-up 
Visit number 
V1a 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Allowed time windows 
Up to -21 days 
0 days 
±3 day(s) 
Within 3 days 
of V3 
±3 day(s) 
±3 day(s) 
±3 day(s) 
Up to 
+7 day(s) 
Procedures and assessments 
Screening 
 
Baseline 
(day 1) 
 
W1 
(day 7) 
 
Baseline 
(day 1) 
 
W2 
(day 14 
from V4) 
W4 
(day 28 from 
V4) 
W6 
(day 42 from 
V4)/early 
termination 
W7 
Informed consent 
X 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
Smoking history 
X 
 
 
 
 
 
 
 
Prior medication and treatment 
history 
X 
 
 
 
 
 
 
 
Complete physical examinationb 
X 
 
 
 
 
 
A 
 
Brief physical examinationb 
 
 
 
A 
A 
A 
 
 
Vital signs measurementbc 
X 
 
 
A 
A 
A 
A 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
Clinical chemistrybd 
X 
X 
X 
A 
A 
A 
A 
 
Urine/serum β-HCG test for women 
of child bearing potentialbe 
X 
 
 
 
 
 
 
 
Hematology (eosinophils)f 
X 
 
 
A 
A 
A 
A 
 
Sputum sampling for eosinophilsg 
X 
 
 
A 
A 
A 
A 
 
Urinalysish 
X 
 
 
 
 
 
A 
 
PET/CT scan 
 i 
 
X 
X 
 
A 
A 
A 
 
ACQ-6 for entry criterion 
A 
 
 
 
 
 
 
 
Electrocardiographyb 
X 
 
 
 
 
 
 
 


 
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Study period 
Pretreatment 
Phase 1 
Phase 2 
Follow-up 
Visit number 
V1a 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Allowed time windows 
Up to -21 days 
0 days 
±3 day(s) 
Within 3 days 
of V3 
±3 day(s) 
±3 day(s) 
±3 day(s) 
Up to 
+7 day(s) 
Procedures and assessments 
Screening 
 
Baseline 
(day 1) 
 
W1 
(day 7) 
 
Baseline 
(day 1) 
 
W2 
(day 14 
from V4) 
W4 
(day 28 from 
V4) 
W6 
(day 42 from 
V4)/early 
termination 
W7 
Spirometry 
X 
 
 
A 
A 
A 
A 
 
ADAbj 
 
 
 
A 
A 
 
A 
 
Blood collection for biomarker 
analysis 
 
 
 
A 
A 
A 
A 
 
AQLQ 
 
 
 
A 
A 
A 
A 
 
Randomization 
 
 
 
A 
 
 
 
 
Study drug infusion 
 
 
 
A 
 
 
 
 
Adverse event inquiry 
X 
X 
X 
A 
A 
A 
A 
A 
Concomitant medication inquiry 
X 
X 
X 
A 
A 
A 
A 
A 
a Screening visit (visit 1) will take place up to 21 days before the V2 visit. It is understood that not all procedures can be completed on the same day. In 
particular, the patient may need to return to satisfy the medication hold for screening pre-bronchodilator FEV1. 
b Physical examination, vital signs, blood samples, and ECG should be obtained before spirometry procedures and IP administration.  
c Vital signs measurements will include blood pressure, pulse, respiratory rate, body temperature, and blood oxygen saturation (SpO2). Height and weight 
measurements are required only at screening visit. 
d The clinical chemistry will include a complete metabolic panel. 
e  A serum β-HCG pregnancy test will be administered at V1 only, for all participating women of childbearing potential. Urine β-HCG tests will be performed for 
all participating women of childbearing potential, at V2, V3, V5, V6, and V7, prior to performance of PET/CT scan. 
f Hematology will include a complete blood count with differential. The results of the differential blood tests performed after drug administration will be 
blinded. If there is a medical need to review these results, the investigator will contact the medical monitor. 
g The results of the sputum eosinophil assessments performed after study drug administration will be blinded. If there is a medical need to review these results, 
the investigator will contact the medical monitor. 
h  A complete urinalysis will be performed at the screening visit, visit 4, and visit 7; a urine dipstick test for glucose will be performed prior to each PET/CT scan.  
i  Patients should be observed for 1 hour following completion of PET/CT scan. 


 
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j Blood samples for ADA assessment will be collected at baseline (before study drug administration) and other scheduled time points, and upon observation of 
any severe hypersensitivity reaction (eg, anaphylaxis). 
k Randomization can occur any time from determining that the patient qualifies for Part 2 up to study drug infusion. Patient qualification is based on meeting 
both of the following 2 steps: 1) ∆GLPG ≤10% versus V2 [for reproducibility] and 2) ∆GLPG≥5% versus HC [for signal] to study drug infusion. 
A=patients with asthma only; ACQ-6=6-item Asthma Control Questionnaire; ADA=anti-drug antibodies; AQLQ=Asthma Quality of Life Questionnaire; 
β-HCG= beta human chorionic gonadotropin; CBC=complete blood count; CT=computerized tomography; HC=healthy control subjects only; PET=positron 
emission tomography; V=visit; W=week; X=patients with asthma and healthy control subjects 
 
 
 
 
 
 
 


 
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2.2. 
Randomization and Blinding 
This is a randomized, double-blinded, placebo-controlled, parallel-group study. After the 2 
baseline PET/CT scans and successful completion of all requirements (Part 1), patients will be 
randomly assigned 1:1 in a double-blind fashion to receive either placebo or iv 3.0 mg/kg 
reslizumab. In order to maintain the blind, each patient will be assigned a unique identifier number 
and all reference to the patient will be by using this identifier. 
Patients will be randomly assigned to treatment groups by means of a computer-generated 
randomization list. The specifications for randomization will be under the responsibility and 
oversight of Teva Global Statistics. The output of the randomization process will be a patient 
randomization list. 
The sponsor’s clinical personnel involved in the study will be blinded to the study drug identity 
until the database is locked for analysis and the treatment assignment is revealed, with the 
exception of the bioanalytical group who will not be blinded to facilitate ADA sample analysis 
and an un-blinded person who will be responsible for randomization assignment. Additionally, in 
order to maintain the study blind, blood and sputum eosinophil levels assessed after study drug 
administration will not be available to investigators, their blinded staff, the sponsor, and blinded 
members of the clinical research organization. There will be un-blinded data management, un-
blinded site staff, and an un-blinded CRA who will not sit on the study team and be responsible 
for un-blinded eosinophil data. 
In case of a serious adverse event, pregnancy, or in cases when 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. When a blind is broken, the 
patient will be withdrawn from the study and the event will be recorded on 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. 
At the time of analysis (after the end of study), after receiving unblinding request from Teva statistician, 
the service provider will provide the unblinded treatment assignment according to the processes defined 
in the relevant Standard Operating Procedure (SOP). 
2.3. 
Data Monitoring Committee 
Data Monitoring Committee will not be used during this study  
2.4. 
Sample Size and Power Considerations 
This study is exploratory in nature; therefore, no formal hypothesis testing is planned. Based on 
clinical and practical considerations, 5 healthy subjects and 10 eosinophilic asthma patients (5 
patients treated with reslizumab, and 5 patients treated with placebo) is considered adequate for: 
1. a validation of the ability of PET/CT to differentiate patients with eosinophilic asthma 
from HC subjects, 
2. an evaluation of the effect of reslizumab versus placebo on inflammation of the lungs. 


 
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2.5. 
Sequence of Planned Analyses 
2.5.1. 
Planned Interim Analyses 
There will be no formal interim analysis for this study. 
2.5.2. 
Final Analyses and Reporting 
All analyses identified in this Statistical Analysis Plan will be performed after the end of study as 
defined in the study protocol. This Statistical Analysis Plan and any corresponding amendments 
will be approved before database lock, in accordance to SOP GBP_RD_702 (Statistical Analysis 
Plan). 
The randomization codes will not be unblinded until this Statistical Analysis Plan has been 
approved and issued. 


 
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3. 
ANALYSIS SETS 
3.1.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all randomized patients (Part 2). In this analysis 
set, treatment will be assigned according to the treatment to which patients were randomized, 
regardless of which treatment they actually received. This analysis set will be used for the analysis 
and summarization of primary efficacy and supportive primary efficacy and secondary efficacy 
endpoints, for summarization of patients demographics (Summary 15.1.2.2) and patients baseline 
characteristics (15.1.2.4) for Part 2 and also, for summarization and listing of protocol violations 
for Part 2 (Summary 15.1.7.2). 
3.1.2. 
Safety Analysis Set 
The safety analysis set will include all patients who receive at least 1 dose of study drug/placebo. 
In this analysis set, treatment will be assigned based on the treatment patients actually received, 
regardless of the treatment to which they were randomized. 
The safety analysis set will be used for safety analyses of Part 2 of the study. In addition, safety 
analyses may present safety data from both Part 1 based on all enrolled analysis set (section 3.1.4) 
and Part 2 of the study based on the safety analysis set, as deemed necessary.  
3.1.3. 
Full Analysis Set 
The full analysis set (FAS) will include all patients in the ITT analysis set who receive at least 1 
dose of study drug and have at least 1 post-baseline efficacy assessment. This analysis set will be 
used for summarization and reporting of all efficacy endpoints and also for exploratory endpoints 
(Part 2). 
3.1.4. 
Enrolled Analysis Set 
The enrolled analysis set will include all participants enrolled to Part 1 of the study, including 
healthy subjects and patients with eosinophilic asthma. This analysis set will be used for 
establishing initial validation of PET/CT scan (Part 1), summarization and reporting of study 
participants (HCs and patients) disposition (Summary 15.1.1.1), study participants demographics 
(Summary 15.1.2.1) and baseline characteristics data (Summary 15.1.2.3) of Part 1 and also, for 
summary and listing of protocol violations for all study participants (Part 1) (Summary 15.1.7.1). 
 


 
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4. 
GENERAL ISSUES FOR DATA ANALYSIS 
4.1. 
General 
Descriptive statistics for continuous variables include n, mean, standard deviation (SD), median, 
minimum, and maximum.  
Descriptive statistics for categorical variables include patient counts and percentages (n, %). 
Categories for missing data will be presented if necessary.  
Correlation will be calculated using Spearman’s Rho correlation. 
4.2. 
Specification of Baseline Values 
For Part 2, baseline is the last observed data before the first dose of study drug (i.e, Visit 4, Day 
1), unless otherwise noted. For assessing changes from baseline in PET/CT signal as surrogate of 
lung inflammation in patients with asthma at each post-randomization visit, the baseline is the 
average of two measurements at visits 2 and 3 of Part 1. See Table 1 (section 2.1). 
4.3. 
Handling Withdrawals and Missing Data 
Overall mean scores for AQLQ (Asthma Quality of Life Questionnaire at each visit of Part 2) and 
ACQ-6 (6-item Asthma Control Questionnaire for entry criterion at Screening for patients with 
asthma only) will be calculated for patients who answer all the questions. For the item analysis, 
the mean of the score by domain will be computed if all questions of the domain are answered.   
For the AQLQ questionnaire, if a lot of missing data are observed, it will be dealt with by imputing 
mean values where more than half of the responses to a subscale will be present, as sensitive 
analysis (Apfelbacher et al. 2012).   
For all other variables, only the observed data from the evaluable patients/subjects up to study 
completion or study withdrawal will be used in the statistical analyses, i.e., there is no plan to 
impute missing data for other variables. 
4.4. 
Study Days and Visits 
For 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 summary (this includes scheduled and 
unscheduled assessments).  
Study days are numbered relative to the first day of study drug administration. The start of 
treatment (Day 1, Visit 4) 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 treatment start (i.e., 
..., –2, –1, 1, 2, ...; with day 1 being the first day of study drug administration and day –1 being the 
day before the first day of study drug administration). For details of study days and visits, see 
Table 1. 
 


 
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5. 
STUDY POPULATION 
5.1. 
General 
With the exception of brief physical examination reported in Part 2 only (see Table 1), where only 
ITT analysis set will be used and ACQ-6 questionnaire used for entry criteria at Screening for 
patients with asthma only, all analyses detailed in section 5 will be based on the enrolled analysis 
set (Part 1) and on the ITT analysis set (Part 2) as well, unless otherwise specified. 
For analysis performed on the enrolled analysis set, summaries will be presented by study 
participants status (Healthy Control Subjects (HCs), n=5)) vs. patients with asthma, n=10) and 
overall (n=15).  
For analysis performed on the ITT analysis set, FAS or safety set summaries will be presented by 
treatment group (reslizumab (n=5) vs. placebo, n=5)) and overall (n=10). 
5.2. 
Patient Disposition 
For Part 1, data from patients screened, subjects/patients enrolled, not enrolled (i.e., screen failure 
and reason for failure), subjects/patients completed Part 1, subjects/patients who withdraw from 
Part 1 with reason for withdrawal. For Part 2, patients enrolled but not randomized (and reason for 
not randomized), patients who are randomized (ITT analysis set), patients randomized but not 
treated, safety, and full analysis sets, patients who complete the study and patients who withdraw 
from the study with reason for withdrawal, will be summarized using descriptive statistics 
(Summary 15.1.1.1).  
5.3. 
Demographics and Baseline Characteristics 
Patients and HC subjects demographics: age (years), sex (male , female), height (cm), weight (kg), 
body mass index (BMI, kg/m2), ethnicity (Not Hispanic or Latino, Hispanic or Latino, unknown) 
, race (white, black or African American, Asian, American Indian or Alaskan Native, Native 
Hawaiian or other Pacific Islander, other), and baseline characteristics including tobacco usage: 
smoker or not, current or former user (never used, formerly used, currently uses), number of non-
smoking years, number of smoking years, number of packs per days, will be summarized for Part 
1 based on the enrolled analysis set (Summaries 15.1.2.1 and 15.1.2.3) and for Part 2 based on the 
ITT analysis set (Summaries 15.1.2.2 and 15.1.2.4), using descriptive summary statistics.   
Airway reversibility testing using spirometry will be summarized for Part 1 using the enrolled 
analysis set and for Part 2 using the ITT analysis set (Summaries 15.1.3.1 and 15.1.3.2, 
respectively). 
Similarly, clinical laboratory tests (see Table 4 of the protocol) performed at screening visit will 
be summarized for serum laboratory chemistry tests, serum laboratory hematology tests, and 
urinalysis laboratorty tests based on the enrolled analysis set (Summaries 15.1.4.1, 15.1.4.2, and 
15.1.4.3, respectively). 
Serum β-HCG test performed at screening will be summarized (n, %) by beta-HCG category 
(negative, borderline, and positive) and participants group (HCs, asthma patients) based on 
enrolled analysis (Summary 15.1.4.4). Positive/borderline values will be listed by individual 
participants for the enrolled analysis set. 


 
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Vital signs at screening visit, including pulse rate, systolic/diastolic blood pressure, respiratory 
rate, temperature and oxygen saturation, will be summarized, by participants group (HCs, asthma 
patients), for enrolled analysis set (Summary 15.1.5.1). 
Moreover,  number and percentages of patients/subjects (Part 1) with at least one abnormal 
physical examination finding at screening visit will be  summarized, by participants group and 
overall, based on the enrolled analysis set (Summary 15.1.6.1). Similarly, for Part 2, number and 
percentages of patients with at least one abnormal physical examination finding at each visit will 
be summarized by visit (4, 5, 6, and 7) and treatment group (reslizumab, placebo and overall) based 
on the safety analysis set (Summary 15.3.4.1).  
Any physical examination finding that is judged by the investigator as clinically significant will 
be considered as an adverse event and listed as such. 
5.4. 
Medical History 
All medical history will be coded using the latest available version of Medical Dictionary for 
Regulatory Activities (MedDRA). 
The incidence of general medical history abnormalities will be summarized using descriptive 
statistics (n, %) by system organ class (SOC) and preferred term. Patients/subjects are counted 
only once in each preferred term and SOC category. Summaries will be presented by study 
participants group (Asthma patients versus HC subjects) and overall (Summary 15.1.7.1) based on 
the enrolled analysis set, and by treatment group (Reslizumab versus Placebo) and overall 
(Summary 15.1.7.2) based on safety analysis set.  
Asthma/allergic history are recorded on the CRF. The incidence of following asthma/allergic 
histories (asthma, chronic sinusitis, atopic dermatitis, aspirin rhinitis, ever received allergy shots, 
presence of pets at home, food allergy, eosinophilic esophagitis, asthma exacerbations requiring 
systemic corticosteroids within the last 12 months, patient was hospitalized or visited the 
emergency department for asthma within the last 12 month, history of intubation for asthma 
exacerbation, history of ICU admission for asthma exacerbation, days missed from school/work 
due to asthma in the last 12 months) will be summarized, by study participants group, based on 
the enrolled analysis set (Summary 15.1.7.3) and by treatment group, based on the safety analysis 
set (Summary 15.1.7.4), using descriptive statistics. Patients are counted only once in 
asthma/allergic histories. 
The anteriority of the first diagnosis and of the most recent event and the number of events will be 
summarized by asthma/ allergies history abnormalities.  
The ACQ-6 is a validated asthma assessment tool performed at Screening (Visit 1) as entry criterion six 
questions self-assessments questionnaire completed by the patients only. The Healthy subjects do not 
use this tool. Each question on the ACQ-6 is scored on 7-point scale ranging from 0 to 6, and the total 
score is the mean of all responses (see Appendix A of the protocol and Juniper et al (1999)). The total 
score will be summarized, by treatment group, based on the ITT analysis set using descriptive statistics 
(Summary 15.1.7.5). 
 


 
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Nasal polyps history are recorded on the CRF. The incidence of nasal polyps history abnormalities 
will be summarized using descriptive statistics (n, %). Patients/subjects are counted only once. 
Sinus surgery performed (Y/N), anteriority of the surgery (years), diagnosed by CT scan (Y/N), 
anteriority of the CT scan (years) and anosmia will be summarized, by study participants group 
based on the enrolled analysis set for Part I (Summary 15.1.7.6), and by treatment group based on 
the safety analysis set for Part II (Summary 15.1.7.7), using descriptive statistics.  
 
5.5. 
Prior therapy and Medication 
Any prior medication, treatment, or procedure a patient/subject has had within 4 weeks before 
screening and stopped before the first study visit (screening) will be recorded on the CRF.  
Generic or trade name, indication, and dosage will be recorded. The sponsor will encode all therapy 
and medication according to the latest version of the World Health Organization drug dictionary 
(WHO Drug) 
The incidence of prior therapies and medications will be summarized using descriptive statistics 
(n, %) by therapeutic class and preferred term and study participants, based on the enrolled analysis 
set for Part I (Summary 15.1.8.1), and by therapeutic class/preferred term and treatment group 
based on the safety analysis set for Part II (Summary 15.1.8.2). Patients/subjects are counted only 
once in each therapeutic class category, and only once in each preferred term category. Prior 
therapies and medications will include all medications taken and therapies administered before the 
first day of study drug administration. 
For details of allowed prior medications (with restrictions) and not allowed medications during the 
study, see section 5.3 of the protocol. 
5.6. 
Electrocardiography 
A 12-lead ECG values collected at Screening (ECG mean hear rate, PR interval, QRS duration, 
QT interval, QTcB interval, QTcF interval, and RR interval) and the proportion of normal ECG, 
non-clinically significant abnormality and clinically significant abnormality at screening will be 
summarized, by study participants group and overall based on the enrolled analysis set (Summary 
15.1.9.1) and safety analysis set (Summary 15.1.9.2), using descriptive statistics (n, %). 
 
5.7. 
Childbearing Potential and Methods of Contraception 
For female patients, information related to childbearing potential, and menopause will be collected. 
Childbearing potential (Y/N), birth control method [combined (estrogen and gestagen) oral 
contraceptives, hormone implants, hormone rings, contraceptive patch, hormones injectables, 
progesterone only hormonal contraception, other] , barrier methods of contraception (diaphragm 
with spermicide, portio cap with spermicide, condoms with spermicide, other), intrauterine device 
(copper, hormonal, none), abstinence (Y/N), surgically sterilized (Y/N), menopause age, 
documented hysterectomy (Y/N), bilateral oophorectomy or salpingectomy (Y/N) will be 
summarized, using descriptive summary statistics,  by study participants group and overall based 


 
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on the enrolled analysis set (Summary 15.1.10.1), and by treatment group and overall based on the 
safety analysis set (Summary 15.1.10.2). 
A serum β-HCG pregnancy test will be performed at V1 (Screening) only, for all participating 
women of childbearing potential. Data will be summarized (n, %) by beta-HCG category 
(negative, borderline, and positive) and participants group (HCs, asthma patients) based on 
enrolled analysis (Summary 15.1.4.4), and will be listed. 
Urine β-HCG tests will be performed, for all participating women of childbearing potential, at V2, 
V3, V5, V6, and V7, prior to performance of PET/CT scan and will be listed. 
5.8. 
Study Protocol Violations 
Subjects/patients with any protocol violations (as recorded in protocol violation CRF) during the 
study will be summarized by violation classification category and overall using descriptive 
statistics (n, %) for the enrolled analysis set (Part 1: Summary 15.1.11.1) and for the ITT analysis 
set (Part 2: Summary 15.1.11.2). Subjects/patients will be counted only once in each violation 
category for the summary purpose. Data will be listed. 
All instances of medication errors, overdose, misuse, abuse, off-label use, and occupational 
exposure will be summarized in category “Non-Compliance to study investigational medical 
product (IMP).” 
For definition of protocol violations, see sections 11.1.2 and 7.3 of the protocol. 
 


 
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6. 
EFFICACY ANALYSIS 
6.1. 
General 
The study is composed of two parts with two primary objectives.  
The enrolled analysis set will be used for the part 1 analysis (summaries and listings). Summaries 
will be presented by participants status [HC subjects (n=5) vs. patients with asthma (n=10)] and 
overall. 
The ITT analysis set will be used for the summaries and presentations of the primary and secondary 
efficacy endpoints and the FAS analysis set will be used for all efficacy and exploratory analyses 
for the Part 2 data. Summaries will be presented by treatment group (reslizumab vs. placebo) and 
overall.  
 
6.2. 
Primary Efficacy Endpoint and Analysis 
6.2.1. 
Definition 
The primary efficacy measure for this study is the change in GLG as assessed by PET/CT.  
Part 1 of the study will validate this measure by comparing this assessment between HC subjects 
and patients with eosinophilia asthma.  
In Part 1, the primary efficacy endpoint is the intra-patient variability (reproducibility measurement) in 
each group and inter-group variability between HC group and individual patients with eosinophilic 
asthma. 
In Part 2, only patients with eosinophilic asthma will be assessed for GLG at 2, 4, and 6 weeks, 
after randomization to placebo or treatment with a single dose of reslizumab. 
In Part 2, the primary efficacy endpoint is the change from baseline to week 4 in GLG (ΔGLG). 
 
The radiology center at 
 will determine the following:  
GLG is the total FDG uptake in the whole lung. 
A region of interest (ROI) is drawn around lung boundary in each axial slice. SUVmean and area 
of each ROI is recorded. Using the formula: area*slice thickness, the volume of each slice is 
calculated. Then SUVmean of each slice is multiplied by the volume of the corresponding slice, 
which will represent the total FDG uptake in one slice. This product for each slice is summed over 
number of slices to provide GLG of that lung for each subject/patient as follows: 
GLG=∑(𝑎𝑎𝑎𝑎𝑎𝑎𝑎𝑎∗𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠𝑠 𝑡𝑡ℎ𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖𝑖∗𝑆𝑆𝑆𝑆𝑆𝑆 𝑚𝑚𝑚𝑚𝑚𝑚𝑚𝑚)
𝑛𝑛
1
 
n=number of slices 
 
Intra-subject/patient variability (reproducibility measurement (Part 1) : 


 
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Below is the calculation to determine the intra-individual variability between PET/CT scans as 
measured by GLG for HC subjects and patients with eosinophilic asthma. The accepted variability 
within each group is ≤10% and will be calculated as follows: 
Relative difference of GLG (HCs) = (GLG2-GLG1)/GLG1  (For HC subjects) 
Relative difference of GLG (patients with eosinophilic asthma) = (GLG4-GLG3)/GLG3   (For 
patients) 
1= First measurement (HCs) 
2= Second measurement (HCs) 
3= First measurement (patients with eosinophilic asthma) 
4= Second measurement (patients with eosinophilic asthma) 
A 10% variability (measured as a relative difference between the first measurement and second 
measurement) between PET/CT scans as measured by GLG within each group (HCs, n=5) and patients 
(n=10), will be considered as the maximum allowed intra-group variability. 
 
Relative differences between the first (V2) and second (V3) measurements will be summarized, by 
total/regional lung and patients/HC group, using descriptive summary statistics, based on enrolled 
analysis set (Summary 15.2.1.1). 
Variability between HC group and individual patients with eosinophilic asthma (Part 1):  
The planned method to assess whether the difference in GLG measure between HC subjects, as a 
group, and individual patients (one-by-one) with eosinophilic asthma is ≥5% will be calculated as 
follows: 
 For Females: Relative difference of GLG = (GLG6i-GLG5f)/GLG5f, i.e., difference in GLG 
(based on average of 2 measurements) between each individual patient with asthma and the 
mean of HC group, for females. 
 For Males: Relative difference of GLG = (GLG6i-GLG5m)/GLG5m, i.e., difference in GLG 
(based on average of 2 measurements) between each individual patient with asthma and the 
mean of HC group, for males. 
5=average of 2 GLG measurements (1 and 2) of all HCs by sex 
6=average 2 GLG measurements (3 and 4) for each individual asthma patients 
GLG6i will be calculated for each individual male/female patient using his/her two GLG 
measurements at V2 and V3 (Part 1). If this amount is ≥ 5% then the patient will be randomized. 
Relative differences in GLG measures between the HC group and individual patients with asthma 
will be summarized for each sex, by total lung/regional lung, using descriptive summary statistics, 
based on enrolled analysis set (Summaries 15.2.1.2 and 15.2.1.3). 
 
Relative change from baseline to week X in GLG (ΔGLG) (Part 2): 
ΔGLG = (GLGwX –GLGbaseline)/GLGbaseline 


 
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wX= post-randomization week (week 2 /V5, week 4/V6, and week 6/V7). 
GLG Baseline= the average of two measurements at Visits 2 and 3 of Part 1 (see section 4.2 of the 
SAP).  
 
SUV mean: 
SUV is a well validated measure which normalizes FDG uptake by any particular object/tissue 
volume by the administered dose and either total body weight or total body surface area. Regions 
of interest (ROIs) will be drawn manually around the outer boundaries of the lung on every 
transverse slice passing through the lung on fused FDG PET/CT images from each subject. The 
trachea and main stem bronchi will be excluded from the ROIs to capture only the inflammation 
in the lung parenchyma. Lung sectional mean standardized uptake value (sSUV mean) and the 
area of the lung ROI will be recorded from each slice. Subsequently, the sectional lung volume 
(sLV) will be calculated from each slice by multiplying the lung ROI area (in centimeters squared) 
by 0.4 (slice thickness 4 mm). The sectional lung glycolysis (sLG) will be determined by 
multiplying sLV and lung sSUV mean from each slice. The lung volume (LV) will be calculated 
by adding all the sLV from slices passing through the lung, and the global lung glycolysis (GLG) 
will be determined by adding all the sLG from slices passing through the lung. 
Finally, the lung SUV mean will be calculated as follows: 
SUV = GLG/LV. 
Similar methodology is applied to lymph nodes and bone marrow. See section 6.4.3 of this SAP. 
6.2.2. 
Primary Efficacy Analysis 
For Part 1, intra-group variability and variability between HC group and individual patients with 
eosinophilic asthma data and all variables which enter into these calculations will be listed.  
 
For Part 2, change in GLG from baseline to each of the postbaseline visits (2, 4, and 6 weeks, after 
randomization) will be summarized, using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum), by treatment group (reslizumab vs placebo) for total and regional lung based 
on ITT and FAS. The difference in mean changes from baseline between reslizumab and placebo will also 
be summarized and reported (Summaries 15.2.2.1 to 15.2.2.8). 
 
No inferential statistics will be used for the primary endpoints analyses. 
6.2.3. 
Supportive Primary Efficacy Endpoint Analysis 
The supportive primary efficacy endpoint is the change from baseline to week 4 in LP SUVmean (Avg 
SUVmean). 
 
The same statistical methods used for the analysis of the primary efficacy endpoints of Part 2 above will 
be used to summarize the supportive primary efficacy endpoints (Summaries 15.2.2.1 to 15.2.2.8).  


 
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6.2.4. 
Sub-Group Analyses 
No subgroup analysis will be performed for this study. 
6.3. 
Secondary Efficacy Endpoints and Analysis.  
The secondary efficacy endpoints will be descriptively summarized using the same statistical 
methods used for the primary efficacy endpoint of Part 2 above. In addition, to demonstrate the 
relationship between the benefit observed on imaging (PET/CT scan) with the secondary 
endpoints, the correlation between the change from baseline to week 4 for each secondary endpoint 
and change from baseline to week 4 in GLG (ΔGLG) will be calculated using Spearman’s Rho. 
No inferential statistics will be used for the secondary endpoints analyses. 
6.3.1. 
Blood Eosinophil Count 
6.3.1.1. 
Definition 
The first secondary efficacy endpoint is change from baseline (Day 1/Visit 4) to weeks 2, 4, and 6 
in blood eosinophil count.  
6.3.1.2. 
Analysis 
Blood eosinophil count value and change from baseline to each of the post-baseline visits (2, 4, 
and 6 weeks, after randomization) will be descriptively summarized, by treatment group, based on 
the ITT and FAS. The difference in mean changes from baseline between reslizumab and placebo, 
and Spearman’s Rho will also be summarized and reported (Summaries 15.2.3.1 and 15.2.3.2). 
 
6.3.2. 
Forced Expiratory Volume (FEV1) 
6.3.2.1. 
Definition 
FEV1 will be measured using spirometry. The FEV1 is the volume of air which can be forcibly 
exhaled from the lungs in the first second, measured in liters. 
The second secondary efficacy endpoint is the change from baseline (Day 1/Visit 4) to weeks 2, 
4, and 6 in FEV1. 
6.3.2.2. 
Analysis 
FEV1 value and change from baseline to each of the post-baseline visits (2, 4, and 6 weeks, after 
randomization) will be descriptively summarized, by treatment group, based on the ITT and FAS. 
The difference in mean changes from baseline between reslizumab and placebo, and Spearman’s 
Rho will also be summarized and reported (Summaries 15.2.3.3 and 15.2.3.4). 
 


 
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6.3.3. 
Fractional Exhaled Nitric Oxide (FeNO) Measurements 
6.3.3.1. 
Definition 
The third secondary efficacy endpoint is change from baseline to weeks 2, 4, and 6 in FeNO 
measurements.  
6.3.3.2. 
Analysis 
FeNO measurements and change from baseline to each of the post-baseline visits (2, 4, and 6 
weeks, after randomization) will be descriptively summarized, by treatment group, based on the 
ITT and FAS. The difference in mean changes from baseline between reslizumab and placebo, and 
Spearman’s Rho will also be summarized and reported (Summaries 15.2.3.5 and 15.2.3.6). 
 
6.3.4. 
AQLQ score  
6.3.4.1. 
Definition 
The fourth secondary efficacy endpoint is change from baseline (Day 1/Visit 4) to weeks 2, 4 and 
6 in AQLQ. 
The AQLQ+12 is a modified version of the standardized self-administered AQLQ questionnaire, 
which was developed to measure functional impairments experienced by adults ≥17 years of age. 
The AQLQ+12 is valid for patients aged 12 to 70 years and includes 32 questions/items in 4 
domains: asthma symptoms (12 questions: 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 29, 30), activity 
limitation by asthma (11 questions: 1 to 5, 11, 19, 25, 28, 31, 32), emotional function (5 questions: 
7, 13, 15, 21, 27) and exposure to environmental stimuli (4 questions: 9, 17, 23, 26). Patients are 
asked to recall their experiences during the previous 2 weeks and score their response options to 
each of the questions on a 7-point scale where 7 = no impairment and 1 = severe impairment.  
The questionnaire is analyzed directly from the scores recorded. First, the overall AQLQ score is 
calculated as the mean of all 32 responses for each patient and the individual domain scores are 
the means of the responses within each domain for each patient. For details of the AQLQ+12 
questionnaire, see Appendix B of the protocol and Juniper et al (1992). 
AQLQ scores were recorded at Visits 4 (Baseline, Day 1), 5, 6 and 7 of Part 2 (see Table 1).  
6.3.4.2. 
Analysis 
Mean AQLQ scores and change from baseline to each of the post-baseline visits (2, 4 and 6 weeks 
after randomization) will be descriptively summarized, for overall score, and each domain,  and 
treatment group, based on the ITT and FAS. The difference in mean changes from baseline 
between reslizumab and placebo, and Spearman’s Rho will also be summarized and reported 
(Summaries 15.2.3.7 and 15.2.3.8).   
 
6.4. 
Exploratory Efficacy Endpoints Analysis 
No inferential statistics will be used for exploratory efficacy endpoints and analyses. 


 
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6.4.1. 
Biological Markers of Inflammation and Asthma: IgE, DPP4, 25-hydroxy  
vitamin D, eotaxin-1, -2, and -3, TARC, MCP-1 and MCP-4, ILC2 
6.4.1.1. 
Definition 
Blood samples for assessment of biological markers of inflammation and asthma will be collected at Visits 
4, 5, 6, and 7 and processed using the procedures in place at the investigational center 
 
 
6.4.1.2. 
Analysis 
Change from baseline (Day 1/Visit 4) to each of the post-baseline visits (2, 4, and 6 weeks after 
randomization) in biological markers of inflammation and asthma, will be summarized using 
descriptive statistics (n, mean, standard deviation, median, minimum, and maximum) by treatment 
group, based on FAS. The difference in mean changes from baseline between reslizumab and 
placebo will also be summarized and reported for each biological marker (Summary 15.2.4.1). 
In addition, to explore the relationship between the benefit observed on imaging (PET/CT scan) 
with the exploratory biomarker endpoints, the correlation between the change from baseline to 
week 4 for each biomarker endpoint and change from baseline to week 4 in GLG (ΔGLG) will be 
calculated using Spearman’s Rho. 
 
6.4.2. 
Biological Lung Function Variables: FVC, PEFR, FEF25%-75% 
6.4.2.1. 
Definition 
Forced vital capacity (FVC), PEPR, and FEF25%-75% will be measured at baseline (Visit 4) and 
post-baseline visits 5, 6 and 7, using spirometry (see section 6.2 of the protocol). 
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.  The PEFR 
is the peak expiratory flow rate, measured in L/min. 
Spirometry will be conducted according to American Thoracic Society/European Respiratory 
Society 2005 procedural guidelines. The National Health and Nutrition Survey III reference 
equations will be used. 
6.4.2.2. 
Analysis 
FVC, PEPR, and FEF25%-75% values and change from baseline to each of the post-baseline visits 
(2, 4, and 6 weeks after randomization) will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum, and maximum), by treatment group based on FAS. The 
difference in mean changes from baseline between reslizumab and placebo will also be 
summarized and reported for each lung function variable (Summary 15.2.4.2). 
In addition, correlation between change from baseline to week 4 in FVC, PEPR, and FEF25%-75% 
and change from baseline to week 4 in GLG (ΔGLG) will be calculated using Spearman’s Rho 
correlation.  


 
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6.4.3. 
Upper-body Uptake of FDG in Lymph Nodes and Bone Marrow 
6.4.3.1. 
Definition 
The uptake of FDG in the lymph nodes and bone marrow of the upper body (lower limit of iliac 
crest) as measured by the PET/CT imaging parameters indicated for the primary efficacy variable 
(see section 6.1.2 of the protocol and section 6.2.1 of the SAP). 
6.4.3.2. 
Analysis 
Change in values of uptake of FDG in the lymph nodes and bone marrow of the upper body from 
baseline (the average of 2 measurements at V2 and V3 of Part 1) to each of the post-baseline visits 
(weeks 2, 4, and 6 after randomization) will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum, and maximum), by treatment group based on FAS. The 
difference in mean changes from baseline between reslizumab and placebo will also be 
summarized and reported for total lymph node inflammation and total bone marrow inflammation 
(Summary 15.2.4.3). 
 
6.4.4. 
Sputum Eosinophils  
6.4.4.1. 
Definition 
For those patients who can produce sputum, sputum sampling for eosinophils will be performed 
at Visits 4, 5, 6, and 7.  
6.4.4.2. 
Analysis 
Change in values of sputum eosinophils from baseline (Day 1/Visit 4) to each of the post-baseline 
visits (weeks 2, 4, and 6 after randomization) will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum), by treatment group based on FAS. 
The difference in mean changes from baseline between reslizumab and placebo will also be 
summarized and reported (Summary 15.2.4.4). 
In addition, correlation between change from baseline to week 4 in sputum eosinophils and change 
from baseline to week 4 in GLG (ΔGLG) will be calculated using Spearman’s Rho correlation.  
 


 
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7. 
MULTIPLE COMPARISONS AND MULTIPLICITY 
No adjustments will be made for the preplanned multiple comparisons/endpoints. 


 
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8. 
SAFETY ANALYSIS 
8.1. 
General 
The safety analyses for Part 2 of the study will be presented by treatment group and overall, based 
on the safety analysis set. 
In addition, safety analysis for Part 1, based on the enrolled analysis set, will be presented by study 
participants status (HCs vs patients with asthma) and overall. 
Combined safety analysis presenting safety data for Part 1 and Part 2 of the study may be provided, 
as deemed necessary. 
Individual listings will also be provided.  
 
8.2. 
Adverse Events 
All adverse events will be coded using the latest available version of the Medical Dictionary for 
Regulatory Activities (MedDRA), associated with five levels of classifications: a System Organ 
Class (SOC), a High Level Group Term (HLGT), a High Level Term (HLT), a Preferred Term 
(PT) and a lowest Level Term (LLT).  
Only Treatment Emergent Adverse Event (TEAE), defined as events occurring after the first drug 
administration and until the end of the study, will be presented, based on Safety analysis set.  
Similarly, AEs occurring between ICF signing and end of Part 1 will be presented based on 
Enrolled analysis set. 
In the AE summary tables 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 
by treatment group, and overall as following: 
- 
All AEs sorted by SOC and PT based on Safety analysis set (Summary 15.3.1.1) and on 
Enrolled analysis set (Summary 15.3.1.2) 
- 
All AEs sorted by PT based on Safety analysis set (Summary 15.3.1.3) and on Enrolled 
analysis set (Summary 15.3.1.4) 
- 
Treatment-related AE sorted by SOC and PT based on Safety analysis set (Summary 
15.3.1.5) 
- 
Serious AE sorted by SOC and PT based on Safety analysis set (Summary 15.3.1.6) 
- 
Non serious AE sorted by SOC and PT based on Safety analysis set (Summary 15.3.1.7) 
- 
AE sorted by SOC, PT and severity based on Safety analysis set (Summary 15.3.1.8). 
Asthma deterioration will be descriptively summarized for safety analysis set (Summary 15.3.1.9). 
Patient listings of serious adverse events and adverse events leading to withdrawal will be 
presented. Suspected anaphylaxis/hypersensitivity and CPK reactions will be listed individually 
(Listings 16.2.8.12 and 16.2.8.13). 


 
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8.3. 
Death 
If one or more patients die during the study, a listing of deaths will be provided (Listing 16.2.7.4). 
8.4. 
Clinical Laboratory Tests 
Laboratory values and changes from baseline (Visit 4 or the last available value pre-dosing study 
medication) to endpoint (Visit 7) in laboratory test  results (in standard international (SI) units)) 
will be presented, by treatment group and overall, using descriptive summary statistics (n, mean, 
SD, median, min, max), based on the safety analysis set (Part 2), for serum chemistry (Summary 
15.3.2.1), and for serum hematology values and changes from baseline to each post-baseline visit 
(Summary 15.3.2.2). Urinalysis tests performed at Visits 4 and 7 will be summarized in Summary 
15.3.2.3. Specific clinical laboratory tests performed at Screening (Visit 1) and at various visits 
throughout the study are presented in Table 2 below.  
 
Table 2. 
Clinical Laboratory Tests 
Serum Chemistry 
Hematology 
Urinalysis 
β human chorionic gonadotropin (HCG)a 
calcium 
phosphate 
sodium 
potassium 
chloride 
creatinine 
glucose 
blood urea nitrogen (BUN) 
cholesterol (low density lipoprotein 
[LDL]/high density lipoprotein 
[HDL]/total)a 
triglyceridesa 
uric acid 
alanine aminotransferase (ALT) 
aspartate aminotransferase (AST) 
lactate dehydrogenase (LDH) 
gamma-glutamyl transpeptidase (GGT) 
alkaline phosphatase 
bicarbonate or carbon dioxide 
creatinine phosphokinase 
total protein 
albumin 
total bilirubin 
direct bilirubin 
indirect bilirubin 
hemoglobin 
hematocrit 
red blood cell (RBC) count 
RBC indices 
platelet count 
white blood cell (WBC) count, and 
differential count and percentage 
− absolute neutrophil count 
(ANC) 
− polymorphonuclear leukocytes 
(neutrophils) 
− lymphocytes 
− eosinophils 
− monocytes 
− basophils 
− atypical lymphocytes 
− other (to include band 
granulocytes) 
international normalized ratio (INR) 
Β-HCGa 
protein 
glucose 
ketones 
blood (hemoglobin) 
pH 
specific gravity 
microscopic 
− bacteria 
− red blood cells (RBCs) 
− white blood cells (WBCs) 
 
a Assessed at the screening visit only. 


 
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Shifts (below, within, and above the normal range) from baseline (Visit 4) to each post-baseline 
visit (hematology) and to endpoint (Visit 7, serum chemistry and urinalysis) will be summarized, 
by treatment group and overall based on the safety analysis set (Part 2), using patient counts (n) 
for each serum chemistry lab test (Summary 15.3.2.4), for each hematology lab test (Summary 
15.3.2.5), and for each urinalysis lab test (Summary 15.3.2.6). 
The incidence of post-baseline (including scheduled, unscheduled, and withdrawal visits) 
potentially clinically significant abnormal (PCS) abnormal values will be summarized for serum 
chemistry, hematology and urinalysis laboratory tests (Summaries 15.3.2.7, 15.3.2.8, and 15.3.2.9, 
respectively), using descriptive statistics (n, %) with the criteria for potentially clinically 
significant specified in Table 3 below. 
 


 
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Table 3. 
Criteria for Potentially Clinically Significant Laboratory Values 
Test 
Criterion value* 
Alanine aminotransferase (ALT) 
≥ 3x ULN 
Aspartate aminotransferase (AST) 
≥ 3x ULN 
Alkaline phosphatase 
≥ 3x ULN 
Gamma-glutamyl transpeptidase (GGT) 
≥ 3x ULN 
Lactate dehydrogenase (LDH) 
≥ 3x ULN 
Blood urea nitrogen (BUN) 
≥ 10.71 mmol/L 
Creatinine 
≥ 177 mmol/L 
Uric acid Men 
≥ 625 mmol/L 
Uric acid Women 
≥ 506 mmol/L 
Bilirubin (total) 
≥ 34.2 mmol/L 
Hematology 
Hematocrit Men 
< 0.37 L/L 
Hematocrit Women 
< 0.32 L/L 
Hemoglobin Men 
≤ 115 g/L 
Hemoglobin Women 
≤ 95 g/L 
Hemoglobin Adolescents (12 to 17 years) 
≤ 100 g/L 
White blood cell (WBC) counts 
≤ 3 x 109/L 
≥ 20 x 109/L 
Eosinophils 
≥ 10% 
Absolute neutrophil counts (ANC) 
≤ 1 x 109/L 
Platelet counts 
≤ 75 x 109/L  
 
≥ 700 x 109/L 
Urinalysis 
Blood (HGB) 
≥2 unit increase from baseline 
Glucose 
≥ 2 unit increase from baseline 
Ketones 
≥ 2 unit increase from baseline 
Total protein 
≥ 2 unit increase from baseline 
* ULN=upper limit of normal range. 
 
 
 
 
 


 
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For Creatine phosphokinase (CPK) parameter, no PSC will be calculated but the grading scale of 
the Guidance for Industry Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
Enrolled in Preventive Vaccine Clinical Trials will be used to classify subjects in the four 
following grades (Summary 15.3.2.9) : 
Table 4. Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers 
 
Mild (Grade 1) 
Moderate (Grade 2) 
Severe (Grade 3) 
Potentially Life Threatening (Grade 4) 
CPK 
1.25 – 1.5 x ULN 
1.6 – 3.0 x ULN 
3.1 – 10x ULN 
> 10 x ULN 
 
8.4.1. 
Other Clinical Laboratory Tests 
Human chorionic gonadotropin tests (β-HCG) in serum will be performed at screening (Visit 1) only for all 
participating women of child bearing potential. Urine β-HCG tests will be performed for all participating 
women of child bearing potential at V2, V3, V4, V5, V6, and V7, before study drug administration and 
before each PET/CT scan.   
Capillary blood glucose will be performed before each PET/CT scan (V2, V3, V5, V6 and V7) to 
check the glucose level. If a threshold is raised (determined by the investigator), the scan is 
canceled or postponed. Test results (in standard international (SI) units)) will be presented, by 
treatment group and overall, using descriptive summary statistics (n, mean, SD, median, min, 
max), based on the enrolled analysis set (Part 1) and safety analysis set (Part 2). 
 
8.5. 
Physical Examinations 
Complete physical examinations, including height and weight (to be obtained at screening visit 
only) are to be performed at Visit 1 and Visit 7.   
The “full” physical examination should include the following organ systems: General appearance; 
Head, Eyes, Ears, Nose, and Throat; Chest and Lung; Heart; Abdomen; Musculoskeletal; Skin; 
Lymph Nodes; and Neurological.  
The “brief” physical examination recorded at Visits 4, 5, and 6 (Part 2) only should include at 
minimum the following organ systems: General appearance; Head, Eyes, Ears, Nose, and Throat; 
Chest and Lung; and Heart.  
Any physical examination finding that is judged by the investigator as clinically significant will 
be considered as an adverse event, recorded on the CRF in the same way and will then be displayed 
with AEs (Summaries 15.3.1). 
Newly occurring abnormalities in the physical examinations will be identified and listed.  
Only percentages of subjects with physical abnormalities will be displayed in the safety part 
(Summary 15.3.4.1). 
 


 
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8.6. 
Vital Signs 
Vital signs (blood pressure, respiratory rate, body temperature, pulse, and blood oxygen saturation 
(SpO2) will be measured at Screening (Visit 1) and at Visits 4, 5, 6 and 7. All vital signs results 
outside of the reference ranges will be judged by the investigator as belonging to one of the 
following categories: 
• 
abnormal and not clinically significant 
• 
abnormal and clinically significant 
 
Any abnormal vital sign value that is judged by the investigator as clinically significant will be recorded on 
the source documentation, transcribed to the CRF as an adverse event. 
Summary statistics for vital signs: blood pressure, respiratory rate, body temperature, pulse, and 
SpO2 will be presented at baseline (visit 4), visit 5, visit 6 and visit 7 and will include: 
 Vital signs values and changes from baseline (Visit 4) to each post-baseline visit will be 
summarized, by treatment group, based on the safety analysis set, using descriptive 
statistics (Summary 15.3.3.1). Individual listings will also be provided. 
 Summaries of potentially clinically significant (PCS) abnormal values will include all post-
baseline values (including scheduled, unscheduled, and withdrawal visits). The incidence 
of potentially clinically significant abnormal values will be summarized (Summary 
15.3.3.2) using descriptive statistics (n, %) with the criteria for potential clinical 
significance abnormal values specified in Table 5 below. 
Note that in order to qualify as potentially clinically significant abnormal, a value needs to meet 
both criteria below: i.e., have a value beyond the criterion value and a change of at least the 
magnitude specified in the change relative to baseline column. 
Table 5. 
Criteria for Potentially Clinically Significant Vital Signs 
Vital Sign 
Criterion value 
Change relative to baseline 
Pulse 
>100 bpm 
Increase of ≥30 
 
<50 bpm 
Decrease of ≥30 
Systolic blood pressure 
>160 mm Hg 
Increase of ≥30 
 
<90 mm Hg 
Decrease of ≥30 
Diastolic blood pressure 
>100 mm Hg 
Increase of ≥12 
 
<50 mm Hg 
Decrease of ≥12 
Respiratory rate 
>24 breaths/min 
Increase of ≥10 
 
<6 breaths/min 
Not applicable 
Temperature 
<96.5°Fahrenheit 
Not applicable 
 
>100.5°Fahrenheit 
Increase of ≥2 
SpO2 
pulse oximeter <88% 
 


 
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8.7. 
Electrocardiography 
Any abnormal ECG value that is judged by the investigator at the screening visit (or at unscheduled visit if 
applicable) as clinically significant will be recorded as an adverse event.  
The incidence of patients meeting PCS thresholds for each QTc Bazett and Fridericia interval will be 
summarized (Summary 15.3.X.X) using descriptive statistics (n, %). 
The predefined threshold values for absolute QTc Bazett and Fridericia interval prolongations at baseline 
are > 450 msec and > 500 msec. 
 
8.8. 
Concomitant Medications or Therapies  
Concomitant therapies and medications, including medications that are taken on an as needed basis 
and occasional therapies, will be monitored during the study. Details of prohibited medications 
can be found in Section 5.3 of the study protocol. All concomitant medications will be coded using 
the latest version of the WHO Drug dictionary. 
The incidence of prior medications taken prior to study drug administration at Baseline (Visit 4) 
and reported at Visit 2 and 3 will be summarized using descriptive statistics (n,%), sorted by 
therapeutic class category and preferred term, according participant/treatment group based on 
enrolled analysis set (Summary 15.3.6.1) and on safety analysis set (Summary 15.3.6.2).  
The incidence of concomitant medications i.e., medications taken after the study drug 
administration at baseline during Part 2, will be summarized, by treatment group based on safety 
analysis set (Summary 15.3.6.3).  
Patients/subjects are counted only once in each therapeutic class, and only once in each preferred 
term category.       
                                                                           
 
 
 


 
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9. 
TOLERABILITY VARIABLES AND ANALYSIS 
Since this is a single-dose study, Tolerability was not specifically defined for this study. 
 


 
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10. 
IMMUNOGENICITY ANALYSIS 
ADA blood samples for serum ADA assay will be obtained at baseline before study drug administration 
(Visit 4) and at Visits 5, 7 and at possible unscheduled visits. Descriptive summary statistics will be 
provided using descriptive analysis (n, %) for each visit, indicated if tests are positive or negative at each 
timepoint (Summary 15.3.7.1). Samples from placebo-treated patients will not be analyzed. See section 
1.3 of the SAP. 
 
 


 
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11. 
STATISTICAL SOFTWARE 
All data listings, summaries, and statistical analyses will be generated using SAS® version 9.4 or 
later. 
 


 
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12. 
REFERENCES 
 
Apfelbacher et al. Validity of two common asthma-specific quality of life questionnaires: Juniper 
mini asthma quality of life questionnaire and Sydney asthma quality of life questionnaire. Health 
and Quality of Life Outcomes 2012, 10:97 
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. 
American Thoracic Society/European Respiratory Society 2005 procedural guidelines. 
SAS Institute Inc. 2011. SA/STAT User’s Guide. Cary, NC: SAS Institute Inc.