Clinical trial NCT03029000
Conditions: Healthy Participants
Sponsor: Teva Branded Pharmaceutical Products R&D, Inc.
Start date: 2017-08-02; Completion date: 2017-10-30
Enrollment: 1 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A multi-center, open-label, single-arm clinical study to assess effects of a 5-day regimen of 10 micrograms per kilogram (mcg/kg) of tbo-filgrastim administered subcutaneously daily on the mobilization of cluster of differentiation 34+ (CD34+) cells in at least 60 healthy male and female participants. The pharmacokinetics, pharmacodynamics, safety, tolerability, and immunogenicity of tbo-filgrastim will be assessed.

Detailed description:

Arms: arm 1: Participants will receive tbo-filgrastim 10 mcg/kg of body weight, subcutaneously on the morning of Days 1 to 5.

The actual dose of tbo-filgrastim administered to each, individual participant will be calculated at baseline according to his or her body weight and that specific dose (10 mcg/kg of body weight) for each, individual participant will remain the same for all consecutive daily doses.

If the collection goal will not meet after the first apheresis on Day 5, tbo-filgrastim 10 mcg/kg of body weight will be administered subcutaneously for up to 3 additional days (Days 6 to 8) followed by daily apheresis to reach the cumulative collection goal.
Interventions: intervention 1: Tbo-filgrastim
Intervention descriptions: intervention 1: solution for subcutaneous injection

Protocol documents:
Prot_SAP_000.pdf: 
Clinical Study Protocol with Amendment 01 
(including Statistical Analysis Plan) 
A Single-Arm Study of the Effect of a 5-day Regimen of Tbo-Filgrastim 10 μg/kg of Body 
Weight Administered Subcutaneously on Peripheral Stem Cell Mobilization in Healthy 
Donors 
Study Number TV44688-ONC-30054 
NCT03029000 
Protocol with Amendment 01 Approval Date: 12 April 2017 


Uncontrolled Study–Peripheral Stem Cell Mobilization 
Clinical Study Protocol with Amendment 01 
Study TV44688-ONC-30054 
1 
 
 
Clinical Study Protocol 
Study Number TV44688-ONC-30054 
A Single-Arm Study of the Effect of a 5-day Regimen of Tbo-Filgrastim 10 μg/kg of Body 
Weight Administered Subcutaneously on Peripheral Stem Cell Mobilization in Healthy 
Donors 
Efficacy and Safety Study (Phase 3) 
IND number: 103188 
Protocol Approval Date: 16 August 2016 
Protocol with Amendment 01 Approval Date: 12 April 2017 
Sponsor 
Monitor 
Teva Pharmaceutical Industries Ltd. 
5 Basel Street 
Petach Tikva, 4951033, Israel 
 
 
Sponsor’s Authorized Representative 
 
  
Merckle GmbH of Teva Group 
Sponsor’s Medical Expert 
Sponsor’s Representative of Global 
Patient Safety and Pharmacovigilance 
 
 
Teva ratiopharm 
Phone: 
 
Cel: 
 
 
 
 
 
Teva ratiopharm 
Phone: 
 
Cel: 
 
 
This clinical study will be conducted in accordance with current Good Clinical Practice (GCP) as directed by the 
provisions of the International Council for Harmonisation (ICH); United States (US) Code of Federal Regulations 
(CFR) and European Union (EU) Directives and Regulations (as applicable in the region of the study); local country 
regulations; and the sponsor’s Standard Operating Procedures (SOPs). 
Confidentiality Statement 
This document contains confidential and proprietary information (including confidential commercial information 
pursuant to 21CFR§20.61) and is a confidential communication of TEVA Pharmaceutical Industries Ltd. The 
recipient agrees that no information contained herein may be published or disclosed without written approval from 
the sponsor. 
© 2017 Teva Pharmaceuticals Industries Ltd. All rights reserved. 


 
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AMENDMENT HISTORY 
The protocol for study TV44688-ONC-30054 (original protocol dated 16 August 2016) has been 
amended and reissued as follows: 
Amendment 01 
12 April 2017 
0 patients randomized/enrolled to date 
The Summary of Changes to the Protocol includes the corresponding reason/justification for 
each change and is provided in Section 17. 
 


 
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INVESTIGATOR AGREEMENT 
 


 
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CLINICAL LABORATORY AND OTHER DEPARTMENTS AND 
INSTITUTIONS 
Sponsor’s Authorized Representative 
 
 
Merckle GmbH of Teva Group 
Sponsor’s Medical Expert 
. 
 
Teva ratiopharm 
Phone: 
 
Cel: 
 
Email: 
 
Contract Research Organization and Monitor 
 
 
 
 
Phone: 
 
Fax: 
 
Sponsor’s Representative of Global Patient Safety and Pharmacovigilance 
 
 
Teva ratiopharm 
Phone: 
 
Cel: 
 
Email: 
 
Central Clinical Laboratory 
 
 
Bioanalytical Pharmacokinetics Evaluation 
 


 
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Bioanalytical Immunogenicity Evaluation 
Global Bioassays and Technology 
Teva Pharmaceuticals Ltd. 
145 Brandywine Pkwy 
West Chester, PA 19380, USA 
Pharmacogenomics/Biomarker Evaluation 
To be determined 


 
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CLINICAL STUDY PERSONNEL CONTACT INFORMATION 
For medical issues, contact the physician listed below: 
 
 
 
24-Hour Safety Hotline: 
Phone: 
 
24 Hour Safety Hotline: 
Fax: 
 
Fax: 
 
Study Coordinating Investigator:  
  
Phone: 
 
Fax: 
 
For operational issues, contact the operational lead listed below:  
 
 
 
Phone: 
 
Email: 
 
For protocol issues, contact the study leader listed below:  
 
 
Merckle GmbH of Teva Group 
Phone: 
 
Cel: 
 
Email: 
 
For serious adverse events:  
Send the Serious Adverse Event Transmittal Form to the Teva US Patient Safety and 
Pharmacovigilance Department via email 
 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 
Protocol with Amendment 01 
Study Number: TV44688-ONC-30054 
Title of Study: A Single-Arm Study of the Effect of a 5-day Regimen of Tbo-Filgrastim 
10 μg/kg of Body Weight Administered Subcutaneously on Peripheral Stem Cell Mobilization in 
Healthy Donors 
Sponsor: Teva Pharmaceutical Industries Ltd. 
Investigational New Drug (IND) Number: 103188 
Name of Active Ingredient: tbo-filgrastim (also known as XM02; and recombinant methionyl 
human granulocyte colony-stimulating factor [r-metHuG-CSF]) 
Name of Investigational Medicinal Product: tbo-filgrastim solution for subcutaneous (sc) 
injection 
Type and Phase of the Study: Efficacy and safety (Phase 3) 
Number of Investigational Centers Planned: Approximately 20 
Country Planned: United States of America 
Planned Study Period: Approximately fourth quarter (Q4) 2016 to Q4 2017 
Number of Healthy Donors Planned: At least 60 healthy male and female donors will be 
enrolled to obtain at least 55 evaluable donors. A donor will be included in the analysis set of 
evaluable donors if he/she received the 5-day regimen of tbo-filgrastim 10 μg/kg of body weight 
(BW) administered sc, day 5 apheresis was performed as planned, and a quantifiable count of 
CD34+ cells was measured in the blood collected in the day 5 apheresis. 
Study Population: Healthy male and female donors aged 18 to 60 years, inclusive; of at least 
50 kg BW; with a body mass index (BMI) of more than 18.5 and less than 35.0 kg/m2. 
Primary Objective: The primary objective of the study is to demonstrate that a 5-day regimen 
of tbo-filgrastim 10 μg/kg of BW administered sc yields sufficient number of CD34+ cells in a 
single apheresis in healthy donors. 
Secondary Objectives: The secondary objectives of this study are: 
• to evaluate the effects of a 5- to 8-day regimen of tbo-filgrastim 10 μg/kg of BW 
administered sc on the yield of CD34+ cells after multiple aphereses in healthy 
donors 
• to characterize the pharmacodynamic effect of an at least 5-day regimen of tbo-
filgrastim 10 μg/kg of BW administered sc on absolute neutrophil count (ANC) and 
CD34+ cell count in healthy donors 
• to characterize the pharmacokinetics of r-metHuG-CSF during a 5-day regimen of 
tbo-filgrastim 10 μg/kg of BW administered sc in healthy donors 
• to characterize the safety and immunogenicity of an at least 5-day regimen of tbo-
filgrastim 10 μg/kg of BW administered sc in healthy donors 


 
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Exploratory Objectives: The exploratory objectives of the study are: 
• to characterize the immunophenotype profile of tbo-filgrastim stimulated cells 
collected during apheresis 
• to explore the potential correlation between genetic polymorphisms and response to 
tbo-filgrastim in healthy donors 
Primary Efficacy Endpoint: 
• percentage of donors with at least 2 x 106 CD34+ cells/kg of recipient BW collected 
after the first apheresis on day 5 
Secondary Efficacy Endpoints: 
• percentage of donors with at least 2 x 106 CD34+ cells/kg of donor baseline BW 
collected after the first apheresis on day 5 
• percentage of donors with at least 5 x 106 CD34+ cells/kg of recipient BW collected 
after the first apheresis on day 5 
• number of aphereses necessary to collect at least 5 x 106 CD34+ cells/kg of recipient 
BW 
Safety Endpoints: 
• occurrence of adverse events 
• clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis) test 
results 
• vital sign measurements (blood pressure [BP], pulse, respiratory rate, and body 
temperature) 
• electrocardiogram (ECG) findings 
• physical examination findings 
• use of concomitant medication 
• local tolerability at the injection site 
• sonographic findings for splenomegaly 
Immunogenicity Endpoints: 
• incidence and characteristics (eg, titer, neutralizing activity) of anti-drug antibodies 
(ADA) at pre-dose, 15 days, 5 weeks, and 3 months after the last dose of tbo-
filgrastim 
Pharmacokinetics Endpoints: 
The following pharmacokinetic parameters will be calculated from concentration-time data using 
non-compartmental methods, when possible: 
• maximum observed serum r-metHuG-CSF concentration on day 4 (Cmax) in the donor 


 
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• time to maximum observed serum r-metHuG-CSF concentration on day 4 (tmax) in the 
donor 
• area under the serum r-metHuG-CSF concentration-time curve from time 0 to 
24 hours (AUC0-24) on day 4 in the donor 
Pharmacodynamic Endpoints: 
• maximum observed peripheral CD34+ cell count (CD34+Cmax) between day 1 (pre-
dose) and before the first apheresis on day 5 in the donor 
• area under the effect curve for peripheral CD34+ cell count (CD34+AUEC) from time 0 
to before the first apheresis on day 5 in the donor 
• maximum absolute neutrophil count (ANCmax) in peripheral blood between day 1 
(pre-dose) and before the first apheresis on day 5 in the donor 
• area under the effect curve for absolute neutrophil count (ANCAUEC) from time 0 to 
before the first apheresis on day 5 in the donor 
Exploratory Endpoints: 
• to characterize the immunophenotype profile of the cells collected during the first 
apheresis on day 5 
• to assess potential correlation between genetic polymorphism and the response to tbo-
filgrastim (eg, efficacy, pharmacokinetics, safety, and tolerability) 
Follow-Up Investigation in Recipients: 
Objectives: 
• to assess the incidence of primary graft failure after transplantation in recipients  
• to assess engraftment and survival status in recipients 
Endpoints: 
The following endpoints will be evaluated in cases when transplantation occurred within 
6 months of collection from the donor:  
• number of recipients with primary graft failure (defined as ANC never reaching 
≥0.5 x 109/L until day 21 after transplantation) 
• engraftment and survival status in the recipient up to 1 year after the transplantation 
General Design and Methods: 
This is an 18-week, multi-center, open-label, single-arm clinical study to assess effects of a 5-
day regimen of 10 μg/kg of BW of tbo-filgrastim administered sc daily on the mobilization of 
CD34+ cells in at least 60 healthy male and female donors. The pharmacokinetics, 
pharmacodynamics, safety, tolerability, and immunogenicity of tbo-filgrastim will be assessed. 
The immunophenotype profile of tbo-filgrastim stimulated cells will be assessed. 
This study will consist of a 28-day screening period, a 3-day baseline period, a 5-day treatment 
period with tbo-filgrastim, and a follow-up period of 3 months for the donor. After the informed 
consent has been obtained from the donor and recipient, the study will start with a screening 


 
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assessment. On the morning of days 1 to 5, donors will receive tbo-filgrastim 10 μg/kg of BW 
administered sc. Apheresis will be conducted on day 5 after the day 5 dose of tbo-filgrastim 
according to schedule at the investigational center. For the respective donor, tbo-filgrastim will 
be administered at the same time with a window of ±2 hours. Injections will be continued for up 
to 3 additional days after day 5 with a cumulative collection goal of at least 5 x 106 
CD34+ cells/kg of recipient BW, if the cumulative collection goal of 5 x 106/kg of recipient BW 
CD34+ cells is not met after this first apheresis on day 5. A maximum of 4 aphereses in total will 
be permitted. Blood samples will be drawn for the determination of CD34+ cell count, ANC, and 
serum r-metHuG-CSF concentrations starting at day 1 (pre-dose), daily during the tbo-filgrastim 
treatment period, and before the first apheresis on day 5. The immunophenotype profile of cells 
collected from the first apheresis on day 5 will be characterized. Safety will be assessed 
throughout the study by monitoring of adverse events, local tolerability, vital signs, ECG 
recordings, spleen sonography, use of concomitant medications, physical examination, and 
clinical laboratory tests. In addition, immunogenicity will be evaluated during 3 follow-up visits 
during 3 months after the last dose of tbo-filgrastim. A blood sample will be drawn on day 1 (or 
at the next possible visit) for a pharmacogenomic assessment. 
Donors who received at least 1 dose of tbo-filgrastim will have follow-up safety and 
immunogenicity evaluation procedures and assessments performed at the end-of-study visit, 
which is defined as approximately 3 months after the last dose of tbo-filgrastim. Donors who test 
ADA positive and have ADA titer greater than baseline titer at the last blood sample collection 
will be monitored every 3 months after that, until titers return to baseline values. 
Follow–Up Investigation in Recipients: 
A follow-up investigation will be conducted in all recipients to assess graft failure (defined as 
ANC never reaching ≥0.5 x 109/L until day 21 after transplantation) in cases when 
transplantation occurred within at least 6 months of collection. Additionally, information on 
engraftment (eg, occurrence of acute and chronic graft-versus-host disease and grade, date of 
disease relapse, white blood cell (WBC) count, ANC, and platelet count) and survival (eg, date 
of death/reason for death if applicable) status will be recorded up to 1 year after the 
transplantation. 
Method of Randomization and Blinding: 
Not applicable as this is a single-arm open-label study. 
Investigational Medicinal Product: 
Tbo-filgrastim is provided in single-use 2 mL vials containing 1 mL solution of 300 µg/mL of 
tbo-filgrastim for sc injection. 
Investigational Medicinal Product Dose, Route of Administration, and Administration 
Rate: 
Tbo-filgrastim 10 µg/kg of BW will be administered sc on days 1 to 5. The actual dose of tbo-
filgrastim to be administered to each individual donor will be calculated at baseline according to 
his or her BW and that specific dose for each donor will remain the same for all consecutive 
daily doses. 
During sc injections, donors will be in a semi-supine position. Tbo-filgrastim will be 
administered sc in the morning, at the same time for the respective donor with a window of 


 
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±2 hours. Injections will be continued for up to 3 additional days after day 5 with a cumulative 
collection goal of at least 5 x 106 CD34+ cells/kg of recipient BW, if the collection goal of 
5 x 106/kg CD34+ cells/kg is not met after the first apheresis on day 5. 
Duration of Donor Participation: 
Each donor will participate in this study for approximately 18 weeks. Participation will begin 
with a screening visit within 28 days before baseline. Donors who continue to meet study 
inclusion and exclusion criteria will participate in a treatment period with tbo-filgrastim of at 
least 5 days and a follow-up safety evaluation period of up to 3 months after the last dose of tbo-
filgrastim. Donors that test ADA positive at the last blood sample collection will be monitored 
every 3 months after that, until titers return to baseline values. 
Criteria for Inclusion: Donors may be enrolled in this study only if they meet all of the 
following criteria:  
a. Written informed consent is obtained from the donor. 
b. Written informed consent is obtained from the recipient who must be aged ≥18 years. 
c. Person is eligible as a donor according to the local institutional requirements. 
d. (Revision 1) The donor is male or female, aged between 18 and 60 years, inclusive. 
e. (Revision 1) The donor has a BW of at least 50 kg. 
f. (Revision 1) The donor has a BMI of more than 18.5 and less than 35.0 kg/m2. 
g. The donor is in good health as determined by medical and psychiatric history, 
physical examination, ECG recordings, serum chemistry, hematology, coagulation, 
urinalysis, and serology. 
h. Women may be included only if they have a negative beta human chorionic 
gonadotropin (β-hCG) test at baseline, are sterile (defined as documented 
hysterectomy, bilateral oophorectomy or bilateral salpingectomy, or congenitally 
sterile), or postmenopausal (defined as no menses for 12 months without alternative 
medical cause and increased follicle stimulating hormone [FSH] of above 35 U/L in 
women not using hormonal contraception or hormonal replacement therapy). Women 
of childbearing potential whose male partners are potentially fertile (ie, no 
vasectomy) must use highly effective birth control methods for the duration of the 
study and for 30 days after the last tbo-filgrastim administration. 
• Highly effective birth control methods are considered methods that can achieve a 
failure rate of less than 1% per year when used consistently and correctly. 
Such methods include: 
o Combined estrogen and progestogen hormonal contraception (oral, 
intravaginal, transdermal) associated with inhibition of ovulation; these 
should be initiated at least 7 days before the first dose of the 
investigational medicinal product (IMP). 


 
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o Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation; these should be initiated at least 
7 days before the first dose of the IMP. 
o Intrauterine device and intrauterine hormone-releasing system need to be 
in place at least 2 months before screening. 
o Bilateral tubal occlusion 
o Vasectomized partner provided he is the sole sexual partner and has 
received medical assessment of the surgical process 
o Sexual abstinence is only considered a highly effective method if defined 
as refraining from heterosexual intercourse in the defined period. The 
reliability of sexual abstinence needs to be evaluated in relation to the 
duration of the clinical study and the preferred and usual lifestyle of the 
study participants. Periodic abstinence (eg, calendar, ovulation, 
symptothermal, post-ovulation methods), declaration of abstinence for the 
duration of a study, and withdrawal are not acceptable methods of 
contraception  
i. Men must be sterile; or if they are potentially fertile/reproductively competent (not 
surgically [eg, vasectomy] or congenitally sterile) and their female partners are of 
childbearing potential, must use acceptable birth control methods for the duration of 
the study and 30 days after the last tbo-filgrastim administration. 
• Acceptable birth control methods that result in a failure rate of more than 1% per 
year include: male condom with or without spermicide. The combination of male 
condom with either cap, diaphragm, or sponge with spermicide (double barrier 
methods) is also considered acceptable but not highly effective methods of birth 
control. 
j. The donor has a negative alcohol urine test and a negative urine drug screen. 
k. (Revision 1) The donor must be willing and able to comply with study restrictions. 
l. (New criterion) The donor is human leukocyte antigen (HLA)-matched or 
haploidentical-related to the recipient. 
Criteria for Exclusion: Donors will not be enrolled in this study if they meet any of the 
following criteria: 
a. The donor currently has or had a history of any clinically relevant gastrointestinal, 
hematologic, respiratory, psychiatric, renal, hepatic, cardiac, metabolic (eg, fructose 
intolerance), neurological, or any other disease or condition which may influence the 
physiological metabolic turnover (eg, severe endocrine diseases, febrile condition, 
severe infections), which may interfere with the study objectives, or which could 
expose the donor to undue risk through the participation in the clinical study. 
b. The donor has had: (1) a trauma or surgery in the past 2 months; (2) a clinically 
relevant illness within 4 weeks before the first dose of tbo-filgrastim; (3) any acute 
illness within 1 week before the first dose of tbo-filgrastim; or (4) symptoms of any 
clinically relevant or acute illness at baseline. 


 
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c. The donor has existence or recent history of persistent pulmonary infiltrates, recent 
pneumonia, recent bronchitis, recurrent lung infections, or history or evidence of any 
lung disease including asthma, or current symptoms of upper respiratory tract 
infection. In the case of pneumonia, donor may be screened 12 weeks after cessation 
of antibiotic treatment. 
d. The donor has findings of splenomegaly on sonography at screening, defined by 
length of spleen more than 12.3 cm and clinical judgment. 
e. The donor has a history of malignancy, including hematologic malignancy, except for 
appropriately treated non-melanoma skin carcinoma in the last 5 years. 
f. The donor has a clinically significant deviation from normal in ECG recordings or 
physical examination findings, as determined by the investigator. 
g. The donor is pregnant or lactating, or was pregnant in the previous 6 months, or 
intends to get pregnant during the study or within 30 days after the last dose of tbo-
filgrastim. 
h. The donor has habitually consumed, within the last 2 years, more than 21 units of 
alcohol per week, or has a history or evidence of alcohol, narcotic, or any other 
substance abuse as defined by the Diagnostic and Statistical Manual of Mental 
Disorder, Fifth Edition (DSM-V, American Psychiatric Association 2013). Note: A 
unit of alcohol is equal to 1 ounce (29.6 mL) of hard liquor, 5 ounces (148 mL) of 
wine, or 8 ounces (236.8 mL) of beer. 
i. The donor has taken any of the following IMPs, medicinal products, or substances: 
− Any IMP within 30 days or 5 half-lives (whichever is longer) before the first dose 
of tbo-filgrastim, or in the case of a new chemical entity, 3 months or 5 half-lives 
(whichever is longer) before the first dose of tbo-filgrastim. 
− Known history of treatment with blood-cell colony-stimulating factors. 
− Current or recent (within 4 weeks) treatment with lithium. 
j. The donor has donated plasma within 7 days before screening or has donated blood 
within 56 days before screening. 
k. The donor has 1 or more clinical laboratory test value(s) outside the range specified 
below, or any other clinically significant laboratory abnormality as determined by the 
investigator or medical monitor: 
− Hemoglobin ≤12.5 g/dL (women) and hemoglobin ≤13.5 g/dL (men) 
− Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) values of 
>3 x the upper limit of the normal range (ULN) 
− Total bilirubin of >2 x ULN 
− Findings of cholestasis (eg, abnormal values of alkaline phosphatase) 
l. (Revision 1) The donor has a positive test result for human immunodeficiency virus 
(HIV), hepatitis B surface antigen, antibodies to hepatitis C virus, immunoglobulin M 


 
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(IgM) antibodies to cytomegalovirus, human T-lymphotropic virus, West Nile virus, 
malaria, or syphilis. 
m. The donor has a documented or self-reported history of tuberculosis or recent travel 
to countries of endemic disease (last 8 weeks). 
n. (Revision 1) The donor has, after resting for 5 minutes, increased blood pressure (BP) 
(defined as systolic BP in seated position of more than 145 mm Hg or diastolic BP in 
seated position of more than 95 mm Hg), or low BP (defined as systolic BP in seated 
position of less than 90 mm Hg or diastolic BP in seated position of less than 
45 mm Hg). (Only 2 rechecks of the donor’s BP are permitted for eligibility 
purposes.) 
o. The donor has, after resting for 5 minutes, a pulse in seated position of less than 45 or 
more than 90 beats per minute. (Only 2 rechecks of the donor’s pulse are permitted 
for eligibility purposes.) 
p. The donor is unwilling to refrain from vigorous exercise (eg, strenuous or 
unaccustomed weight lifting, running, bicycling) from 72 hours before day 1 until 
day 15. 
q. The donor is unlikely to comply with the study protocol or is unsuitable for any other 
reasons, as judged by the investigator. 
r. The donor has a history of autoimmune disease, including rheumatic diseases and 
thyroid disorders. 
s. The donor has a history of deep vein thrombosis or pulmonary embolism. 
t. The donor has thrombocytopenia defined as platelet count <150 x 109 cells/L at 
screening or at baseline. 
u. The donor has a history of bleeding problems (eg, hemophilia, thrombocytopenia, 
idiopathic thrombocytopenic purpura, clotting factor deficiencies or disorders). 
v. The donor has positive hemoglobin-solubility test. 
w. The donor has a history of iritis or episcleritis. 
x. The donor has a history of significant hypersensitivity, intolerance, or allergy to tbo-
filgrastim or any other E. coli-derived product or excipient, or other medicinal 
product, food, or substance, unless approved by the investigator. 
Measures and Time Points: 
Primary Efficacy Measure and Time Point: Apheresis will be conducted on day 5 after the 
day 5 dose of tbo-filgrastim according to schedule at the investigational center. Samples will be 
taken from the apheresis product to evaluate that at least 2 x 106 CD34+ cells/kg of recipient BW 
have been collected after the first apheresis on day 5. Apheresis will be conducted according to 
institutional guidelines and local procedures. 
Secondary Efficacy Measures and Time Points 
If the collection goal is not met after the first apheresis on day 5, tbo-filgrastim 10 μg/kg of BW 
sc will be administered daily for up to 3 additional days (days 6 to 8) followed by daily apheresis 


 
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to reach the cumulative collection goal of 5 x 106 CD34+ cells/kg of recipient BW. Samples will 
be taken from the apheresis product on each collection day to evaluate that the cumulative 
collection goal of least 5 x 106 CD34+ cells/kg of recipient BW have been collected. A 
maximum of 4 aphereses will be permitted. 
Pharmacokinetic Measures and Time Points: Serial blood samples will be drawn for all 
donors for the determination of serum r-metHuG-CSF concentrations pre-dose on 
days 1 (0 hour), 2 (24 hours), 3 (48 hours), 4 (72 hours), post-dose on day 4 (74, 76, and 
80 hours), pre-dose on day 5 (96 hours), and post-dose on day 5 (98 hours). 
Pharmacodynamic Measures and Time Points: Serial blood samples for the determination of 
ANC and CD34+ cells count will be drawn pre-dose on days 1 (0 hour), 2 (24 hours), 
3 (48 hours), 4 (72 hours), post-dose on day 4 (74, 76, and 80 hours), pre-dose on 
day 5 (96 hours), and post-dose on day 5 (98 hours). 
If the collection goal of 5 x 106 CD34+ cells/kg of recipient BW is not met after the first 
apheresis on day 5, tbo-filgrastim 10 μg/kg of BW will be administered sc daily for up to 
3 additional days (days 6 to 8) followed by daily apheresis to reach the cumulative collection 
goal of 5 x 106 CD34+ cells/kg of recipient BW. Blood samples for the determination of CD34+ 
cell count and ANC will be drawn pre-dose on days 6 (120 hours), 7 (144 hours), and 
8 (168 hours). 
Safety Measures and Time Points: 
Clinical laboratory test results (serum chemistry, hematology, and coagulation) will be evaluated 
at screening, baseline , daily during the treatment period with tbo-filgrastim, and at the follow-up 
visit at day 15 (±5 days) after the last dose of tbo-filgrastim, or at early termination (ET). 
Urinalysis will be performed at screening, baseline, and at the follow-up visit on 
day 15 (±5 days) after the last dose of tbo-filgrastim, or at ET. 
A physical examination will be performed at screening and at the follow-up visit on 
day 15 (±5 days) after the last dose of tbo-filgrastim, or at ET. 
Body weight will be measured at screening and at baseline. 
An ECG will be recorded at screening and on day 15 (±5 days) after the last dose of 
tbo-filgrastim, or at ET. 
Vital signs (BP, pulse, respiratory rate, and body temperature) will be measured at screening, 
baseline, daily during the treatment period with tbo-filgrastim, and at the follow-up visit at 
day 15 (±5 days) after the last dose of tbo-filgrastim, or at ET. On dosing days, vital signs will be 
measured at 1 hour post-dose. 
Adverse events will be recorded at screening, baseline, daily during the treatment period with 
tbo-filgrastim, and at the follow-up visits on day 15 (±5 days), and at week 5 (±5 days) after the 
last dose of tbo-filgrastim, or at ET. 
Use of prior and concomitant medications, including over the counter (OTC) medication and 
herbal/nutritional supplements, will be recorded at screening, baseline, daily during the treatment 
period with tbo-filgrastim, and at the follow-up visit on day 15 (±5 days), or at ET. Use of 
concomitant granulocyte colony-stimulating factor (G-CSFs) will be reviewed at 
week 5 (±5 days) and at month 3 (±7 days) after the last dose of tbo-filgrastim. 


 
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Women of childbearing potential must have a negative serum β-hCG test at screening and 
baseline. A β-hCG test in serum must be conducted at the follow-up visit on day 15 (±5 days) 
after the last dose of tbo-filgrastim, or at ET. 
Local tolerability at the injection site (pain, erythema, ecchymosis, and induration) will be 
assessed 20 minutes and 1 hour after each daily administration of tbo-filgrastim. 
Spleen sonography will be performed at screening, on day 5, and at the follow-up visit on day 
15 (±5 days) after the last dose of tbo-filgrastim, or at ET. If more than 5 days of tbo-filgrastim 
administration is required, an additional spleen sonography will be performed after the last 
apheresis. In case an increase in spleen size was found after the last apheresis and this has not 
improved on day 15 (±5 days) after the last dose of tbo-filgrastim, further assessments will be 
necessary for follow-up until increase in spleen size is not considered relevant anymore by the 
investigator. 
Immunogenicity Measures and Variables: 
Blood samples for analysis of ADA will be obtained for all donors at baseline and at the follow-
up visits on day 15 (±5 days), week 5 (±5 days), and month 3(±7 days) after the last dose of tbo-
filgrastim, or at ET. Donors who test ADA positive and have ADA titer greater than baseline 
titer in the last collected blood sample will be followed up for immunogenicity assessment 
(additional samples will be collected every 3 months) until titers return to baseline values. 
Exploratory Measure and Variables: 
The immunophenotype profile of the cells collected during the first apheresis on day 5 will be 
characterized by assessment of the following markers: CD3, CD4, CD8, CD14, CD16, CD19, 
CD45, and CD56. Other markers will be assessed as applicable. 
A blood sample will be drawn on day 1 (or if not possible, at the next possible visit) for future 
genetic analyses of response to tbo-filgrastim, including association with efficacy, 
pharmacokinetics, safety, and tolerability. 
Measures and Variables in the Follow-Up Investigation in Recipients: 
Primary graft failure (defined as ANC never reaching ≥0.5 x 109/L until day 21 after the 
transplantation) will be assessed when transplantation occurred at least within 6 months of 
collection. Variables that can have an effect on the outcome regarding graft failure will also be 
collected. Data may include age, sex, body weight, HLA-match, ABO-match, conditioning 
regimen, underlying viral infection status, concomitant use of myelosuppressive therapy, 
allosensitization, number of stem cell transplantations (first or repeated), underlying 
hematological disease, occurrence of graft-versus-host disease, status of T-cells in the apheresis 
product (eg, depleted). Information on engraftment (eg, occurrence of acute and chronic graft-
versus-host disease and grade, date of disease relapse, WBC count, ANC, and platelet count) and 
survival (eg, date of death/reason for death if applicable) status will be recorded up to 1 year 
after the transplantation from the recipient’s medical records. 


 
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Prohibited Medications Before and During the Study: 
The following medications will not be allowed before and during this study: 
• Any investigational medicinal product within 30 days or 5 half-lives (whichever is 
longer) before the first dose of tbo-filgrastim, or in the case of a new chemical entity, 
3 months or 5 half-lives (whichever is longer) before the first dose of tbo-filgrastim. 
• Having ever received treatment with blood-cell colony-stimulating factors. 
• Current or recent (within 4 weeks) treatment with lithium. 
Allowed and prohibited medications should follow local institutional requirements for healthy 
donors of peripheral blood progenitor cells (PBPC) in case they are stricter than the ones listed in 
the exclusion criteria/list of prohibited medications. 
Statistical Considerations 
Sample Size Rationale: 
A sample size of 55 evaluable donors will provide 89.5% power to test the primary endpoint at a 
nominal significance level of 2.5% using a one-sided exact test for a single proportion. The null 
hypothesis is that the proportion of donors achieving the minimal count of CD34+ cells is less 
than 90%, and sample size calculation was performed under the assumption that the proportion 
of donors achieving the minimal count of CD34+ cells is 99%. 
A sample size of at least 60 donors, treated with a 5-day regimen of tbo-filgrastim 10 μg/kg of 
BW administered sc is considered adequate for assessment of safety. Since the power to test the 
primary endpoint decreases to less than 60% if there are less than 54 evaluable donors, 
enrollment will continue beyond the planned 60 donors until the target sample size of 
55 evaluable donors is achieved. 
Analysis of Primary Efficacy Endpoint: 
The primary endpoint is the percentage of donors with at least 2 x 106 CD34+ cells/kg of 
recipient BW collected in the first apheresis on day 5. The null hypothesis for the primary 
analysis is that the proportion of donors that achieve at least 2 x 106 CD34+ cells/kg of recipient 
BW collected in the first apheresis on day 5 is less than 90%. The analysis will be conducted 
using a one-sided exact test for a single proportion at a nominal significance level of 2.5%. 
The proportion of donors achieving at least 2 x 106 CD34+ cells/kg of recipient BW collected in 
the first apheresis on day 5 and the corresponding two-sided 95% confidence intervals (CI) 
calculated using the exact Clopper-Pearson confidence limits will be presented. 
The analysis set of evaluable donors will be used for the primary efficacy analysis. Laboratory 
data sourced from the local laboratory will be used for the primary efficacy analysis. 
Analysis of Secondary Efficacy Endpoints: 
The analysis of the primary efficacy endpoint will be repeated for the secondary endpoint of the 
percentage of donors with at least 2 x 106 CD34+ cells/kg of donor baseline BW collected after 
the first apheresis on day 5. 
Descriptive statistics will be provided for all secondary endpoints. In addition, 95% CI for 
proportions will be provided where applicable. 


 
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The analysis set of evaluable donors will be used for the secondary endpoints. Laboratory data 
sourced from the local laboratory will be used for the secondary efficacy analysis. 
Safety Analyses: 
Safety data per visit and change from baseline will be summarized descriptively. 
The safety analysis set will be used for safety analysis. 
Pharmacokinetic Analysis: 
Descriptive statistics will be provided for the pharmacokinetic parameters. 
The pharmacokinetic analysis set will be used for the pharmacokinetic analysis. 
Pharmacodynamic Analysis: 
Descriptive statistics will be provided for the pharmacodynamic parameters. 
The pharmacodynamic analysis set will be used for the pharmacodynamic analysis. 
Immunogenicity Analysis: 
Results of immunogenicity assessment will be listed. 
If more than 2 donors are confirmed positive to ADA , a summary of immune response incidence 
(number and percentage of positive to ADA) and immunogenicity characterization profile (eg, 
titration and neutralization) will be provided. 
For donors who test ADA positive and have ADA titer greater than baseline titer will be 
followed up for immunogenicity assessment every 3 months until titers return to baseline value. 
This data will be reported outside of the study database. 
The safety analysis set will be used for immunogenicity analysis. 
Exploratory Analysis: 
The immunophenotype profile of the collected cells will be summarized descriptively. 
Analysis in the Follow-up Investigation for the Recipients: 
The incidence and percentage of graft failures (defined as ANC never reaching ≥0.5 x 109/L by 
day 21) for all cells collected and transplanted within 6 months of collection will be provided 
using descriptive statistics and reported in the Clinical Study Report (CSR). 
For the long-term follow-up in the recipients the incidence and percentage of graft failures will 
be provided using descriptive statistics. Data for the follow-up period in recipients for up to 
1 year will be recorded in a separate database and analyzed using descriptive statistics. These 
data will be reported as an addendum to the CSR. 
Interim Analysis: 
Interim analysis for futility will be performed after 15, 30, and 45 donors undergo day 5 
apheresis. This study will be declared futile if 2 or more donors that were included in the analysis 
set of evaluable donors do not achieve the minimal count of 2 x 106 CD34+ cells/kg of recipient 
BW collected in the first apheresis on day 5. 


 
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TABLE OF CONTENTS 
TITLE PAGE ...................................................................................................................................1 
AMENDMENT HISTORY .............................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS ..............4 
CLINICAL STUDY PERSONNEL CONTACT INFORMATION ...............................................6 
CLINICAL STUDY PROTOCOL SYNOPSIS...............................................................................7 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ................................................27 
1. 
BACKGROUND INFORMATION ...........................................................................29 
1.1. 
Introduction .................................................................................................................29 
1.2. 
Name and Description of the Investigational Medicinal Product ...............................30 
1.3. 
Findings from Clinical Studies ...................................................................................30 
1.3.1. 
Clinical Pharmacology Studies ...................................................................................30 
1.3.2. 
Clinical Safety and Efficacy Studies ..........................................................................31 
1.3.2.1. 
Clinical Safety ............................................................................................................31 
1.3.2.2. 
Clinical Efficacy .........................................................................................................31 
1.4. 
Known and Potential Benefits and Risks to Donors ...................................................32 
1.4.1. 
Known and Potential Benefits and Risks of Tbo-Filgrastim ......................................32 
1.4.1.1. 
Benefits of Tbo-Filgrastim .........................................................................................32 
1.4.1.2. 
Risks of Tbo-Filgrastim ..............................................................................................32 
1.4.2. 
Overall Benefit and Risk Assessment for this Study ..................................................33 
1.5. 
Selection and Justification of Dose .............................................................................34 
1.6. 
Compliance Statement ................................................................................................35 
1.7. 
Study Population and Justification .............................................................................35 
1.8. 
Location and Study Duration ......................................................................................35 
2. 
PURPOSE OF THE STUDY AND STUDY OBJECTIVES .....................................36 
2.1. 
Purpose of the Study ...................................................................................................36 
2.2. 
Study Objectives .........................................................................................................36 
2.2.1. 
Primary Objective .......................................................................................................36 
2.2.2. 
Secondary Objectives .................................................................................................36 
2.2.3. 
Exploratory Objectives ...............................................................................................36 
2.3. 
Study Endpoints ..........................................................................................................36 


 
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2.3.1. 
Primary Efficacy Endpoint .........................................................................................36 
2.3.2. 
Secondary Efficacy Endpoints ....................................................................................37 
2.4. 
Safety Endpoints .........................................................................................................37 
2.5. 
Immunogenicity Endpoint ..........................................................................................37 
2.6. 
Pharmacokinetic Endpoints ........................................................................................37 
2.7. 
Pharmacodynamic Endpoints .....................................................................................38 
2.8. 
Exploratory Endpoints ................................................................................................38 
2.9. 
Follow-Up Investigation in Recipients .......................................................................38 
2.9.1. 
Objectives ...................................................................................................................38 
2.9.2. 
Endpoints ....................................................................................................................38 
3. 
STUDY DESIGN .......................................................................................................39 
3.1. 
General Study Design and Methods ...........................................................................39 
3.2. 
Justification for Study Design ....................................................................................40 
3.3. 
Primary and Secondary Efficacy Measure and Time Points ......................................40 
3.3.1. 
Primary Efficacy Measure and Time Points ...............................................................40 
3.3.2. 
Secondary Efficacy Measure and Time Points ...........................................................40 
3.4. 
Safety and Tolerability Measures and Time Points ....................................................40 
3.5. 
Pharmacokinetic and Pharmacodynamic Measures and Time Points ........................41 
3.5.1. 
Pharmacokinetic Measures and Time Points ..............................................................41 
3.5.2. 
Pharmacodynamic Measures and Time Points ...........................................................41 
3.6. 
Immunogenicity Measures and Variables ..................................................................42 
3.7. 
Exploratory Measures and Variables ..........................................................................42 
3.8. 
Measures for the Follow-Up Investigation in Recipients ...........................................42 
3.8.1. 
Graft Failure ................................................................................................................42 
3.8.2. 
Long-term Follow-up ..................................................................................................43 
3.9. 
Randomization and Blinding ......................................................................................43 
3.10. 
Maintenance of Randomization and Blinding ............................................................43 
3.11. 
Investigational Medicinal Product Used in the Study ................................................43 
3.12. 
Investigational Medicinal Product Supply and Accountability ..................................43 
3.12.1. 
Storage and Security ...................................................................................................43 
3.12.2. 
Accountability .............................................................................................................43 
3.13. 
Duration of Donor Participation and Justification ......................................................44 
3.14. 
Stopping Rules and Discontinuation Criteria .............................................................44 


 
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3.15. 
Source Data Recorded on the Case Report Form .......................................................44 
3.16. 
Study Procedures and Assessments ............................................................................45 
3.16.1. 
Procedures at Screening (Visit 1) ...............................................................................49 
3.16.2. 
Procedures at Baseline and During Tbo-Filgrastim Treatment Period 
(Visits 2 to 5) ..............................................................................................................49 
3.16.2.1. 
Baseline (Visit 2, Days -5 to -3) .................................................................................49 
3.16.2.2. 
Tbo-filgrastim Treatment Period (Visits 3 to 6, Days 1 to 4) .....................................50 
3.16.2.3. 
Tbo-filgrastim Treatment Period (Visit 7, Day 5) ......................................................50 
3.16.2.4. 
Tbo-filgrastim Treatment Period (Visits 8 to 10, Days 6 to 8) ...................................51 
3.16.3. 
Follow-up Period ........................................................................................................51 
3.16.3.1. 
Visit 11 (Day 15 [±5 days]) or Early Termination .....................................................51 
3.16.3.2. 
Visit 12 (Week 5 [±5 days]) .......................................................................................52 
3.16.3.3. 
Visit 13/End-of-Study Visit (Month 3 [±7 days]) ......................................................52 
3.16.4. 
Unscheduled Visits .....................................................................................................52 
4. 
SELECTION AND WITHDRAWAL OF DONORS ................................................53 
4.1. 
Donor Inclusion Criteria .............................................................................................53 
4.2. 
Donor Exclusion Criteria ............................................................................................54 
4.3. 
Justification for Key Inclusion and Exclusion Criteria...............................................56 
4.4. 
Withdrawal Criteria and Procedures ...........................................................................56 
4.5. 
Lost to Follow-Up.......................................................................................................57 
5. 
TREATMENT OF DONORS.....................................................................................58 
5.1. 
Investigational Medicinal Product Administered During the Study ...........................58 
5.2. 
Restrictions .................................................................................................................58 
5.3. 
Prior and Concomitant Medication or Treatment .......................................................58 
5.4. 
Procedures for Monitoring Donor Compliance ..........................................................59 
5.5. 
Total Blood Volume for Safety, Pharmacokinetics, and Pharmacodynamics ............59 
6. 
ASSESSMENT OF EFFICACY ................................................................................60 
6.1. 
Primary Efficacy Measure and Justification ...............................................................60 
7. 
ASSESSMENT OF SAFETY .....................................................................................61 
7.1. 
Adverse Events ...........................................................................................................61 
7.1.1. 
Definition of an Adverse Event ..................................................................................61 
7.1.2. 
Recording and Reporting of Adverse Events .............................................................62 
7.1.3. 
Severity of an Adverse Event .....................................................................................62 


 
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7.1.4. 
Relationship of an Adverse Event to Tbo-Filgrastim .................................................63 
7.1.5. 
Serious Adverse Events ..............................................................................................63 
7.1.5.1. 
Definition of a Serious Adverse Event .......................................................................63 
7.1.5.2. 
Expectedness ...............................................................................................................64 
7.1.5.3. 
Reporting a Serious Adverse Event ............................................................................65 
7.1.6. 
Protocol-Defined Adverse Events for Expedited Reporting ......................................66 
7.1.7. 
Withdrawal Due to an Adverse Event ........................................................................66 
7.1.8. 
Overdose of Tbo-Filgrastim .......................................................................................67 
7.1.9. 
Protocol Deviations Because of an Adverse Event ....................................................67 
7.2. 
Pregnancy ...................................................................................................................67 
7.3. 
Medication Error and Special Situations ....................................................................68 
7.4. 
Clinical Laboratory Tests ...........................................................................................68 
7.4.1. 
Serum Chemistry, Hematology, Coagulation, and Urinalysis ....................................69 
7.4.2. 
Other Clinical Laboratory Tests .................................................................................70 
7.4.2.1. 
Human Chorionic Gonadotropin Tests .......................................................................70 
7.4.2.2. 
Urine Drug Screen ......................................................................................................70 
7.4.2.3. 
Alcohol Urine Test .....................................................................................................70 
7.5. 
Vital Signs ..................................................................................................................70 
7.6. 
Electrocardiography ....................................................................................................71 
7.7. 
Physical Examinations ................................................................................................71 
7.9. 
Concomitant Medication or Treatment .......................................................................71 
7.10. 
Spleen Sonography .....................................................................................................71 
7.11. 
Assessment of Local Tolerability and Pain ................................................................72 
7.12. 
Methods and Time Points of Assessing, Recording, and Analyzing Safety 
Data .............................................................................................................................73 
8. 
ASSESSMENT OF PHARMACOKINETICS, PHARMACODYNAMICS, 
IMMUNOGENICITY, IMMUNOPHENOTYPING, AND 
PHARMACOGENOMICS .........................................................................................74 
8.1. 
Pharmacokinetic Assessment ......................................................................................74 
8.1.1. 
Specimen Sampling and Handling ..............................................................................74 
8.1.2. 
Shipment and Analysis of Samples ............................................................................74 
8.2. 
Pharmacodynamic Assessments .................................................................................74 
8.2.1. 
Blood Sampling and Handling....................................................................................75 


 
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8.2.2. 
Shipment and Analysis of Samples ............................................................................75 
8.3. 
Immunogenicity Assessment ......................................................................................75 
8.3.1. 
Specimen Sampling and Handling ..............................................................................75 
8.3.2. 
Shipment and Analysis of Samples ............................................................................75 
8.4. 
Pharmacogenomic Assessment ...................................................................................75 
8.4.1. 
Specimen Sampling and Handling ..............................................................................76 
8.4.2. 
Shipment and Analysis of Samples ............................................................................76 
8.5. 
Assessment of Apheresis Product ...............................................................................76 
8.5.1. 
Apheresis Product Specimen Sampling and Handling ...............................................76 
8.5.2. 
Shipment and Analysis of Samples ............................................................................76 
8.5.3. 
Methods and Timing of Assessing, Recording, and Analyzing 
Immunophenotyping Data ..........................................................................................76 
8.5.3.1. 
Specimen Sampling and Handling ..............................................................................77 
8.5.3.2. 
Shipment and Analysis of Samples ............................................................................77 
9. 
STATISTICS ..............................................................................................................78 
9.1. 
Sample Size and Power Considerations .....................................................................78 
9.2. 
Analysis sets ...............................................................................................................78 
9.2.1. 
Intent-to-Treat Analysis Set ........................................................................................78 
9.2.2. 
Safety Analysis Set .....................................................................................................78 
9.2.3. 
Analysis Set of Evaluable Donors ..............................................................................78 
9.2.4. 
Per-Protocol Analysis Set ...........................................................................................78 
9.2.5. 
Additional Analysis Sets.............................................................................................79 
9.2.5.1. 
Pharmacokinetic Analysis Sets ...................................................................................79 
9.2.5.2. 
Pharmacodynamic Analysis Sets ................................................................................79 
9.3. 
Data Handling Conventions ........................................................................................79 
9.3.1. 
Handling Withdrawals and Missing Data ...................................................................79 
9.4. 
Study Population .........................................................................................................79 
9.4.1. 
Donor Disposition .......................................................................................................79 
9.4.2. 
Demographic and Baseline Characteristics ................................................................79 
9.5. 
Efficacy Analysis ........................................................................................................79 
9.5.1. 
Primary Efficacy Endpoint .........................................................................................79 
9.5.2. 
Secondary Efficacy Endpoints ....................................................................................80 
9.5.3. 
Planned Method of Analysis .......................................................................................80 


 
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9.5.3.1. 
Primary Efficacy Analysis ..........................................................................................80 
9.5.3.2. 
Sensitivity Analysis ....................................................................................................80 
9.5.3.3. 
Secondary Efficacy Analysis ......................................................................................80 
9.6. 
Pharmacokinetic Analysis and Endpoints ..................................................................80 
9.7. 
Pharmacodynamic Analysis and Endpoints................................................................81 
9.8. 
Exploratory Analysis and Endpoints ..........................................................................81 
9.9. 
Immunogenicity Analysis ...........................................................................................81 
9.9.1. 
Analysis of the Follow-Up Investigation in Recipients ..............................................81 
9.10. 
Multiple Comparisons and Multiplicity......................................................................81 
9.11. 
Safety Endpoints and Analyses ..................................................................................81 
9.11.1. 
Safety Analysis ...........................................................................................................82 
9.11.2. 
Local Tolerability Variables and Analysis .................................................................82 
9.12. 
Pharmacogenomic Analysis........................................................................................82 
9.13. 
Immunophenotyping Analysis ....................................................................................82 
9.14. 
Planned Interim Analysis ............................................................................................82 
9.15. 
Reporting Deviations from the Statistical Plan ..........................................................83 
10. 
DIRECT ACCESS TO SOURCE DATA AND DOCUMENTS ...............................84 
11. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................85 
11.1. 
Protocol Amendments and Protocol Deviations and Violations ................................85 
11.1.1. 
Protocol Amendments ................................................................................................85 
11.1.2. 
Protocol Violations .....................................................................................................85 
11.2. 
Information to Study Personnel ..................................................................................85 
11.3. 
Study Monitoring ........................................................................................................86 
11.4. 
Clinical Product Complaints .......................................................................................86 
11.4.1. 
Product Complaint Information Needed from the Investigational Center ..................87 
11.4.2. 
Handling of Tbo-filgrastim at the Investigational Center ...........................................87 
11.4.3. 
Adverse Events or Serious Adverse Events Associated with a Product 
Complaint ...................................................................................................................87 
11.4.4. 
Documenting a Product Complaint ............................................................................88 
11.5. 
Audit and Inspection ...................................................................................................88 
12. 
ETHICS ......................................................................................................................89 
12.1. 
Informed Consent .......................................................................................................89 


 
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12.2. 
Competent Authorities and Independent Ethics Committees/Institutional 
Review Boards ............................................................................................................89 
12.3. 
Confidentiality Regarding Study Donors and Recipients ...........................................89 
12.4. 
Declaration of the End of Clinical Study ....................................................................90 
12.5. 
Registration of the Clinical Study...............................................................................90 
13. 
DATA HANDLING, DATA QUALITY CONTROL, AND RECORD 
KEEPING ...................................................................................................................91 
13.1. 
Data Collection ...........................................................................................................91 
13.2. 
Data Quality Control ...................................................................................................91 
13.3. 
Archiving of Case Report Forms and Source Documents ..........................................92 
13.3.1. 
Sponsor Responsibilities .............................................................................................92 
13.3.2. 
Investigator Responsibilities .......................................................................................92 
14. 
FINANCING AND INSURANCE .............................................................................94 
15. 
REPORTING AND PUBLICATION OF RESULTS ................................................95 
16. 
REFERENCES ...........................................................................................................96 
17. 
SUMMARY OF CHANGES TO PROTOCOL .........................................................97 
17.1. 
Amendment 01 Dated 12 April 2017 ..........................................................................97 
APPENDIX A. DATA COLLECTION IN THE RECIPIENTS OF PERIPHERAL 
BLOOD PROGENITOR CELLS .............................................................................106 


 
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LIST OF TABLES 
Table 1: 
Study Procedures and Assessments for the Donor .....................................................46 
Table 2: 
Prohibited Medications ...............................................................................................59 
Table 3: 
Clinical Laboratory Tests ...........................................................................................69 
Table 4: 
Allowed Time Windows for Vital Signs Measurement .............................................71 
Table 5: 
Severity Assessment of Local Tolerability .................................................................72 
Table 6: 
Allowed Time Windows for Deviations from Time Points for Local 
Tolerability Assessment ..............................................................................................72 
Table 7: 
Allowed Time Windows for Deviations from Pharmacokinetic and 
Pharmacodynamic Sampling Times ...........................................................................74 
Table 8: 
Changes to the Protocol Amendment 01 ....................................................................97 
 


 
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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Table of Abbreviations 
Abbreviation 
Term 
β-hCG 
beta human chorionic gonadotropin 
ADA 
anti-drug antibodies 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
ANCAUEC 
area under the effect curve for absolute neutrophil count 
ANCmax 
maximum absolute neutrophil count 
ASBMT 
American Society for Blood and Marrow Transplantation 
AST 
aspartate aminotransferase 
AUC0-24 
area under the serum r-metHuG-CSF concentration-time curve from time 0 to 24 hours 
BP 
blood pressure 
BMI 
body mass index 
BW 
body weight 
CD34+AUEC 
area under the effect curve for peripheral CD34+ cell count 
CD34+Cmax 
maximum observed peripheral CD34+ cell count 
CDMS 
clinical data management system 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
Cmax 
maximum observed serum r-metHuG-CSF concentration 
CRO 
contact research organization 
CSR 
Clinical Study Report 
DNA 
deoxyribonucleic acid 
DSM-V 
Diagnostic and Statistical Manual of Mental Disorders 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
ET 
early termination 
EU 
European Union 
FDA 
Food and Drug Administration (US) 
FSH 
follicle stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
HCT 
hematopoietic cell transplantation 
HIV 
human immunodeficiency virus 


 
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Abbreviation 
Term 
HLA 
human leukocyte antigen 
IB 
Investigator’s Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IgM 
Immunoglobulin M 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
iv 
intravenous, intravenously 
LDH 
lactate dehydrogenase 
LSO 
local safety officer 
n 
number 
OTC 
over-the-counter 
PBPC 
peripheral blood progenitor cell 
q.s. 
quantum sufficiat 
r-metHuG-CSF 
recombinant methionyl human granulocyte colony-stimulating factor 
RSI 
reference safety information 
sc 
Subcutaneous, subcutaneously 
SGOT 
serum glutamic oxaloacetic transaminase 
SmPC 
Summary of Product Characteristics 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
tmax 
time to maximum observed serum r-metHuG-CSF concentration 
UDS 
urine drug screen 
ULN 
upper limit of the normal range 
USA 
United States of America 
WBC 
white blood cell 


 
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1. 
BACKGROUND INFORMATION 
1.1. 
Introduction 
Hematopoietic cell transplantation (HCT) has become an increasingly important therapy for 
donors with hematologic malignancies. Mobilization and collection of peripheral blood 
progenitor cells (PBPC) is critical part of the HCT procedure. Mobilization of PBPC in related or 
unrelated donors with a granulocyte colony-stimulating factor (G-CSF) is an established and 
widely accepted therapy in the United States of America (USA). The American Society for 
Blood and Marrow Transplantation (ASBMT) 2014 Guidelines for Peripheral Blood Progenitor 
Cell Mobilization for Autologous and Allogeneic Hematopoietic Cell Transplantation (Duong 
HK et al 2014) recommend filgrastim (NEUPOGEN®1) 10 μg/kg of body weight (BW) as a 
single dose of 10 μg/kg of BW once daily, or 5 μg/kg of BW twice daily, with apheresis 
beginning on the fifth day as the preferred growth factor for mobilization of PBPC in healthy 
donors. These consensus guidelines support the use of filgrastim as a standard of care, despite 
the fact that filgrastim is not approved for this indication by the Food and Drug Administration 
(FDA). 
Tbo-filgrastim was approved in the USA in 2012 (Teva Pharmaceutical Industries Ltd, Petach 
Tikva, Israel) under the trade name GRANIX®2 for the indication of reduction in the duration of 
severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive 
therapy associated with a clinically significant incidence of febrile neutropenia. 
In the European Union (EU), tbo-filgrastim is registered as a biosimilar to NEUPOGEN (EU) 
under the trade name TEVAGRASTIM®3. TEVAGRASTIM is indicated for: 
1. The reduction in the duration of neutropenia and the incidence of febrile neutropenia in 
patients treated with established cytotoxic chemotherapy for malignancy (with the 
exception of chronic myeloid leukaemia and myelodysplastic syndromes) 
2. The reduction in the duration of neutropenia in patients undergoing myeloablative 
therapy followed by bone marrow transplantation considered to be at increased risk of 
prolonged severe neutropenia. 
3. In patients, children or adults, with severe congenital, cyclic, or idiopathic neutropenia 
with an absolute neutrophil count (ANC) of ≤0.5 x 109/L, and a history of severe or 
recurrent infections, long term administration of TEVAGRASTIM is indicated to 
increase neutrophil counts and to reduce the incidence and duration of infection-related 
events. 
4. The treatment of persistent neutropenia (ANC less than or equal to 1.0 x 109/L) in 
patients with advanced human immunodeficiency virus (HIV) infection, in order to 
                                                 
1 NEUPOGEN® is a registered trademark of Amgen Inc. 
2 GRANIX® is a registered trademark of Teva Pharmaceutical Industries Ltd. in the United States of America. 
3 TEVAGRASTIM® is a registered trademark of Teva Pharmaceutical Industries Ltd. in the European Union. 


 
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reduce the risk of bacterial infections when other options to manage neutropenia are 
inappropriate. 
5. Mobilization of PBPC in normal donors and for mobilization of PBPC in patients 
undergoing myelosuppressive or myeloablative therapy followed by autologous PBPC 
transplantation. 
Filgrastim binds to G-CSF receptors and stimulates proliferation of CD34+ cells and neutrophils. 
Granulocyte colony-stimulating factor is known to stimulate differentiation commitment and 
some end-cell functional activation, which increase neutrophil counts and activity. Use of 
biosimilar G-CSFs for mobilization of PBPC has been supported by investigative studies in the 
EU (Andreola et al 2012; Publicover et al 2013; Schmitt et al 2013; Danylesko et al 2016). 
Administration of biosimilar filgrastim products in the EU was demonstrated to be effective in 
stem cell mobilization with comparable safety and efficacy results to NEUPOGEN as measured 
by CD34+ yields, both in healthy donors and patients. 
A medical need exists in the USA for a short-acting G-CSF that is FDA-approved for stem cell 
mobilization in healthy donors before allogeneic PBPC transplantation. Clinical efficacy and 
pharmacology data available to date for tbo-filgrastim indicate that GRANIX may be well suited 
to meet this need. 
This study is designed to investigate the efficacy, safety, pharmacokinetics, and immunogenicity 
of tbo-filgrastim in the mobilization of PBPC in healthy donors before allogeneic PBPC 
transplantation. The immunophenotype profile of cells collected during apheresis will be 
evaluated. A follow-up investigation in recipients will be conducted to assess graft failure 
(defined as ANC never reaching ≥0.5 x 109/L until day 21 after transplantation) in cases when 
transplantation occurred within at least 6 months of collection. 
1.2. 
Name and Description of the Investigational Medicinal Product 
Tbo-filgrastim (also known as XM02) is a non-glycosylated recombinant methionyl human 
granulocyte colony-stimulating factor (r-metHuG-CSF) manufactured by recombinant 
deoxyribonucleic acid (DNA) technology using the bacterium strain E. coli K802. 
1.3. 
Findings from Clinical Studies 
1.3.1. 
Clinical Pharmacology Studies 
Two single-blind, randomized, 2-way crossover, single-dose studies were performed in healthy 
subjects to compare the pharmacokinetics of tbo-filgrastim and filgrastim (NEUPOGEN [EU]). 
Study XM02-01-LT compared the pharmacokinetics of tbo-filgrastim and filgrastim (in healthy 
male subjects, when both treatments were administered subcutaneously (sc) at a dose of 5 or 
10 μg/kg of BW). Study XM02-05-DE compared the pharmacokinetics of tbo-filgrastim and 
filgrastim in healthy male and female subjects, when both treatments were administered at 5 or 
10 μg/kg of BW intravenously (iv) or sc. Overall, the results from both studies demonstrate that 
tbo-filgrastim is bioequivalent to filgrastim with respect to the ANC-time profile, the CD34+ 
count-time profile, and the rate and the extent of absorption. 


 
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1.3.2. 
Clinical Safety and Efficacy Studies 
1.3.2.1. 
Clinical Safety 
TEVAGRASTIM is approved for mobilization of PBPC in normal donors before allogeneic 
PBPC transplantation in the EU. For further details on the safety of TEVAGRASTIM in normal 
donors please see the TEVAGRASTIM Summary of Product Characteristics (SmPC) or the 
Investigator’s brochure (IB). 
During clinical studies 541 cancer patients and 188 healthy subjects were exposed to 
TEVAGRASTIM. The safety of single sc and iv doses of 5 and 10 μg/kg of BW of tbo-filgrastim 
and filgrastim (NEUPOGEN [EU]) have been studied in healthy male and female subjects in 
Studies XM02-01-LT and XM02-05-DE. Tbo-filgrastim and filgrastim were found to be safe and 
well tolerated in these studies. Headache and myalgia as well as skeletal pain in Study XM02-01-
LT and back pain in Study XM02-05-DE were the most frequent adverse events related to tbo-
filgrastim. These adverse events were of mild to moderate intensity. Based on clinical 
observations, no difference was observed after a single sc or iv dose between tbo-filgrastim and 
the reference product (filgrastim) with respect to their safety profile. 
The most commonly reported undesirable effect was mild to moderate transient musculoskeletal 
pain. Leukocytosis (white blood cells [WBC] >50 x 109/L) was observed in 41% of healthy 
donors and transient thrombocytopenia (platelets <100 x 109/L) following filgrastim and 
leukapheresis was observed in 35% of donors. Transient, minor increases in alkaline 
phosphatase, lactate dehydrogenase (LDH), serum glutamic oxaloacetic transaminase (SGOT), 
and uric acid have been reported in healthy donors receiving filgrastim; these were without 
clinical sequelae. Exacerbation of arthritic symptoms and symptoms suggestive of severe allergic 
reactions have been reported very rarely (<1/10,000). Headaches, believed to be caused by 
filgrastim, have been reported in PBPC studies in donors. 
Common (≥1/100 to <1/10), but generally asymptomatic, cases of splenomegaly and very rare 
(<1/10,000) cases of splenic rupture have been reported in healthy donors and patients after 
administration of G-CSFs. In post-marketing experience in healthy donors, pulmonary adverse 
events (eg, hemoptysis, pulmonary hemorrhage, lung infiltration, dyspnea, and hypoxia) have 
been reported. Capillary leak syndrome, which can be life-threatening if treatment is delayed, has 
been reported uncommonly (≥1/1000 to <1/100) in cancer patients undergoing chemotherapy 
and healthy donors undergoing PBPC mobilization after administration of G-CSF. 
1.3.2.2. 
Clinical Efficacy 
Published EU studies provide further evidence for the comparability of the Teva biosimilar G-
CSF (TEVAGRASTIM and RATIOGRASTIM) to NEUPOGEN (EU) for the mobilization of 
PBPC. 
Publicover et al 2013 retrospectively collected data for 154 patients undergoing PBPC harvest 
before autologous stem cell transplantation between January 2009 and December 2011 using 
RATIOGRASTIM. One hundred and thirty one patients who underwent the procedure between 
January 2006 and September 2008 receiving NEUPOGEN (EU) were used as a control. The 
authors found no statistically significant difference between the 2 groups when comparing 
CD34+ predictors, including the total number of CD34+ cells collected, number of days required 
for collection, or time to engraftment. 


 
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Andreola et al 2012, in a prospective study, analyzed 14 patients affected by hematological 
malignancies (4 with non-Hodgkin's lymphoma, 2 with Hodgkin's disease, and 8 with multiple 
myeloma) who received the combination of TEVAGRASTIM and plerixafor as a first line 
mobilizing therapy. The median number of circulating CD34+ cells on day 4 was 16 (3–42)/μL; 
plerixafor was administered to all, except 1 subject who had already had 42 CD34+ cells/μL on 
day 4. On day 5, after plerixafor administration, the median number of circulating CD34+ cells 
had risen to 60/μL (14–138). All patients underwent leukapheresis and 2.0 x 106/kg of BW 
CD34+ cells were collected in a median number of procedures of 1. 
Schmitt et al 2013, in a prospective study, compared the efficacy and safety of mobilization of 
PBPC by the G-CSF biosimilar XM02 (RATIOGRASTIM, TEVAGRASTIM, BIOGRASTIM) 
to NEUPOGEN (EU) in 11 healthy donors per group. Donors received a standard dose of 
10 µg/kg of BW administered sc twice daily for 4 days. On the morning of day 5, the 9th dose of 
10 µg/kg of BW was administered sc and 2 hours later leukapheresis was performed. The target 
leukapheresis yield was 5 x 106 CD34+ cells/kg of recipient BW. If a second leukapheresis was 
necessary, the donor received a 10th dose in the evening of day 5 and an 11th dose in the morning 
of day 6. In healthy donors receiving the G-CSF biosimilar XM02, the median WBC count in the 
peripheral blood was 50.8 G/L (43.3 G/L for NEUPOGEN [EU]) and the median CD34+ cell 
count was 65.8/mm³ (50.9/mm³ for NEUPOGEN [EU]). In a mean of 1.45 (1.27 for 
NEUPOGEN [EU]) leukapheresis procedures, a median of 356 x 106 (358 x 106 for 
NEUPOGEN [EU]) CD34+ cells were collected. After transplantation, engraftment to 
ANC >0.5 x 109/L was within a median of 14 days. The authors concluded that efficacy and 
safety of the G-CSF biosimilar XM02 were comparable to NEUPOGEN (EU). 
Danylesko et al 2016, in a prospective study, included 24 patients with acute myeloid leukemia 
and myelodysplastic syndrome receiving allogenic transplants from human leukocyte antigen 
(HLA)-matched sibling donors. The donors received 10 µg/kg of BW TEVAGRASTIM 
administered sc for 4 days. In the morning of day 5 they underwent leukapheresis. The target 
yield was 5 x 106 CD34+ cells/kg of recipient BW. The number of CD34+ cell/kg of recipient 
BW was 2.52 to 35.4 x 106 (median 10.2 x 106). The mean number of leukapheresis procedures 
was 1.3. Engraftment was ANC >0.5 x 109/L and >1 x 109/L within a median of 13 days and 
13.5 days. 
1.4. 
Known and Potential Benefits and Risks to Donors 
1.4.1. 
Known and Potential Benefits and Risks of Tbo-Filgrastim 
1.4.1.1. 
Benefits of Tbo-Filgrastim 
This study will be conducted in healthy donors; therefore no direct clinical benefits are expected 
for donors. 
1.4.1.2. 
Risks of Tbo-Filgrastim 
The safety of tbo-filgrastim in healthy donors administered for the mobilization of PBPC before 
allogeneic PBPC transplantation can be deduced from the broad experience with healthy donors 
who received G-CSF for mobilization of PBPC. Very common (≥1/10) adverse events include 
leukocytosis, thrombocytopenia, headache, and musculoskeletal pain. Common (≥1/100 to 
<1/10) adverse events include elevated alkaline phosphatase and elevated LDH. Uncommon 


 
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(≥1/1000 to <1/100) adverse events include: splenic disorders, increased SGOT, hyperuricemia, 
capillary leak syndrome, rheumatoid arthritis exacerbation, severe allergic reaction, and 
glomerulonephritis. The most relevant areas of risk are hematological malignancies, pulmonary 
adverse effects, splenic disorders, capillary leak syndrome, and vascular events. 
In healthy donors, pulmonary adverse events (eg, hemoptysis, pulmonary hemorrhage, lung 
infiltrates, dyspnea, and hypoxia) have been reported very rarely (<1/10000) in post-marketing 
experience; hemoptysis resolved with discontinuation of administration of medicinal product. 
Donors with a recent history of pulmonary infiltrates or pneumonia may be at higher risk. 
Occurrence of pulmonary complaints such as cough, fever, and dyspnea in combination with 
radiological signs of pulmonary infiltrates as well as the deterioration of pulmonary function can 
be first signs of acquired respiratory distress syndrome. 
Capillary leak syndrome has been reported uncommonly (≥1/1000 to <1/100) in donors with 
cancer undergoing chemotherapy and healthy donors undergoing mobilization of PBPC after 
administration of G-CSFs. Capillary leak syndrome is characterized by hypotension, 
hypoalbuminemia, edema, and hemoconcentration. Donors who develop symptoms of capillary 
leak syndrome should be closely monitored and receive standard symptomatic treatment, which 
may include a need for intensive care. 
Additional information regarding safety is given in the IB. 
1.4.2. 
Overall Benefit and Risk Assessment for this Study 
Safety information for tbo-filgrastim in healthy donors is derived from the broad experience in 
healthy donors who receive G-CSF for mobilization of PBPC, the SmPC for TEVAGRASTIM, 
and studies conducted in the EU where TEVAGRASTIM is marketed as a biosimilar to 
NEUPOGEN (EU) and is approved for the indication of mobilization of PBPC in normal donors 
before allogeneic PBPC transplantation. 
As outlined in the prescribing information of NEUPOGEN (USA), alveolar hemorrhage and 
hemoptysis are known risks when NEUPOGEN is used in healthy donors undergoing collection 
of PBPC. Although, to date, no such events have been observed in healthy donors or healthy 
subjects treated with TEVAGRASTIM in clinical studies, inclusion and exclusion criteria in the 
proposed study are selected to minimize this risk. 
The preponderance of evidence demonstrates that tbo-filgrastim is generally safe and well 
tolerated, but can be accompanied by known adverse effects in healthy donors. Splenomegaly is 
a well-characterized adverse effect of G-CSFs or derivatives in healthy donors, therefore 
inclusion and exclusion criteria in the proposed study are selected to minimize this risk. 
Concerns regarding the long-term safety of G-CSF injections in healthy donors have been raised 
over the last 10 years. However, after extensive investigation, the World Marrow Donor 
Association released a statement in 2012 to be included in consent forms, that “studies following 
large numbers of unrelated donors have shown that the risk of developing cancer within several 
years after the use of G-CSF is not increased compared with donors not receiving G-CSF” 
(Shaw et al 2015). This should apply also to tbo-filgrastim. 


 
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Actions Taken to Prevent or Minimize Risks 
Based on the safety profile of tbo-filgrastim, this protocol includes a risk mitigation scheme for 
the study that minimizes the possible risks in healthy donors participating in the study. The risk 
mitigation scheme includes tailored inclusion and exclusion criteria (eg, exclusion of donors with 
a history of malignancy, pulmonary infiltrates or pneumonia, recurrent lung infections or history 
of lung disease, splenomegaly, deep vein thrombosis or pulmonary embolus, or clinically 
significant deviation from normal electrocardiogram), safety monitoring during the treatment 
period with tbo-filgrastim, and follow-up visits. 
Inclusion and Exclusion Criteria 
Since certain medical conditions may put donors at increased risk to develop adverse events, the 
inclusion and exclusion criteria used in this study (see Section 4.1, Section 4.2) have been 
carefully selected to minimize risk. 
Overall Assessment of Benefits and Risks 
Clinical study results of tbo-filgrastim in the EU, experience with the use of tbo-filgrastim, and 
post-marketing surveillance demonstrate that tbo-filgrastim can be administered to healthy 
donors for the indication of mobilization of PBPC before allogeneic PBPC transplantation. The 
potential risks to healthy donors can be assessed from the broad experience in healthy donors 
who receive G-CSF for mobilization of PBPC. 
The most relevant areas of risk are, pulmonary adverse effects, splenic disorders, capillary leak 
syndrome, and vascular events. The most commonly reported undesirable effect in healthy 
donors was mild to moderate transient musculoskeletal pain. Leukocytosis and transient 
thrombocytopenia after G-CSF administration and leukapheresis were observed. Steps are taken 
to manage any cases of splenomegaly, which is a well-characterized adverse effect of G-CSFs in 
healthy donors. 
The assessment of the likelihood of these events occurring in healthy donors was evaluated, 
while taking into consideration that administration of tbo-filgrastim at the given dose is approved 
for use in healthy donors in the EU for the indication of mobilization of PBPC in healthy donors 
before allogeneic PBPC transplantation. Based on the overall benefit-risk assessment and the 
precautions taken into account in this protocol, it is concluded that tbo-filgrastim 10 μg/kg of 
BW administered sc daily for 5 to 8 consecutive days to healthy male and female donors 
followed by apheresis on day 5 and for a maximum of 3 more aphereses on days 6 to 8 has an 
acceptable benefit-risk ratio. 
Strict inclusion and exclusion criteria, safety monitoring, and intensive supervision will ensure 
the appropriate clinical use of tbo-filgrastim, without putting the healthy donors at an 
unacceptable risk. In summary, the potential risks for the healthy donors included in this study 
are outweighed by the potential benefits that may result from clinical development of tbo-
filgrastim for use in the USA in healthy donors for mobilization of PBPC and allogeneic 
transplantation in patients. 
1.5. 
Selection and Justification of Dose 
The dose of tbo-filgrastim to be evaluated in this open-label study is 10 μg/kg of BW 
administered sc daily for 5 to 8 consecutive days. This dose is the recommended dose of 


 
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NEUPOGEN being used off-label for the mobilization of PBPC in healthy donors before 
allogeneic transplantation in the ASBMT 2014 Guidelines (Duong HK et al 2014). The dose of 
tbo-filgrastim for this indication is directly related to the dose of NEUPOGEN, since in the EU, 
TEVAGRASTIM is a biosimilar to NEUPOGEN. Furthermore, this is the approved dose of 
TEVAGRASTIM in the EU for the mobilization of PBPC in healthy donors before allogeneic 
PBPC transplantation. 
1.6. 
Compliance Statement 
This study will be conducted in full accordance with the International Council for Harmonisation 
(ICH) Harmonised Tripartite Guideline for Good Clinical Practice (GCP) E6 and any applicable 
national and local laws and regulations (eg, Title 21 Code of Federal Regulations [21CFR] 
Parts 11, 50, 54, 56, 312, and 314). 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 donors 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 tbo-filgrastim(s) as described in the IB or prescribing information. 
The principal investigator at each investigational center has the overall responsibility for the 
conduct and administration of the clinical study at that investigational center 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 
At least 60 healthy male and female donors will be enrolled to obtain at least 55 evaluable 
donors. Donors aged 18 to 60 years, inclusive, with a body mass index (BMI) of more than 18.5 
and less than 35.0 kg/m2 who meet the eligibility criteria (Sections 4.1 and 4.2) are planned to be 
enrolled. A donor will be considered evaluable if he/she received the 5-day regimen of tbo-
filgrastim 10 μg/kg of BW administered sc, day 5 apheresis was performed as planned, and a 
quantifiable count of CD34+ cells was measured in the collected blood. 
1.8. 
Location and Study Duration 
This study is planned to be conducted in the USA (for donors and recipients) at approximately 
20 investigational centers. It is expected to start in the fourth quarter (Q4) 2016 and the duration 
of the study will be approximately 18 weeks for each donor. Investigational centers will be 
added, if needed. Expected study period (until Q4 2017) may be extended as needed. 


 
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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 support USA marketing authorization for tbo-filgrastim 
(GRANIX) for the indication of mobilization of PBPC in healthy donors before allogeneic PBPC 
transplantation. 
2.2. 
Study Objectives 
2.2.1. 
Primary Objective 
The primary objective of this study is to demonstrate that a 5-day regimen of tbo-filgrastim 
10 μg/kg of BW administered sc yields sufficient number of CD34+ cells in a single apheresis in 
healthy donors. 
2.2.2. 
Secondary Objectives 
The secondary objectives of the study are: 
• to evaluate the effects of a 5- to 8-day regimen of tbo-filgrastim 10 μg/kg of BW 
administered sc on the yield of CD34+ cells after multiple aphereses in healthy 
donors 
• to characterize the pharmacodynamic effect of at least a 5-day regimen of 
tbo-filgrastim 10 μg/kg of BW administered sc on ANC and CD34+ cell count in 
healthy donors 
• to characterize the pharmacokinetics of recombinant methionyl human granulocyte 
colony-stimulating factor (r-metHuG-CSF) during a 5-day regimen of tbo-filgrastim 
10 μg/kg of BW administered sc in healthy donors 
• to characterize the safety and immunogenicity of at least a 5-day regimen of 
tbo-filgrastim 10 μg/kg of BW administered sc in healthy donors 
2.2.3. 
Exploratory Objectives 
The exploratory objectives of this study are: 
• to characterize the immunophenotype profile of tbo-filgrastim stimulated cells 
collected during apheresis 
• to explore the potential correlation between genetic polymorphisms and response to 
tbo-filgrastim in healthy donors 
2.3. 
Study Endpoints 
2.3.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percentage of donors with at least 2 x 106 CD34+ cells/kg 
of recipient BW collected after the first apheresis on day 5. 


 
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2.3.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• percentage of donors with at least 2 x 106 CD34+ cells/kg of donor baseline BW 
collected after the first apheresis on day 5 
• percentage of donors with at least 5 x 106 CD34+ cells/kg of recipient BW collected 
after the first apheresis on day 5 
• number of apheresis necessary to collect at least 5 x 106 CD34+ cells/kg of recipient 
BW 
2.4. 
Safety Endpoints 
The safety endpoints are: 
• occurrence of adverse events 
• clinical laboratory (serum chemistry, hematology, coagulation, and urinalysis) test 
results 
• vital sign measurements (blood pressure [BP], pulse, respiratory rate, and body 
temperature) 
• electrocardiogram (ECG) findings 
• physical examination findings 
• use of concomitant medication 
• local tolerability at the injection site 
• sonographic findings for splenomegaly 
2.5. 
Immunogenicity Endpoint 
The immunogenicity endpoints are the incidence and characteristics (eg, titer, neutralizing 
activity) of anti-drug antibodies (ADA) at pre-dose, 15 days, 5 weeks, and 3 months after the last 
dose of tbo-filgrastim. 
2.6. 
Pharmacokinetic Endpoints 
The following pharmacokinetic parameters will be calculated from concentration-time data using 
non-compartmental methods, when possible: 
• maximum observed serum r-metHuG-CSF concentration on day 4 (Cmax) in the donor 
• time to maximum observed serum r-metHuG-CSF concentration on day 4 (tmax) in the 
donor 
• area under the serum r-metHuG-CSF concentration-time curve from time 0 to 
24 hours (AUC0-24) on day 4 in the donor 


 
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2.7. 
Pharmacodynamic Endpoints 
The pharmacodynamic endpoints are: 
• maximum observed peripheral CD34+ cell count (CD34+Cmax) between day 1 
(pre-dose) and before the first apheresis on day 5 in the donor 
• area under the effect curve for peripheral CD34+ cell count (CD34+AUEC) from time 0 
to before the first apheresis on day 5 in the donor 
• maximum absolute neutrophil count (ANCmax) in peripheral blood between day 1 
(pre-dose) and before the first apheresis on day 5 in the donor 
• area under the effect curve for absolute neutrophil count (ANCAUEC) in peripheral 
blood from time 0 to before the first apheresis on day 5 in the donor 
2.8. 
Exploratory Endpoints 
The exploratory endpoints are: 
• to characterize the immunophenotype profile of the cells collected during the first 
apheresis on day 5. 
• to assess potential correlation between genetic polymorphism and the response to 
tbo-filgrastim (eg, efficacy, pharmacokinetics, safety, and tolerability) 
2.9. 
Follow-Up Investigation in Recipients 
2.9.1. 
Objectives 
The objectives of the follow-up investigation in recipients are: 
• to assess the incidence of primary graft failure after transplantation in recipients 
• to assess engraftment and survival status in recipients 
2.9.2. 
Endpoints 
The following endpoints will be evaluated in cases when transplantation occurred within 
6 months of collection from the donor: 
• number of recipients with primary graft failure (defined as ANC never reaching 
≥0.5 x 109/L until day 21 after transplantation) 
• engraftment and survival status in the recipient up to 1 year after the transplantation 


 
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3. 
STUDY DESIGN 
3.1. 
General Study Design and Methods 
This is an 18-week, multi-center, open-label, single-arm, clinical study to assess effects of a 
5-day regimen of 10 μg/kg of BW of tbo-filgrastim administered sc daily on the mobilization of 
CD34+ cells in at least 60 healthy male and female donors. The pharmacokinetics, 
pharmacodynamics, safety, tolerability, and immunogenicity of tbo-filgrastim will be assessed. 
The immunophenotype profile of tbo-filgrastim stimulated cells will be assessed. 
The study will consist of a 28-day screening period, a 3-day baseline period, a 5-day treatment 
period with tbo-filgrastim, and a follow-up period of 3 months for the donor. After the informed 
consent has been obtained from the donor and recipient, the study will start with a screening 
assessment. On the morning of days 1 to 5, donors will receive tbo-filgrastim 10 μg/kg of BW 
administered sc. Apheresis will be conducted on day 5 after the day 5 dose of tbo-filgrastim 
according to schedule at the investigational center. For the respective donor, tbo-filgrastim will 
be administered at the same time with a window of ±2 hours. Injections will be continued for up 
to 3 additional days after day 5 with a cumulative collection goal of at least 5 x 106 CD34+ 
cells/kg of recipient BW, if the collection goal of 5 x 106 CD34+ cells/kg is not met after this 
first apheresis on day 5. A maximum of 4 aphereses in total will be permitted. Blood samples 
will be drawn for the determination of CD34+ cell count, ANC, and serum r-metHuGCSF 
concentrations on day 1 (pre-dose), daily during the tbo-filgrastim treatment period, and before 
the first apheresis on day 5. The immunophenotype profile of cells collected from the first 
apheresis on day 5 will be characterized. Safety will be assessed throughout the study by 
monitoring of adverse events, local tolerability, vital signs, ECG recordings, spleen sonography, 
use of concomitant medications, physical examination, and clinical laboratory tests. In addition, 
immunogenicity will be evaluated during 3 follow-up visits during 3 months after the last dose of 
tbo-filgrastim. A blood sample will be drawn on day 1 (or at the next possible visit) for a 
pharmacogenomic assessment. 
Donors who received at least 1 dose of tbo-filgrastim will have follow-up safety and 
immunogenicity evaluation procedures and assessments performed at the end-of-study visit, 
which is defined as approximately 3 months after the last dose of tbo-filgrastim. Donors who test 
ADA positive and have ADA titer greater than baseline titer at the last blood sample collection 
will be monitored every 3 months after that, until titers return to baseline values. 
A follow-up investigation will be conducted in all recipients to assess graft failure (defined as 
ANC never reaching ≥0.5 x 109/L until day 21 after transplantation) in cases when 
transplantation occurred within at least 6 months of collection. Additionally, information on 
engraftment (eg, occurrence of acute graft-versus-host disease and grade, occurrence of chronic 
graft-versus-host disease and grade, date of disease relapse, WBC count, ANC, and platelet 
count) and survival (eg, date of death/reason for death if applicable) status will be recorded up to 
1 year after the transplantation.  
The assessments and procedures for donors performed during each study visit are detailed in 
Table 1 and Section 3.16. 
Details for data collection in recipients are given in Appendix A. 


 
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3.2. 
Justification for Study Design 
Administration of filgrastim before mobilization of PBPC is the standard of care supported by 
the ASBMT 2014 Guidelines. In the EU, tbo-filgrastim is marketed as a biosimilar to 
NEUPOGEN (EU) as TEVAGRASTIM, and is indicated for mobilization of PBPC in healthy 
donors before allogeneic PBPC transplantation. 
Healthy adult male and female donors aged 18 to 60 years, inclusive who meet clinical and 
laboratory inclusion and exclusion criteria for mobilization of PBPC will be enrolled in the 
study. A single-arm study provides sufficient evidence to support the fact that a 5-day regimen of 
tbo-filgrastim 10 μg/kg of BW administered sc yields 2 x 106 CD34+ cells/kg of recipient BW in 
a single apheresis. No other G-CSF is approved for this indication in the USA. 
3.3. 
Primary and Secondary Efficacy Measure and Time Points 
A description of the efficacy measure is provided in Section 6. 
3.3.1. 
Primary Efficacy Measure and Time Points 
Apheresis will be conducted on day 5 after the day 5 dose of tbo-filgrastim according to schedule 
at the investigational center. Samples will be taken from the apheresis product to evaluate that at 
least 2 x 106 CD34+ cells/kg of recipient BW have been collected after the first apheresis on 
day 5. Apheresis will be conducted according to institutional guidelines and local procedures. 
3.3.2. 
Secondary Efficacy Measure and Time Points 
If the collection goal is not met after the first apheresis on day 5, tbo-filgrastim 10 μg/kg of BW 
sc will be administered daily for up to 3 additional days (days 6 to 8) followed by daily apheresis 
to reach the cumulative collection goal of 5 x 106 CD34+ cells/kg of recipient BW. Samples will 
be taken from the apheresis product on each collection day to evaluate that the cumulative 
collection goal of at least 5 x 106 CD34+ cells/kg of recipient BW has been met. A maximum of 
4 aphereses in total will be permitted. 
3.4. 
Safety and Tolerability Measures and Time Points 
The following safety and tolerability measures will be assessed throughout the study at the time 
points specified in Table 1. 
• Clinical laboratory tests (chemistry, hematology, and coagulation) will be performed 
at screening, baseline, daily during the treatment period with tbo-filgrastim, and at the 
follow-up visit on day 15 (±5 days) after the last dose of tbo-filgrastim, or at early 
termination (ET). 
• Urinalysis will be performed at screening, baseline, and on day 15 (±5 days) after the 
last dose of tbo-filgrastim, or at ET. 
• A physical examination will be performed at screening and at the follow-up visit on 
day 15 (±5 days) after the last dose of tbo-filgrastim, or at ET. 
• Body weight will be measured at screening and at baseline. 


 
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• An ECG will be recorded at screening and on day 15 (±5 days) after the last dose of 
tbo-filgrastim, or at ET. 
• Vital signs (BP, pulse, respiratory rate, and body temperature) will be measured at 
screening, at baseline, daily during the treatment period with tbo-filgrastim, and at the 
follow-up visit on day 15 (±5 days) after the last dose of tbo-filgrastim, or at ET. On 
dosing days, vital signs will be measured 1 hour post-dose. 
• Adverse events will be recorded at screening, baseline, daily during the treatment 
period with tbo-filgrastim, and at the follow-up visits on day 15 (±5 days) and 
week 5 (±5 days) after the last dose of tbo-filgrastim, or at ET. 
• Use of prior and concomitant medications, including over the counter (OTC) 
medication and herbal/nutritional supplements, will be recorded at screening, 
baseline, daily during the treatment period with tbo-filgrastim, and at the follow-up 
visiton day 15 (±5 days), or at ET. Use of concomitant G-CSFs will be reviewed at 
week 5 (±5 days) and at month 3 (±7 days) after the last dose of tbo-filgrastim. 
• Women of childbearing potential must have a negative serum beta human chorionic 
gonadotropin (β-hCG) test at screening and baseline. A β-hCG test in serum must be 
conducted at the follow-up visit on day 15 (±5 days) after the last dose of tbo-
filgrastim, or at ET. 
• Local tolerability at the injection site (pain, erythema, ecchymosis, and induration) 
will be assessed at 20 minutes and 1 hour after each of the daily doses of 
tbo-filgrastim. 
• Spleen sonography will be performed at screening, on day 5, and at the follow-up 
visit on day 15 (±5 days) after the last dose of tbo-filgrastim, or at ET. If more than 
5 days of tbo-filgrastim administration is required, an additional spleen sonography 
will be performed after the last apheresis. In case splenomegaly was found after the 
last apheresis and this has not improved at the follow-up visit on day 15 (±5 days) 
after the last dose of tbo-filgrastim, further assessments are necessary for follow-up 
until increase in spleen size is not considered relevant anymore by the investigator. 
3.5. 
Pharmacokinetic and Pharmacodynamic Measures and Time Points 
3.5.1. 
Pharmacokinetic Measures and Time Points 
Blood samples will be drawn (5 mL) for measurement of individual serum concentration of 
r-metHuG-CSF pre-dose on days 1 (0 hour), 2 (24 hours), 3 (48 hours), 4 (72 hours), post-dose 
on day 4 (74, 76, and 80 hours), pre-dose on day 5 (96 hours), and post-dose on day 5 (98 hours). 
A description of the pharmacokinetic assessments is included in Section 8.1. 
3.5.2. 
Pharmacodynamic Measures and Time Points 
Serial blood samples for the determination of ANC and CD34+ cells count (5 mL each) will be 
drawn pre-dose on days 1 (0 hour), 2 (24 hours), 3 (48 hours), 4 (72 hours), post-dose on 
day 4 (74, 76, and 80 hours), pre-dose on day 5 (96 hours), and post-dose on day 5 (98 hours). 


 
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If the collection goal of 5 x 106 CD34+ cells/kg of recipient BW is not met after the first 
apheresis on day 5, tbo-filgrastim 10 μg/kg of BW sc will be administered daily for up to 
3 additional days (days 6 to 8) followed by daily apheresis to reach the cumulative collection 
goal of 5 x 106 CD34+ cells/kg. Blood samples will be drawn for the determination of ANC and 
CD34+ cell count (5 mL each) pre-dose on days 6 (120 hours), 7 (144 hours), and 8 (168 hours). 
3.6. 
Immunogenicity Measures and Variables 
Blood samples (5 mL) for analysis of ADA will be obtained for all donors at baseline and at the 
follow-up visits at approximately 15 days (±5 days), 5 weeks (±5 days), and 3 months (±7 days) 
after the last dose of tbo-filgrastim, or at ET. Donors who test ADA positive and have ADA titer 
greater than baseline titer in the last collected blood sample will be followed up for 
immunogenicity assessment (additional samples will be collected every 3 months) until titers 
return to baseline values. 
3.7. 
Exploratory Measures and Variables 
The immunophenotype profile of the cells collected during the first apheresis on day 5 will be 
characterized by assessment of the following markers: CD3, CD4, CD8, CD14, CD16, CD19, 
CD45, and CD56. Other markers will be assessed as applicable. 
A blood sample (6 mL) will be drawn on day 1, or if not possible, at the next possible visit, for 
future genetic analyses of response to tbo-filgrastim, including association with efficacy, 
pharmacokinetics, safety, and tolerability. 
3.8. 
Measures for the Follow-Up Investigation in Recipients 
3.8.1. 
Graft Failure 
Primary graft failure (defined as ANC never reaching ≥0.5 x 109/L until day 21 after 
transplantation) will be assessed when transplantation occurred at least within 6 months of 
collection. Variables that can have an effect on the outcome regarding graft failure will also be 
collected. Data may include but are not limited to: age, sex, body weight, HLA-match, ABO-
match, conditioning regimen, underlying viral infection status, concomitant use of 
myelosuppressive therapy, allosensitization, number of stem cell transplantations (first or 
repeated), underlying hematological disease, date of transplantation, type of transplant, 
modification of the apheresis product before transplantation (eg T-cell depleted), occurrence of 
graft-versus-host disease. 
Potential additional cell products like cells from umbilical cord blood, cells from other allogeneic 
source, or autologous cells that were transplanted in parallel/in addition to the apheresis product 
may also be documented. 


 
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3.8.2. 
Long-term Follow-up 
Information on engraftment (eg, occurrence of acute and chronic graft-versus-host disease and 
grade, date of first discharge form hospital after transplant, date of disease relapse, WBC count, 
ANC, and platelet count), date of repeated PBPC transplantation if applicable, and survival (eg, 
date of death/reason for death if applicable) status will be recorded up to 1 year after the 
transplantation from the recipient’s medical records. Details for data collection in recipients are 
given in Appendix A. 
3.9. 
Randomization and Blinding 
This is a single arm open-label study and there is no blinding. 
3.10. 
Maintenance of Randomization and Blinding 
Not applicable. 
3.11. 
Investigational Medicinal Product Used in the Study 
The investigational medicinal product (IMP) is provided in single-use 2 mL vials containing 
1 mL solution of 300 µg/mL of tbo-filgrastim for sc injection. The product is a sterile, clear, 
colorless, preservative-free solution containing tbo-filgrastim (300 μg/mL), glacial acetic acid 
(0.60 mg/mL), sorbitol (50.0 mg/mL), polysorbate 80 (0.055 mg/mL), sodium hydroxide 
(quantum sufficiat [q.s.] to pH 4.20), and water for injection (q.s. to 1.00 mL). 
Additional details may be found in the IB. A more detailed description of administration 
procedures is given in Section 5.1. 
3.12. 
Investigational Medicinal Product Supply and Accountability 
3.12.1. 
Storage and Security 
Tbo-filgrastim must be kept in a securely locked, substantially constructed cabinet or enclosure, 
with limited access and should be stored and maintained in a temperature-controlled refrigerated 
environment (2 to 8°C) according to the labeled storage conditions. 
Tbo-filgrastim will be stored in original containers until dispensed. 
Only authorized personnel will have access to the tbo-filgrastim at the investigational centers. 
The personnel at each investigational center involved in the study will be responsible for correct 
storage and handling of tbo-filgrastim. 
3.12.2. 
Accountability 
Each tbo-filgrastim shipment will include a packing slip listing the contents of the shipment, 
IMP return instructions, and any applicable forms. 
The investigator is responsible for ensuring that deliveries of tbo-filgrastim and other study 
materials from the sponsor are correctly received, recorded, handled, stored safely and properly 
in accordance with the CFR and local regulations, and used in accordance with this protocol. 


 
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Tbo-filgrastim accountability records must be maintained at the investigational center at all 
times. The identification number of the donor, the date, batch code, expiration date, and quantity 
of tbo-filgrastim will be recorded. 
During the study, used tbo-filgrastim vials should be discarded at the investigational center 
according to IMP disposal SOPs at the investigational center. At study conclusion, all unused 
tbo-filgrastim vials can be destroyed only upon the sponsor’s approval. Documented evidence of 
destruction should be made available to the sponsor. 
At the conclusion of the study, the investigator or designee will prepare an overall summary of 
all IMP supplies received and used for the study. The investigator, pharmacist or IMP 
administrator, and monitor must verify that no IMP supplies remain in the investigator’s 
possession. 
3.13. 
Duration of Donor Participation and Justification 
Each donor will participate in the study for approximately 18 weeks. Participation will begin 
with a screening visit within 28 days before baseline. Donors who continue to meet study 
inclusion and exclusion criteria will participate in a treatment period with tbo-filgrastim of at 
least 5 days and a follow-up safety evaluation period of 3 months after the last dose of tbo-
filgrastim. Donors that test ADA positive at the last blood sample collection will be monitored 
every 3 months after that, until titers return to baseline values. 
3.14. 
Stopping Rules and Discontinuation Criteria 
The study may be terminated by the sponsor for any reason at any time. For example, the 
sponsor should terminate the study in the event of: 
• New toxicological or pharmacological findings or safety issues invalidate the earlier 
positive benefit-risk assessment. 
A donor may discontinue/be withdrawn from 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 
donor from the study at any time for any reason (eg, protocol violation or deviation as defined in 
Section 11.1.2, noncompliance, or adverse event). A recipient can be withdrawn from the study 
only if consent is withdrawn.  
Interim analysis for futility will be performed after 15, 30, and 45 donors undergo day 5 
apheresis. The study will be stopped if 2 or more donors that were included in the analysis set of 
evaluable donors do not achieve the minimal count of 2 x 106 CD34+ cells/kg of recipient BW 
collected in the first apheresis on day 5. 
3.15. 
Source Data Recorded on the Case Report Form 
All donor and recipient data must have supportive original source documentation in the medical 
records or equivalent, before they are transcribed to the electronic case report form (eCRF). 
Copies of the recipient’s source data may be filed at the investigational center of the donor and 
will be considered original source data. Data may not be recorded directly on the eCRF and 


 
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considered as source data unless the sponsor provides written instructions specifying which data 
are permitted to be recorded directly to the eCRF. 
If data are processed from other institutions or means (eg, clinical laboratory, central image 
center) the results will be sent to the investigational center, where they will be retained but not 
transcribed to the eCRF, unless otherwise noted in the protocol. These data may also be sent 
electronically to the sponsor (or organization performing data management) for direct entry into 
the clinical database (see Section 13.1). All data from other institutions will be available to the 
investigator. 
The eCRFs are filed in the sponsor’s central file. 
3.16. 
Study Procedures and Assessments 
Study procedures and assessments with their time points are summarized in Table 1. Detailed 
by-visit information is provided starting with Section 3.16.1. Detailed descriptions of each 
assessment are provided in Section 6 (efficacy assessments), Section 7 (safety assessments), and 
Section 8 (pharmacokinetic and other assessments). Some procedures and assessments may be 
performed outside the investigational center by a homecare service provider, as applicable. 


 
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Table 1: 
Study Procedures and Assessments for the Donor 
Study period 
Screening 
Baseline 
Tbo-filgrastim treatment perioda 
Follow-up perioda 
Visit number 
V1 
V2 
V3 to V6 
V7 
V8 to V10 
V11 
V12 
V13 
Procedures and assessments 
Within 28 days 
before baseline 
Days -5 to -3 
Days 1 to 4 
Day 5 
Days 6 to 8b 
Day 15 
after last 
dose 
(±5 days) 
or ET visit 
Week 5 (±5 days) 
after last dosec 
Month 3 (±7 days) 
after last dose 
End-of-Study 
Visitc 
Hours post-dose 
 
 
0 to 80 
96 
120 to 168 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion and exclusion criteria 
X 
X 
 
 
 
 
 
 
Medical and psychiatric history 
X 
X 
 
 
 
 
 
 
Prior medication and procedure 
history 
X 
X 
 
 
 
 
 
 
Enrollment 
 
X 
 
 
 
 
 
 
Clinical laboratory testsd 
X 
X 
X 
X 
X 
X 
 
 
Urinalysis 
X 
X 
 
 
 
X 
 
 
Serologye 
X 
 
 
 
 
 
 
 
Urine drug screen and urine alcohol 
test 
X 
X 
 
 
 
 
 
 
Physical examinationf 
X 
 
 
 
 
X 
 
 
Measurement of body weight 
X 
X 
 
 
 
 
 
 
Electrocardiogramg 
X 
 
 
 
 
X 
 
 
Vital signs measurements 
X 
X 
Xh 
Xh 
Xh 
X 
 
 
Spleen sonography 
X 
 
 
X 
Xi 
X 
 
 
Serum β-hCG test in women of 
childbearing potential 
Xj 
Xj 
 
 
 
Xj 
 
 


 
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Study period 
Screening 
Baseline 
Tbo-filgrastim treatment perioda 
Follow-up perioda 
Visit number 
V1 
V2 
V3 to V6 
V7 
V8 to V10 
V11 
V12 
V13 
Procedures and assessments 
Within 28 days 
before baseline 
Days -5 to -3 
Days 1 to 4 
Day 5 
Days 6 to 8b 
Day 15 
after last 
dose 
(±5 days) 
or ET visit 
Week 5 (±5 days) 
after last dosec 
Month 3 (±7 days) 
after last dose 
End-of-Study 
Visitc 
Hours post-dose 
 
 
0 to 80 
96 
120 to 168 
 
 
 
FSH test for post-menopausal 
women 
X 
 
 
 
 
 
 
 
Adverse events inquiry 
X 
X 
X 
X 
X 
X 
X 
 
Tbo-filgrastim administrationk 
 
 
X 
X 
Xl 
 
 
 
Local tolerabilitym 
 
 
X 
X 
X 
 
 
 
Blood samples for pharmacokinetics 
 
 
Xn 
Xn 
 
 
 
 
Blood samples for 
pharmacodynamics 
 
  
Xn 
Xn 
Xo 
 
 
 
Blood sample for 
pharmacogenomics 
 
 
Xp 
 
 
 
 
 
Blood sample for serum ADA 
analysisq 
 
X 
 
 
 
X 
X 
X 
Apheresis 
 
 
 
X 
X 
 
 
 
Blood sample from the apheresis 
product for number of ANC and 
CD34+ cells 
 
 
 
X 
X 
 
 
 
Blood sample from the apheresis 
product for immunophenotypingr 
 
 
 
X 
 
 
 
 
Concomitant medications inquiry 
 
 
X 
X 
X 
X 
Xs 
Xs 
a Some procedures and assessments may be performed outside the investigational center by a homecare service provider, as applicable.. 
b Days 6 to 8 procedures are only to be performed if the cumulative collection goal of 5 x 106 CD34+ cells/kg of recipient BW is not met after the first apheresis 
on day 5. 


 
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c The adverse events and concomitant medications inquiry can be conducted by telephone. The blood sample for ADA can be drawn locally in case it is not feasible for the donor 
to return to the investigational center (eg, long travel distance). 
d Blood samples (10 mL) for clinical laboratory tests (serum chemistry, hematology, and coagulation). Blood samples for a hemoglobin-solubility test (2 mL) will be drawn at 
screening. 
e Blood sample (16 mL) for serology assessments (HIV Type I and II, hepatitis B surface antigen, antibodies to hepatitis C virus, IgM antibodies to cytomegalovirus, human T 
lymphotropic virus Type I and II, West Nile virus, malaria, and syphilis). 
f Including height(only at screening). 
g Donors must remain in a supine position for at least 5 minutes before a 12-Lead ECG is recorded. The ECG will be recorded before scheduled blood draws or vital signs 
measurements, where applicable.  
h Vital signs (BP, pulse, respiratory rate, and body temperature) will be measured 1 hour post-dose. 
i If more than 5 days of tbo-filgrastim administration is required, an additional spleen sonography will be conducted after the last apheresis. In case splenomegaly was found after 
the last apheresis and this has not improved on day 15 (±5 days), further assessments are necessary for follow-up until increase in spleen size is not considered relevant anymore 
by the investigator. The sonography can be performed also locally in case it is not feasible for the donor to return to the investigational center (eg, long travel distance). The data 
have to be transferred to the investigational center and provided to the sponsor. 
j Women of childbearing potential must have a negative β-hCG test in serum at screening and at baseline. The β-hCG test must be conducted at the follow-up visit on day 15 (±52 
days)) after the last dose of tbo-filgrastim, or at ET 
k The actual dose of tbo-filgrastim to be administered to each donor will be calculated at baseline according to his/her BW and that specific dose for each donor will remain the 
same for all 5 consecutive daily doses, and the 3 additional doses if required. The donor will receive tbo-filgrastim 10 μg/kg of BW administered sc in the morning of each day at 
the same time (±2 hours) for the respective donor. 
l If the collection goal of 5 x 106 CD34+ cells/kg of recipient BW is not met after the first apheresis on day 5, tbo-filgrastim 10 μg/kg of BW will be administered sc daily for up to 
3 additional days followed by daily apheresis to meet the cumulative collection goal of at least 5 x 106 CD34+ cells/kg of recipient BW. 
m Skin will be assessed for local tolerability at the injection site (pain, erythema, ecchymosis, and induration) at 20 minutes and 1 hour after each dose of tbo-filgrastim. 
n Serial blood samples will be drawn for all donors for the determination of pharmacodynamics (CD34+ cell count, ANC [both analyzed at the local laboratory], and 
pharmacokinetics (serum metHuG-CSF [5 mL]) concentrations pre-dose on days 1 (0 hour), 2 (24 hours), 3 (48 hours), 4 (72 hours), post-dose on day 4 (74, 76, and 80 hours), 
pre-dose on day 5 (96 hours), and post-dose on day 5 (98 hours). 
o Serial blood samples (5 mL) will be drawn on days 6 to 8 for the determination of CD34+ cell count and ANC pre-dose on days 6 (120 hours), 7 (144 hours), or 8 (168 hours) in 
case tbo-filgrastim is administered. The samples will be analyzed at the local laboratory. 
p A blood sample (6 mL) will be drawn on day 1 (or at the next possible visit). 
q Blood samples (5 mL) will be drawn for analysis of ADA. Donors who test ADA positive and have ADA titer greater than baseline titer at the last blood sample collection will 
be monitored every 3 months after that, until titers return to baseline values. 
r A sample will be taken from the apheresis product collected during the first apheresis on day 5 for assessment of the following markers: CD3, CD4, CD8, 
CD14, CD16, CD19, CD45, and CD56. Other markers will be assessed as applicable. 
s Only concomitant G-CSFs need to be recorded. 
β-hCG=beta human chorionic gonadotropin; ADA=anti-drug antibodies; ANC=absolute neutrophil count; BP=blood pressure; BW=body weight; ECG=electrocardiogram, 
ET=early termination, FSH=follicle stimulating hormone; HIV=human immunodeficiency virus; IgM=immunoglobulin M; sc=subcutaneous; V=visit. 


 
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3.16.1. 
Procedures at Screening (Visit 1) 
A signed and dated informed consent form (ICF) will be obtained from both the donor and 
recipient before any screening procedures commence (see Section 12.1). Assessments conducted 
as part of routine medical care and performed during the screening period (28 days before 
baseline can be used as protocol-specific assessments, even if performed before ICF signature. 
Donors and recipients will acknowledge and agree to the possible use of this information for the 
study by signing the ICF. 
The screening visit (visit 1) will take place not more than 28 days before baseline (visit 2). The 
following procedures will be performed; details are given in Table 1: 
• Obtain written informed consent before any study-related procedures are performed. 
• Review inclusion and exclusion criteria. 
• Review medical and psychiatric history. 
• Review prior medication and procedure history. 
• Perform clinical laboratory tests. 
• Perform a urinalysis. 
• Perform serology assessments. 
• Perform a urine drug screen (UDS) and alcohol urine test. 
• Perform a physical examination (including height). 
• Perform measurement of body weight. 
• Record an ECG. 
• Perform vital signs measurements. 
• Perform spleen sonography. 
• Perform a serum β-hCG test or an FSH test. 
• Inquire regarding adverse events. 
A donor who is screened but not enrolled, eg, because inclusion and exclusion criteria were not 
met or enrollment did not occur within the specified time, may be considered for screening again 
if, eg, there is a change in the donor’s medical background. 
3.16.2. 
Procedures at Baseline and During Tbo-Filgrastim Treatment Period 
(Visits 2 to 5) 
3.16.2.1. Baseline (Visit 2, Days -5 to -3) 
Donors who meet the inclusion and exclusion criteria at visit 1 will continue to visit 2, when 
baseline assessments will be conducted. 
The following procedures will be performed; details are given in Table 1. 
• Review inclusion and exclusion criteria. 


 
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• Review medical and psychiatric history. 
• Review prior medication and procedure history. 
• Enrollment 
• Perform clinical laboratory tests. 
• Perform urinalysis. 
• Perform UDS and alcohol urine test. 
• Perform measurement of body weight. 
• Perform vital signs measurements. 
• Perform a serum β-hCG test. 
• Inquire regarding adverse events. 
• Collect blood sample for serum ADA analysis. 
A donor who is not eligible for administration of the first dose on the basis of results of baseline 
assessments (eg, because inclusion and exclusion criteria were not met or enrollment did not 
occur within the specified time) may be retested according to investigator’s judgment. 
3.16.2.2. Tbo-filgrastim Treatment Period (Visits 3 to 6, Days 1 to 4) 
The following procedures and assessments will be performed; details are given in Table 1: 
• Perform clinical laboratory tests. 
• Perform vital signs measurements (1 hour post-dose). 
• Inquire regarding adverse events. 
• Administer tbo-filgrastim. 
• Assess local tolerability. 
• Collect blood samples for pharmacokinetics. 
• Collect blood samples for pharmacodynamics. 
• Collect blood samples for pharmacogenomics. 
• Inquire regarding concomitant medication. 
3.16.2.3. Tbo-filgrastim Treatment Period (Visit 7, Day 5) 
The following procedures and assessments will be performed; details are given in Table 1: 
• Perform clinical laboratory tests. 
• Perform vital signs measurements (1 hour post-dose). 
• Perform spleen sonography. 
• Inquire regarding adverse events. 


 
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• Administer tbo-filgrastim. 
• Assess local tolerability. 
• Collect blood samples for pharmacokinetics. 
• Collect blood samples for pharmacodynamics. 
• Perform apheresis. 
• Take a sample from the apheresis product for number of ANC and CD34+ cells. 
• Take a sample from the apheresis product for immunophenotyping. 
• Inquire regarding concomitant medication. 
3.16.2.4. Tbo-filgrastim Treatment Period (Visits 8 to 10, Days 6 to 8) 
The following procedures and assessments will be performed if the collection goal of 
5 x 106 CD34+ cells/kg of recipient BW has not been met after the first apheresis on day 5; 
details are given in Table 1: 
• Perform clinical laboratory tests. 
• Perform vital signs measurements (1 hour post-dose). 
• Perform spleen sonography after the last apheresis. 
• Inquire regarding adverse events. 
• Administer tbo-filgrastim. 
• Evaluate local tolerability. 
• Collect a blood sample for pharmacodynamics. 
• Perform apheresis. 
• Take a sample from the apheresis product for number of ANC and CD34+ cells. 
• Inquire regarding concomitant medication. 
3.16.3. 
Follow-up Period 
3.16.3.1. Visit 11 (Day 15 [±5 days]) or Early Termination 
The following procedures and assessments will be performed; details are given in Table 1: 
• Perform clinical laboratory tests. 
• Perform urinalysis. 
• Perform a physical examination. 
• Record an ECG. 
• Perform vital signs measurements. 
• Perform spleen sonography. 
• Perform a serum β-hCG test. 
• Inquire regarding adverse events. 


 
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• Collect blood samples for serum ADA analysis. 
• Inquiry regarding concomitant medication. 
3.16.3.2. Visit 12 (Week 5 [±5 days]) 
The following procedures will be performed; details are given in Table 1: 
• Inquire regarding adverse events. 
• Collect blood samples for serum ADA analysis. 
• Inquire regarding concomitant G-CSF administration. 
3.16.3.3. Visit 13/End-of-Study Visit (Month 3 [±7 days]) 
The following procedures will be performed; details are given in Table 1. 
• Collect blood samples for serum ADA analysis. 
• Inquire regarding concomitant G-CSF administration. 
3.16.4. 
Unscheduled Visits 
An unscheduled visit may be performed at any time during the study at the donor’s request and 
as deemed necessary by the investigator. The date and reason for the unscheduled visit will be 
recorded on the eCRF 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: 
• Inquire regarding concomitant medication. 
• Perform vital signs measurements. 
• Inquire regarding adverse events. 
• Perform spleen sonography at the discretion of the investigator. 
Other procedures may be performed at the discretion of the investigator. 


 
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4. 
SELECTION AND WITHDRAWAL OF DONORS 
Prospective waivers (exceptions) from study inclusion and exclusion criteria to allow donors to 
be enrolled are not granted by Teva (see Section 11.1.2). 
Changes to inclusion or exclusion criteria are indicated below and detailed in Section 17. 
4.1. 
Donor Inclusion Criteria 
Donors may be enrolled in this study only if they meet all of the following criteria: 
a. Written informed consent is obtained from the donor. 
b. Written informed consent is obtained from the recipient who must be aged ≥18 years. 
c. Person is eligible as a donor according to the local institutional requirements. 
d. (Revision 1) The donor is male or female, aged between 18 and 60 years, inclusive. 
e. (Revision 1) The donor has a BW of at least 50 kg. 
f. (Revision 1) The donor has a BMI of more than 18.5 and less than 35.0 kg/m2. 
g. The donor is in good health as determined by medical and psychiatric history, 
physical examination, ECG recordings, serum chemistry, hematology, coagulation, 
urinalysis, and serology. 
h. Women may be included only if they have a negative β-hCG test at baseline, are 
sterile (defined as documented hysterectomy, bilateral oophorectomy or bilateral 
salpingectomy, or congenitally sterile), or postmenopausal (defined as no menses for 
12 months without alternative medical cause and increased FSH of above 35 U/L in 
women not using hormonal contraception or hormonal replacement therapy).  
Women of childbearing potential whose male partners are potentially fertile (ie, no 
vasectomy) must use highly effective birth control methods for the duration of the 
study and for 30 days after the last tbo-filgrastim administration.  
• Highly effective birth control methods are considered methods that can achieve a 
failure rate of less than 1% per year when used consistently and correctly. 
Such methods include: 
○ Combined estrogen and progestogen hormonal contraception (oral, intravaginal, 
transdermal) associated with inhibition of ovulation; these should be initiated at 
least 7 days before the first dose of the IMP. 
○ Progestogen-only hormonal contraception (oral, injectable, implantable) 
associated with inhibition of ovulation; these should be initiated at least 7 days 
before first dose of IMP. 
○ Intrauterine device and intrauterine hormone-releasing system need to be in place 
at least 2 months before screening. 
○ Bilateral tubal occlusion 


 
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○ Vasectomized partner provided he is the sole sexual partner and has received 
medical assessment of the surgical process 
○ Sexual abstinence is only considered a highly effective method if defined as 
refraining from heterosexual intercourse in the defined period. The reliability of 
sexual abstinence needs to be evaluated in relation to the duration of the clinical 
study and the preferred and usual lifestyle of the study participant. Periodic 
abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods), 
declaration of abstinence for the duration of a study, and withdrawal are not 
acceptable methods of contraception. 
i. Men must be sterile; or if they are potentially fertile/reproductively competent (not 
surgically [eg, vasectomy] or congenitally sterile) and their female partners are of 
childbearing potential, must use acceptable birth control methods for the duration of 
the study and 30 days after the last tbo-filgrastim administration. 
○ Acceptable birth control methods that result in a failure rate of more than 1% per 
year include male condom with or without spermicide. The combination of male 
condom with either cap, diaphragm, or sponge with spermicide (double barrier 
methods) is also considered acceptable but not highly effective methods of birth 
control. 
j. The donor has a negative alcohol urine test and a negative UDS. 
k. (Revision 1) The donor must be willing and able to comply with study restrictions. 
l. (New criterion) The donor is HLA-matched or haploidentical-related to the recipient. 
4.2. 
Donor Exclusion Criteria 
Donors will not be enrolled in this study if they meet any of the following criteria: 
a. The donor currently has or had a history of any clinically relevant gastrointestinal, 
hematologic, respiratory, psychiatric, renal, hepatic, cardiac, metabolic (eg, fructose 
intolerance), neurological, or any other disease or condition which may influence the 
physiological metabolic turnover (eg, severe endocrine diseases, febrile condition, 
severe infections), which may interfere with the study objectives, or which could 
expose the donor to undue risk through the participation in the clinical study. 
b. The donor has had: (1) a trauma or surgery in the past 2 months; (2) a clinically 
relevant illness within 4 weeks before the first dose of tbo-filgrastim; (3) any acute 
illness within 1 week before the first dose of tbo-filgrastim; or (4) symptoms of any 
clinically relevant or acute illness at baseline. 
c. The donor has existence or recent history of persistent pulmonary infiltrates, recent 
pneumonia, recent bronchitis, recurrent lung infections, or history or evidence of any 
lung disease including asthma, or current symptoms of upper respiratory tract 
infection. In the case of pneumonia, donor may be screened 12 weeks after cessation 
of antibiotic treatment. 
d. The donor has findings of splenomegaly on sonography at screening, defined by 
length of spleen more than 12.3 cm and clinical judgment. 


 
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e. The donor has a history of malignancy, including hematologic malignancy, except for 
appropriately treated non-melanoma skin carcinoma in the last 5 years. 
f. The donor has a clinically significant deviation from normal in ECG recordings or 
physical examination findings, as determined by the investigator. 
g. The donor is pregnant or lactating, or was pregnant in the previous 6 months, or 
intends to get pregnant during the study or within 30 days after the last dose of tbo-
filgrastim.  
h. The donor has habitually consumed, within the past 2 years, more than 21 units of 
alcohol per week, or has a history or evidence of alcohol, narcotic, or any other 
substance abuse as defined by the Diagnostic and Statistical Manual of Mental 
Disorder, Fifth Edition (DSM-V, American Psychiatric Association 2013). Note: A 
unit of alcohol is equal to 1 ounce (29.6 mL) of hard liquor, 5 ounces (148 mL) of 
wine, or 8 ounces (236.8 mL) of beer. 
i. The donor has taken any of the following IMPs, medicinal products, or substances: 
− Any IMP within 30 days or 5 half-lives (whichever is longer) before the first dose 
of tbo-filgrastim, or in the case of a new chemical entity, 3 months or 5 half-lives 
(whichever is longer) before the first dose of tbo-filgrastim. 
− Known history of treatment with blood-cell colony-stimulating factors. 
− Current or recent (within 4 weeks) treatment with lithium. 
j. The donor has donated plasma within 7 days before screening or has donated blood 
within 56 days before screening. 
k. The donor has 1 or more clinical laboratory test value(s) outside the range specified 
below, or any other clinically significant laboratory abnormality as determined by the 
investigator or medical monitor: 
− hemoglobin ≤12.5 g/dL (women) and hemoglobin ≤13.5 g/dL (men) 
− alanine aminotransferase (ALT) or aspartate aminotransferase (AST) increase of 
>3 x the upper limit of the normal range (ULN) 
− total bilirubin of >2 x ULN 
− Findings of cholestasis (eg, abnormal values of alkaline phosphatase) 
l. (Revision 1) The donor has a positive test result for HIV, hepatitis B surface antigen, 
antibodies to hepatitis C virus, immunoglobulin M (IgM) antibodies to 
cytomegalovirus, human T-lymphotropic virus, West Nile virus, malaria, or syphilis. 
m. The donor has a documented or self-reported history of tuberculosis or recent travel 
to countries of endemic disease (last 8 weeks). 
n. (Revision 1) The donor has, after resting for 5 minutes, increased BP (defined as 
systolic BP in seated position of more than 145 mm Hg or diastolic BP in seated 
position of more than 95 mm Hg), or low BP (defined as systolic BP in seated 
position of less than 90 mm Hg or diastolic BP in seated position of less than 45 mm 
Hg). (Only 2 rechecks of the donor’s BP are permitted for eligibility purposes.) 


 
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o. The donor has, after resting for 5 minutes, a pulse in seated position of less than 45 or 
more than 90 beats per minute. (Only 2 rechecks of the donor’s pulse are permitted 
for eligibility purposes.) 
p. The donor is unwilling to refrain from vigorous exercise (eg, strenuous or 
unaccustomed weight lifting, running, bicycling) from 72 hours before day 1 and until 
day 15. 
q. The donor is unlikely to comply with the study protocol or is unsuitable for any other 
reasons, as judged by the investigator. 
r. The donor has a history of autoimmune disease, including rheumatic diseases and 
thyroid disorders. 
s. The donor has a history of deep vein thrombosis or pulmonary embolism. 
t. The donor has thrombocytopenia defined as platelet count <150 x 109 cells/L at 
screening or at baseline. 
u. The donor has a history of bleeding problems (eg, hemophilia, thrombocytopenia, 
idiopathic thrombocytopenic purpura, clotting factor deficiencies or disorders). 
v. The donor has a positive hemoglobin-solubility test. 
w. The donor has a history of iritis or episcleritis. 
x. The donor has a history of significant hypersensitivity, intolerance, or allergy to 
tbo-filgrastim or any other E. coli-derived product or excipient, or other medicinal 
product, food, or substance, unless approved by the investigator. 
4.3. 
Justification for Key Inclusion and Exclusion Criteria 
Key inclusion and exclusion criteria and safety monitoring will be followed to minimize 
potential risks to donors. In healthy donors, pulmonary adverse effects and cases of 
splenomegaly (and rarely splenic rupture) have been reported. Donors with a history of 
pulmonary illness and splenomegaly at screening will not be enrolled. 
4.4. 
Withdrawal Criteria and Procedures 
In accordance with the Declaration of Helsinki each donor is free to withdraw from the study at 
any time. The investigator also has the right to withdraw a donor 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 donor, or in the event of lack of cooperation. In addition, a donor may 
be withdrawn from the study as described in Section 3.14, Section 3.16.3.1, and Section 7.1.7. 
Should a donor decide to withdraw after administration of tbo-filgrastim, or should the 
investigator decide to withdraw the donor, all efforts will be made to complete and report all 
safety and immunogenicity observations for all required follow-up visits. In addition, a complete 
evaluation at the time of the donor’s withdrawal should be made and an explanation given as to 
why the donor is withdrawing or being withdrawn from the study. 
The reason for and date of withdrawal from treatment with tbo-filgrastim and the reason for and 
date of withdrawal from the study must be recorded on the source documentation and transcribed 


 
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to the eCRF. If a donor or a recipient 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 donor or recipient is referred to the care of 
a health care professional, or until a determination of a cause unrelated to tbo-filgrastim or study 
procedure is made). The specific event or test result must be recorded on the source 
documentation and transcribed to the eCRF. 
In case of withdrawal, the procedures and assessments as indicated in Table 1 for ET will be 
performed. 
A donor who is enrolled but not evaluable will be replaced with another eligible donor to ensure 
that at least 55 donors are evaluable. 
4.5. 
Lost to Follow-Up 
A donor will be considered lost to follow-up if he/she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the investigational center. The following actions must be 
taken if the donor fails to return to the investigational center for a required study visit: 
• The investigational center must attempt to contact the donor and reschedule the 
missed visit as soon as possible and counsel the donor on the importance of 
maintaining the assigned visit schedule and ascertain whether or not the donor wishes 
to and/or should continue in the study. 
• In cases in which the donor is deemed lost to follow-up, the investigator or designee 
must make every effort to regain contact with the donor (where possible, 3 telephone 
calls and, if necessary, a certified letter to the donor’s last known mailing address or 
local equivalent methods). These contact attempts should be documented in the 
donor’s medical record. 
• Should the donor continue to be unreachable, he/she will be considered to have 
withdrawn from the study with a primary reason of ‘lost to follow-up’. 


 
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5. 
TREATMENT OF DONORS 
5.1. 
Investigational Medicinal Product Administered During the Study 
On the mornings of days 1 to 5, tbo-filgrastim 10 μg/kg of BW will be administered sc at the 
same time for a respective donor (±2 hours). The actual dose of tbo-filgrastim to be administered 
to each individual donor will be calculated at baseline according to his/her BW and that specific 
dose for each donor will remain the same for all doses. If the collection goal of at least 
5 x 106 CD34+ cells/kg of recipient BW is not met after the first apheresis, tbo-filgrastim 
administration will be continued for up to 3 additional days after day 5 with a cumulative 
collection goal of at least 5 x 106 CD34+ cells/kg. Dose reduction of tbo-filgrastim for safety 
reasons is left to the judgment of the investigator. 
Tbo-filgrastim will be supplied as described in Section 3.11. Before administration, each 
tbo-filgrastim vial should be visually inspected for particulate matter and discoloration. The 
actual daily dose will be taken from vials containing 300 µg/mL tbo-filgrastim. The calculated 
volume of solution should be extracted from the vial immediately before administration. 
Tbo-filgrastim solution should not be stored in single-use syringes. 
Tbo-filgrastim will be administered sc by trained clinical study staff daily. Injection sites are 
either the abdomen (except for the 2-inch area around the navel), or the front of the middle 
thighs, or the upper outer areas of the buttocks, or the upper back portion of the upper arms. The 
injection site should be varied daily at a different skin area of the same body part. Tbo-filgrastim 
should not be injected into an area that is tender, red, bruised or hard, or that has scars or stretch 
marks. 
5.2. 
Restrictions 
Donors will be required to comply with the following restrictions: 
• No alcohol may be consumed 72 hours before day 1 and throughout the tbo-filgrastim 
treatment period. 
• The donors should be willing to refrain from vigorous exercise from 72 hours before 
day 1 until day 15. 
• The donors should inform the investigational center staff of any event which could 
interfere with the execution of the study. 
There are no additional restrictions in this study. 
5.3. 
Prior and Concomitant Medication or Treatment 
Any prior or concomitant medication, treatment, or procedure a donor has had within 30 days 
before the first dose of tbo-filgrastim and up to day 15 (±5 days), will be recorded on the eCRF. 
After that only concomitant G-CSFs need to be recorded up to month 3 (±7 days) (the end of the 
follow-up period). Trade name and/or international non-proprietary name, indication, and dose 
will be recorded. The sponsor will encode all medication and treatment according to the World 
Health Organization drug dictionary. 


 
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The following medications will not be allowed before or during this study: 
• Any investigational medicinal product within 30 days or 5 half-lives (whichever is 
longer) before the first dose of tbo-filgrastim, or in the case of a new chemical entity, 
3 months or 5 half-lives (whichever is longer) before the first dose of tbo-filgrastim. 
• Having ever received treatment with blood-cell colony-stimulating factors. 
• Current or recent (within 4 weeks) treatment with lithium. 
Allowed and prohibited medications should follow local institutional requirements for healthy 
donors of PBPC in case they are stricter than the ones listed in the exclusion criteria/list of 
prohibited medications in this protocol. 
Examples of prohibited medications are included in Table 2. 
Table 2: 
Prohibited Medications 
Colony-Stimulating Factors 
darbepoetin 
pegfilgrastim 
epoetin alfa 
plerixafor 
filgrastim 
sargramostim 
tbo-filgrastim 
Other 
lithium 
At each visit after the screening visit, until day 15 (±5 days) after the last tbo-filgrastim 
administration, the investigator will ask donors whether they have taken any medications (other 
than tbo-filgrastim), including OTC medications, vitamins, or herbal or nutritional supplements, 
since the previous visit. After that, up to month 3 (±7 days) (the end of the follow-up period), the 
investigator will ask donors only about concomitant G-CSFs. 
5.4. 
Procedures for Monitoring Donor Compliance 
The investigator will be responsible for monitoring donor compliance. If the investigator or the 
sponsor determines that the donor is not in compliance with the study protocol, the investigator 
and the sponsor should determine whether the donor should be withdrawn. 
5.5. 
Total Blood Volume for Safety, Pharmacokinetics, and 
Pharmacodynamics  
The total maximum blood volume that can be collected for each donor in this study is 
approximately 300 mL. Details are given in the laboratory manual. 


 
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6. 
ASSESSMENT OF EFFICACY 
6.1. 
Primary Efficacy Measure and Justification 
Apheresis will be conducted on day 5 after the day 5 dose of tbo-filgrastim according to schedule 
at the investigational center. Samples will be taken from the apheresis product to evaluate that at 
least 2 x 106 CD34+ cells /kg of recipient BW have been collected after the first apheresis on 
day 5. Apheresis will be conducted according to institutional guidelines and local procedures. A 
cell number of at least 2 x 106 CD34+ cells/kg of recipient BW is the generally accepted minimal 
dose to result in successful engraftment after transplantation (Duong et al 2014). 


 
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7. 
ASSESSMENT OF SAFETY 
In this study, safety will be assessed by qualified study personnel by evaluating reported adverse 
events, use of concomitant medications, clinical laboratory tests (hematology, chemistry, and 
coagulation), urinalysis, vital signs measurements, ECG recordings, physical examination 
results, local tolerability assessments, pregnancy testing, and spleen sonography as described 
below. Immunogenicity will also be assessed. 
7.1. 
Adverse Events 
7.1.1. 
Definition of an Adverse Event 
An adverse event is any untoward medical occurrence in a subject 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 donor has signed the ICF 
should be recorded and reported as an adverse event. 
An adverse event can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study, or of any concurrent disease, whether or not 
considered related to tbo-filgrastim. A new condition or the worsening of a pre-existing 
condition will be considered an adverse event. Stable chronic conditions (such as arthritis) that 
are present before study entry and do not worsen during this study will not be considered adverse 
events. 
Accordingly, an adverse event can include any of the following: 
• intercurrent illnesses 
• physical injuries 
• events possibly related to concomitant medication 
• significant worsening (change in nature, severity, or frequency) of the disease under 
study or other pre-existing conditions 
• drug interactions 
• events occurring during diagnostic procedures or during any washout phase of this 
study 
• laboratory or diagnostic test abnormalities that result in the withdrawal of the subject 
from the study, are associated with clinical signs and symptoms or a serious adverse 
event, require medical treatment or further diagnostic work-up, or are considered by 
the investigator to be clinically significant 
(Note: Abnormal laboratory test results at the screening visit that preclude a donor 
from entering the study or receiving study treatment are not considered adverse 
events.) 


 
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7.1.2. 
Recording and Reporting of Adverse Events 
For adverse event recording, the study period is defined for each donor as the time period from 
signature of the ICF through week 5 (±5 days) of the follow-up period. 
All adverse events that occur during the defined study period must be recorded on the source 
documentation and transcribed onto the eCRF, regardless of the severity of the event or judged 
relationship to tbo-filgrastim and/or apheresis procedure. For serious adverse events, the Serious 
Adverse Event Form must also be completed and the serious adverse event must be reported 
immediately (see Section 7.1.5.3.1). Serious adverse events occurring to a donor after week 5 
(±5 days) of the follow-up period should be reported to the sponsor if the investigator becomes 
aware of them, following the procedures described in Section 7.1.5.3.1. The investigator does not 
need to actively monitor donors for adverse events after week 5 (±5 days) of the follow-up 
period). 
At each contact with the donor, the investigator or designee must question the donor 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 eCRF 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 or 
stabilized or returned to baseline, or until the donor is referred for continued care to another 
health care professional, or until a determination of a cause unrelated to tbo-filgrastim 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 tbo-filgrastim, treatment administered, and outcome for each adverse event must 
be recorded on the source documentation and transcribed onto the eCRF. 
The relationship of each adverse event to tbo-filgrastim treatment and study procedures, and the 
severity and seriousness of each adverse event, as judged by the investigator, must be recorded 
as described below. 
7.1.3. 
Severity of an Adverse Event 
The severity of each adverse event must be recorded as 1 of the following 3 choices: 
Mild: 
No limitation of usual activities 
Moderate: Some limitation of usual activities 
Severe: 
Inability to carry out usual activities 


 
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7.1.4. 
Relationship of an Adverse Event to Tbo-Filgrastim 
The relationship of an adverse event should be attributed to tbo-filgrastim and/or the apheresis 
procedure. These 2 categories will be captured on the eCRF. The relationship of an adverse event 
to tbo-filgrastim 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 tbo-filgrastim. 
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 tbo-filgrastim. 
• 
It could readily have been produced by the donor’s 
clinical state, environmental or toxic factors, or other 
modes of therapy administered to the donor. 
• 
It does not follow a known pattern of response to tbo-
filgrastim. 
• 
It does not reappear or worsen when the tbo-
filgrastim 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 
tbo-filgrastim 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 tbo-filgrastim. 
• 
It cannot be reasonably explained by the known 
characteristics of the donor’s clinical state, 
environmental or toxic factors or other modes of 
therapy administered to the donor. 
• 
It disappears or decreases on cessation or reduction in 
dose. There are important exceptions when an 
adverse event does not disappear after 
discontinuation of tbo-filgrastim, yet a relationship to 
tbo-filgrastim clearly exists. 
• 
It follows a known pattern of response to tbo-
filgrastim. 
7.1.5. 
Serious Adverse Events 
7.1.5.1. 
Definition of a Serious Adverse Event 
A serious adverse event is an adverse event occurring at any dose that results in any of the 
following outcomes or actions: 
• death 
• a life-threatening adverse event (ie, the donor was at immediate risk of death from the 
event as it occurred); does not include an event that, had it occurred in a more severe 
form, might have caused death 


 
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• 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 donor signed the ICF will not be considered 
serious adverse events, unless there was worsening of the preexisting condition 
during the donor’s participation in this study. 
• persistent or significant disability or incapacity (refers to a substantial disruption of 
one’s ability to conduct normal life functions) 
• a congenital anomaly or birth defect 
• an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the donor 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 
All occurrences of possible IMP-induced liver injury that meet Hy’s law criteria, defined as all 
of the below, must be reported by the investigator to the sponsor as a serious adverse event: 
• ALT or AST elevation of >3 x  ULN 
• total bilirubin elevation of >2 x ULN 
• absence of initial findings of cholestasis (ie, no substantial increase of alkaline 
phosphatase) 
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 IB. 
The sponsor’s Global Patient Safety and Pharmacovigilance will determine the expectedness for 
all serious adverse events. 
For the purpose of suspected unexpected serious adverse reaction (SUSAR) reporting, the 
version of the IB at the time of occurrence of the SUSAR applies. 


 
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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 tbo-filgrastim, 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 donors for adverse events after week 5 (±5 days) of the follow-up 
period. . 
Serious adverse events occurring to a donor after the after week 5 (±5 days) of the follow-up 
period. should be reported to the sponsor if the investigator becomes aware of them and indicate 
if the investigator sees any potential relationship of the event to the tbo-filgrastim or the 
apheresis procedure. 
The serious adverse event form should be sent to the Teva US Patient Safety & 
Pharmacovigilance Department via email at 
. 
The following information should be provided to record the event accurately and completely: 
• study number 
• investigator and investigational center identification 
• donor number 
• onset date and detailed description of adverse event 
• investigator’s assessment of the relationship of the adverse event to the tbo-filgrastim 
and/or apheresis procedure (no reasonable possibility, reasonable possibility) 
Additional information may include the following: 
• age and sex of donor 
• date of first dose of tbo-filgrastim 
• date and amount of last administered dose of tbo-filgrastim 
• 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 


 
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• for an adverse event resulting in death: 
− cause of death (whether or not the death was related to tbo-filgrastim) 
− 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 tbo-filgrastim, 
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. 
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 Local safety office (LSO)/Contract Research Organization (CRO) 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. 
7.1.5.3.2. Sponsor Responsibility 
If a serious unexpected adverse event is believed to be related to the tbo-filgrastim or study 
procedures, the sponsor will take appropriate steps to notify all investigators participating in 
sponsored clinical studies of tbo-filgrastim and 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 tbo-filgrastim 
7.1.6. 
Protocol-Defined Adverse Events for Expedited Reporting 
No protocol-defined adverse events for expedited reporting were identified for this study. 
7.1.7. 
Withdrawal Due to an Adverse Event 
Any donor 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 donor is withdrawn wholly or in 
part because of an adverse event, both the adverse events page and termination page of the eCRF 
will be completed at that time. Donors who withdraw from the study will be invited for the 


 
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follow-up visits. The donor will be monitored at the discretion of the investigator (eg, until the 
event has resolved or stabilized, until the donor is referred to the care of a health care 
professional, or until a determination of a cause unrelated to the tbo-filgrastim or study 
procedure is made). The investigator must inform the medical monitor as soon as possible of 
each donor who is being considered for withdrawal due to adverse events. Additional reports 
must be provided when requested. 
If a donor is withdrawn from the study for multiple reasons that include adverse events, the 
termination page of the eCRF 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. In case the discontinuation of the donor from the study was the need to 
take a prohibited medication, the reason for discontinuation would be the need to take a 
prohibited medication, not the adverse event. 
7.1.8. 
Overdose of Tbo-Filgrastim 
Any dose of tbo-filgrastim, whether administered intentionally or unintentionally, in excess of 
that prescribed must be immediately reported to the sponsor. 
7.1.9. 
Protocol Deviations Because of an Adverse Event 
If a donor experiences an adverse event or medical emergency, deviations from the protocol may 
be allowed on a case-by-case basis. To ensure donor safety, after the event has stabilized or 
treatment has been administered (or both), the investigator or other physician in attendance must 
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 donor should continue to participate in the study. 
7.2. 
Pregnancy 
All pregnancies of women participating in the study and female partners of men participating in 
the study, if applicable, that occur during the study or within 30 days of the last tbo-filgrastim 
administration, are to be reported immediately to the physician identified in the Clinical Study 
Personnel Contact Information section of this protocol, and the investigator must provide the 
LSO/CRO with the pregnancy form. Female partners of men participating in the study who 
become pregnant will be asked to sign an ICF and will be monitored for the outcome of the 
pregnancy (including spontaneous, elective, or voluntary abortion) 
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). 
The investigator is not required to report patients who are found to be pregnant between 
screening and baseline, provided no protocol-related procedures were applied. 
All donors or female partners of men participating in the study who become pregnant will be 
monitored for the outcome of the pregnancy (including spontaneous or voluntary termination). 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, 


 
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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 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 medication that is not in accordance with the study protocol should be 
reported on the eCRF either as a violation, if it meets the violation criteria specified in the 
protocol (Section 11.1.2), or as a deviation, in the donors source documents, regardless of 
whether an adverse event occurs as a result. All instances of incorrect medication administration 
should be categorized on the eCRF as “Non-Compliance to the 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, 
donor, 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. 
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 


 
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A laboratory test result that is judged by the investigator as clinically significant will be recorded 
on the source documentation, transcribed to the eCRF as an adverse event, and monitored as 
described in Section 7.1.2. An event may include a laboratory or diagnostic test abnormality 
(once confirmed by repeated testing) that results in the withdrawal of the donor from the study or 
further diagnostic work-up. 
In addition, potentially clinically significant values may be predefined by the sponsor for 
selected laboratory test variables (Section 7.4) and, if so, will be documented in the statistical 
analysis plan or other relevant documents (eg, medical monitoring plan or laboratory analysis 
plan). 
7.4.1. 
Serum Chemistry, Hematology, Coagulation, and Urinalysis 
Clinical laboratory tests (serum chemistry, hematology, coagulation, and urinalysis) will be 
performed at the time points detailed in Table 1. Clinical laboratory tests will be performed using 
the central laboratory. Specific laboratory tests to be performed are provided in Table 3. 
Table 3: 
Clinical Laboratory Tests 
Serum Chemistry 
Hematology and Coagulation 
Urinalysis 
Calcium 
Phosphate 
Sodium 
Potassium 
Chloride 
Creatinine 
Glucose 
Blood urea nitrogen (BUN) 
Low density lipoprotein (LDL) 
High density lipoprotein (HDL) 
Triglycerides 
Urate 
Alanine aminotransferase (ALT) 
Aspartate aminotransferase (AST) 
Lactate dehydrogenase (LDH) 
Gamma-glutamyl transpeptidase 
(GGT) 
Alkaline phosphatase 
Bicarbonate 
Carbon dioxide 
Protein 
Albumin 
Bilirubin 
Direct bilirubin 
Hemoglobin 
Hematocrit 
Erythrocytes 
Platelets 
Leucocytes 
− Neutrophils 
− Lymphocytes 
− Eosinophils 
− Monocytes 
− Basophils 
Lymphocytes atypical 
Prothrombin International 
Normalized Ratio (INR) 
Protein 
Glucose 
Ketones 
Hemoglobin 
pH 
Specific gravity 
Microscopic tests 
− Bacteria 
− Erythrocytes 
− Leucocytes 
− Crystals 
− Casts 


 
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7.4.2. 
Other Clinical Laboratory Tests 
Other clinical laboratory tests will be performed to ensure the safety of the donors, but will not 
be used to assess the safety of the tbo-filgrastim. 
At screening, donors will have serology tests for HIV type I and II, hepatitis B surface antigen, 
antibodies to hepatitis C virus, IgM antibodies to cytomegalovirus, human T-lymphotropic virus 
type I and II, West Nile virus, malaria, and syphilis. 
At screening donors will have a hemoglobin-solubility test. 
In addition, at screening, female donors who are post-menopausal will have a blood test for FSH 
concentration as indicated in Table 1. 
7.4.2.1. 
Human Chorionic Gonadotropin Tests 
The serum β-hCG test will be performed in women of child-bearing potential at screening 
(visit 1) and as indicated in Table 1, and if clinically indicated, thereafter. Treatment with tbo-
filgrastim will be discontinued in any female donor who becomes pregnant during the study. 
Procedures for reporting the pregnancy are provided in Section 7.2. 
7.4.2.2. 
Urine Drug Screen 
A UDS will be performed at the time points specified in Table 1. The UDS detects the presence 
of prohibited drugs, including amphetamines, barbiturates, benzodiazepines, cannabinoids, 
cocaine metabolites, and opiates. If a drug noted above cannot be tested in urine, an alternative 
matrix (eg, serum) may be considered acceptable. The sponsor’s medical expert must be made 
aware in advance of, and provide approval for, drugs in the screen to which this will apply. A 
positive result for any of the above drugs or their metabolites will preclude the donor from 
enrollment or continued participation in the study. 
7.4.2.3. 
Alcohol Urine Test 
An alcohol urine test will be performed at the time points listed in Table 1. 
7.5. 
Vital Signs 
Vital signs (BP, pulse, respiratory rate, and body temperature) will be measured at the time 
points detailed in Table 1. 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 
Before BP and pulse are measured, the donor must be resting in a seated position for at least 
5 minutes. (The same position and arm should be used each time vital signs are measured for a 
given donor.) 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 eCRF as an adverse event, and 
monitored as described in Section 7.1.2. 


 
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The allowed time windows for vital signs measurements are described in Table 4. 
Table 4: 
Allowed Time Windows for Vital Signs Measurement 
Nominal Assessment Time 
Allowed Time Window 
Post-dose 1 hour 
±10 minutes 
Day 15 
±5 days 
In addition, potentially clinically significant values may be predefined by the sponsor for 
selected vital signs (see Section 9) and, if so, will be documented in the statistical analysis plan 
or other relevant documents (eg, medical monitoring plan). 
7.6. 
Electrocardiography 
A 12-lead ECG will be recorded at the time points detailed in Table 1. Donors must remain in a 
supine position for at least 5 minutes before the ECG is recorded. The ECG will be recorded 
before scheduled blood draws or vital signs measurements, where applicable. A qualified 
physician will be responsible for interpreting the ECG. Any ECG finding that is judged by the 
investigator as clinically significant will be considered an adverse event, recorded on the source 
documentation, transcribed to the eCRF, and monitored as described in Section 7.1.2. 
7.7. 
Physical Examinations 
Physical examinations will be performed at the time points detailed in Table 1. A physical 
examination will include at minimum skin, respiratory, cardiovascular, gastrointestinal, 
neurological, and lymphatic assessments, and will include height. Symptoms (eg, bone pain, 
arthralgia, rhinitis, headache) should trigger a physical examination at the discretion of the 
investigator. 
Any physical examination finding that is judged by the investigator as clinically significant will 
be considered an adverse event, recorded on the eCRF, and monitored as described in 
Section 7.1.2. 
7.8. 
Body Weight 
Body weight will be measured at screening and at baseline. 
7.9. 
Concomitant Medication or Treatment 
Use of concomitant medication or treatment will be monitored throughout the study. Details of 
prohibited medications are given in Section 5.3. 
7.10. 
Spleen Sonography 
Spleen sonography with special attention to spleen size (maximum length) will be performed at 
the time points listed in Table 1. In addition, the examination will be performed if a donor 
complains of pain in the left upper quadrant of the abdomen or in the left shoulder. 


 
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Any abnormal findings or changes (worsening) compared to the screening value assessed by the 
investigator as clinically significant should be reported as an adverse event, recorded on the 
eCRF, and monitored as described in Section 7.1.2. 
7.11. 
Assessment of Local Tolerability and Pain 
An assessment of local tolerability (eg, pain, erythema, ecchymosis, induration) will be 
conducted at the time points listed in Table 1. The allowed time windows for these assessments 
are provided in Table 6. For donors whose symptoms do not resolve within that period, 
assessments will proceed on a daily basis until resolution, as long as donors are at the 
investigational center, and thereafter at each visit. 
Erythema, ecchymosis, and induration will be considered only if they reach a diameter of at least 
5 mm. The surface diameter in millimeters should be recorded and erythema, induration, and 
ecchymosis at the injection site will be graded according to measurements: Absent, 5 mm to 
≤50 mm (mild), >50 to ≤100 mm (moderate), and >100 mm (severe). Induration must be 
assessed by careful superficial palpation avoiding pressuring or squeezing the injection site. 
Severity of local tolerability symptoms should be assessed as described in Table 5. Severe cases 
should be recorded as an adverse event at the discretion of the investigator, recorded on the 
eCRF, and monitored as described in Section 7.1.2. Appropriate treatment may be provided if 
necessary, in which case it must be recorded as concomitant medication. 
Table 5: 
Severity Assessment of Local Tolerability 
Symptom 
 Severity grade 
Parameter 
Pain 
0 
Absent 
1 
Painful on touch 
2 
Pain on moving 
3 
Spontaneously painful 
Erythema 
Record surface diameter in mm, if ≥5 mm 
Ecchymosis 
Record surface diameter in mm, if ≥5 mm 
Induration 
Record surface diameter in mm, if ≥5 mm 
 
Table 6: 
Allowed Time Windows for Deviations from Time Points for Local 
Tolerability Assessment 
Nominal assessment time post-dose 
Allowed time window 
20 minutes 
±10 minutes 
1 hour 
±20 minutes 


 
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7.12. 
Methods and Time Points of Assessing, Recording, and Analyzing 
Safety Data 
All adverse events will be reviewed on a periodic basis by the Study Leader/medical monitor 
according to the safety monitoring plan (eg, scheduled safety reviews for tbo-filgrastim) as 
interim/preliminary safety databases become available. In addition, safety data will be evaluated 
periodically and ad hoc (if necessary) in the Product Safety Group. 


 
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8. 
ASSESSMENT OF PHARMACOKINETICS, 
PHARMACODYNAMICS, IMMUNOGENICITY, 
IMMUNOPHENOTYPING, AND PHARMACOGENOMICS 
8.1. 
Pharmacokinetic Assessment 
Blood samples (5 mL) will be collected for determining serum concentration of the r-metHuG-
CSF via venipuncture or indwelling catheter at the time points detailed in Table 1. 
Every effort must be made to obtain the pharmacokinetic samples at the scheduled time points 
and within the allowed windows for sampling times, as defined in Table 7. 
Table 7: 
Allowed Time Windows for Deviations from Pharmacokinetic and 
Pharmacodynamic Sampling Times 
Scheduled sampling time (after 
administration) 
Day 
Allowed deviation 
0 hour 
Day 1 pre-dose 
0 to 30 minutes 
24 hours 
Day 2 pre-dose 
0 to 30 minutes 
48 hours 
Day 3 pre-dose 
0 to 30 minutes 
72 hours 
Day 4 pre-dose 
0 to 30 minutes 
74 hours 
Day 4 (2 hours post-dose) 
±15 minutes 
76 hours 
Day 4 (4 hours post-dose) 
±15 minutes 
80 hours 
Day 4 (8 hours post-dose) 
±15 minutes 
96 hours 
Day 5 pre-dose 
0 to 30 minutes 
98 hours 
Day 5 (2 hours post-dose) 
±15 minutes 
8.1.1. 
Specimen Sampling and Handling 
The dates and times of tbo-filgrastim administration and the date and time point of each 
pharmacokinetic sample will be recorded on the source documentation and transcribed to the 
eCRF. Sample handling instructions will be given in the laboratory manual. 
8.1.2. 
Shipment and Analysis of Samples 
Serum samples for all donors will be shipped from the investigational center to the central 
laboratory, where they will be stored until shipped to the sponsor or designee for analysis. 
Details on the shipment and analysis of samples will be given in the laboratory manual. 
8.2. 
Pharmacodynamic Assessments 
Blood samples (5 mL) for the determination of ANC and CD34+ for pharmacodynamics 
assessments will be drawn via venipuncture or indwelling catheter at the time points detailed in 


 
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Table 1. Every effort must be made to obtain the pharmacodynamic samples at the scheduled 
sampling times or within the allowed windows for sampling times, as defined in Table 7. 
8.2.1. 
Blood Sampling and Handling 
Sampling and handling for pharmacodynamics assessments will be performed according to local 
standards. 
8.2.2. 
Shipment and Analysis of Samples 
The measurements of ANC and CD34+ will be performed by the local laboratory and will be 
documented within the eCRF. 
8.3. 
Immunogenicity Assessment 
Blood samples (5 mL) will be collected via venipuncture or indwelling catheter for ADA 
analysis at the time points detailed in Table 1. Every effort must be made to obtain the ADA 
samples at the scheduled sampling times. 
Analysis of ADA will be conducted with a 3-tier method. All samples will be first analyzed with 
a screening assay. Samples screened positive will then be subjected to confirmation. Confirmed 
positive samples will be further analyzed to determine ADA titer and the drug-neutralizing 
activity. 
The date and time of administration of tbo-filgrastim and the date and time of each ADA sample 
will be recorded on the source documentation and transcribed onto the eCRF. 
8.3.1. 
Specimen Sampling and Handling 
Details on specimen sampling and handling will be given in the laboratory manual. 
8.3.2. 
Shipment and Analysis of Samples 
Anti-drug antibody serum samples from baseline, day 15 (±5 days), week 5 (±5 days) and month 
3 (±7 days) follow-up for all donors will be shipped from the investigational center (or another 
location at the 5 week (±5 days) and 3 month (±7 days) follow-up) to the central laboratory 
identified in the front matter of this protocol. Details on shipment and analysis of 
immunogenicity assessments will be given in the laboratory manual. 
8.4. 
Pharmacogenomic Assessment 
Blood samples (6 mL) for pharmacogenetic assessments will be collected from all donors in the 
study who signed the ICF for the pharmacogenetic assessments at the time point detailed in 
Table 1. Pharmacogenetic assessments may be conducted only as part of an ancillary study. Each 
donor will sign a separate ICF for pharmacogenetic assessment. Participation in the genetic 
research is optional. Patients who do not wish to participate in the pharmacogenetic research may 
still participate in the study. 
Pharmacogenetic assessment potentially includes the association of DNA variations with clinical 
responses to tbo-filgrastim (eg, efficacy, pharmacokinetics, safety, and tolerability). The final list 
of genes that might be investigated will be selected at a later stage before the analysis to allow 


 
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updating with new scientific information. Genetic analysis could also include sequencing of the 
whole genome if required. 
Pharmacogenetic assessment may be performed based on study results. Samples will be used 
only for investigations related to response to tbo-filgrastim or related IMPs. 
8.4.1. 
Specimen Sampling and Handling 
Blood tubes will be labeled with the donor code number. After DNA extraction at a central 
laboratory, the samples will be labeled with a new code (ie, double coding), so that genomic data 
will not be recorded with a donor number. 
Samples will be stored for a period of up to 15 years from the last donor last visit in the study 
and then destroyed. 
8.4.2. 
Shipment and Analysis of Samples 
Blood samples for pharmacogenetic assessments will be stored at ≤–70ºC (if ≤–70ºC storage is 
not possible at the investigational center, store at –20ºC) and sent to the central laboratory on dry 
ice. After DNA extraction, the samples will be stored at ≤–70ºC and labeled with a new code (ie, 
double coding), so that genomic data will not be recorded with a donor number. Data will be 
kept confidential and stored separately. 
Samples will be transported frozen with sufficient dry ice for 4 days by courier. 
Sample analyses will be performed if and when required. Since new techniques continue to be 
developed, the method and laboratory that will be recommended for the analysis cannot be 
anticipated. 
8.5. 
Assessment of Apheresis Product 
The assessment of the apheresis product is conducted to determine if sufficient number of 
CD34+ cells have been collected and to characterize the type of cells in the apheresis product by 
immunophenotyping. 
8.5.1. 
Apheresis Product Specimen Sampling and Handling 
Assessments of ANC and CD34+ cells in the apheresis product will be conducted according to 
local standards. 
8.5.2. 
Shipment and Analysis of Samples 
The measurements of ANC and CD34+ in the apheresis product will be performed by the local 
laboratory and will be documented within the eCRF. 
8.5.3. 
Methods and Timing of Assessing, Recording, and Analyzing 
Immunophenotyping Data 
Blood samples for characterization of the phenotype profile of the tbo-filgrastim stimulated cells 
from the apheresis product will be taken at the time points detailed in Table 1. Every effort must 
be made to obtain the immunophenotype samples at the scheduled sampling time. 


 
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The date and time of administration of tbo-filgrastim and the date and time of the 
immunophenotype sample will be recorded on the source documentation and transcribed onto the 
eCRF. 
Immunophenotype analysis includes assessment of the following markers: CD3, CD4, CD8, 
CD14, CD16, CD19, CD45, and CD56. Other markers will be assessed as applicable. 
Immunophenotype analysis will be conducted in a central laboratory. 
8.5.3.1. 
Specimen Sampling and Handling 
Blood samples for all donors will be shipped from the investigational center to the central 
laboratory, where they will be analyzed. Details of specimen sampling and handling will be 
provided in the laboratory manual.  
8.5.3.2. 
Shipment and Analysis of Samples 
Details of shipment and analysis of samples will be provided in the laboratory manual. 


 
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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 
A sample size of 55 evaluable donors will provide 89.5% power to test the primary endpoint at a 
nominal significance level of 2.5% using a one-sided exact test for a single proportion. The null 
hypothesis is that the proportion of donors achieving the minimal count of CD34+ cells is less 
than 90%, and sample size calculation was performed under the assumption that the proportion 
of donors achieving the minimal count of CD34+ cells is 99%. 
A sample size of at least 60 donors, treated with a 5-day regimen of tbo-filgrastim 10 μg/kg of 
BW administered sc is considered adequate for assessment of safety. Since the power to test the 
primary endpoint decreases to less than 60% if there are less than 54 evaluable donors, 
enrollment will continue beyond the planned 60 donors until the target sample size of 
55 evaluable donors is achieved. 
9.2. 
Analysis sets 
9.2.1. 
Intent-to-Treat Analysis Set 
The intent-to-treat (ITT) analysis set will include all enrolled donors, regardless of whether or 
not a donor was administered tbo-filgrastim. 
9.2.2. 
Safety Analysis Set 
The safety analysis set will include all donors who receive at least 1 dose of tbo-filgrastim. 
9.2.3. 
Analysis Set of Evaluable Donors  
The analysis set of evaluable donors will include donors that meet all of the following criteria: 
• received the 5-day regimen of tbo-filgrastim 10 μg/kg of BW administered sc 
• day 5 apheresis was performed as planned 
• a quantifiable count of CD34+ cells in the blood collected in the day 5 apheresis was 
measured 
9.2.4. 
Per-Protocol Analysis Set 
The per-protocol analysis set is a subset of the evaluable analysis set including only donors 
without protocol violations. 


 
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9.2.5. 
Additional Analysis Sets 
9.2.5.1. 
Pharmacokinetic Analysis Sets 
The pharmacokinetic analysis set will include those donors in the safety analysis set who have at 
least 1 calculated pharmacokinetic parameter for tbo-filgrastim. 
9.2.5.2. 
Pharmacodynamic Analysis Sets 
The pharmacodynamic analysis set will include those donors in the safety analysis set who have 
at least 1 calculated pharmacodynamic parameter. 
9.3. 
Data Handling Conventions 
For all variables, only the observed data will be used in the statistical analyses. 
9.3.1. 
Handling Withdrawals and Missing Data 
There is no plan to estimate missing data. Sensitivity analysis methods to evaluate the impact of 
missing data on the analysis of the primary endpoint will be provided in the statistical analysis 
plan. 
9.4. 
Study Population 
The ITT analysis set (see Section 9.2.1) will be used for all study population summaries unless 
otherwise noted. 
9.4.1. 
Donor Disposition 
Data from donors screened, donors enrolled, donors enrolled but not treated and reason, donors 
in the ITT, safety, per protocol, evaluable, pharmacokinetic, and pharmacodynamic analysis sets, 
donors who complete the study, and donors who withdraw from the study will be summarized 
using descriptive statistics. Data from donors who withdraw from the study will also be 
summarized by reason for withdrawal using descriptive statistics. 
9.4.2. 
Demographic and Baseline Characteristics  
Donor demographic and baseline characteristics, including medical and procedure history, prior 
medications, and ECG findings, will be summarized using descriptive statistics. For continuous 
variables, descriptive statistics (number, mean, standard deviation, median, minimum, and 
maximum) will be provided. For categorical variables, donor counts and percentages will be 
provided. Categories for missing data will be presented if necessary. 
9.5. 
Efficacy Analysis 
9.5.1. 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the percentage of donors with at least 2 x 106 CD34+ cells/kg 
of recipient BW collected in the first apheresis on day 5. 


 
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9.5.2. 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are 
• Percentage of donors with at least 2 x 106 CD34+ cells/kg of donor baseline BW 
collected after the first apheresis on day 5 
• Percentage of donors with at least 5 x 106 CD34+ cells/kg of recipient BW collected 
after the first apheresis on day 5. 
• Number of aphereses necessary to collect at least 5 x 106 CD34+ cells/kg of recipient 
BW. 
9.5.3. 
Planned Method of Analysis 
The analysis set of evaluable donors (see Section 9.2.3) will be used for all efficacy analyses. 
9.5.3.1. 
Primary Efficacy Analysis 
The null hypothesis for the primary analysis is that the proportion of donors that achieve at least 
2 x 106 CD34+ cells/kg of recipient BW collected in the first apheresis on day 5 is less than 90%. 
The analysis will be conducted using a one-sided exact test for a single proportion at a nominal 
significance level of 2.5%. 
The proportion of donors achieving at least 2 x 106 CD34+ cells/kg of recipient BW collected in 
the first apheresis on day 5 and the corresponding two-sided 95% confidence intervals (CI) 
calculated using the exact Clopper-Pearson confidence limits will be presented. 
The analysis set of evaluable donors will be used for the primary efficacy analysis. Laboratory 
data sourced from the local laboratory will be used for the primary efficacy analysis. 
9.5.3.2. 
Sensitivity Analysis 
The per-protocol analysis set will be used for sensitivity analysis. 
9.5.3.3. 
Secondary Efficacy Analysis 
The primary efficacy analysis described in Section 9.5.3.1 will be repeated for the secondary 
endpoint of the percentage of donors with at least 2 x 106 CD34+ cells/kg of donor baseline BW 
collected after the first apheresis on day 5. 
Descriptive statistics will be provided for all secondary endpoints. In addition, 95% CI for 
proportions will be provided where applicable. 
The analysis set of evaluable donors will be used for the secondary endpoints. Laboratory data 
sourced from the local laboratory will be used for the secondary efficacy analysis. 
9.6. 
Pharmacokinetic Analysis and Endpoints 
Descriptive statistics will be provided for the pharmacokinetic parameters. 
The pharmacokinetic analysis set will be used for the pharmacokinetic analysis. 
The pharmacokinetic endpoints are defined in Section 2.6. 


 
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9.7. 
Pharmacodynamic Analysis and Endpoints 
Descriptive statistics will be provided for the pharmacodynamic parameters. 
The pharmacodynamic analysis set will be used for the pharmacodynamic analysis. 
The pharmacodynamic endpoints are defined in Section 2.7. 
9.8. 
Exploratory Analysis and Endpoints 
The immunophenotype profile of the collected cells will be summarized descriptively. 
Exploratory endpoints are defined in Section 2.4. 
9.9. 
Immunogenicity Analysis 
Results of immunogenicity assessment will be listed. 
If more than 2 donors are confirmed positive to ADA , a summary of immune response incidence 
(number and percentage of positive to ADA) and immunogenicity characterization profile (eg, 
titration and neutralization) will be provided. 
For donors who test ADA positive and have ADA titer greater than baseline titer will be 
followed up for immunogenicity assessment 3 months until titers return to baseline value. This 
data will be reported outside of the study database. 
The safety analysis set will be used for immunogenicity analysis. 
9.9.1. 
Analysis of the Follow-Up Investigation in Recipients 
The incidence and percentage of graft failures (defined as ANC never reaching ≥0.5 x 109/L by 
day 21) for all cells collected and transplanted within 6 months of collection will be provided 
using descriptive statistics and reported in the CSR. 
Data for the follow-up period in recipients for up to 1 year will be recorded in a separate 
database and analyzed using descriptive statistics. These data will be reported as an addendum to 
the clinical study report. 
9.10. 
Multiple Comparisons and Multiplicity 
No correction for multiplicity is needed for the futility interim analyses. The decision rule of the 
final analysis is: reject the null hypothesis if not more than 1 donor that was included in the 
analysis set of evaluable donors does not achieve the minimal count of 2 x 106 CD34+ cells/kg of 
recipient BW collected in the first apheresis on day 5. The study will be declared futile in the 
interim analyses if 2 or more donors do not meet this criterion (see Section 2.3.1). 
9.11. 
Safety Endpoints and Analyses 
Safety endpoints are defined in Section 2.4. 
Safety data per visit and change from baseline will be summarized descriptively. The safety 
analysis set will be used for safety analyses. For continuous variables, descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum) will be provided for actual values 


 
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and changes from baseline to each time point. For categorical variables, donor counts, and 
percentages will be provided. 
9.11.1. 
Safety Analysis 
All adverse events will be coded using the Medical Dictionary for Regulatory Activities. Each 
donor 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), 
adverse events determined by the investigator to be related to the tbo-filgrastim (ie, reasonable 
possibility; see Section 7.1.4) (defined as related or with missing relationship) (overall and by 
severity), adverse events related to the apheresis procedure, serious adverse events, and adverse 
events leading to withdrawal from the study. Donor listings of serious adverse events and 
adverse events leading to withdrawal will be presented.  
Changes in laboratory, ECG recordings, vital signs, urinalysis, physical examination, local 
tolerability, and spleen sonography measurement results will be summarized descriptively. All 
values will be compared with prespecified boundaries to identify potentially clinically significant 
changes or values, and such values will be listed and summarized. 
The use of concomitant medications will be listed and summarized by therapeutic class using 
descriptive statistics. Concomitant medications will include all medications taken while the 
donor is treated with tbo-filgrastim.  
If any donor dies during the study, a listing of deaths will be provided and all relevant 
information will be discussed in the donor narrative included in the CSR. 
9.11.2. 
Local Tolerability Variables and Analysis 
Injection site reaction results (pain, erythema/redness, ecchymosis, and induration) will be listed 
and summarized. 
9.12. 
Pharmacogenomic Analysis 
To date, no appropriate pharmacogenomic markers for the assessment of tbo-filgrastim have 
been identified in healthy donors. Samples will be retained for potential future analyses. 
9.13. 
Immunophenotyping Analysis 
The immunophenotype profile of the cells collected during the first apheresis on day 5 will be 
characterized by assessment of the following markers: CD3, CD4, CD8, CD14, CD16, CD19, 
CD45, and CD56. Other markers will be assessed as applicable. 
9.14. 
Planned Interim Analysis 
Interim analysis for futility will be performed after 15, 30, and 45 donors undergo day 5 
apheresis. The study will be declared futile if 2 or more donors that were included in the analysis 
set of evaluable donors do not achieve the minimal count of 2 x 106CD34+ cells/kg of recipient 
BW collected in the first apheresis on day 5. 


 
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9.15. 
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 donor confidentiality is maintained in accordance with national and local requirements. 
The investigator must maintain the original records (ie, source documents) of each donor’s data 
at all times. Copies of the recipient’s source data may be filed at the investigational center of the 
donor and will be considered original source data. Examples of source documents are hospital 
records, office visit records; examining physician’s finding or notes, consultant’s written opinion 
or notes, laboratory reports, IMP inventory, tbo-filgrastim label records, diary data, 
protocol-required worksheets, and eCRFs that are used as the source (Section 3.15). 
The investigator will maintain a confidential donor identification list that allows the 
unambiguous identification of each donor. 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 donors 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 donors 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 
donor, the investigator, or the sponsor to protocol-specific inclusion and exclusion criteria, 
primary objective variable criteria, or GCP guidelines; noncompliance to tbo-filgrastim 
administration; use of prohibited medications. Protocol violations will be identified and recorded 
by investigational center personnel in the eCRF. 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 
donor from the study or permit the donor to continue in the study, with documented approval 
from the medical expert. The decision will be based on ensuring the safety of the donor 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 donor 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 donor 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 donor 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 donors and recipients have signed the ICF and the study is conducted according 
to applicable SOPs, the protocol, and other written instructions and regulatory guidelines. 
The study monitor is the primary association between the sponsor and the investigator. The main 
responsibilities of the study monitor are to visit the investigator before, during, and after the 
study to ensure adherence to the protocol, that all data are correctly and completely recorded and 
reported, and that informed consent is obtained and recorded for all donors and recipients before 
they participate in the study and when changes to the consent form are warranted, in accordance 
with IEC/IRB approvals. 
The study monitor(s) will contact the investigator and visit the investigational center at regular 
intervals throughout the study. The study monitor will be permitted to check and verify the 
various records (eCRFs and other pertinent source data records, including specific electronic 
source document [Section 3.15]) relating to the study to verify adherence to the protocol and to 
ensure the completeness, consistency, and accuracy of the data being recorded. If eCRFs are 
used for the study, the study monitor will indicate verification by electronically applying source 
document verification flags to the eCRF 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 
quality or characteristics of clinical IMP supplies or clinical device supplies used in a clinical 
research study sponsored by Teva. Examples of a product 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 
• device not working correctly or appears defective in some manner 


 
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Each investigational center will be responsible for reporting a possible clinical product complaint 
by completing the product complaint form provided by Teva and sent via email to 
 within 48 hours of becoming aware of the issue. 
For complaints involving the IMP, all relevant samples should be sent back to the sponsor for 
investigative testing whenever possible. 
11.4.1. 
Product Complaint Information Needed from the Investigational Center 
In the event that the product complaint form cannot be completed, the investigator will obtain the 
following information, as available: 
• investigational center number and principal investigator name 
• name, phone number, and address of the source of the complaint 
• clinical protocol number 
• donor identifier (donor study number) and corresponding visit numbers, if applicable 
• product name and strength 
• donor number, bottle, and kit numbers (if applicable) 
• product available for return Yes/No 
• product was taken or used according to protocol Yes/No 
• description or nature of complaint 
• associated serious adverse event Yes/No 
• date and name of person receiving the complaint 
Note: Reporting a product 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 obtain any outstanding information. 
11.4.2. 
Handling of Tbo-filgrastim 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 tbo-filgrastim. 
If it is determined that the investigational center must return all tbo-filgrastim, the sponsor will 
provide the information needed to handle the return. 
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). 


 
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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 donor. 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 
donor 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 donor. The donor 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 donor 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 donor’s willingness to participate in 
the study will be documented in the ICF, which will be signed and personally dated by the donor 
and by the person who conducted the informed consent discussion. The investigator will keep the 
original ICFs, and copies will be given to the donors. It will also be explained to the donors that 
the donor is free to refuse participation in the study and free to withdraw from the study at any 
time without prejudice to future treatment. 
Adult donors with a legally acceptable representative should provide informed consent according 
to national and local requirements. 
Informed consent will be obtained from all recipients in the study in a manner similar to the 
process described for donors. The recipients’ willingness to participate in the study will be 
documented in an ICF designed for the recipients. Recipients will only be allowed to participate 
in the study if they are aged ≥18 years and if informed consent has been obtained from the donor. 
Donors will only be allowed to participate in the study if the recipient has provided informed 
consent.  
12.2. 
Competent Authorities and Independent Ethics 
Committees/Institutional Review Boards 
Before this study starts, the protocol will be submitted to the national and local competent 
authority and to each IEC/IRB for review. As required, the study will not start at a given 
investigational center before the IEC/IRB and competent authority (where applicable) for the 
investigational center give written approval or a favorable opinion. 
12.3. 
Confidentiality Regarding Study Donors and Recipients 
The investigator must ensure that the privacy of the donors and recipients, including their 
identity and all personal medical information, will be maintained at all times. In eCRFs and other 
documents or image material submitted to the sponsor, donors and recipients will be identified 
not by their names, but by an identification number. 


 
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Personal medical information may be reviewed for the purpose of 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 
For investigational centers located in the EU, a declaration of the end of the clinical study will be 
made according to the procedures outlined in Directive 2001/20/EC, Article 10(c); for other 
countries, national and local regulations will be followed. 
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 eCRFs that are specifically designed for this study. The data 
collected on the eCRFs 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 eCRFs must be completed for each donor and recipient who provided informed 
consent. Copies of the recipient’s source data may be filed at the investigational center of the 
donor and will be considered original source data. Recipient information will be documented in 
the corresponding eCRF. Donor and recipient identity should not be discernible from the data 
provided on the eCRF. 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) the 
results will be sent to the investigational center, where they will be retained but not entered in the 
eCRF, 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 eCRF unless otherwise specified in the 
protocol. All data from other sources will be available to the investigators. 
For donors 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 eCRF. 
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 


 
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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. 
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 ICFs 
• donor and recipient identification lists 
• case report forms for each donor on a per-visit basis 
• data from other sources (eg, central laboratory, bioanalytical laboratory, central image 
center) 
• safety reports 
• financial disclosure reports/forms 
• reports of receipt, use, and disposition of the tbo-filgrastim 
• 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 


 
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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 
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 
tbo-filgrastim 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 donor 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 coordinating 
investigator. The final report is signed by the sponsor and, if applicable, by the coordinating 
investigator. 
When the sponsor generates reports from the data collected in this study for presentation to 
competent authorities, drafts may be circulated to the coordinating investigator for comments 
and suggestions. An endorsement of the final report will be sought from the coordinating 
investigator. 
All unpublished information given to the investigator by the sponsor shall not be published or 
disclosed to a third party without the prior written consent of the sponsor. The primary 
publication from this study will report the results of the study in accordance with the 
“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 
Andreola G, Babic A, Rabascio C, Negri M, Martinelli G, Laszlo D. Plerixafor and Filgrastim 
XM02 (Tevagastrim) as a first line peripheral blood stem cell mobilisation strategy in patients 
with multiple myeloma and lymphoma candidated to autologous bone marrow transplantation. 
Eur J Haematol 2012;88(2):154-8. 
Danylesko I, Sareli R, Bloom-Varda N, Yerushalmi R, Shem-Tov N, Shimoni A, et al. 
Biosimilar Filgrastim (Tevagrastim, XM02) for allogenic hematopoietic stem cell mobilization 
and transplantation in patients with acute myelogenous leukemia/myelodysplastic syndromes. 
Biol Blood Marrow Transplant 22(2016):277-83. 
Duong HK, Savani BN, Copelan E, Devine S, Costa LJ, Wingard JR, et al. Peripheral blood 
progenitor cell mobilization for autologous and allogeneic hematopoietic cell transplantation: 
guidelines from the American Society for Blood and Marrow Transplantation. Biol Blood 
Marrow Transplant 2014;20(9):1262-73. 
GRANIX [US Prescribing Information]. North Wales, PA. North Wales, PA. Teva 
Pharmaceutical Industries Ltd. Updated December 2014. 
International Committee of Medical Journal Editors (ICMJE). Recommendations for the 
Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals. Available 
at http://www.icmje.org/recommendations/. Accessed 02 July 2014. 
Publicover A, Richardson DS, Davies A, Hill KS, Hurlock C, Hutchins D, et al. Use of a 
biosimilar granulocyte colony-stimulating factor for peripheral blood stem cell mobilization: an 
analysis of mobilization and engraftment. Br J Haematol 2013;162(1):107-11. 
Schmitt M, Xu X, Hilgendorf I, Schneider C, Borchert K, Gläser D, et al. Mobilization of PBSC 
for allogeneic transplantation by the use of the G-CSF biosimilar XM02 in healthy donors. Bone 
Marrow Transplant 2013;48:922-5. 
Shaw BE, Confer DL, Hwang W, Pulsipher MA. A review of the genetic and long-term effects 
of G-CSF injections in healthy donors: a reassuring lack of evidence for the development of 
haematological malignancies. Bone Marrow Transplant 2015;50:334-40. 
TEVAGRASTIM [Summary of Product Characteristics]. Ulm, Germany. ratiopharm GmbH. 
March 2014. 


 
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17. 
SUMMARY OF CHANGES TO PROTOCOL 
17.1. 
Amendment 01 Dated 12 April 2017 
The primary reason for this amendment is to clarify and adjust some of the inclusion and 
exclusion criteria in consultation with the investigators. This amendment is considered to be 
substantial (ie, requires approval by competent authority, IEC, and/or IRB) by the sponsor’s 
Authorized Representative. Changes are unlikely to affect the safety or rights (physical or mental 
integrity) of the patients in this clinical study or the scientific value of the clinical study. 
Table 1 (Study Procedures and Assessments) and the protocol synopsis have been revised to 
reflect changes described in Table 8. 
Table 8: 
Changes to the Protocol Amendment 01 
Original text with changes shown 
New wording 
Reason/Justification for change 
<Section number of section with change> <Other section
 affected by this change>: 
Title page, CLINICAL LABORATORY AND OTHER DEPARTMENTS AND INSTITUTIONS 
Sponsor’s Authorized 
Representative 
 
 
 
 
 
 
 
Teva Pharmaceutical Industries 
Ltd.Merckle GmbH of Teva 
Group 
Sponsor’s Authorized 
Representative 
 
Merckle GmbH of Teva Group 
New sponsor’s authorized 
representative appointed for this 
amendment. 
© 20167 Teva Pharmaceuticals 
Industries Ltd. All rights reserved. 
© 2017 Teva Pharmaceuticals 
Industries Ltd. All rights reserved. 
Not applicable 


 
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CLINICAL STUDY PERSONNEL CONTACT INFORMATION, APPENDIX A 
For protocol issues, contact 
the study leader listed 
below:  
 
 
 
Merckle GmbH of Teva 
GroupTeva Pharmaceuticals 
Ltd. 
Phone: 
 
Cel: 
 
 
Email: 
 
 
For protocol issues, contact 
the study leader listed 
below:  
 
 
Merckle GmbH of Teva 
Group 
Phone: 
 
Cel: 
 
Email: 
 
Change in personnel. 
LIST OF ABBREVIATIONS AND DEFINITIONs OF TERMS 
IgM=Immunoglobulin M 
IgM=Immunoglobulin M 
Abbreviation was added 
Section 1.1 Introduction, Section 2.9.1 Objectives, Appendix A 
A follow-up investigation in 
human leukocyte antigen (HLA)
matched siblings or matched 
unrelated recipients will be 
conducted to assess graft failure 
(defined as ANC never reaching 
≥0.5 x 109/L until day 21 after 
transplantation) in cases when 
transplantation occurred within at 
least 6 months of collection. 
A follow-up investigation in 
recipients will be conducted to 
assess graft failure (defined as 
ANC never reaching ≥0.5 x 109/L 
until day 21 after transplantation) 
in cases when transplantation 
occurred within at least 6 months 
of collection. 
Correction for better readability 
Section 1.7 Study Population and Justification 
Donors aged 18 to 5560 years, 
inclusive, with a body mass 
index (BMI) of more than 18.5 
and less than 350.0 kg/m2 who 
meet the eligibility criteria 
(Sections 4.1 and 4.2) are 
planned to be enrolled. 
Donors aged 18 to 60 years, 
inclusive, with a body mass 
index (BMI) of more than 18.5 
and less than 35.0 kg/m2 who 
meet the eligibility criteria 
(Sections 4.1 and 4.2) are 
planned to be enrolled. 
Increase of upper limit of age and 
BMI to align with standard of care 
practices at the transplant centers. 


 
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Section 1.8 Location and Study Duration 
This study is planned to be 
conducted in the USA (for 
donors and recipients) at 
approximately 
120 investigational centers. 
This study is planned to be 
conducted in the USA (for 
donors and recipients) at 
approximately 20 investigational 
centers. 
Increase of number of centers to 
facilitate recruitment. 
Section 2.3.2 Secondary Efficacy Endpoints, Section 9.5.2 Secondary Efficacy Endpoints, Section 9.5.3.3 
Secondary Efficacy Analysis 
The secondary efficacy 
endpoints are: 
• 
percentage of donors 
with at least 2 x 106 
CD34+ cells/kg of 
donor baseline BW 
collected after the first 
apheresis on day 5 
The secondary efficacy 
endpoints are: 
• 
percentage of donors 
with at least 2 x 106 
CD34+ cells/kg of 
donor baseline BW 
collected after the first 
apheresis on day 5 
Specification of which body weight 
will be used for the analysis of the 
secondary efficacy endpoint. 
Section 2.9. Follow-Up Investigation in Recipients: Section 2.9.1 Objectives, Appendix A 
• 
to assess the incidence 
of primary graft failure 
from after 
transplantation in 
HLA matched siblings 
or matched unrelated 
recipients 
• 
to assess the incidence 
of primary graft failure 
after transplantation in 
recipients 
Clarification for better readability. 
Section 2.9.2 Endpoints, Appendix A 
The following endpoints will be 
evaluated in cases when 
transplantation occurred within 
6 months of collection from the 
matching donor: 
The following endpoints will be 
evaluated in cases when 
transplantation occurred within 
6 months of collection from the 
donor: 
The word “matching” was deleted 
for better readability. 


 
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Original text with changes shown 
New wording 
Reason/Justification for change 
Section 3.4 Safety and Tolerability Measures and Time Points (bullet points 1, 2, 3, 4, 5, 6, 7, 8, and 10), 
Section 3.6 Immunogenicity Measures and Variables, Section 3.16.3.1 Visit 11 (Day 15 [±5 days]) or Early 
Termination, Section 5.3 Prior and Concomitant Medication and Treatment, Table 4 Allowed Time Windows 
for Vital Signs Measurements, Section 8.3.2 Shipment and Analysis Samples 
eg, Clinical laboratory tests 
(chemistry, hematology, and 
coagulation) will be performed at 
screening, baseline, daily during 
the treatment period with tbo-
filgrastim, and at the follow-up 
visit on day 15 (±52 days) after 
the last dose of tbo-filgrastim, or 
at early termination (ET). 
Clinical laboratory tests 
(chemistry, hematology, and 
coagulation) will be performed at 
screening, baseline, daily during 
the treatment period with tbo-
filgrastim, and at the follow-up 
visit on day 15 (±5 days) after the 
last dose of tbo-filgrastim, or at 
early termination (ET). 
The time window for Visit 11 
(day 15) has been extended to 
(±5 days) instead of (±2 days) to 
provide the donors with more 
flexibility to attend the visit. 
Section 3.4 Safety and Tolerability Measures and Time Points (bullet 3), Section 3.16.2.1 Baseline (Visit 2, 
Days -5 to -3) bullet 8, Section 3.16.2.2 Tbo-filgrastim Treatment Period (Visits 3 to 6, Days 1 to 4) bullet 2, 
Section 3.16.2.3 Tbo-filgrastim Treatment Period (Visit 7, Day 5) bullet 2, Section 3.16.2.4 Tbo-filgrastim 
Treatment Period (Visits 8 to 10, Days 6 to 8) bullet 2, Section 3.16.3.1 Visit 11 (Day 15 [±5 days]) or Early 
Termination bullet 3 
A full physical examination 
(including height and weight) 
will be performed at screening. 
An abbreviated physical 
examination will be performed at 
baseline, daily during the 
treatment period with tbo
filgrastim, and at the follow-up 
visit on day 15 (±52 days) after 
the last dose of tbo-filgrastim, or 
at ET. 
A physical examination will be 
performed at screening and at the 
follow-up visit on 
day 15 (±5 days) after the last 
dose of tbo-filgrastim, or at ET. 
Physical examination will be 
performed only at 2 visits to reduce 
the burden on the donors. 
Section 3.4 Safety and Tolerability Measures and Time Points (bullet 4) 
• 
Body weight will be 
measured at screening 
and at baseline. 
• 
Body weight will be 
measured at screening 
and at baseline. 
Bullet 4 was added to specify the 
time points for the measurement of 
body weight. 


 
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Section 3.16 Study Procedures and Assessments 
Study procedures and 
assessments with their time 
points are summarized in 
Table 1. Detailed by-visit 
information is provided starting 
with Section 3.16.1. Detailed 
descriptions of each assessment 
are provided in Section 6 
(efficacy assessments), Section 7 
(safety assessments), and 
Section 8 (pharmacokinetic and 
other assessments). Some 
procedures and assessments may 
be performed outside the 
investigational center by a 
homecare service provider, as 
applicable. 
Study procedures and 
assessments with their time 
points are summarized in 
Table 1. Detailed by-visit 
information is provided starting 
with Section 3.16.1. Detailed 
descriptions of each assessment 
are provided in Section 6 
(efficacy assessments), Section 7 
(safety assessments), and 
Section 8 (pharmacokinetic and 
other assessments). Some 
procedures and assessments may 
be performed outside the 
investigational center by a 
homecare service provider, as 
applicable. 
A sentence was added to provide the 
possibility for homecare services to 
reduce the burden for the donors. 
Section 3.16.1 Procedures at Screening (Visit 1) bullet 9 
Perform a full physical 
examination (including height). 
Perform a physical examination 
(including height). 
Clarification for type of physical 
examination and measurement of 
height at screening. 
Section 3.16.1 Procedures at Screening (Visit 1) bullet 10, Section 3.16.2.1 Baseline (Visit 2, Days -5 to -3) 
bullet 8 
• Perform 
measurement of 
body weight. 
• Perform 
measurement of 
body weight. 
A bullet was added to clarify that the 
body weight needs to be measured at 
baseline because it will be used for 
the analysis of the secondary 
efficacy endpoint. 
Section 4 SELECTION AND WITHDRAWAL OF DONORS 
Changes to inclusion or 
exclusion criteria are indicated 
below and detailed in Section 17. 
Changes to inclusion or 
exclusion criteria are indicated 
below and detailed in Section 17. 
A sentence was added to alert to the 
changes of inclusion and exclusion 
criteria. 
Section 4.1 Donor Inclusion Criteria 
d. (Revision 1) The donor is male 
or female, aged between 18 and 
6055 years, inclusive. 
d. (Revision 1) The donor is male 
or female, aged between 18 and 
60 years, inclusive. 
Increase of upper limit of age to 
align with standard of care practices 
at the transplant centers. 
e. (Revision 1) The donor has a 
BW between of at least 50 and 
120 kg, inclusive. 
e. (Revision 1) The donor has a 
BW of at least 50 kg. 
The upper limit of body weight was 
deleted to align with standard of care 
practices at the transplant centers. 
f. (Revision 1) The donor has a 
BMI of more than 18.5 and less 
than 305.0 kg/m2. 
f. (Revision 1) The donor has a 
BMI of more than 18.5 and less 
than 35.0 kg/m2. 
Increase of upper limit of BMI to 
align with standard of care practices 
at the transplant centers. 


 
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k. (Revision 1) The donor must 
be willing and able to comply 
with study restrictions and to 
remain at the investigational 
center for the required duration 
of the study treatment period. 
k. (Revision 1) The donor must 
be willing and able to comply 
with study restrictions. 
Correction. 
l. (New criterion) The donor is 
human leukocyte antigen 
(HLA)-matched or 
haploidentical-related to the 
recipient. 
l. (New criterion) The donor is 
human leukocyte antigen 
(HLA)-matched or 
haploidentical-related to the 
recipient. 
A new inclusion criterion was added 
for clarification of the type of donor. 
Section 4.2 Donor Exclusion Criteria, Section 7.4.2 Other Clinical Laboratory Tests 
l. The donor has a positive test 
result for HIV, hepatitis B 
surface antigen, antibodies to 
hepatitis C virus, 
immunoglobulin (IgM) 
antibodies to cytomegalovirus, 
human T-lymphotropic virus, 
West Nile virus, malaria, or 
syphilis. 
l. The donor has a positive test 
result for HIV, hepatitis B 
surface antigen, antibodies to 
hepatitis C virus, 
immunoglobulin (IgM) 
antibodies to cytomegalovirus, 
human T-lymphotropic virus, 
West Nile virus, malaria, or 
syphilis. 
Clarification for the type of 
cytomegalovirus test required. 
n. The donor has, after resting for 
5 minutes, increased BP (defined 
as systolic BP in seated position 
of more than 1450 mm Hg or 
diastolic BP in seated position of 
more than 950 mm Hg), or low 
BP (defined as systolic BP in 
seated position of less than 
90 mm Hg or diastolic BP in 
seated position of less than 
45 mm Hg). 
n. The donor has, after resting for 
5 minutes, increased BP, (defined 
as systolic BP in seated position 
of more than 145 mm Hg or 
diastolic BP in seated position of 
more than 95 mm Hg), or low BP 
(defined as systolic BP in seated 
position of less than 90 mm Hg 
or diastolic BP in seated position 
of less than 45 mm Hg). 
Increase of limits of increased blood 
pressure to align with standard of 
care practices at the transplant 
centers. 


 
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Original text with changes shown 
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Reason/Justification for change 
Section 7.7 Physical Examinations 
Full and abbreviated pPhysical 
examinations will be performed 
at the time points detailed in 
Table 1. A full physical 
examination will include at 
minimum skin, respiratory, 
cardiovascular, gastrointestinal, 
neurological, and lymphatic 
assessments, and will include 
height and weight (height and 
weight only at screening). The 
abbreviated physical examination 
will comprise the following 
organ systems of interest: 
respiratory, cardiovascular, 
gastrointestinal, and lymphatic 
systems. At baseline, the 
abbreviated physical examination 
will also include weight. 
Physical examinations will be 
performed at the time points 
detailed in Table 1. A physical 
examination will include at 
minimum skin, respiratory, 
cardiovascular, gastrointestinal, 
neurological, and lymphatic 
assessments, and will include 
height. 
Physical examination will be 
performed only at 2 visits to reduce 
the burden on the study participants. 
To clarify that height will be 
measured only at screening. 
Section 7.8 Body Weight 
Body weight will be measured at 
screening and at baseline. 
Body weight will be measured at 
screening and at baseline. 
A new section was added to specify 
the time points for measurement of 
body weight. 
Section 8.2.1 Blood Sampling and Handling 
Details on blood sSampling 
and handling for 
pharmacodynamics 
assessments will be given in 
the laboratory 
manualperformed according to 
local standards. 
Sampling and handling for 
pharmacodynamics 
assessments will be performed 
according to local standards. 
Correction 
Section 8.2.2 Shipment and Analysis of Samples 
The measurements of ANC 
and CD34+ will be performed 
by the local laboratory and 
will be documented within the 
eCRF. Details on the shipment 
and analysis of samples for 
pharmacodynamics 
assessments will be given in 
the laboratory manual. 
The measurements of ANC 
and CD34+ will be performed 
by the local laboratory and 
will be documented within the 
eCRF. 
Correction 


 
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Original text with changes shown 
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Reason/Justification for change 
Section 8.3.2 Shipment and Analysis of Samples 
Anti-drug antibody serum 
samples from baseline, day 15 
(±52 days), week 5 (±52 days) 
and month 3 (±7 days) follow-up 
for all donors will be shipped 
from the investigational center 
(or another location at the 5 week 
(±52 days) and 3 month 
(±7 days) follow-up) to the 
central laboratory identified in 
the front matter of this protocol. 
Anti-drug antibody serum 
samples from baseline, day 15 
(±5 days), week 5 (±5 days) and 
month 3 (±7 days) follow-up for 
all donors will be shipped from 
the investigational center (or 
another location at the 5 week 
(±5 days) and 3 month (±7 days) 
follow-up) to the central 
laboratory identified in the front 
matter of this protocol. 
Correct a typo in week 5 from 
(±2 days) to (±5 days). 
Section 8.5.1 Apheresis Product Specimen Sampling and Handling 
Assessments of ANC and 
CD34+ cells in the apheresis 
product will be conducted 
according to local standards. 
Details on specimen sampling 
and handling will be given in a 
laboratory manual. 
Assessments of ANC and 
CD34+ cells in the apheresis 
product will be conducted 
according to local standards. 
Correction 
Section 8.5.2 Shipment and Analysis of Samples 
The measurements of ANC 
and CD34+ in the apheresis 
product will be performed by 
the local laboratory and will 
be documented within the 
eCRF.Details of shipment and 
analysis of samples will be 
provided in the laboratory 
manual. 
The measurements of ANC 
and CD34+ in the apheresis 
product will be performed by 
the local laboratory and will 
be documented within the 
eCRF. 
Correction 
Section 8.5.3.1 Specimen Sampling and Handling 
Blood samples for all donors will 
be shipped from the 
investigational center to the 
central laboratory, where they 
will be stored until shipped to the 
sponsor or designee for 
analysisanalyzed. 
Blood samples for all donors will 
be shipped from the 
investigational center to the 
central laboratory, where they 
will be analyzed. 
Clarification 


 
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Appendix A 
Donors will only be allowed to 
participate in the study if the 
corresponding matching recipient 
has provided informed consent. 
Donors will only be allowed to 
participate in the study if the 
corresponding recipient has 
provided informed consent. 
Clarification 
Engraftment status will be 
monitored using ANC, 
occurrence of acute and chronic 
Graft-versus-Host Disease and 
grade of Graft-versus-Host 
Disease, prophylactic and 
concomitant therapies to reduce 
occurrence of graft rejection and 
of Graft-versus-Host Disease, 
white blood cell count, platelet 
count, date of first discharge 
from hospital after 
transplantation, disease relapse, 
and date of repeated PBPC 
transplantation, as applicable. 
Engraftment status will be 
monitored using ANC, 
occurrence of acute and chronic 
Graft-versus-Host Disease and 
grade of Graft-versus-Host 
Disease, prophylactic and 
concomitant therapies to reduce 
occurrence of graft rejection and 
of Graft-versus-Host Disease, 
white blood cell count, platelet 
count, date of first discharge 
from hospital after 
transplantation, disease relapse, 
and date of repeated PBPC 
transplantation, as applicable. 
Included more detail for data to 
be collected on recipients. 
 


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APPENDIX A. DATA COLLECTION IN THE RECIPIENTS OF 
PERIPHERAL BLOOD PROGENITOR CELLS 
Study Number: TV44688-ONC-30054 
Title of Study: A Single-Arm Study of the Effect of a 5-day Regimen of Tbo-Filgrastim 
10 μg/kg of Body Weight Administered Subcutaneously on Peripheral Stem Cell Mobilization in 
Healthy Donors 
Sponsor: Teva Pharmaceutical Industries Ltd. 
Investigational New Drug (IND) Number: 103188 
Name of Active Ingredient: tbo-filgrastim (also known as XM02 and recombinant methionyl 
human granulocyte colony-stimulating factor [r-metHuG-CSF]) 
Name of Investigational Medicinal Product: tbo-filgrastim solution for subcutaneous (sc) 
injection 
Type and Phase of the Study: Efficacy and safety (Phase 3) 
For medical issues, contact the physician listed below: 
 
 
 
24-Hour Safety Hotline: 
Phone: 
 
24.-Hour Safety Hotline: 
Fax: 
 
Fax: 
 
Study Coordinating Investigator: 
  
Phone: 
 
Fax: 
 
For operational issues, contact the operational lead listed below: 
 
 
 
Phone: 
 
Email: 
 
For protocol issues, contact the study leader listed below: 
 
 
Merckle GmbH of Teva Group 
Phone: 
 
Cel: 
 
Email: 
 


 
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107 
Background: 
Tbo-filgrastim (also known as XM02) is a non-glycosylated recombinant methionyl human 
granulocyte colony-stimulating factor (r-metHuG-CSF) manufactured by recombinant 
deoxyribonucleic acid technology using the bacterium strain E. coli K802. Tbo-filgrastim was 
approved in the United States of America in 2012 (Teva Pharmaceutical Industries Ltd, Petach 
Tikva, Israel) under the trade name GRANIX®1 for the indication of reduction in the duration of 
severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive 
therapy associated with a clinically significant incidence of febrile neutropenia. 
A donor will only be enrolled into this clinical study if the identified matched recipient of the 
apheresis product provides informed consent that his or her data can be recorded for up to 1 year 
to assess cell engraftment as per protocol. Donors of peripheral blood progenitor cells (PBPCs) 
and the matched recipient may not be located at the same investigational center. No study-
specific visits are necessary for the recipient because only data that are evaluated and recorded 
during the routine treatment and follow-up of the recipient will be processed. The treating 
physician of the PBPC recipient will provide data related to engraftment to the investigational 
center of the donor, where this data can then be entered into the electronic case report form 
(eCRF). 
The recipient needs to provide informed consent before data collection. 
Objectives in Recipients: 
• to assess the incidence of primary graft failure after transplantation in recipients 
• to assess engraftment and survival status in recipients 
Endpoints in Recipients: 
The following endpoints will be evaluated in cases when transplantation occurred within 
6 months of collection from the donor: 
• number of recipients with primary graft failure (defined as absolute neutrophil count 
[ANC] never reaching ≥0.5 x 109/L until day 21 after transplantation) 
• engraftment and survival status in the recipient up to 1 year after the transplantation 
Format of data to be provided: 
Data recorded by the physician of the PBPC recipient for up to 1 year after transplantation will 
be provided to the investigator at the investigational center of the donor. Copies of the recipient’s 
source data may be filed at the investigational center of the donor and will be considered original 
source data. Recipient data will be documented in the corresponding eCRF. Donor and recipient 
identity should not be discernible from the data provided on the eCRF. 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. 
                                                 
1 GRANIX® is a registered trademark of Teva Pharmaceutical Industries Ltd. 


 
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108 
The data will be provided, as either copies of the relevant parts of the recipient medical record, 
medical reports, or data collection forms that could be used for this study. 
The investigator at the investigational center of the donor will be responsible to transcribe the 
data into the eCRF. 
Schedule of data collection: 
1. Informed Consent 
The investigator, or a qualified person designated by the investigator, should fully inform the 
recipient of all pertinent aspects of the study, including the written information approved by the 
Independent Ethics Committee (IEC)/ Institutional Review Board (IRB). All written and oral 
information about the study will be provided in a language as nontechnical as practical to be 
understood by the recipient. The recipient 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 
recipient before any data can be used in the study and after the aims, methods, anticipated 
benefits, and potential hazards are explained, according to the IEC/IRB requirements. The 
recipient’s willingness to participate in the study will be documented in the informed consent 
form (ICF), which will be signed and personally dated by the recipient and by the person who 
conducted the informed consent discussion. The investigator will keep the original ICF, and a 
copy will be given to the recipient. It will also be explained to the recipient that the recipient is 
free to refuse participation in the study and free to withdraw from the study at any time without 
prejudice to future treatment. Adult recipients with a legally acceptable representative should 
provide informed consent according to national and local requirements. Recipients will only be 
allowed to participate in the study if they are aged ≥18 years and if informed consent has been 
obtained from the donor. Donors will only be allowed to participate in the study if the 
corresponding  recipient has provided informed consent. 
2. Baseline Data 
Recipient data that might have an impact on engraftment success will be collected. Data may 
include but are not limited to: age, sex, body weight, underlying hematological disease, 
concomitant use of myelosuppressive therapy, allosensitization, number of stem cell transplants 
(first or repeated), underlying viral infection status, human leukocyte antigen (HLA)-match, 
ABO-match, and conditioning regimen, date of transplantation, type of transplant (related, 
unrelated, or syngeneic), modification of the apheresis product before transplantation. 
3. Primary Graft Failure on Day 21 after Transplantation 
On day 21 the recipient will be assessed for primary graft failure. This will be documented by 
recording the first day the recipient reached an ANC ≥0.5 x 109/L within 21 days after 
transplantation. In case an ANC of ≥0.5 x 109/L is not reached by day 21, the recipient will be 
considered as having experienced primary graft failure. 
Potential additional cell products like cells from umbilical cord blood, cells from other allogeneic 
source, or autologous cells that were transplanted in parallel/in addition to the apheresis product 
will also be documented. 


 
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109 
4. Assessment of Engraftment Status on Day 21, Day 100, and 1 Year after Transplantation 
The following data will be collected from recipient assessments that are closest to (on or before) 
day 21, day 100, and 1 year after PBPC transplantation: 
Engraftment status will be monitored using ANC, occurrence of acute and chronic Graft-versus-
Host Disease and grade of Graft-versus-Host Disease, prophylactic and concomitant therapies to 
reduce occurrence of graft rejection and of Graft-versus-Host Disease, white blood cell count, 
platelet count, date of first discharge from hospital after transplantation, disease relapse, and date 
of repeated PBPC transplantation, as applicable. 
Survival status including date of death and reason for death will also be collected.