Clinical trial NCT02730299
Conditions: Hematological Malignancies Acute Lymphoblastic Leukemia (ALL) Acute Myelogenous Leukemia (AML) Chronic Myelogenous Leukemia (CML) Myelodysplastic Syndrome (MDS) Lymphoma Acute Leukemia
Sponsor: Gamida Cell ltd
Start date: 2016-12-16; Completion date: 2025-02-07
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study is an open-label, controlled, multicenter, international, Phase III, randomized study of transplantation of NiCord® versus transplantation of one or two unmanipulated, unrelated cord blood units in patients with acute lymphoblastic leukemia or acute myeloid leukemia, myelodysplastic syndrome, chronic myeloid leukemia or lymphoma, all with required disease features rendering them eligible for allogeneic transplantation.

Detailed description:
Successful blood and marrow transplantation (BMT) requires the infusion of a sufficient number of hematopoietic stem/progenitor cells (HSPCs), capable of both homing to the bone marrow and regenerating a full array of hematopoietic cell lineages with early and late repopulating ability in a timely fashion.

A major drawback of Umbilical Cord Blood (UCB) is the low stem cell dose available for transplantation, compared to mobilized peripheral blood (PB) or bone marrow. This low stem cell dose can compromise the chances of engraftment and contributes to delayed kinetics of neutrophil and platelet recovery, as well as other transplant outcomes.

The aim of ex vivo expansion of cord blood is to provide a graft with sufficient numbers of cells that have rapid and robust in vivo neutrophil and platelet producing potential to enable successful transplantation.

NiCord® is a stem/progenitor cell-based product composed of ex vivo expanded allogeneic cells from one entire unit of UCB. NiCord® utilizes the small molecule nicotinamide (NAM), as an epigenetic approach to inhibit differentiation and to increase the migration, bone marrow (BM) homing and engraftment efficiency of Hematopoietic Progenitor Cells (HPC) expanded in ex vivo cultures. The chief aim of the study is to compare the safety and efficacy of NiCord® single ex-vivo expanded cord blood unit transplantation to unmanipulated cord blood unit transplantation in patients with hematological malignancies following conditioning therapy.

Arms: arm 1: NiCord® is a cryopreserved stem/progenitor cell based product comprised of:

1. ex vivo expanded, umbilical cord blood-derived hematopoietic CD34+ progenitor cells (NiCord® cultured fraction (CF))
2. the non-cultured cell fraction of the same Cord Blood Unit (CBU) (NiCord® Non-cultured Fraction (NF)) consisting of mature myeloid and lymphoid cells.

Both fractions, i.e. NiCord® CF and NiCord® NF, will be kept frozen until they are thawed and infused on the day of transplantation. arm 2: None
Interventions: intervention 1: NiCord® (omidubicel) intervention 2: Cord Blood Unit
Intervention descriptions: intervention 1: None intervention 2: Cord blood unit

Protocol documents:
Prot_000.pdf: 
 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 1 
Study Title 
A Multicenter, Randomized, Phase III Registration Trial of Transplantation of NiCord®, 
Ex Vivo Expanded, Umbilical Cord Blood-derived, Stem and Progenitor Cells, versus 
Unmanipulated Umbilical Cord Blood for Patients with Hematological Malignancies 
 
Study Chairs 
____________________  
 
 
____________________  
____________________ ________________________________________  
Clinical Phase: 
 
 
Phase III  
Product:  
 
 
 
NiCord® 
IND Number: 
 
 
14459 
EudraCT Number:  
2016-000704-28  
 
Sponsor  
Gamida Cell Ltd. 
PO Box 34670 
Jerusalem 91340 
Israel 
Tel: 972-2-6595666 
Fax:  972-2-6595616 
 
Director, Medical Affairs: 
____________________  
Protocol No.:  
 
 
 
GC P#05.01.020 
Amendment #: 
 
 
 
VI 
Dated:  
 
 
 
 
 
January 22, 2019 
 
This clinical study will be conducted in accordance with the Sponsor's Standard 
Operating Procedures (SOPs), this protocol, current Good Clinical Practice (GCP), the 
Declaration of Helsinki, the provisions of International Conference on Harmonization 
(ICH) Guidelines and all local applicable laws and regulations. 
 
CONFIDENTIAL 
The information in this document is considered privileged and confidential, and may not be disclosed to 
others except to the extent necessary to obtain Institutional Review Board (IRB)/Ethics Committee (EC) 
approval, written informed consent and the approval of local regulatory authorities as required by local law. 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 2 
TABLE OF CONTENTS 
1. ................. INVESTIGATOR’S AGREEMENT ..............................................................15 
2. ................. STUDY SYNOPSIS .......................................................................................16 
3. ................. INTRODUCTION ..........................................................................................27 
3.1. ............. The unmet need in HSCT ...............................................................................27 
3.2. ............. The use of DCBT and ex vivo expansion to overcome the cell dose limitation 
in CBT ............................................................................................................28 
3.3. ............. Rationale for the development of NiCord® ....................................................29 
3.4. ............. Gamida Cell expansion technology ................................................................30 
3.5. ............. Clinical experience with NiCord® and CordIn™ ...........................................31 
3.5.1. .......... Study GC P#01.01.020 ...................................................................................34 
3.5.2. .......... Study GC P#03.01.020 ...................................................................................36 
3.5.3. .......... Study GC P#02.01.020 ...................................................................................38 
3.5.4. .......... Study GC P#01.01.030 ...................................................................................38 
3.5.5. .......... Study GC P#04.01.020/030 ............................................................................38 
3.6. ............. Overall Risk Benefit .......................................................................................38 
3.7. ............. Rationale for study design and dosages ..........................................................39 
3.7.1. .......... Study population .............................................................................................39 
3.7.2. .......... CBU cell dose .................................................................................................40 
3.7.3. .......... Selection of CBUs ..........................................................................................41 
3.7.4. .......... Conditioning regimens ....................................................................................41 
3.7.5. .......... Study endpoints ..............................................................................................42 
4. ................. STUDY OBJECTIVES, HYPOTHESIS AND STUDY ENDPOINTS .........45 
4.1. ............. Objectives .......................................................................................................45 
4.2. ............. Definition of study endpoints .........................................................................46 
4.2.1. .......... Date of randomization ....................................................................................46 
4.2.2. .......... Date of transplant ............................................................................................46 
4.2.3. .......... Neutrophil engraftment ...................................................................................46 
4.2.4. .......... Platelet engraftment ........................................................................................47 
4.2.5. .......... Grade 2/3 Bacterial Infections and grade 3 Viral infections ..........................47 
4.2.6. .......... Invasive fungal infection ................................................................................47 
4.2.7. .......... Duration of primary hospitalization ................................................................47 
4.2.8. .......... Days alive and out of hospital ........................................................................47 


 
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NiCord® Phase III HM Protocol 
 
Page 3 
4.2.9. .......... Overall survival ..............................................................................................47 
4.2.10. ........ Disease Relapse ..............................................................................................48 
4.2.11. ........ Disease-free survival ......................................................................................49 
4.2.12. ........ Non-Relapse Mortality ...................................................................................49 
4.2.13. ........ Relapse Mortality ............................................................................................49 
4.2.14. ........ Acute GvHD ...................................................................................................49 
4.2.15. ........ Chronic GvHD ................................................................................................49 
4.2.16. ........ Immune Reconstitution ...................................................................................50 
4.2.17. ........ Health-Related Quality of Life (HQL) ...........................................................50 
4.2.17.1. ..... FACT-BMT ....................................................................................................50 
4.2.17.2. ..... EQ-5D .............................................................................................................50 
4.2.18. ........ Safety and Tolerability of NiCord® Transplantation ......................................51 
4.2.19. ........ Other Definitions ............................................................................................51 
4.2.19.1. ..... Response Criteria for Acute Leukemia ...........................................................51 
4.2.19.2. ..... Complete Morphologic Remission for CML from Prior Blast Crisis ............51 
4.2.19.3. ..... CML Stages ....................................................................................................51 
4.2.19.4. ..... Response Criteria for Lymphoma ...................................................................52 
5. ................. STUDY POPULATION .................................................................................54 
5.1. ............. Number of patients .........................................................................................54 
5.2. ............. Analysis populations .......................................................................................54 
5.3. ............. Eligibility criteria ............................................................................................55 
6. ................. CONCOMITANT MEDICATIONS AND SUPPORTIVE CARE ................55 
6.1. ............. Previous medications ......................................................................................60 
6.2. ............. Disallowed concomitant medications .............................................................60 
6.3. ............. Conditioning regimen .....................................................................................60 
6.3.1. .......... Radiotherapy (Regimen A) .............................................................................62 
6.3.2. .......... Fludarabine Administration (Regimens A and B) ..........................................62 
6.3.3. .......... Cyclophosphamide (CY) Administration (Regimen A.2) ..............................63 
6.3.4. .......... Thiotepa Administration (Regimen A.1 and B) .............................................63 
6.3.5. .......... Busulfan Administration (Regimen B) ...........................................................63 
6.3.6. .......... Dose adjustment formulas ..............................................................................64 
6.4. ............. GvHD prophylaxis medications .....................................................................64 
6.5. ............. Acute & Chronic GvHD Treatment ................................................................65 


 
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NiCord® Phase III HM Protocol 
 
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6.6. ............. Venous Access ................................................................................................65 
6.7. ............. Infusion Support .............................................................................................65 
6.8. ............. Supportive Cytokine Therapy .........................................................................65 
6.9. ............. Blood Products................................................................................................65 
6.10. ........... Engraftment Syndrome ...................................................................................66 
6.11. ........... Infection Prophylaxis and Surveillance ..........................................................66 
6.11.1. ........ Anti-viral Prophylaxis ....................................................................................66 
6.11.2. ........ Anti-bacterial Prophylaxis ..............................................................................67 
6.11.3. ........ PCP Prophylaxis .............................................................................................67 
6.11.4. ........ Fungal Prophylaxis .........................................................................................67 
6.11.5. ........ Toxoplasmosis Prophylaxis ............................................................................67 
6.11.6. ........ CMV Surveillance ..........................................................................................67 
6.11.7. ........ HHV6 Surveillance .........................................................................................67 
6.11.8. ........ EBV Surveillance ...........................................................................................67 
6.11.9. ........ Adenovirus Intervention Guideline ................................................................68 
6.11.10. ...... Intravenous Immune Globulin ........................................................................68 
6.11.11. ...... Identification of Infectious Agents – Recommendations ...............................68 
6.11.11.1.... Blood Cultures ................................................................................................68 
6.11.11.2.... Blood Culture Procedure ................................................................................68 
6.11.11.3.... Additional Identification Procedures ..............................................................68 
6.11.12. ...... Treatment of Infections ...................................................................................69 
6.11.13. ...... Discharge Instructions and Follow-up ............................................................69 
6.12. ........... Nutrition ..........................................................................................................69 
6.13. ........... Guidelines for Infusing a Second Stem Cell Product .....................................69 
6.14. ........... Investigational Agents ....................................................................................69 
6.15. ........... Other Medications ..........................................................................................69 
7. ................. DETAILED STUDY PLAN ...........................................................................77 
7.1. ............. Pre-screening activities search for matching CBUs .......................................77 
7.2. ............. Screening Assessments ...................................................................................78 
7.2.1. .......... Informed Consent and Registration ................................................................78 
7.2.2. .......... Eligibility and Baseline Assessments ((_________weeks prior to 
randomization) ................................................................................................79 
7.3. ............. Randomization ................................................................................................83 


 
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NiCord® Phase III HM Protocol 
 
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7.4. ............. CBU shipment and receipt ..............................................................................83 
7.4.1. .......... NiCord® arm – CBU shipment and receipt at the production site ..................83 
7.4.2. .......... NiCord® arm – post production release and shipping ....................................83 
7.4.3. .......... Unmanipulated CBU arm – CBU shipment and receipt at the clinical site ....84 
7.5. ............. Post Randomization Follow-Up .....................................................................84 
7.6. ............. Transplant Suitability Confirmation: (within 24 hours prior to start of 
conditioning) ...................................................................................................85 
7.7. ............. Myeloablative Conditioning ...........................................................................85 
7.8. ............. Transplantation Day (Day 0) ..........................................................................86 
7.8.1. .......... Preparation and Infusion of NiCord® or the Unmanipulated CBU(s) ............86 
7.8.1.1. ....... Preparation and Infusion of the Unmanipulated CBU(s) ...............................86 
7.8.1.2. ....... Thawing and Infusion of NiCord® on Day 0 ..................................................87 
7.8.2. .......... Evaluation and Treatment of IPQC/FPQC Safety Tests Failure ....................88 
7.8.3. .......... Post Transplantation Follow-Up (Day 0 to 1) ................................................88 
7.9. ............. Scheduled treatment visits Post Transplant (as detailed in Table 4: 
Evaluations and examinations flow sheet) .....................................................89 
7.9.1. .......... Scheduled Daily Assessments Post Transplant up to ANC Engraftment or 
Primary Graft Failure ......................................................................................89 
7.9.2. .......... Scheduled Visits Post Transplant on Days 7, 14 (±3), 21 (±3), 28 (±3), 35 
(±3), 42 (±3), 56 (±3), 70/ Day (±14) 100/ Day (±21) 180/ Day (±21) 270/ 
Day (±21) 365 .................................................................................................89 
7.9.3. .......... Administration of Health-Related Quality of Life Measures .........................92 
7.9.4. .......... Assessment of Medical Resource Utilization (MRU) ....................................93 
7.9.5. .......... Evaluation and Treatment of Graft Failure .....................................................93 
7.9.6. .......... Early Withdrawal From Follow-up ................................................................94 
7.9.7. .......... Criteria for Early Withdrawal .........................................................................94 
7.10. ........... Optional Long term follow-up ........................................................................95 
7.11. ........... Data reporting .................................................................................................95 
7.11.1. ........ Criteria for Forms Submission........................................................................95 
8. ................. STUDY MEDICATION .................................................................................96 
8.1. ............. Description ......................................................................................................96 
8.1.1. .......... NiCord® ..........................................................................................................96 
8.2. ............. CBU Supply ....................................................................................................96 
8.3. ............. Manufacturing .................................................................................................96 


 
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NiCord® Phase III HM Protocol 
 
Page 6 
8.3.1. .......... Out of Specification Results ...........................................................................97 
8.3.1.1. ....... NiCord® CF OOS ...........................................................................................97 
8.3.1.2. ....... NiCord® NF OOS ...........................................................................................98 
8.4. ............. Handling of NiCord® ......................................................................................98 
8.5. ............. Shipment .........................................................................................................98 
9. ................. SAFETY MONITORING ............................................................................100 
9.1. ............. Definitions ....................................................................................................100 
9.1.1. .......... Adverse Event (AE) ......................................................................................100 
9.1.2. .......... Infusion Reaction ..........................................................................................100 
9.1.3. .......... Serious Adverse Event (SAE) ......................................................................100 
9.1.4. .......... Suspected Adverse Reaction .........................................................................101 
9.1.5. .......... Causality .......................................................................................................101 
9.1.6. .......... Expectedness .................................................................................................101 
9.1.7. .......... Toxicity Grading ...........................................................................................101 
9.1.8. .......... Expedited Reporting .....................................................................................102 
9.2. ............. Observation, Detection and Recording of AEs and SAEs ............................102 
9.3. ............. Follow-up of AEs and SAEs .........................................................................104 
9.4. ............. Medical Monitor Review ..............................................................................105 
9.5. ............. Clinical Laboratory Evaluations ...................................................................105 
9.6. ............. Pregnancy .....................................................................................................105 
9.7. ............. Patient Withdrawal from Study Procedures due to Adverse Events ............106 
9.8. ............. DMC Reporting ............................................................................................106 
9.9. ............. Regulatory Authorities and IRB/ECs ...........................................................106 
10. .............. STATISTICAL METHODOLOGY .............................................................108 
10.1. ........... Study Design and Objectives ........................................................................108 
10.1.1. ........ Accrual ..........................................................................................................108 
10.1.2. ........ Randomization ..............................................................................................108 
10.1.3. ........ Primary Endpoint ..........................................................................................109 
10.1.4. ........ Primary Hypothesis ......................................................................................109 
10.1.5. ........ Sample Size and Power Considerations .......................................................109 
10.1.6. ........ Overall mortality and “reverse” results ........................................................110 
10.2. ........... Interim Analysis and Stopping Guidelines ...................................................110 
10.2.1. ........ Data Monitoring Committee .........................................................................110 


 
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NiCord® Phase III HM Protocol 
 
Page 7 
10.2.2. ........ Guidelines for Safety Monitoring .................................................................111 
10.2.1. ........ Interim Analysis for Efficacy and Futility ....................................................112 
10.3. ........... Analysis Populations ....................................................................................112 
10.3.1. ........ Demographics and Baseline Characteristics .................................................113 
10.4. ........... Analysis Plan ................................................................................................113 
10.4.1. ........ Timing of final analyses and statistical significance levels ..........................113 
10.4.2. ........ Analysis of the Primary Endpoint.................................................................114 
10.4.2.1. ..... Secondary Analysis of Time to Neutrophil Engraftment .............................115 
10.4.3. ........ Analysis of Secondary Endpoints .................................................................115 
10.4.3.1. ..... Incidence of bacterial infection grades 2-3 or invasive fungal infection by 100 
days following transplantation ......................................................................116 
10.4.3.2. ..... Days alive and out of hospital in the first 100 days following transplantation
 ......................................................................................................................116 
10.4.3.3. ..... Platelet engraftment by 42 days following transplantation ..........................117 
10.4.4. ........ Analysis of Tertiary Endpoint ......................................................................117 
10.4.4.1. ..... Non-relapse mortality by 210 days following randomization ......................117 
10.4.5. ........ Analysis of Exploratory Endpoints ...............................................................117 
10.4.5.1. ..... Neutrophil engraftment by 16 days following transplantation .....................117 
10.4.5.2. ..... Time from transplantation to platelet engraftment .......................................117 
10.4.5.3. ..... Duration of primary hospitalization ..............................................................118 
10.4.5.4. ..... Non-relapse mortality by 130 days following randomization ......................118 
10.4.5.5. ..... Non-relapse mortality by 15 months following randomization ....................118 
10.4.5.6. ..... Overall survival at 210 days following randomization .................................119 
10.4.5.7. ..... Overall survival by 15 months following randomization .............................119 
10.4.5.8. ..... Disease-free survival by 15 months following randomization .....................119 
10.4.5.9. ..... Neutrophil engraftment by 42 days following transplantation .....................119 
10.4.5.10.... Acute GvHD grade II-IV by 100 days following transplantation ................120 
10.4.5.11.... Acute GvHD grade III-IV by 100 days following transplantation ...............120 
10.4.5.12.... Chronic GvHD (mild/moderate/severe) by 180 days following transplantation
 ......................................................................................................................120 
10.4.5.13.... Chronic GvHD (mild/moderate/severe) by 1 year following transplantation
 ......................................................................................................................121 
10.4.5.14.... Secondary graft failure by 1 year following transplantation ........................121 
10.4.5.15.... Grade 3 viral infections by 180 days following transplantation ...................121 


 
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NiCord® Phase III HM Protocol 
 
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10.4.5.16.... Grade 3 viral infections by 1 year following transplantation .......................121 
10.4.5.17.... Relapse by 15 months following randomization ..........................................121 
10.4.5.18.... Relapse mortality by 15 months following randomization ...........................122 
10.4.5.19.... Immune Reconstitution .................................................................................122 
10.4.5.20.... Health-Related Quality of Life .....................................................................122 
10.4.6. ........ Subgroup Analysis ........................................................................................123 
10.5. ........... Missing data ..................................................................................................123 
10.5.1. ........ Loss to follow-up in the primary analysis of the primary endpoint .............124 
10.5.2. ........ Loss to follow-up in the primary analyses of the secondary endpoints ........124 
10.5.3. ........ Sensitivity analyses for missing data ............................................................125 
10.6. ........... Safety and Tolerability of NiCord® transplantation .....................................125 
10.7. ........... Analysis Plan Deviations ..............................................................................126 
10.8. ........... Statistical Software .......................................................................................126 
10.9. ........... Long-term Follow-up (optional) ...................................................................126 
11. .............. CLINICAL DATA MANAGEMENT ..........................................................127 
11.1. ........... Data Quality Assurance ................................................................................127 
11.2. ........... Data Collection .............................................................................................127 
11.3. ........... Source Documents ........................................................................................127 
11.4. ........... Staff Training ................................................................................................128 
11.5. ........... Data Monitoring ............................................................................................128 
APPENDIX A. SCREENING SCHEDULE .................................................................129 
APPENDIX B. GVHD CLASSIFICATION ................................................................130 
APPENDIX C. SAFETY DATA REPORTING ...........................................................133 
APPENDIX D. COMMON ADVERSE EVENTS .......................................................135 
APPENDIX E. COMMON TERMINOLOGY CRITERA FOR ADVERSE .... EVENTS 
V4.03 (CTCAE) 
 
(U.S.DEPARTMENT_OF_HEALTH_AND_HUMAN_SERVICES 
 
2009) ....................................................................................................137 
APPENDIX F. DRUG LABELS ..................................................................................138 
APPENDIX G. INFECTION GRADING .....................................................................139 
APPENDIX H. EUROPEAN LEUKEMIANET GUIDELINES .................................148 
APPENDIX I. STATISTICAL ANNEX ......................................................................149 
APPENDIX J. LONG TERM FOLLOW-UP OBSERVATIONAL STUDY 
 
STATISTIC PLAN ...............................................................................150 


 
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NiCord® Phase III HM Protocol 
 
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APPENDIX K. PROTOCOL AMENDMENT SUMMARY .......................................151 
REFERENCES ................................................................................................................152 
 
 
LIST OF TABLES 
Table 1: ...... Overview of ongoing clinical studies of NiCord® ..........................................32 
Table 2: ...... Response Definitions for Lymphoma .............................................................53 
Table 3: ...... Conditioning regimens ....................................................................................61 
Table 4: ...... Evaluations and examinations flow sheet .......................................................71 
Table 5: ...... Follow-Up Assessments for Patients Who Do Not Receive a Transplant 
within 90 Days of Randomization ..................................................................76 
Table 6: ...... Required Patient-reported Outcomes Data Collectiona ..................................93 
Table 7: ...... Probabilities of observing that the 180-day overall mortality is higher in the 
NiCord® group under different scenarios when total sample size is 120 .....110 
Table 8: ...... Operating characteristics of sequential testing procedure for 130 Day 
Mortality from a simulation study with 100,000 replications ......................112 
Table 9: ...... GvHD classification ......................................................................................130 
Table 10: ... Clinical manifestations and staging of acute graft versus host disease ........130 
Table 11: ... NIH Global Severity of chronic GvHD ........................................................131 
Table 12: ... Safety Data Reporting for transplanted patients ...........................................133 
Table 13: ... Safety Data Reporting for Post Randomization Patients Who Do Not Receive 
a Transplant Within 90 Days following Randomization ..............................134 
Table 14: ... CML Response Criteria ................................................................................148 
Table 15: ... Protocol Amendment Summary ...................................................................151 
 
LIST OF FIGURES 
Figure 1: .... Study Scheme .................................................................................................25 
Figure 2: .... CBU Selection ................................................................................................26 


 
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NiCord® Phase III HM Protocol 
 
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List of Abbreviations 
Ab 
Antibody 
ABW 
Actual Body Weight 
AE 
Adverse Event 
AEP 
ANC-Engrafted Population 
ALL 
Acute Lymphoblastic Leukemia  
ALT 
Alanine Transaminase 
AML 
Acute Myelogenous Leukemia  
ANC 
Absolute Neutrophil Count 
AP/PA position 
Anteriorposterior/Posterioranterior Position 
APL 
Acute Promyelocytic Leukemia 
ASHI/EFI 
American Society for Histocompatibility and 
Immunogenetics/European Federation for Immunogenetics 
AST 
Aspartate Transaminase 
AT 
As Treated 
AUC 
Area Under the Curve 
BAL 
Bronchoalveolar Lavage 
B CELL 
Bone Marrow Lymphocyte Cells (CD19+) 
BID 
Twice a day 
BM 
Bone Marrow 
BMT 
Bone Marrow Transplant 
BMTS 
Bone Marrow Transplantation Subscale 
BSA 
Body Surface Area 
CB 
Cord Blood 
CBB 
Cord Blood Bank 
CBC 
Complete Blood Count 
CBT 
Cord Blood Transplant 
CBU 
Cord Blood Unit 
cDLCO 
Corrected Diffusing Capacity of the Lungs for Carbon Monoxide 
CF 
Cultured Fraction 
CFU 
Colony-forming Units 
CHR 
Complete Hematologic Response 
CI 
Cumulative Incidence 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CML 
Chronic myeloid leukemia 
CMR 
Complete Molecular Response 
CMMoL 
Chronic myelomonocytic leukemia 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
COA 
Certificate of Analysis 
CoNS 
Coagulase-Negative Staphylococci 
CR 
Complete Remission 
CRA 
Clinical Research Associate 
(e-) CRFs 
(Electronic) Case Report Forms 
CRO 
Contract Research Organization 
CSA 
Cyclosporin A 
CSF 
Cerebrospinal Fluid 
CT 
Computed Tomography  
CTCAE 
Common Terminology Criteria for Adverse Events 
CY 
Cyclophosphamide Administration 
(c/p/m) CyR 
(Complete/Partial/Minor) Cytogenectic Response 
DCC 
Data Coordinating Center 
DCBT 
Double Cord Blood Transplant 


 
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DLCO 
Diffusing Capacity of the Lungs for Carbon Monoxide 
DMC 
Data Monitoring Committee 
DNA 
Desoxyribonucleic Acid 
DRI 
Disease Risk Index 
EBMT 
European society for Blood and Marrow Transplantation 
EBV 
Epstein-Barr Virus 
EC 
Ethics Committee 
EKG 
Electrocardiography 
EMA 
European Medicines Agency 
EVCTM 
EudraVigilence Clinical Trial Module 
FACS 
Fluorescence-Activated Cell Sorting 
FACT-BMT 
Functional Assessment of Cancer Therapy – Bone Marrow Transplant 
Module 
FACT-G 
Functional Assessment of Cancer Therapy - General 
FBS 
Fetal Bovine Serum  
FEV1 
Forced Expiratory Volume in One Second  
FISH 
Fluorescent In Situ Hybridization 
FLT3 
Fms Related Tyrosin Kinase 
FLT3-L 
Flt3-Ligand  
FPQC 
Final Process Quality Controls 
FVC 
Forced Vital Capacity  
FWE 
Family-wise Error Rate 
GC 
Gamida Cell 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony-Stimulating Factor 
GFR 
Glomerular Filtration Rate 
GMF 
Grocott Methenamine Silver 
GvHD 
Graft-versus-host Disease 
HCG 
Human Chorionic Gonadotropin 
HCV  
Hepatitis C Virus 
HBcAb 
Hepatitis B core Antibody 
HBsAg 
Hepatitis B surface Antigen 
HHV  
Human Herpesvirus 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
HPC 
Hematopoietic Progenitor Cells 
HQL 
Health-related Quality of Life 
HRCT 
High-Resolution Computed Tomography 
HSC 
Hematopoietic Stem Cells 
HSCT 
Hematopoietic Stem Cell Transplantation 
HSPCs 
Hematopoietic Stem/Progenitor Cells  
HSV 
Herpes Simplex Virus 
HTLV 
Human T-Lymphotropic Virus 
IB 
Investigator Brochure 
IBW 
Ideal Body Weight 
IC 
Informed Consent 
ICH 
International Conference on Harmonization  
ID 
Identify Document 
Ig 
Immunoglobulin 
IL6 
Interleukin 6 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug 
IPQC 
In-process Quality Controls 
IPS 
Idiopathic Pneumonia Syndrome 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 12 
IPSS 
International Prognostic Scoring System 
IRB 
Institutional Review Board 
ISO 
International Organization for Standardization 
ITT 
Intent to Treat 
IUD 
Intrauterine contraceptive Device 
IV 
Intravenous 
LVEF 
Left Ventricular Ejection Fraction 
MARTs 
Mono-ADP-ribosyltransferases 
MDS 
Myelodysplastic Syndrome  
MFI 
Mean Fluorescence Intensity 
MLL  
Myeloid/Lymphoid Leukemia 
MM 
Medical Monitor 
MMF 
Mycophenolate Mofetil 
MMR 
Major Molecular Response 
MMUD 
Mismatched Unrelated Donor 
MRD 
Minimal Residual Disease 
MRI 
Magnetic Resonance Imaging 
MRU 
Medical Resources Utilization 
MS 
Mass Spectrometry 
MS CA 
Member States Competent Authority 
MUD 
Matched Unrelated Donor 
MUGA 
Multi Gated Acquisition Scan 
N/A 
Not Applicable 
NAD+ 
Nicotinamide Adenine Dinucleotide 
NAM 
Nicotinamide 
NCI 
National Cancer Institute 
NF 
Non-cultured Fraction 
NIH 
National Institutes of Health 
NK CELL 
Natural Killer Cytotoxic Lymphocyte Cells (CD56+/CD16+cells) 
NOD/SCID  
Non-Obese Diabetic Background, Severe Combined 
Immunodeficiency  
NOS 
Not Otherwise Specified 
NP 
Nurse Practitioner  
NRM 
Non Relapse Mortality 
OOS 
Out of Specification 
PA 
Physician Assistant 
PaO2 
Partial Pressure of Oxygen 
PARPs 
Poly-ADP-ribose Polymerases 
PB 
Peripheral Blood 
PBSC 
Peripheral Blood Stem Cell 
PCP 
Pneumocystis Pneumonia 
PCR 
Polymerase Chain Reaction 
PEP 
Platelet-Engrafted Population 
PI 
Principal Investigator 
PMN 
Polymorphonuclear Leukocytes  
PO 
By Mouth, or Oral Administration of a Drug 
PT 
Preferred Term 
PTLD 
Post-Transplant Lymphoproliferative Disorder 
QC 
Quality Control 
QOL 
Quality Of Life 
QP 
Qualified Person 
RBC 
Red Blood Cell 
Rh 
Rhesus 
RPR 
Rapid Plasma Reagin 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 13 
RSV 
Respiratory Syncytial Virus 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Subcutaneous 
SCD 
Sickle Cell Disease 
SCF 
Stem Cell Factor  
SCID 
Severe Combined Immunodeficiency  
SCT 
Stem Cell Transplant 
SLM 
Study Logistics Manager 
SOC 
System Organ Class 
SOP 
Standard Operating Procedures 
SP 
Safety Population 
SPRT 
Sequential Probability Ratio Test 
SRC 
SCID Repopulating Cells 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBI 
Total Body Irradiation 
T CELL 
Thymus derived lymphocytes (CD3+ cells; CD4+/CD8+ cells) 
TDM 
Therapeutic Drug Monitoring 
TID 
Three Times a Day Administration of a Drug 
TKI 
Tyrosine Kinase Inhibitor 
TNC 
Total Nucleated Cell 
TP 
Transplanted Population 
TPO 
Thrombopoietin 
TRM 
Transplant-related Mortality 
UA 
Urinalysis 
UCB 
Umbilical Cord Blood  
UCBU 
Unmanipulated Cord Blood Unit 
UCBT 
Umbilical Cord Blood Transplantation 
VZV 
Varicella-zoster Virus  
WBC 
White Blood Cell 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 14 
SPONSOR PROTOCOL APPROVAL PAGE 
 
Protocol Title: A Multicenter, Randomized, Phase III Registration Trial of 
Transplantation of NiCord®, Ex Vivo Expanded, Umbilical Cord Blood-derived, Stem 
and Progenitor Cells, versus Unmanipulated Umbilical Cord Blood for Patients with 
Hematological Malignancies 
 
 
Clinical Phase 
 
 
 
Phase III  
 
 
Protocol Number:   
 
GC P#05.01.020 
Amendment Number:  
 
VI 
Dated:  
 
 
 
 
 
January 22, 2019 
 
Approved by: 
 
Director, Medical Affairs  
 
____________________  
 
 
___________________________________  
___________________________ 
Signature   
 
 
 
 
 
 
 
 
 
Date 
 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 15 
Protocol Title: A Multicenter, Randomized, Phase III Registration Trial of 
Transplantation of NiCord®, Ex Vivo Expanded, Umbilical Cord Blood-derived, Stem 
and Progenitor Cells, versus Unmanipulated Umbilical Cord Blood for Patients with 
Hematological Malignancies 
 
Clinical Phase: 
 
 
 
Phase III  
Protocol Number:   
 
GC P#05.01.020 
Amendment Number:  
 
VI 
Dated:  
 
 
 
 
 
January 22, 2019 
1. 
INVESTIGATOR’S AGREEMENT 
I have carefully read the foregoing protocol including all appendices and agree that it 
contains all the necessary information for conducting the study safely. 
I will conduct this study in strict accordance with this protocol and according to the 
current GCP regulations and will attempt to complete the study within the time 
designated. 
 
I will provide copies of the protocol and all other information relating to pre-clinical and 
prior clinical experience submitted by the Sponsor to all personnel responsible to me who 
participate in the study. I will discuss this information with them to ensure that they are 
adequately informed regarding the drug and conduct of the study. 
 
I agree to keep records on all subject information (CRFs, shipment, and all other 
information collected during the study) in accordance with the current GCP and local 
regulations. 
 
_______________________________ 
 
Principal Investigator’s Name 
 
 
_______________________________ 
 
Signature 
 
 
_______________________________ 
 
Date 
 
 
_______________________________ 
 
Institution 
 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 16 
2. 
STUDY SYNOPSIS 
Protocol Number 
GC P# 05.01.020 
Protocol Title  
A Multicenter, Randomized, Phase III Registration Trial of Transplantation of NiCord®, 
Ex Vivo Expanded, Umbilical Cord Blood-derived, Stem and Progenitor Cells, versus 
Unmanipulated Umbilical Cord Blood for Patients with Hematological Malignancies 
Planned Geographical Distribution 
Multicenter, multinational  
Clinical Phase 
Phase III, Registration 
Investigational Product 
NiCord® is a cryopreserved stem/progenitor cell-based product comprised of: 
1) Ex vivo expanded, umbilical cord blood-derived hematopoietic CD34+ progenitor cells 
(NiCord® cultured fraction (CF))  
2) The non-cultured cell fraction of the same CBU (NiCord® Non-cultured Fraction (NF)) 
consisting of mature myeloid and lymphoid cells.  
Both fractions, i.e., NiCord® CF and NiCord® NF, will be kept frozen until they are 
thawed and infused on the day of transplantation. 
Study Duration 
The planned total duration for each patient is ____________________ from the signing 
of informed consent to the last follow-up 15 months following randomization. The trial 
ends when all patients have completed their last follow-up. Patients who enroll in the 
optional long-term follow up sub-study will be followed for up to 5 years post-
transplantation. 
Study Objectives  
The overall study objective is to compare the safety and efficacy of NiCord® single ex 
vivo expanded cord blood unit transplantation to unmanipulated cord blood unit 
transplantation in patients with hematological malignancies following conditioning 
therapy as follows:  
 
Primary Objective: 
Assess the time to neutrophil engraftment following transplantation. 
Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) ≥ 0.5 
x 109/L on 3 consecutive measurements on different days with subsequent donor 
chimerism (≤10% host cells by peripheral blood chimerism or bone marrow chimerism if 
peripheral blood chimerism is not available) The day of neutrophil engraftment is 
designated as the first of the 3 consecutive measurements and must occur on or before 42 
days post transplant (and also prior to infusion of any additional stem cell product). 
 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 17 
Secondary Objective: 
Assess the following endpoints. 
Secondary Endpoints: 
• Incidence of grade 2/3 bacterial or invasive fungal infections by 100 days 
following transplantation 
• Days alive and out of hospital in the first 100 days following transplantation 
• Platelet engraftment by 42 days following transplantation 
Tertiary Endpoint: 
• Non-relapse mortality by 210 days following randomization 
Exploratory Endpoints: 
• Neutrophil engraftment by 16 days following transplantation 
• Time from transplantation to platelet engraftment 
• Duration of primary hospitalization 
• Non-relapse mortality by 130 days and 15 months following randomization 
• Overall survival at 210 days and 15 months following randomization 
• Disease-free survival at 15 months following randomization 
• Neutrophil engraftment by 42 days following transplantation 
• Acute GvHD grade II-IV and III-IV by 100 days following transplantation 
• Chronic GvHD (mild/moderate/severe) by 180 days and 1 year following 
transplantation 
• Secondary graft failure by 1 year following transplantation 
• Grade 3 viral infections by 180 days and 1 year following transplantation 
• Safety and tolerability of NiCord® transplantation  
• Relapse by 15 months following randomization 
• Relapse mortality by 15 months following randomization 
• Immune reconstitution at 28, 70, 100, 180, and 365 days following 
transplantation 
• Supplemental immune reconstitution assessments at a central laboratory 
(optional) 
• Health-related quality of life 
• Long-term clinical outcomes up to 5 years following transplantation (optional) 
Study Hypothesis 
NiCord® as a standalone graft will improve post-transplant outcomes compared to 
Unmanipulated CBT. 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 18 
Study Design  
This study is an open-label, controlled, multicenter, international, Phase III, randomized 
study comparing transplantation of NiCord® to transplantation of one or two 
unmanipulated, unrelated cord blood units in patients with hematological malignancies 
for whom allogenic SCT is currently a recommended and potentially lifesaving treatment, 
all with required disease features rendering them eligible for allogeneic transplantation. 
Number of Patients  
The study will randomize 120 eligible patients ____________________ ratio to receive 
either NiCord® or unmanipulated cord blood transplantation.  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_________________________________________________________ 
 
Eligibility Criteria 
Patients 12-65 years of age with a diagnosis of hematological malignancy who are 
candidates for unrelated cord blood transplantation, with qualifying HLA-matched UCB 
units with sufficient pre-cryopreserved total nucleated cell dose and CD34+ cell dose, as 
follows: 
Treatment CBU #1:  
Patients must have a partially HLA-matched CBU: the unit must be HLA-matched at 4-
6/6 HLA class I (HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high resolution) 
loci with the patient. There must be at least one allele match at DRB1. The CBU must 
have a pre-cryopreserved (post processing) total CD34+ cell count of ______________ as 
well as a pre-cryopreserved (post processing) total nucleated cell count _____________ 
and total nucleated cell dose____________________. The CBU will have undergone 
volume reduction (both plasma and red blood cell depletion) prior to cryopreservation. 
− Treatment CBU #1 will be used for the NiCord® arm or for the control 
arm in case of either single or double CBT. 
− Verification typing (confirmatory typing) must be completed before CBU 
shipment. 
Treatment CBU #2 (to be used for the control arm in case of double cord 
transplantation):  
In case treatment CBU #1 is HLA-matched at 5-6/6 and contains a pre-cryopreserved 
(post processing) total nucleated cell dose of ____________________, OR a pre-
cryopreserved (post processing) CD34+ cell dose of ____________________, a second 
CBU must be added for the control arm, as a double CBT.  
In case treatment CBU #1 is HLA-matched at 4/6 and contains a pre-cryopreserved (post 
processing) total nucleated cell dose of ____________________, OR a pre-cryopreserved 
(post processing) CD34+ cell dose of  ___________________, a second CBU must be 
added for the control arm, as a double CBT. 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 19 
The determination of using a single or double cord if randomized to the control arm must 
be made by the investigator prior to randomization. 
− Treatment CBU #2 must be HLA-matched at 4-6/6 HLA class I (HLA-A 
& HLA-B, low resolution) and II (HLA-DRB1, high resolution) loci with 
the patient. There must be at least one allele match at DRB1. Treatment 
CBUs #1 and #2 must have a combined pre-cryopreserved (post 
processing) total nucleated cell dose of ____________________. 
Detailed eligibility criteria are provided below; note that all eligibility testing must be 
completed and resulted, and entered into ____________________ before 
randomization: 
Inclusion Criteria 
1. Patients must be 12-65 years of age at the time of randomization 
2. Patients with one of the following hematological malignancies: 
• Acute lymphoblastic leukemia (ALL) at one of the following stages: 
___________________________________________________________ 
___________________________________________________________ 
___________________________________________________________ 
• Acute myelogenous leukemia (AML) at one of the following stages: 
• ___________________________________________________________ 
• ___________________________________________________________ 
______________________________________________________________ 
• Chronic myelogenous leukemia (CML) at one of the following phases: 
• ___________________________________________________________ 
• ___________________________________________________________ 
_____________________________________________________________ 
• CMMoL or MDS/CMMoL overlap ________________________ 
• Myelodysplastic Syndrome (MDS) with history of one or more of the 
following:  
• ___________________________________________________________ 
• ___________________________________________________________ 
_____________________________________________________________ 
Biphenotypic/undifferentiated/Prolymphocytic/Dendritic Cell Leukemias and 
Natural Killer Cell Malignancies____________________________, adult T-cell 
leukemia/lymphoma  
• Lymphoma, meeting one or more of the following criteria: 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 20 
o Burkitt’s lymphoma ____________________________, 
OR 
o High risk lymphomas ____________________________, 
OR 
o Chemotherapy-sensitive (defined as at least stable disease) 
lymphomas____________________________.  
 
(Patients with CLL are not eligible regardless of disease status) 
3. CBU criteria as described above. 
4. Patients who will be starting conditioning prior to NiCord release for infusion 
(i.e., NiCord arrival on site in adequate condition) must have an additional 
partially HLA-matched CBU reserved as a backup to the NiCord arm in case of 
production failure. The backup CBU must be HLA-matched at 4-6/6 HLA class I 
(HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high resolution) loci 
with the patient. A second back-up CBU is recommended to be added in the 
below cases: 
 If the back-up CBU is HLA-matched at 5 or 6/6, and contains a pre-
cryopreserved (post processing) total nucleated cell dose of 
___________________, OR a pre-cryopreserved (post processing) CD34+ 
cell dose of ___________________,   
 If the back-up CBU is HLA-matched at 4/6, and contains a pre-
cryopreserved (post processing) total nucleated cell dose of 
___________________, OR a pre-cryopreserved (post processing) CD34+ 
cell dose of ___________________. 
In case of two back-up CBUs, the second back-up CBU must also be HLA-
matched at 4-6/6 HLA class I (HLA-A & HLA-B, low resolution) and II (HLA-
DRB1, high resolution) loci with the patient. The back-up CBUs are 
recommended to have a combined pre-cryopreserved (post processing) total 
nucleated cell dose of at least ___________________. 
5. Patient’s Performance score ≥70% by Karnofsky or Lansky 
6. Patient has sufficient physiologic reserves including: 
a. Cardiac: __________________________________________________ 
_________________________________________________________ 
b. Pulmonary __________________________________________________ 
_________________________________________________________ 
c. Renal: __________________________________________________ 
_________________________________________________________ 
d. Hepatic: __________________________________________________ 
_________________________________________________________ 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 21 
7. Females of childbearing potential, defined 
__________________________________________________ 
__________________________________________________________________
__________________________________________________________________ 
__________________________________________________________________
__________________________________________________________________ 
__________________________________________________________________
__________________________________________________________________ 
__________________________________________________________________
__________________________________________________________________ 
_________________________________________________________ 
8. Patient (or legal guardian) signs the written informed consent after being aware of 
the nature of the patient’s disease and willingly consents to the treatment program 
after being informed of alternative treatments, potential risks, benefits, and 
discomforts. 
Exclusion Criteria 
1. MDS or CML with “marked” or “3+” fibrosis 
2. CLL 
3. Fewer than 21 days have elapsed since initiation of the patient's last 
chemotherapy cycle and the initiation of the stem cell transplant preparative 
regimen __________________________________________________ 
_________________________________________________________ 
4. Persistent clinically significant toxicities 
__________________________________________________ 
_________________________________________________________ 
5. Evidence of donor specific anti-HLA antibodies to the selected treatment CBU #1 
(MFI>3000 to HLA A, B, C, or DRB1) 
6. Evidence of HIV infection or HIV positive serology 
7. Evidence of active Hepatitis B or Hepatitis C as determined by serology or PCR 
8. Pregnancy __________________________________________________ 
_________________________________________________________ 
9. Active malignancy other than that for which the UCB transplant is being 
performed within 12 months of enrollment.  Fully resected cutaneous squamous 
cell or basal cell carcinoma or cervical carcinoma in situ within 12 months of 
enrollment will be permitted.   
10. Evidence of uncontrolled bacterial, fungal or viral infections or severe 
concomitant diseases, 
__________________________________________________ 
_________________________________________________________ 
 
11. Patients with presence of leukemic blasts in the central nervous system (CNS)  


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 22 
12. Patients with an 8/8 allele level HLA-matched and readily available related or 
unrelated donor (whose stem cells can be collected in a timely manner without 
jeopardizing recipient outcome). Patients who have haploidentical related donors 
or syngeneic donors will not be excluded 
13. Prior allogeneic hematopoietic stem cell transplant 
14. Allergy to bovine products, gentamicin, or to any other product that may interfere 
with the treatment  
15. Psychologically incapable 
__________________________________________________ 
__________________________________________________________________
_________________________________________ 
_________________________________________________________ 
16. Enrolled in another interventional clinical trial or received an investigational 
treatment within 30 days prior to the anticipated date of randomization 
__________________________________________________ 
_________________________________________________________  
 
Treatment Description 
Once qualifying CBUs have been identified and the patient (or legal guardian) signs the 
informed consent form (ICF), the patient will be screened for the study. 
Eligibility testing must be completed and resulted, and entered into 
____________________ prior to randomization.  Eligible patients will be randomized 
in a _________ ratio to receive either NiCord® or unmanipulated cord blood 
transplantation. 
NiCord® transplantation: 
The CBU chosen for production (treatment CBU #1) will be shipped from the Cord 
Blood Bank (CBB) to the manufacturing site. 
Upon release, NiCord® CF + NF will be shipped to the clinical site before 
transplantation. 
NiCord® CF will be thawed and infused first, followed by the NiCord® NF. 
If NiCord® fails to meet its required release specifications and patient conditioning has 
already started, the backup CBU/s or a different backup source of stem cells will be 
transplanted.  
Unmanipulated cord blood transplantation: 
The CBU (treatment CBU #1) or two CBUs (treatment CBU #1 and #2) chosen for 
transplantation will be shipped from the CBB to the clinical site before transplantation. 
Conditioning Regimens 
Prior to the start of conditioning the investigator must confirm patient suitability 
for transplant according to standard site practice. 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 23 
The conditioning regimen will consist of one of the options below.  
________________________________________________________________________ 
________________________________________________________________________
________________________________________________________________________ 
________________________________________________________________________ 
________________________________________________________________________
________________________________________________________________________ 
_________________________________________________________ 
Regimen A.1 (Day -11 to -2): 
• Total Body irradiation (TBI) _____________________ 
• Fludarabine: _____________________ 
• Thiotepa _____________________ 
Regimen A.2 (Day -8 or -7 to -1): 
• Total Body irradiation (TBI) _____________________ 
• Fludarabine: _____________________ 
• Cyclophosphamide _____________________ 
Regimen B (Day -7 to -3): 
• Thiotepa _____________________ 
• Busulfan _____________________ 
• Fludarabine _____________________ 
The GvHD prophylaxis regimen will consist of Mycophenolate Mofetil (MMF) and a 
calcineurin inhibitor (Tacrolimus or Cyclosporine).  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
___________________________. 
Statistical Considerations 
Method of primary analysis:  
The primary objective is to compare time from transplant to neutrophil engraftment 
between patients allocated to receive NiCord® transplantation and those allocated to 
receive unmanipulated cord blood transplantation. 
Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) ≥ 0.5 
x 109/L on 3 consecutive measurements on different days with subsequent donor 
chimerism (≤ 10% host cells by peripheral blood chimerism or bone marrow chimerism if 
peripheral blood chimerism is not available) any time on or after the day of engraftment 
up to the earlier of day 100 post-transplant, date of relapse, date of secondary graft 
failure, or date of death. The day of neutrophil engraftment is designated as the first of 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol 
 
Page 24 
the 3 consecutive measurements and must occur on or before 42 days post transplant (and 
also prior to infusion of any additional stem cell product). 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________ 
Thus, the primary analysis, but not all of the secondary analyses, will be conducted on the 
ITT population, i.e., all patients randomized will be included and their group membership 
will be the same as the group to which they were randomized, regardless of what 
treatment they received. Subgroup analyses according to age, disease risk group, disease 
(ALL, AML, MDS, CML and Lymphoma), gender, race/ethnicity, geographical region, 
and intention to perform single/double CBT will be performed as supportive analyses for 
both primary and secondary endpoints.  
Method of allocation: Stratification by minimization 
Patients will be randomized to treatment by NiCord® or by unmanipulated cord blood 
(single or double unit). 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
___________________________  
Interim Analysis and Safety Assessment Guidelines:  
The safety data emerging from this study will be reviewed periodically by an independent 
DMC for safety assessment and to monitor the balance of baseline characteristics 
between treatment groups.  Policies and composition of the DMC are described in the 
DMC Charter. 
In addition to data provided for periodic reviews, the DMC will be provided with 
information regarding _____________________ mortality on a monthly basis, starting 
the first month after the first randomization.     
 


 
GC P#05.01.020 
 Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol                                                                                
Page 25 
Figure 1: 
Study Scheme 
 
 


 
GC P#05.01.020 
 Date: January 22, 2019 (Amdt VI) 
NiCord® Phase III HM Protocol                                                                               Page 26 
Figure 2: 
CBU Selection 
 
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________
___________________________________________________________________________________ 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
 
NiCord® Phase III HM Protocol 
 
Page 27 
3. 
INTRODUCTION 
3.1. 
The unmet need in HSCT 
Successful blood and marrow transplantation (BMT) requires the infusion of a sufficient 
number of hematopoietic stem/progenitor cells (HSPCs), capable of both homing to the 
bone marrow and regenerating a full array of hematopoietic cell lineages with early and 
late repopulating ability in a timely fashion.1  
Several options exist for a stem cell donor for transplantation, but because each option 
has limitations,2 these patients still have an unmet medical need. In most settings, best 
results are offered by HLA-identical sibling transplantation; however, more than two-
thirds of patients awaiting HSCT lack a suitable matched related donor.3 When a matched 
related donor is not available, HSCTs with unrelated donor grafts are the only option. 
Despite the development of large international volunteer donor registries, fewer than 50% 
of unrelated donor searches result in identification and availability of a suitably matched 
donor graft.2,4,5  Donor searches for recipients of non-Northern-European descent result in 
even lower success rates. In addition, prolonged searches for suitable donors increase the 
risk of malignancy recurrence or progression.6 Three alternative sources for stem cells are 
offered for patients for whom a suitable matched related donor or matched unrelated 
donor (MUD) is not available in a timely manner: mismatched unrelated donor (MMUD), 
haploidentical (haplo)–related donor, and Umbilical Cord Blood (UCB). Currently, no 
clear advantage has been demonstrated for any of the three alternative stem cell sources. 
As a result, the same patient evaluated in different transplant centers may be offered 
MMUD, haplo-HSC, or UCB transplantation, depending on center preference and 
experience.5,7 
UCB has been clinically in use over the last 25 years for the treatment of diverse life-
threatening diseases, such as hematological malignancies or genetic blood disorders. 
There are numerous advantages to UCB as a transplantable graft source. These include 
the ease of procurement, the absence of risk to the donor, the reduced risk of 
transmissible infections, and the availability for immediate use, potentially reducing a 
long wait and risk of disease progression - particularly important for patients with acute 
leukemia.8,9 Moreover, the use of CBT allows for a higher mismatch with the recipient, 
without an increased risk of GvHD. Even compared with fully matched donors, UCB is 
associated with decreased acute and chronic GvHD, allowing for the transplantation of 
partially HLA-matched CBUs, with the full cellular repertoire, and without the need for 
T-cell depletion. However, despite the advantages in the use of CBT, its use, especially in 
adults and adolescents, is limited. The medical need for suitable allogeneic grafts is still 
insufficiently met because of the delayed hematopoietic recovery in recipients of CBT, 
with a related increased risk of life-threatening or fatal sequelae.10,11,12,13 Delayed 
hematopoietic recovery can result in an increased occurrence or higher severity of 
infections after transplantation. These infections sometimes lead to substantial organ 
damage, which may be irreversible, and also death. As a consequence, patients require 
longer durations of hospitalization, involving more intensive supportive care measures. 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
 
NiCord® Phase III HM Protocol 
 
Page 28 
A major drawback of UCB is the low stem cell dose available for transplantation, 
compared to mobilized peripheral blood (PB) or bone marrow.9 This low stem cell dose 
can compromise the chances of engraftment and contributes to delayed kinetics of 
neutrophil and platelet recovery, as well as other transplant outcomes.14,15,16,17,18 
3.2. 
The use of DCBT and ex vivo expansion to overcome the cell 
dose limitation in CBT 
The transplant community has been actively engaged in developing methods to address 
the cell dose issue in cord blood transplantation. Several approaches were developed, 
including dual umbilical cord blood transplantation (DCBT) and ex vivo expansion of 
UCB stem cells. Although to date no prospective clinical trials on the efficacy of single 
cord versus double cord in adults have been published, the DCBT has become standard 
practice in CBT for recipients in whom a single CBU of adequate cell dose is 
unavailable.1,19,10,20,21 
However, even with use of higher TNC and CD34+, the outcomes of CBT are still not 
optimal. Engraftment kinetics still parallel those observed with single CBT, despite the 
use of double amounts of TNC and CD34+ cells. In a recently published pediatric study, 
patients with hematologic cancer were randomized to receive either a single or dual 
CBT.22 Both groups received high doses of TNC and CD34+ cells. Despite this, 
neutrophil recovery occurred at a median of 21-23 days after transplantation, comparable 
to neutrophil recovery in adult patients receiving substantially fewer cells.12,13 This may 
suggest a selective qualitative and quantitative insufficiency of cells with short-term 
repopulating activity in UCB grafts.23 
Short-term repopulating cells are reported to provide early hematopoietic reconstitution 
after transplantation, but are distinct from HSC that can reconstitute the entire system 
permanently. Interestingly, while neutrophil and platelet recovery following CBT are 
often substantially delayed, long-term sustained donor cell chimerism appears to be 
similarly achieved even in patients receiving a relatively low TNC dose, as long as 
complications in the initial phase after transplantation are resolved.24 
Ex vivo expansion is still an experimental approach.  The aim of ex vivo expansion of 
cord blood is to provide a graft with sufficient numbers of cells that have rapid and robust 
in vivo neutrophil and platelet producing potential to enable successful transplantation.25 
Delaney et al. and De Lima et al. published the results of two clinical studies employing 
ex vivo expanded cord blood grafts in a double cord configuration, i.e., one CBU is used 
for expansion, while a second CBU is administered unmanipulated.26,27,28  These studies 
demonstrated that the expanded cells contributed to initial myeloid engraftment that 
occurred at a median time of about 15-16 days and platelet engraftment at a median of 
about 40-42 days. The expanded cells were observed as early as one week post 
transplantation but for the most part were lost before or after engraftment, while the 
unmanipulated CBU took over in all of the recipients. A lack of in vivo persistence of the 
expanded graft could be due either to loss of stem cell self-renewal capacity during 
culture and/or to an immune-mediated rejection of the manipulated graft (which is devoid 
of T-cells) by the unmanipulated one. It was therefore suggested that combining an 


 
GC P#05.01.020 
 
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NiCord® Phase III HM Protocol 
 
Page 29 
ex vivo expanded CBU for early hematologic recovery with a CBU for long-term 
sustained haematopoiesis could be an optimal strategy to shorten the neutropenic phase 
following CBT. 
3.3. 
Rationale for the development of NiCord® 
Ideally, a successful expansion technology would obviate the need for DCBT, and in 
most cases would enable the clinician to choose a single CBU for the patient. Most ex 
vivo expansion technologies are successful in expanding a subset of hematopoietic 
progenitor cells (HPCs), which are expected to improve short-term early hematopoietic 
reconstitution; the main concern still remains for preservation of long-term repopulating 
cells in ex vivo cultures.29,30,31 The concern is related not only to the persistence of such 
unique cells in culture, but also to their potential to differentiate and reconstitute blood 
cell lineages including myeloid, T, Natural Killer (NK) and B cells, as efficiently as the 
long-term repopulating cells before expansion.32  
NiCord® is a stem/progenitor cell-based product composed of ex vivo expanded 
allogeneic cells from one entire unit of UCB. NiCord® utilizes the small molecule 
nicotinamide (NAM), ____________________________________________________ 
________________________________________________________________________
____________________________________ 
To evaluate the safety and contribution of the expanded graft to short and long-term 
engraftment, the first-in-human study of NiCord® in hematological malignancies was 
performed in a double configuration, in combination with a second, unmanipulated CBU 
(GC P#01.01.020). In this pilot study, the DCBT platform served as a model to evaluate 
both the safety of use of a manipulated graft and enabled the simultaneous tracking of the 
contribution of NiCord® to short- and long-term hematopoietic recovery and its relative 
contribution to the myeloid and lymphoid hematopoietic lineages reconstitution. This 
study, completed in 2014, demonstrated prompt and durable engraftment of the expanded 
graft in 8 of the 11 transplanted patients and showed its potential for multi-lineage 
hematopoiesis.33 The novel finding of the NiCord® pilot trial was that cord blood-derived 
hematopoietic stem and progenitor cells that are expanded ex vivo for (_________weeks 
are capable of out-competing an unmanipulated cord blood graft and providing both rapid 
engraftment and robust, long-term multilineage hematopoiesis. Results of this study 
justified further evaluation of NiCord® transplanted as a single graft, without the support 
of a second un-manipulated CBU. 
The second study (GC P#03.01.020) evaluated the ability of NiCord® to provide durable 
engraftment as a single graft source. __________________________________________ 
________________________________________________________________________
________________________________________________________________________
_____________________________________________  
The chief aim of the proposed study is to compare the safety and efficacy of NiCord® 
single ex vivo expanded cord blood unit transplantation to unmanipulated cord blood unit 
transplantation in patients with hematological malignancies following conditioning 
therapy. 


 
GC P#05.01.020 
 
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NiCord® Phase III HM Protocol 
 
Page 30 
NiCord® could potentially provide a superior graft for unrelated donor transplantation in 
patients who do not have a matched adult donor option in a timely manner, thereby 
addressing a critical unmet need in the treatment of hematological malignancies. 
3.4. 
Gamida Cell expansion technology 
NiCord® is composed of CB-derived allogeneic stem and progenitor cells expanded ex 
vivo from an entire CBU with cytokines and nicotinamide, a form of the vitamin B3. 
NiCord® comprises: 1) ex vivo expanded, cord blood-derived, hematopoietic CD34+ 
progenitor cells (NiCord® cultured fraction (CF)); and 2) the non-cultured cell fraction of 
the same CBU (NiCord® Non-cultured Fraction (NF)) consisting of mature myeloid and 
lymphoid cells. 
NiCord® CF was initially developed as a fresh product ___________________________ 
________________________________________________________________________
________________________________________________________________________ 
The cryopreservation of NiCord® allows flexibility in the planning and timing of 
transplantation, to accommodate the patient’s disease status and any changes required, as 
resulting from the patient’s medical condition. 
The expansion technology is based on the finding that nicotinamide, the active molecule, 
________________________________________________________________________
________________________________________________________________________ 
The goal of the ex vivo expansion of hematopoietic progenitor cells is to increase their 
numbers while maintaining their self-renewal capacity and their ability to home to the 
bone marrow (BM) and efficiently reconstitute hematopoiesis. _____________________ 
________________________________________________________________________
__________________________________________________________________34  
This discrepancy could be explained, at least in part, by an acquired defect in the BM 
homing capacity of HPC expanded ex vivo,35 which is primarily attributed to their active 
cycling36 accompanied by alterations in adhesion and chemokine receptor expression or 
functionality.37 Strategies to augment the BM homing and engraftment efficacy are 
particularly important to increase clinical applicability of ex vivo expanded CD34+ 
cells.38 
Gamida Cell’s extensive studies discovered that NAM delays differentiation and 
increases the engraftment efficacy of cord-blood derived, purified CD133+ cells cultured 
with a combination of 4-cytokines ___________________________________ for 19-23 
days. ___________________________________________________________________ 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
__________________________________________________________  


 
GC P#05.01.020 
 
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NiCord® Phase III HM Protocol 
 
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To study engraftability ____________________________________________________ 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
___________________________ 
NAM serves as a precursor of nicotinamide ___________________________________ 
________________________________________________________________________
________________________________________________________________________
__________________________________________________________________ 
NAM has also been demonstrated ____________________________________________ 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________ 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
______________________________________________________ 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_________________ 
3.5. 
Clinical experience with NiCord® and CordIn™ 
In addition to NiCord®, Gamida Cell Ltd. has also undertaken to develop CordIn™. 
CordIn™ CF was initially developed as a fresh product (referred to as fresh NiCord® 
CF). NiCord® NF was developed as a cryopreserved product. The manufacture of the 
cryopreserved NiCord® CF and CordIn™ CF are identical until the final DP testing and 
release. The manufacturing steps of the fresh NiCord® and the cryopreserved 
NiCord®/CordIn™ CF are exactly the same until________________________________. 
The NiCord® NF and CordIn™ NF drug products remain identical. CordIn™ is intended 


 
GC P#05.01.020 
 
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NiCord® Phase III HM Protocol 
 
Page 32 
for the treatment of subjects with non-malignant diseases including hemoglobinopathies, 
such as SCD and thalassemia, BM failure syndromes and inherited metabolic disorders. 
The clinical experience with NiCord® and CordIn™ is summarized in Table 1 below. 
Table 1: 
Overview of ongoing clinical studies of NiCord® 
Protocol Number 
(ClinicalTrials.gov 
Number) 
Study Title 
Study 
Status 
Institution/Principal 
Investigator 
GC P#01.01.020 
(NCT01221857a) 
Allogeneic Stem Cell 
Transplantation of 
NiCord®, Umbilical 
Cord Blood-Derived 
Ex Vivo Expanded 
Stem and Progenitor 
Cells, in Combination 
with a Second, 
Unmanipulated Cord 
Blood Unit in Patients 
With Hematological 
Malignancies 
Complete  
Duke University Health System/ 
____________________________
____________________________
____________________________
_____________________Cardinal 
Bernardin Cancer Center, Loyola 
University/ 
____________________________
_______ 
GC P#02.01.020 
(NCT01590628b) 
Allogeneic Stem Cell 
Transplantation of 
NiCord®, Umbilical 
Cord Blood-Derived 
Ex Vivo Expanded 
Stem and Progenitor 
Cells, in Combination 
with a Second, 
Unmanipulated Cord 
Blood Unit in Patients 
with 
Hemoglobinopathies 
Ongoing 
Duke University Health System/ 
____________________________
_____________ 
Cohen Children’s Medical Center 
of New York/ 
____________________________ 


 
GC P#05.01.020 
 
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NiCord® Phase III HM Protocol 
 
Page 33 
Protocol Number 
(ClinicalTrials.gov 
Number) 
Study Title 
Study 
Status 
Institution/Principal 
Investigator 
GC P#03.01.020 
(NCT01816230c) 
Allogeneic Stem Cell 
Transplantation of 
NiCord®, Umbilical 
Cord Blood-derived 
Ex Vivo Expanded 
Stem and Progenitor 
Cells, in Adolescent 
and Adult Patients 
with Hematological 
Malignancies. 
Ongoing 
Duke University Health System/ 
____________________________ 
Hospital Universitario y 
Politécnico La Fe/ 
____________________________ 
Vanderbilt University Medical 
Center/ 
____________________________ 
Hospital Universitari Vall 
d'Hebrón/ 
____________________________ 
AOU San Luigi Gonzaga/ 
____________________________ 
Universitair Medisch Centrum 
Utrecht/ 
____________________________ 
Cedars-Sinai Medical Center/ 
____________________________ 
Cleveland Clinic/ 
____________________________ 
University of Minnesota/ 
____________________________ 
Cardinal Bernardin Cancer Center, 
Loyola 
University/___________________
_________ 
Oregon Health & Science 
University/ 
____________________________ 
Singapore General 
Hospital/____________________
________ 
National University Cancer 
Institute/____________________
________  


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
 
NiCord® Phase III HM Protocol 
 
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Protocol Number 
(ClinicalTrials.gov 
Number) 
Study Title 
Study 
Status 
Institution/Principal 
Investigator 
GC P#01.01.030 
(NCT02504619d) 
Allogeneic Stem Cell 
Transplantation of 
CordIn™, Umbilical 
Cord Blood-Derived 
Ex Vivo Expanded 
Stem and Progenitor 
Cells, in Patients with 
Hemoglobinopathies 
Ongoing 
Benioff Medical Center/ 
____________________________ 
Children’s National Medical 
Center/ 
____________________________ 
Hopital Robert-Debre/ 
____________________________ 
GC P#04.01.020/030 
(NCT02039557e) 
Long Term Follow 
Up for Patients who 
have received 
Allogeneic Stem Cell 
Transplantation of 
NiCord®/CordIn™, 
Umbilical Cord 
Blood-derived Ex 
Vivo Expanded Stem 
and Progenitor Cells. 
Ongoing 
Duke University Health System/ 
____________________________ 
Hospital Universitario y 
Politécnico La Fe/ 
____________________________ 
Hospital Universitari Vall 
d'Hebrón/ 
____________________________ 
a http://clinicaltrials.gov/ct2/show/NCT01221857  
b http://clinicaltrials.gov/ct2/show/NCT01590628 
c https://clinicaltrials.gov/ct2/show/NCT01816230 
d https://clinicaltrials.gov/ct2/show/NCT02504619 
e https://clinicaltrials.gov/ct2/show/NCT02039557 
The subsequent sections describe the clinical studies mentioned above.  
3.5.1. 
Study GC P#01.01.020 
A pilot clinical study of NiCord® in hematological malignancies in combination with a 
second, unmanipulated CBU was completed (GC P#01.01.020). This is a single arm pilot 
study to evaluate the safety of the co-transplantation of NiCord® and an unmanipulated 
CBU to patients with hematological malignancies following myeloablative therapy.  
Patients under the age of 65 years with hematological malignancies and no available 
matched sibling or matched unrelated adult donor were eligible at Duke University 
School of Medicine or Loyola University Medical Center between December 2010 and 
August 2012. Eligibility required the availability of 1 cord blood unit containing at least    
____________________________ of the recipient’s body weight. This unit was 
designated as the unmanipulated unit. The second unit, designated for NiCord® 
expansion, contained at least ___________________________ of the recipient’s body 
weight. When 2 units with at least ___________________________ of the recipient’s 
body weight were available, the best-matched unit was assigned as the unmanipulated 
unit. The cord blood units were required to match the recipient at 4 or more HLA loci by 
intermediate-resolution typing for HLA class I alleles (A and B) and high-resolution 
typing for HLA class II DRB1 alleles. 


 
GC P#05.01.020 
 
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NiCord® Phase III HM Protocol 
 
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The bone marrow conditioning regimen consisted of ____________________ TBI 
delivered in 9 fractions on days –9 to –5, and fludarabine _____________________ was 
given on days –5 to –2 of the transplantation. An optional infusion of _______________ 
cyclophosphamide on days –4 and –3 was given at the discretion of the managing 
physician. GvHD prophylaxis was provided by Tacrolimus and Mycophenolate Mofetil 
starting 4 days before transplantation. Mycophenolate Mofetil and Tacrolimus were 
continued for a minimum of 60 days and 6 months following transplantation, 
respectively. 
Main results are described below and in the Clinical Study Report available upon 
request.33 
Efficacy: Twelve patients were enrolled and transplanted. Eleven of the twelve 
transplanted patients achieved neutrophil engraftment with full donor chimerism (<10% 
host chimerism). Eleven of the twelve transplanted patients were evaluable 
________________________________________________________________________
_________. The median days to neutrophil engraftment in NiCord® recipients achieving 
engraftment was 12.5 days, ranging from 7 days to 26 days. 
________________________________________________________________________
_________. The median days to neutrophil engraftment in NiCord® recipients achieving 
engraftment with NiCord® as the predominating donor source was 10.5 days, ranging 
from 7 days to 18 days. In comparison, historical reports of unmanipulated CB 
transplants estimate the median days to engraftment at 23-27 days with a range of 13-80 
days.39,40,41,10 In a historical control group of 17 patients who received unmanipulated 
DCBT with the same conditioning regimen at the same transplant center, median time to 
engraftment was 25 days (range 13-38).33 
All engrafted patients maintained full donor chimerism throughout follow-up. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
______________________________________________________  
Platelets engraftment was achieved in nine out of eleven patients who received 
NiCord®.________________________________________________________________
____________________________________________. The median time to platelet 
engraftment to 20,000/mm3 was 33 days (range 26-49 days) for all patients transplanted 
with NiCord® and 30 days (range 26-41) for the 7 patients who demonstrated engraftment 
with NiCord®. The median days for platelet recovery to 50,000/mm3 in patients achieving 
engraftment were 36 days. 
Immune reconstitution of engrafted patients was robust. Immune reconstitution analysis 
of the patients last performed at days 100, 180 and 365 post-transplantation also 
demonstrated the recovery of all blood cell lineages including CD3, CD4 and CD8 (T 
cells), CD19 (B cells) and CD56 (NK cells). Immune reconstitution was similar for 
patients engrafting with the NiCord® unit compared to those engrafting with the 
unmanipulated CBU.  


 
GC P#05.01.020 
 
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NiCord® Phase III HM Protocol 
 
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Safety: There was no grade 4 infusion toxicity. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_________.  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_____________________________________________ 
Conclusions: Infusion of NiCord® was well tolerated and provided rapid short-term 
engraftment as well as stable, long-term multi-lineage hematopoiesis. The results of this 
study warranted further studies of NiCord® as a solitary graft source.  
3.5.2. 
Study GC P#03.01.020 
A clinical study of NiCord® in hematological malignancies as a standalone graft source 
________ (GC P#03.01.020). This is a single arm study to evaluate the ability of 
NiCord® to provide durable engraftment as a single graft source in patients with 
hematological malignancies following conditioning therapy.  
The dataset that served as the basis for this Phase III study design comprised patients 
aged 12-65 years old with hematological malignancies and no available matched sibling 
or matched unrelated adult donor that were eligible at multiple international centers 
between ____________________. Eligibility required the availability of a cord blood 
unit containing at least __________ cells as well as a pre-cryopreserved (post-processing) 
total nucleated cell count of __________, and total nucleated cell dose __________. The 
cord blood unit was required to match the recipient at 4 or more HLA loci by 
intermediate-resolution typing for HLA class I alleles (A and B) and high-resolution 
typing for HLA class II DRB1 alleles. 
Multiple conditioning regimens were used, including TBI/Flu/±Cy and Thiotepa/Bu/Flu.  
GvHD prophylaxis was provided by Tacrolimus or Cyclosporine and mycophenolate 
Mofetil starting three days before transplantation. Mycophenolate Mofetil and 
Tacrolimus/Cyclosporine were continued for a minimum of 60 days and 5 months 
following transplantation, respectively. 
Main results are described below. 
Efficacy: __________ patients received NiCord® (___ NiCord®-only recipients and ____ 
patients who received both NiCord® and the backup CBU). All ______ NiCord®-only 
recipients achieved neutrophil engraftment by day 42 with full donor chimerism. 
The median days to neutrophil engraftment in NiCord®-only recipients was ____ days 
post transplant, ranging from ____ days to ____ days.  All but ___ of these patients 
engrafted prior to day 18 post transplant.       


 
GC P#05.01.020 
 
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NiCord® Phase III HM Protocol 
 
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For NiCord®-only recipients, the cumulative incidence of platelet engraftment to 
20k/mm3 and 50k/mm3 at 100 days post transplant was ___% __________ and ____% 
__________  respectively.  ______ patients died prior to day 100 without 20k/mm3 
platelet engraftment, ____ patient failed to engraft platelets at 20k/mm3 by day 100, 
______ patients engrafted 20k/mm3 but not 50k/mm3 by day 100, and ____ patient was 
pending engraftment at last follow-up of 88 days post transplant.  Among the engrafters, 
the median time to engraftment to 20k/mm3 and 50k/mm3 was _____________ 
respectively.  
The overall survival of NiCord®-only recipients at 180 and 365 days was ____% 
__________  and ____% __________ respectively.   
Immune reconstitution of CD4+, CD8+, CD19+, CD56+/16+ in NiCord®-only recipients 
was comparable to unmanipulated cord blood transplantation in historical controls. 
Safety: ______________ experienced secondary graft failure in the year following 
NiCord® transplant.   
For NiCord® alone recipients, the cumulative incidence of non-relapse mortality at day 
100 and day 180 post transplant was _____% __________  and ____% __________  
respectively.  
The incidence of acute GvHD grade II-IV and III-IV at 100 days post NiCord® only 
transplant was _____% __________  and ____% __________  respectively.  __________ 
of the __________ NiCord®-only recipients experienced chronic GvHD in the year 
following NiCord® transplant.  __________ of chronic GvHD was extensive while the 
other __________ were limited. 
Among ____ patients receiving NiCord® (____ NiCord® only recipients and ___ patients 
who received both NiCord® and the backup CBU), no grade 4 infusion toxicity occurred.  
__________ NiCord® __________ had a grade 3 toxicity (atrial fibrillation), __________ 
patients had grade 2 toxicity, __________ patients had grade 1 toxicity, and __________ 
patients had no toxicity within 24-hours post infusion.  __________ infusion toxicities 
(grade 2 serious infusion related hypersensitivity and grade 2 non-serious hypertension) 
were reported as related to NiCord®.   
__________ SAEs were reported in _____ of the ____ NiCord® recipients.  _______ of 
the _____ SAEs reported were determined to be related to NiCord®.  These ____ related 
SAEs included ______ GvHD events and _____ grade 2 infusion-related 
hypersensitivity. 
Of the __________ NiCord®-only recipients, __________ experienced one or more post 
transplant grade 2 or 3 infections.  Of the __________ reported post transplant grade 2 or 
3 infections, a total of __________ grade 3 infections were reported in __________ 
NiCord® only recipients; __________ with a Klebsiella infection at day 325 post 
transplant, __________ with an RSV infection at day 5 post transplant, and __________ 
with __________ infections (Klebsiella at day 111 post transplant, Aspergillus at day 119 
post transplant and Cryptosporidium at day 126 post transplant). 
No new malignancies or autoimmune diseases were reported in any of the transplant 
recipients. 


 
GC P#05.01.020 
 
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NiCord® Phase III HM Protocol 
 
Page 38 
Conclusions: Infusion of NiCord® was well tolerated and provided rapid short term 
neutrophil engraftment as well as stable, long term multilineage hematopoiesis.  Initiation 
of a phase III trial evaluating the efficacy of NiCord® compared to unmanipulated cord 
blood is warranted. 
The enrollment is complete and the follow-up is ongoing. 
3.5.3. 
Study GC P#02.01.020 
The study GC P#02.01.020 entitled: “Allogeneic Stem Cell Transplantation of NiCord®, 
Umbilical Cord Blood-derived Ex Vivo Expanded Stem and Progenitor Cells, in 
Combination with a Second, Unmanipulated Cord Blood Unit in Patients with 
Hemoglobinopathies” is __________ at Duke University Medical Center, NC, USA and 
Cohen Children’s Medical Center of New York. The study is evaluating the 
transplantation of NiCord® in combination with an unmanipulated CBU, for 
hematopoietic support of subjects with Sickle Cell Disease (SCD) and Thalassemia 
major. The study was launched in May 2012.  
3.5.4. 
Study GC P#01.01.030 
The study GC P#01.01.030 entitled: “Allogeneic Stem Cell Transplantation of CordIn™, 
Umbilical Cord Blood-Derived Ex Vivo Expanded Stem and Progenitor Cells, in Patients 
with Hemoglobinopathies” is __________ at Benioff Medical Center and Children’s 
National Medical Center. The study is evaluating the transplantation of CordIn™ as a 
stand alone graft source, for hematopoietic support of subjects with Sickle Cell Disease 
(SCD) and Thalassemia major. The study was launched in May 2015. 
3.5.5. 
Study GC P#04.01.020/030 
The study GC P#04.01.020/030 entitled: “Long Term Follow Up for Patients who have 
received Allogeneic Stem Cell Transplantation of NiCord®/CordIn™, Umbilical Cord 
Blood-derived Ex Vivo Expanded Stem and Progenitor Cells.” is an ongoing long-term 
observational study of patients who have received either a NiCord® or CordIn™ 
transplant.  The overall study objective is to describe the clinical outcomes of patients 
through 5 years post NiCord® or CordIn™ transplantation. 
3.6. 
Overall Risk Benefit 
NiCord® is an allogeneic graft for HSCT composed of CB-derived stem and progenitor 
cells expanded ex vivo from an entire CBU with cytokines and nicotinamide, as well as 
non-cultured mature myeloid and lymphoid cells from the same CBU. NiCord® is 
intended for the treatment of patients who are medically indicated for allogeneic 
hematopoietic stem cell transplantation following preparative conditioning, including 
high risk hematological malignancies. Non-clinical studies have demonstrated that 
culturing CD133+ cells with NAM delays differentiation and increases engraftment 
efficacy. 
UCB is an easily procured stem cell source for allogeneic HSCT, with high availability 
for patients of different ethnic backgrounds. However, its use is limited by delayed 


 
GC P#05.01.020 
 
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NiCord® Phase III HM Protocol 
 
Page 39 
hematopoietic recovery, leading to increased morbidity and mortality post 
transplantation. Several technologies are attempting to improve the kinetics of 
engraftment following CBT, by using dual CBT, whereby one of the CBUs undergoes ex 
vivo manipulation or expansion. Such technologies may shorten the time to neutrophil 
engraftment; however, the long-term durable hematopoietic recovery is provided by the 
second, unmanipulated CBU. 
The DCBT approach adds a measure of safety to the evaluation of novel approaches to ex 
vivo expansion. However, the use of DCBT has not demonstrated any improvement in the 
rates or kinetics of engraftment or survival. Unrelated UCBT with NiCord® make it 
possible to use a single CBT approach. 
Clinical data to date suggest that patients treated with NiCord® can rapidly engraft both 
neutrophils and platelets. Subsequently, patients require a substantially shorter duration 
of hospitalization after transplantation, which is consistent with more rapid recuperation. 
Available patient follow-up indicates a safe profile in terms of the robustness of 
engraftment, and the occurrence of GvHD, as compared to unmanipulated CBT despite 
the use of partially mismatched CBUs. Moreover, the available data show that patients 
treated with NiCord® are able to develop functional hematopoietic systems, with the 
development of myeloid and lymphoid cells, supporting immune recovery. 
As in all cases of allogeneic HSCT, the overall risks of cord blood administration 
following a cytotoxic preparative regimen can be serious and fatal. The potential risks 
associated with cord blood include early death, infusion reactions, GvHD and graft 
failure. The deaths and other adverse events experienced by NiCord® recipients to date 
are common effects of allogeneic stem cell transplantation following conditioning 
regimen therapy. 
The chief aim of the proposed study is to compare, in a randomized trial, the safety and 
efficacy of NiCord® single ex vivo expanded cord blood unit transplantation versus 
unmanipulated cord blood unit transplantation in patients with hematological 
malignancies following conditioning therapy. 
3.7. 
Rationale for study design and dosages 
3.7.1. 
Study population 
As reviewed above, the study will include patients with hematological malignancies for 
whom allogeneic SCT is currently a recommended and potentially lifesaving treatment. 
For ethical reasons, the study will only enroll patients who do not have an adequate 
suitably matched and readily available stem cell donor. 
Pediatrics patients aged 12 to < 18 will be enrolled. Inclusion of adolescent patients is 
justified by the lack of any significant safety or tolerability issues identified to date in 
completed non-clinical and clinical studies, the strong efficacy profile suggested by the 
results of the previous clinical studies, and the similarity between adults and adolescents 
in disease presentation and pathophysiology. 
The diseases are considered by transplanters to be biologically similar in adolescent 
patients of ages 12-18. Adolescent patients usually have a physical mass that is similar to 


 
GC P#05.01.020 
 
Date: January 22, 2019 (Amdt VI) 
 
NiCord® Phase III HM Protocol 
 
Page 40 
that of adults, and are thus prone to the same limitations of CBT. Different patients reach 
this physical mass at different ages, and a clear cut-off cannot be established (as it is 
more linked to body weight than age). In an effort to allow the inclusion of a broad 
adolescent population, children above age 12 are included in this clinical study. 
3.7.2. 
CBU cell dose 
The CBU intended for expansion is required to contain a pre-cryopreserved (post-
processing) total CD34+ cell count of at least __________, as well as a pre-cryopreserved 
(post-processing) total nucleated cell count of at least_________, and a total nucleated 
cell dose of at least _________TNC/kg body weight, a dose predicted to be sufficient in 
size to provide robust and sustained engraftment, based on the current clinical experience 
with NiCord®.  
This CBU will be used for the NiCord® arm or for the control arm in case of either single 
or double CBT: 
In case this CBU is HLA-matched at 5-6/6 and contains a pre-cryopreserved (post 
processing) total nucleated cell dose of <_________TNC/kg, OR a pre-cryopreserved 
(post processing) CD34+ cell dose of <_________ CD34+ cells/kg, a second CBU must 
be added for the control arm, as a double CBT.  
In case this CBU is HLA-matched at 4/6 and contains a pre-cryopreserved (post 
processing) total nucleated cell dose of <_________TNC/kg, OR a pre-cryopreserved 
(post processing) CD34+ cell dose of <_________CD34+ cells/kg, a second CBU must 
be added for the control arm, as a double CBT. 
This determination must be made by the investigator prior to randomization. 
In case of double CBT: The two CBUs must have a combined pre-cryopreserved (post 
processing) total nucleated cell dose of ≥_________TNC/kg.  
These criteria are intended to assure that CBUs of sufficient cell dose and CD34+ cell 
dose are used for both the treatment and the control arms, and reflect the published cut-
offs for cord blood transplantation, since successful CBT is dependent on sufficient CBU 
total nucleated cell dose,42,16,13 and specifically sufficient CD34+ cell dose.39,14,43 The 
criteria for CBU selection for the control group are adapted from the formal guidelines 
for cord blood transplantation.44 
As a safety precaution in case of production failure, an unmanipulated backup UCB unit 
or two CBUs are required for patients who will be starting conditioning prior to NiCord 
release for infusion. It is recommended that these CBU/s comply with the same criteria 
detailed above for the control group. 
In case NiCord® fails to meet its required specifications, and patient conditioning has 
already started, the backup CBU/s or a different backup source of stem cells will be 
transplanted as detailed in section 8.3. 
As transplantation is considered a life-saving intervention in the study population, the 
selection of the optimal CBUs is at the investigator's discretion. 


 
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3.7.3. 
Selection of CBUs 
Decisions on the selection of CBUs are never arbitrary, but rather are based on specific 
histocompatibility data, cell dose, availability, and in some cases the source of the CBU. 
However, there is no clear consensus or evidence-based algorithm as to the hierarchy of 
these factors. Thus, some physicians believe cell dose is of greatest importance, some 
examine CD34+ dose, and others prioritize HLA matching. For this reason, the protocol 
does not specify prioritization rules when more than one eligible CBU is identified. 
With regard to HLA matching, all CBUs, whether intended for treatment or as backup 
CBUs, must be HLA-matched at 4-6/6 HLA class I (HLA-A & HLA-B, low resolution) 
and II (HLA-DRB1, high resolution) loci with the patient. Low level DNA/molecular 
matching is sufficient for HLA class I; however, serologic matching may also be used. 
High resolution matching is required for HLA class II. 
Also, with regards to the use of one or more units not meeting the local applicable 
regulations, all the patients included in the study may be considered of “urgent medical 
need” by the nature of their underlying malignancy, and have a high (>50%) likelihood of 
death without receiving a CBU transplantation. The usage of one or more ineligible units 
with unusual findings (e.g., "incomplete”) will only be permitted when no comparable 
eligible CBU is found, and when this is the best CBU found for this patient. The 
investigator will sign the documentation of urgent medical need; the site will document 
the signed form, the CBU search results and selection rationale in such cases. 
3.7.4. 
Conditioning regimens 
Over the years, a number of different conditioning regimens have been established as 
standard of care for unrelated CB transplantation in adults, generally divided into TBI – 
based versus non-TBI. In this study, the choice of conditioning regimen and GvHD 
prophylaxis agents is kept limited, in order to confirm the use of optimal patient care and 
to allow for clear interpretation of study results, while still providing the flexibility to 
choose between TBI-based and non-TBI regimens, and to allow for individual country 
and site accepted practices and experience.  
In general, each transplant center should commit to use the same conditioning regimen 
and GvHD prophylaxis for all patients transplanted at their center, or according to 
primary diagnosis/age group. The intended practice must be documented prospectively 
for the transplant center. In unique cases where the use of a different conditioning 
regimen is deemed to be in the patient’s best interest, approval from the study chairs must 
be obtained prior to use of the different regimen. 
Regimen A.1 (Day -11 to -2): 
• Total Body irradiation (TBI) _________cGy total or _________cGy total 
• Fludarabine: _________mg/m2 total 
• Thiotepa _________mg/kg total 
Regimen A.2 (Day -8 or -7 to -1): 
• Total Body irradiation (TBI) _________cGy total or _________cGy total 


 
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• Fludarabine: _________mg/m2 total 
• Cyclophosphamide _________mg/kg total 
Due to the high reported TRM of myeloablative regimens utilizing TBI/flu/cy,12 some 
centers have stopped the use of this regimen and have started to use TBI/flu/Thiotepa 
instead. Therefore, the study allows the use of Thiotepa instead of cyclophosphamide in 
Regimen A.1. 
Regimen B (Day -7 to -3): 
• Thiotepa _________mg/kg total 
• Busulfan _________mg/kg total or _________mg/kg total 
• Fludarabine _________mg/m2 total  
3.7.5. 
Study endpoints 
The study aims to compare the safety and efficacy of NiCord® transplantation to 
unmanipulated cord blood unit transplantation in patients with hematological 
malignancies. The primary endpoint is the time to neutrophil engraftment following 
transplantation.  
This endpoint reflects the importance of early engraftment following CBT and the 
consideration of the limited patient population which does not allow demonstrating a 
significant survival benefit of NiCord®. Prompt and robust engraftment of neutrophils is 
the most notable milestone on the way to hematopoietic recovery following stem cell 
transplantation. This can be demonstrated by the delay in neutrophil engraftment 
compared to other stem cell sources.10,11 Recent multicenter publications from the USA 
and from Europe continue to report similar hematopoietic recoveries for both double and 
single UCB, with median 22 and 23 days to neutrophil engraftment in adults.12,13 
Publications reviewing the differences in outcomes between UCB and other graft sources 
consistently report higher non-relapse mortality following CBT, generally attributable to 
inadequate hematopoietic recovery.10,11 Brunstein et al. emphasized that delayed 
engraftment is the single greatest barrier to successful CBT and the most important 
contributor to early NRM.  Ruggeri et al. reported the outcomes of 1268 patients with 
acute leukemia undergoing single CBT in EBMT centers.13  With the finding that longer 
time to engraftment was associated with increased transplant-related mortality and lower 
overall survival, the authors recommended rescue actions for graft failure, such as the 
search for another graft, starting after day 21 following transplant. 
For the secondary endpoints, the trial data may have sufficient power to show an 
improvement in the NiCord® group compared to the Control group and these endpoints 
will be subjected to formal statistical significance testing using Hommel’s method for 
multiple comparisons. The tertiary and exploratory endpoints include (i) those where 
NiCord® is anticipated to be superior to Control, but where there is low statistical power 
to demonstrate this, and (ii) those where NiCord® is anticipated to be no worse than 
Control; the p-values for the tertiary and exploratory endpoints will be presented but the 
family-wise error rate for these endpoints will not be controlled. 


 
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Delayed hematopoietic recovery can result in an increased occurrence or higher severity 
of complications after transplantation, such as infections. These sometimes lead to 
substantial organ damage, which may be irreversible, and also death. As a consequence, 
patients require longer durations of hospitalization, involving more intensive supportive 
care measures. Thus, these events of infections, prolonged hospitalization, and non-
relapse mortality are assessed in the secondary and tertiary endpoints. 
Platelet engraftment will be assessed by the time from transplantation to platelet 
engraftment, and by a secondary endpoint of platelet engraftment by 42 days following 
transplantation. Delayed platelet engraftment is a frequent complication after CBT 
associated with increased TRM and poorer overall survival. Kim et al.45 claimed that 
platelet counts can be used to predict the risk of chronic GvHD development and 
prognosis after allogeneic PB transplantation - overall survival, and NRM. Ramirez et al. 
found that delayed platelet recovery was most common after CBT, in comparison to 
unrelated or sibling BM or PB grafts.20 Delayed platelet recovery adversely impacted 
both TRM and overall survival.  
Rapid hematopoietic recovery is anticipated to reduce the risk of infections. In particular, 
bacterial and fungal infections predominate in the early months after transplant and are 
dependent on rapid and robust neutrophil recovery.46,47,48,49,50,51,52,53 Therefore, an 
additional secondary endpoint will be the incidence of bacterial infections (grade 2-3) and 
invasive fungal infections occurring up to 100 days post transplant. 
In line with the incidence of post-transplant complications, recipients of UCB transplants 
also require longer durations of hospital stay. Ballen et al. compared total hospital length 
of stay in the first 100 days after HSCT in 1577 patients with acute leukemia in remission 
receiving UCB, MUD or MMUD HSCT.54 For adults receiving HSCT using 
myeloablative conditioning, median days alive and out of hospital in the first 100 days 
were 52 for single UCB, 55 for double UCB, 69 for MUD BM, 75 for MUD peripheral 
blood stem cells (PBSC), 63 for MMUD BM and 67 days MMUD PBSC recipients. 
Multivariate analysis showed that UCB recipients had fewer days alive and out of the 
hospital compared to other graft sources. The study will assess the number of days each 
subject is alive and out of hospital in the first 100 days following transplantation as a 
secondary endpoint. 
Such post-transplant complications may result in death, and thus the transplant-related 
mortality, as reflected by non-relapse mortality at 210 days following randomization 
(approximately 6 months post transplant), will be assessed as a tertiary endpoint. 
Further explanations are provided below for the timing of two of the exploratory 
endpoints. 
Viral infections occur primarily throughout the first year after transplant, in parallel to the 
recovery of the immune system. Grade 3 viral infections will be assessed in the context of 
the exploratory endpoints, where NiCord® is anticipated to be no worse than controls, as a 
safety assessment, and therefore will be assessed at a longer-term timepoint of 180 days 
and 1 year following transplantation. 
NiCord® ex vivo expansion is aimed to provide rapid hematopoietic recovery, 
overcoming the known delay in CBT compared to other graft sources. Thus, neutrophil 


 
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engraftment by 16 days following transplantation will be assessed as an additional 
exploratory endpoint, a cut-off which reflects the usual time of neutrophil engraftment in 
matched peripheral blood donor transplants.55,11 


 
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4. 
STUDY OBJECTIVES, HYPOTHESIS AND STUDY 
ENDPOINTS 
4.1. 
Objectives 
The overall study objective is to compare the safety and efficacy of NiCord® single ex 
vivo expanded cord blood unit transplantation to unmanipulated cord blood unit 
transplantation in patients with hematological malignancies following conditioning 
therapy as follows:  
Primary Objective: 
Assess the time to neutrophil engraftment following transplantation. 
Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) ≥ 0.5 
x 109/L on 3 consecutive measurements on different days with subsequent donor 
chimerism (≤10% host cells by peripheral blood chimerism or bone marrow chimerism if 
peripheral blood chimerism is not available). The day of neutrophil engraftment is 
designated as the first of the 3 consecutive measurements and must occur on or before 42 
days post transplant (and also prior to infusion of any additional stem cell product). 
Secondary Objective 
To assess the following: 
Secondary Endpoints: 
• Incidence of grade 2/3 bacterial or invasive fungal infections by 100 days 
following transplantation 
• Days alive and out of hospital in the first 100 days following transplantation 
• Platelet engraftment by 42 days following transplantation 
Tertiary Endpoint: 
• Non-relapse mortality by 210 days following randomization 
Exploratory Endpoints: 
• Neutrophil engraftment by 16 days following transplantation 
• Time from transplantation to platelet engraftment 
• Duration of primary hospitalization 
• Non-relapse mortality by 130 days and 15 months following randomization 
• Overall survival at 210 days and 15 months following randomization 
• Disease-free survival at 15 months following randomization 
• Neutrophil engraftment by 42 days following transplantation 
• Acute GvHD grade II-IV and III-IV by 100 days following transplantation 


 
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• Chronic GvHD (mild/moderate/severe) by 180 days and 1 year following 
transplantation 
• Secondary graft failure by 1 year following transplantation 
• Grade 3 viral infections by 180 days and 1 year following transplantation 
• Safety and tolerability of NiCord® transplantation  
• Relapse by 15 months following randomization 
• Relapse mortality by 15 months following randomization 
• Immune reconstitution at 28, 70, 100, 180, and 365 days following 
transplantation 
• Supplemental immune reconstitution assessments at a central laboratory 
(optional) 
• Health-related quality of life  
• Long-term clinical outcomes up to 5 years following transplantation (optional) 
Study Hypothesis 
NiCord® as a standalone graft will improve post-transplant outcomes compared to 
Unmanipulated CBT. 
4.2. 
Definition of study endpoints 
4.2.1. 
Date of randomization 
The date of randomization is defined as the date that the patient’s treatment assignment is 
issued. 
4.2.2. 
Date of transplant 
The date of transplant is defined as the first date of stem cell infusion following 
randomization, regardless of stem cell source. 
4.2.3. 
Neutrophil engraftment 
Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) ≥ 0.5 
x 109/L on 3 consecutive measurements on different days with subsequent donor 
chimerism (≤ 10% host cells by peripheral blood chimerism or bone marrow chimerism if 
peripheral blood chimerism is not available) at any time on or after the day of 
engraftment up to the earlier of day 100 post-transplant, date of relapse, date of secondary 
graft failure, or date of death. The first day of the three measurements will be designated 
the day of neutrophil engraftment and must occur on or before 42 days post transplant 
(and also prior to infusion of any additional stem cell product).   
Primary graft failure is defined as failure to achieve neutrophil engraftment by day 42 as 
described above. Infusion of a second stem cell product on or prior to Day 42 will be 
considered primary graft failure, with the following exception:  


 
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• Infusion of an additional stem cell product after documented neutrophil 
engraftment will be considered secondary graft failure, even if it occurs on or 
prior to Day 42. 
The date of primary graft failure will be designated as day 43 post transplant. 
Secondary graft failure consists of documented neutrophil engraftment, followed by 
severe neutropenia (<0.5 x 109/L for three or more consecutive laboratory values on 
separate days) with marrow cellularity <5%, without subsequent improvement occurring 
either spontaneously or after growth factor treatment.  Infusion of an additional stem cell 
product after documented neutrophil engraftment will be considered secondary graft 
failure.  The earlier of the first day of severe neutropenia, as defined above, or the date of 
additional stem cell infusion will be designated the date of secondary graft failure.   
4.2.4. 
Platelet engraftment 
Platelet engraftment is defined as the first day of a minimum of 3 consecutive 
measurements on different days such that the patient has achieved a platelet count 
>20x109/L with no platelet transfusions in the preceding 7 days (count day of 
engraftment as one of the preceding 7 days). The first day of the three measurements will 
be designated the day of platelet engraftment and must occur prior to any infusion of a 
second stem cell product. 
4.2.5. 
Grade 2/3 Bacterial Infections and grade 3 Viral infections 
See Appendix G for infection grading criteria.  
4.2.6. 
Invasive fungal infection 
Invasive fungal infection is defined as any grade 3 fungal infection.  See Appendix G for 
infection grading criteria. 
4.2.7. 
Duration of primary hospitalization 
Duration of primary hospitalization is defined as the total number of days from transplant 
to first discharge from the hospital. ________________________________________ 
________________________________________________________________________
__________________. 
4.2.8. 
Days alive and out of hospital 
A day alive and out of hospital is defined as a full day (calendar day) in which the patient 
was alive and not hospitalized. Partial days alive and out of hospital, such as the day of 
admission, day of discharge and day of death, do not count as a day alive and out of 
hospital. The day of transplant will not count as a day alive and out of hospital regardless 
of whether the patient is treated as an inpatient or outpatient. 
4.2.9. 
Overall survival 
Overall survival is defined as the time from the date of randomization to death from any 
cause. 


 
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4.2.10. 
Disease Relapse  
Relapse of malignancy - testing for recurrent malignancy in the blood, marrow or other 
sites will be used to assess relapse after transplantation. For the purpose of this study, 
relapse is defined by either morphological or cytogenetic evidence of AML, ALL, CML, 
or MDS consistent with pre-transplant features.   
Minimal residual disease - minimal residual disease (MRD) is defined by the sole 
evidence of malignant cells by flow cytometry, or fluorescent in situ hybridization 
(FISH), or Southern blot or Western blot, or polymerase chain reaction (PCR), or other 
techniques, in the absence of morphological or cytogenetic evidence of disease in blood 
or marrow.  Since the frequency of testing for minimal residual disease is highly variable 
among centers, and the sensitivity is highly variable among laboratory techniques, 
evidence of minimal residual disease alone will not be sufficient to meet the definition of 
relapse in the context of this trial.  However, minimal residual disease that progresses can 
be considered as relapse and the date of relapse will be the date of detection of minimal 
residual disease, as described below.  
Acute Leukemia - Relapse can be defined as any of the following.  
________________________________________________________________________
______________________________________________________ 
• _______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
______________________________________________________ 
Chronic Myelogenous Leukemia (CML) 
________________________________________________________________________
_____________________________________________Hematologic relapse can be 
diagnosed when: 
________________________________________________________________________
________________________________________________________________________
Cytogenetic relapse can be diagnosed when:  
_____________________________________________________________________
_____________________________________________________________________
_____________________________________________________________________
___________________________. 
MDS 
Relapse can be defined as any of the following. 
________________________________________________________________________
_____________________________________________: 


 
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• _______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
______________________________________________________. 
Lymphoma   
Relapse can be defined according to the criteria in Table 2 and/or one or more of the 
following criteria: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
_________ 
4.2.11. 
Disease-free survival 
Disease-free survival is defined as the time from the date of randomization to the date of 
disease relapse or death from any cause, whichever comes first.     
4.2.12. 
Non-Relapse Mortality 
Non-Relapse mortality is defined as any death not preceded by relapse. 
4.2.13. 
Relapse Mortality 
Relapse mortality is defined as any death preceded by relapse. 
4.2.14. 
Acute GvHD  
Acute GvHD will be staged and graded using the Consensus Conference on Acute GvHD 
grading (Appendix B) at every protocol-specified scheduled visit up to day 180 post 
transplant. The date of GvHD, if applicable, will be assigned as the target visit date 
assigned to the first visit day post transplant on which the maximum symptoms in the 
assessment period meet the definition of acute GvHD. 
4.2.15. 
Chronic GvHD  
Chronic GvHD will be assessed on the day of diagnosis, as well as on day 100, 180, 270 
and year 1 post transplant and classified as mild/moderate/severe according to the 2014 
NIH consensus criteria (Appendix B).  


 
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4.2.16. 
Immune Reconstitution 
Immune reconstitution will be assessed on days 28, 70, 100, 180, and 365. Cellular 
immune recovery will be assessed based on lymphocyte subset analysis to quantify the 
numbers and proportions of different lymphocyte subpopulations (CD3, CD4, CD8, 
CD19, CD56/16).  Additional assessments requested (but not required) are: CD123+ 
(dendritic lymphocytes), CD11c+ (dendritic myeloid cells), CD3+CD56+CD16+ (NKT 
cells), CD45RA+/CD62L+(RTE), CD25+/CD62L+(T-Reg), Total CD25+, 
CD57+/CD28+(CTL), HLA-DR+(Activated), and quantitative immunoglobulins (and 
record of IVIG administrations). In patients enrolled in the optional immune 
reconstitution sub-study, additional exploratory immunologic parameters will be 
assessed.  
4.2.17. 
Health-Related Quality of Life (HQL) 
Patient-reported health-related quality of life (HQL) outcomes will be assessed during the 
trial using two standardized measures including the Functional Assessment of Cancer 
Therapy –Bone Marrow Transplant Module (FACT BMT) and the EuroQol EQ-5D, 
which have been reported in previous trials involving bone marrow transplant 
patients.56,57 
4.2.17.1. FACT-BMT 
The Functional Assessment of Cancer Therapy –Bone Marrow Transplant (FACT-BMT) 
Version 4 is a self-administered instrument designed to assess multidimensional aspects 
of the QOL in BMT patients. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________ 
The FACT-BMT is estimated to take approximately 20 minutes to complete. 
For patients <18 years old, a validated adapted version has been issued, 
________________________________________________________________________
________________________________________________________________________
___________________________. 
4.2.17.2. EQ-5D 
The EQ-5D descriptive system of health-related quality of life states consists of five 
dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) 
each of which can take one of three responses. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________


 
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____________________________________. The EQ-5D is estimated to take 
approximately 1 minute to complete. 
4.2.18. 
Safety and Tolerability of NiCord® Transplantation 
The safety and tolerability of NiCord® transplantation will be evaluated as described in 
section 10.6. 
4.2.19. 
Other Definitions 
4.2.19.1. Response Criteria for Acute Leukemia 
• _______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
______________________________________________________. 
4.2.19.2. Complete Morphologic Remission for CML from Prior 
Blast Crisis 
• _______________________________________________________________
_______________________________________________________________
_____________________________________________. 
4.2.19.3. CML Stages 
Chronic phase is defined as:  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_________ 
Accelerated phase is defined as: 
• _______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
__________________ 


 
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Blasts Crisis is defined as: 
• _______________________________________________________________
______________________________________________________ 
4.2.19.4. Response Criteria for Lymphoma 
Response criteria for lymphoma are described in Table 2 below: 
 


 
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Table 2: 
Response Definitions for Lymphoma58 
Response Definitions for Clinical Trials 
Response  
Definition 
Nodal Masses 
Spleen, Liver 
Bone Marrow 
CR 
Disappearance of all evidence of 
disease 
 
 
 
PR 
Regression of measurable disease 
and no new sites 
 
 
 
SD 
Failure to attain CR/PR or PD 
 
 
 
Relapse disease or PD 
Any new lesion or increase by 
≥50% of previously involved sites 
from nadir 
 
 
 
Abbreviations:  CR, complete remission; FDG [18F]fluorodeoxyglucose; PET, positron emission tomography; CT, computed tomography; PR, partial remission; SPD, sum of the 
product of the diameters; SD, stable disease; PD, progressive disease. 


 
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5. 
STUDY POPULATION 
5.1. 
Number of patients 
The study will randomize 120 eligible patients in a 1:1 ratio to receive either NiCord® or 
unmanipulated cord blood transplantation. 
Any patient may be removed from the study at any time if in the judgment of the 
investigator continuation in the trial is not in the best interests of the patient. Patients may 
also withdraw themselves from the study at any time and for any reason. 
Patients will be defined as screening failures if they are removed from the study before 
randomization or as termination/discontinuation if dropout occurs after randomization. 
Screening failures may be replaced.  
For discontinuation patients who do not withdraw consent, the study investigator will 
make all reasonable efforts to gather information on the clinical outcomes as assessed 
during the usual clinical management of their disease for the duration of their scheduled 
follow-up and to capture this information in the CRF. 
5.2. 
Analysis populations 
The screened population consists of all subjects who signed informed consent. 
Intent-to-Treat (ITT) population includes all patients randomized into the trial, classified 
in the treatment groups to which they were allocated. Analysis of the ITT population 
provides the primary analysis of the primary endpoint, and also the primary analyses of 
the secondary endpoints, tertiary endpoint, and the analyses of the exploratory endpoints 
unless otherwise stated. 
Transplanted (TP) population includes all patients randomized who received a cord blood 
transplant within 90 days following randomization.  Patients are assigned to the treatment 
groups to which they were allocated. Analysis of the TP population provides the analyses 
for the exploratory endpoints that depend on transplant, such as graft versus host disease.   
As treated (AT) population includes all patients randomized who received a cord blood 
transplant within 90 days following randomization, grouped by treatment actually 
performed. Analysis of the AT population is for supportive purposes. 
ANC engrafted population (AEP) includes all subjects who received a cord blood 
transplant within 90 days following randomization and achieved ANC engraftment; 
analysis is focused on the treatment actually performed. Analysis of the AEP population 
is for supportive purposes. 
Platelets engrafted population (PEP) includes all subjects who received a cord blood 
transplant within 90 days following randomization and achieved platelet engraftment; 
analysis is focused on the treatment actually performed. Analysis of the PEP population 
is for supportive purposes. 
Safety population (SP) is identical to the AT population defined above. 


 
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5.3. 
Eligibility criteria 
Patients 12-65 years of age with a diagnosis of hematological malignancy who are 
candidates for unrelated cord blood transplantation, with qualifying HLA-matched UCB 
units with sufficient pre-cryopreserved total nucleated cell dose and CD34+ cell dose, as 
follows: 
• Treatment CBU #1:  
Patients must have a partially HLA-matched CBU: the unit must be HLA-matched at 4-
6/6 HLA class I (HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high resolution) 
loci with the patient. There must be at least one allele match at DRB1. The CBU must 
have a pre-cryopreserved (post processing), total CD34+ cell count of ≥_________ as 
well as a pre-cryopreserved (post processing) total nucleated cell count of 
≥_________and total nucleated cell dose ≥_________TNC/kg. The CBU will have 
undergone volume reduction (both plasma and red blood cell depletion) prior to 
cryopreservation. 
− Treatment CBU #1 will be used for the NiCord® arm or for the control 
arm in case of either single or double CBT. 
− Verification typing (confirmatory typing) must be completed prior to CBU 
shipment 
• Treatment CBU #2 (to be used for the control arm in case of double cord 
transplantation):  
In case treatment CBU #1 is HLA-matched at 5-6/6 and contains a pre-cryopreserved 
(post processing) total nucleated cell dose of <_________TNC/kg, OR a pre-
cryopreserved (post processing) CD34+ cell dose of <_________CD34+ cells/kg, a 
second CBU must be added for the control arm, as a double CBT.  
In case treatment CBU #1 is HLA-matched at 4/6 and contains a pre-cryopreserved (post 
processing), total nucleated cell dose of <_________TNC/kg, OR a pre-cryopreserved 
(post processing), CD34+ cell dose of <_________ CD34+ cells/kg, a second CBU must 
be added for the control arm, as a double CBT. 
The determination of using a single or double cord in the control arm must be made by 
the investigator prior to randomization. 
− Treatment CBU #2 must be HLA-matched at 4-6/6 HLA class I (HLA-A 
& HLA-B, low resolution) and II (HLA-DRB1, high resolution) loci with 
the patient. There must be at least one allele match at DRB1. Treatment 
CBUs #1 and #2 must have a combined pre-cryopreserved (post 
processing) total nucleated cell dose of ≥_________TNC/kg. 
Detailed eligibility criteria are provided below; note that all eligibility testing must be 
completed and resulted, and entered into ________________ before randomization: 
Inclusion Criteria 
1. Patients must be 12-65 years of age at the time of randomization 
2. Patients with one of the following hematological malignancies: 


 
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• Acute lymphoblastic leukemia (ALL) at one of the following stages: 
____________________________________________________________
____________________________________________________________  
_______________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________ 
• Acute myelogenous leukemia (AML) at one of the following stages: 
_______________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
_________________________________ 
• Chronic myelogenous leukemia (CML) at one of the following phases: 
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
________________________________________  
• CMMoL or MDS/CMMoL overlap with spleen size <________ 
• Myelodysplastic Syndrome (MDS) with history of one or more of the 
following: 
__________________________________________________________________
_______________________________________________________________
_______________________________________________________________


 
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_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
___________________ 
• Biphenotypic/undifferentiated/Prolymphocytic/Dendritic Cell Leukemias and 
Natural Killer Cell Malignancies________________________, adult T-cell 
leukemia/lymphoma ________________________ 
• Lymphoma, meeting one of more of the following criteria: Burkitt’s 
lymphoma ________________________ 
OR 
o High risk lymphomas________, including, enteropathy-associated T 
cell lymphoma, or hepatosplenic gammadelta T cell lymphoma 
OR 
o Chemotherapy-sensitive (defined as at least stable disease) lymphomas 
that have failed at least 1 prior regimen of multi-agent chemotherapy 
and are not candidates for an autologous transplant.  
 
(Patients with CLL are not eligible regardless of disease status) 
3. CBU criteria as described above. 
4. Patients who will be starting conditioning prior to NiCord release for infusion 
(i.e., NiCord arrival on site in adequate condition) must have an additional 
partially HLA-matched CBU, reserved as a backup to the NiCord arm in case of 
production failure. The backup CBU must be HLA-matched at 4-6/6 HLA class I 
(HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high resolution) loci 
with the patient. A second backup CBU is recommended to be added in the below 
cases: 
• If the back-up CBU is HLA-matched at 5 or 6/6and contains a pre-
cryopreserved (post processing) total nucleated cell dose of 
<________TNC/kg, OR a pre-cryopreserved (post processing) CD34+ cell 
dose of <________ CD34+ cells/kg 
• If the back-up CBU is HLA-matched at 4/6and contains a pre-
cryopreserved (post processing) total nucleated cell dose of 
<________TNC/kg, OR a pre-cryopreserved (post processing) CD34+ cell 
dose of <________ CD34+ cells/kg 
In case of two back-up CBUs, the second back-up CBU must be HLA-matched at 
4-6/6 HLA class I (HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high 
resolution) loci with the patient. The back-up CBUs are recommended to have a 
combined pre-cryopreserved (post processing) total nucleated cell dose of at least 
________ TNC/kg. 
5. Patient’s Performance score ≥70% by Karnofsky or Lansky 


 
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6. Patient has sufficient physiologic reserves including: 
a. Cardiac: 
____________________________________________________________
____________________________________________________________ 
b. Pulmonary function tests 
____________________________________________________________
____________________________________________ 
c. Renal: 
____________________________________________________________
____________________________________________________________ 
d. Hepatic: 
____________________________________________________________
____________________________________________________________ 
7. Females of childbearing potential, defined as 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
________________________________________________________. 
8. Patient (or legal guardian) signs the written informed consent after being aware of 
the nature of the patient’s disease and willingly consents to the treatment program 
after being informed of alternative treatments, potential risks, benefits, and 
discomforts. 
Exclusion Criteria 
1. MDS or CML with “marked” or “3+” fibrosis 
2. CLL 
3. Fewer than 21 days have elapsed since initiation of the patient's last 
chemotherapy cycle and the initiation of the stem cell transplant preparative 
regimen 
__________________________________________________________________
______________________________________________________ 
4. Persistent clinically significant toxicities that, in the investigator’s opinion, make 
the patient unsuitable for transplant  
5. Evidence of donor specific anti-HLA antibodies to the selected treatment CBU #1 
(MFI>3000 to HLA A, B, C, or DRB1) 
6. Evidence of HIV infection or HIV positive serology 
7. Evidence of active Hepatitis B or Hepatitis C as determined by serology or PCR 


 
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8. Pregnancy, 
__________________________________________________________________
______________________________ 
9. Active malignancy other than that for which the UCB transplant is being 
performed within 12 months of enrollment.  Fully resected cutaneous squamous 
cell or basal cell carcinoma or cervical carcinoma in situ within 12 months of 
enrollment will be permitted.   
10. Evidence of uncontrolled bacterial, fungal or viral infections or severe 
concomitant diseases, 
__________________________________________________________________
______________________________________________________ 
 
11. Patients with presence of leukemic blasts in the central nervous system (CNS)  
12. Patients with an 8/8 allele level HLA-matched and readily available related or 
unrelated donor (whose stem cells can be collected in a timely manner without 
jeopardizing recipient outcome). Patients who have haploidentical related donors 
or syngeneic donors will not be excluded. 
13. Prior allogeneic hematopoietic stem cell transplant 
14. Allergy to bovine products, gentamicin, or to any other product that may interfere 
with the treatment  
15. Psychologically incapable 
__________________________________________________________________
__________________________________________________________________
____________________________________ 
16. Enrolled in another interventional clinical trial or received an investigational 
treatment within 30 days prior to the anticipated date of randomization, 
__________________________________________________________________
__________________________________________________________________
____________________________________________ 


 
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6. 
CONCOMITANT MEDICATIONS AND SUPPORTIVE 
CARE 
Required conditioning and supportive care regimens are outlined below.  Modifications 
and dose adjustments based on toxicity risk according to institutional guidelines may be 
made upon review and approval of a study chairperson. 
6.1. 
Previous medications 
All medications taken by/given to the patient, as a treatment for the primary and 
concomitant diseases within 30 days prior to screening, will be recorded in the patient 
files. 
All chemotherapy and radiotherapy courses administered to the patient, as prior treatment 
for his/her hematological malignancy, will be recorded in the CRF (including treatment 
regimen, number of cycles, and dates). 
6.2. 
Disallowed concomitant medications 
The following medications should not be given post transplant: 
• Any cytokines except G-CSF should not be used (including IL-2 or 
others,__________). 
• The use of Bactrim (sulfamethoxazole and trimethoprim) or methotrexate 
_______________________________________________________________
_________________________________________________________ 
• Maintenance therapies 
_______________________________________________________________
_______________________________________________________________
____ 
• See section 6.14 for limitations regarding the use of investigational agents 
6.3. 
Conditioning regimen 
All patients will receive one of the conditioning regimens shown in Table 3 below.  Each 
transplant center must commit to use the same conditioning regimen for all patients 
transplanted at their center, or according to primary diagnosis/age group. The intended 
practice must be documented prospectively for the transplant center. In unique cases 
where the use of a different conditioning regimen is deemed to be in the patient’s best 
interest, approval from one of the study chairs must be obtained prior to use of the 
different regimen.  Prior to randomization, the investigator will decide and document the 
conditioning regimen intended to be used for transplantation. 


 
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Table 3: 
Conditioning regimens 
Regimen A.1 
Study day 
 
Treatment 
-11 
-10 
-9 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
TBI ____ cGy 
in 8 or 9 
fractionsb 
 
 
x2 
or  
x1 
or  
x0 
x2 
x2 
x2 
x0 
or  
x1 
or  
x2 
 
 
 
REST 
Infusion of 
NiCord® or 
Unmanipulated 
CBU/s 
Fludarabinea 
___ mg/m2 IV 
 
 
 
 
 
 
x 
x 
x 
x 
Thiotepaa 
__mg/kg IV 
x 
x 
 
 
 
 
 
 
 
 
a Adjusted body weight 
b Or TBI ___ cGy, administered as per institutional practice 
Regimen A.2 
     Study day 
 
Treatment 
-8 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
TBI _____ cGy in 8 
fractionsc 
 
 
 
RESTb 
x2 
x2 
x2 
x2 
Infusion of NiCord® or 
Unmanipulated CBU/s 
Fludarabine _____ mg/m2 
IV 
x 
x 
x 
 
 
 
 
Cyclophosphamidea 
____mg/kg IV 
x 
x 
 
 
 
 
 
a Adjusted body weight 
b A day of rest may be included between the last dose of Fludarabine and the start of TBI (as shown above).  
Alternatively, the day of rest may be moved to day -1 without any rest between Fludarabine and TBI (TBI 
on day -5, -4, -3, -2) or the day of rest may be omitted altogether (Cyclophosphamide on day -7 and -6 and 
Fludarabine on day -7, -6 and -5)    
c Or TBI _____ cGy, administered as per institutional practice 
Regimen B 
     Study Day 
 
Treatment 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
Thiotepaa ___mg/kg IV  
x 
x 
 
 
 
REST 
Infusion of NiCord® or 
Unmanipulated CBU/s 
Busulfana ______mg/kg 
IV or weight based dosing 
+ TDM$ 
 
xb 
x  
x  
x  


 
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     Study Day 
 
Treatment 
-7 
-6 
-5 
-4 
-3 
-2 
-1 
0 
Fludarabinea _____mg/m2 
IV  
 
 
x 
x 
x  
a Adjusted body weight 
b Can be added as per institutional practice 
$TDM= therapeutic drug monitoring: aiming for cumulative target AUC (Area Under the Curve) = 
75mg*h/L. Bu levels after 1st dose will be measured at 5min, 1h, 2h and 4h after end of Bu infusion and 
AUC will be calculated based on previously described population PK model.59 
6.3.1. 
Radiotherapy (Regimen A) 
Patients may be treated either in the AP/PA position and/or in the right and left lateral 
position. Compensators or blocks may be used to compensate for the thinner parts of the 
anatomy (head, neck, lower legs and feet).  
Regimen A.1: Total dose will be _______cGy in 8 or 9 fractions over 4 or 5 days. Two 
fractions on the same day will be given at a minimum of 6 hours apart from beam on to 
beam on. Alternatively, a total dose of _____cGy can be administered, fractionated as per 
institutional practice. 
Regimen A.2: A dose of ______cGy will be administered twice daily on days outlined in 
Table 3 for a total dose of _______cGy. Alternatively, a total dose of ______cGy can be 
administered, fractionated as per institutional practice.  
Risks and Toxicities:  
TBI can cause: nausea and vomiting, diarrhea, parotitis (rapid onset within 24-48 hours, 
usually self-limited), generalized mild erythema, hyperpigmentation, fever, mucositis and 
alopecia.  Late effects include: possible growth retardation, vertebral deformities, 
cataracts, probable increased risk of secondary malignant neoplasms, sterility, 
nephropathy, interstitial pneumonitis and veno-occlusive disease. 
6.3.2. 
Fludarabine Administration (Regimens A and B) 
Regimen A.1: Fludarabine ______mg/m2/day will be administered as an IV infusion on 
days -5 through -2. For patients weighing more than 125% of their ideal body weight 
(IBW), Fludarabine will be dosed as per adjusted body weight (see section 6.3.6).  For all 
other patients, dosing is according to the actual body weight. 
Regimen A.2: Fludarabine ______mg/m2/day will be administered as an IV infusion on 
days outlined in Table 3. The dose is calculated based on actual body weight (ABW).  
The dose will be adjusted if the GFR or eGFR is ≤ 70ml/min/m2.   
Regimen B: Fludarabine ______mg/m2/day will be administered as an IV infusion on 
days -5 through -3. For patients weighing more than 125% of their IBW, Fludarabine will 
be dosed as per adjusted body weight (see section 6.3.6 ).  For patients weighing less than 
their IBW, dosing is according to the actual body weight. For all other patients, dosing is 
according to the ideal body weight. 


 
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Refer to Appendix F, ‘Drug Labels’, for risks and toxicities of Fludarabine 
administration. 
6.3.3. 
Cyclophosphamide (CY) Administration (Regimen A.2) 
Refer to Appendix F, ‘Drug Labels’, for risks and toxicities of cyclophosphamide 
administration. 
Cyclophosphamide ______mg/kg/day will be administered on days outlined in Table 3 as 
an IV infusion.  The dose will be administered after a high volume fluid flush and mesna 
administration per institutional guidelines. 
For patients weighing more than 30kg above their IBW, cyclophosphamide will be dosed 
based on the adjusted body weight (see section 6.3.6). For all other patients, dosing is 
according to the actual body weight. 
6.3.4. 
Thiotepa Administration (Regimen A.1 and B) 
Regimen A.1: Thiotepa ____mg/kg/day will be administered as an IV infusion on days -
11 and -10. For patients weighing more than 125% of their IBW, Thiotepa will be dosed 
as per adjusted body weight (see section 6.3.6). For all other patients, dosing is according 
to the actual body weight. 
Regimen B: Thiotepa _____mg/kg/day will be administered as an IV infusion on days -7 
and -6. For patients weighing more than 125% of their IBW, Thiotepa will be dosed as 
per adjusted body weight (see section 6.3.6). For patients weighing less than their IBW, 
dosing is according to the actual body weight. For all other patients, dosing is according 
to the ideal body weight.  
Refer to Appendix F, ‘Drug Labels’, for risks and toxicities of Thiotepa administration. 
6.3.5. 
Busulfan Administration (Regimen B) 
Busulfan ______ mg/kg/day will be administered as an IV infusion or in four separate IV 
infusions every six hours on days -5 (or -6 per institutional practice) through -3. For 
patients weighing more than 125% of their IBW, Busulfan will be dosed as per adjusted 
body weight (see section 6.3.6). For patients weighing less than their IBW, dosing is 
according to the actual body weight. For all other patients, dosing is according to the 
ideal body weight. Alternatively, Busulfan will be dosed according to previously 
described weight based dosing59 + TDM: dose will be adjusted (if necessary) on the 
second day to achieve a cumulative Busulfan exposure (AUC) after 3 days of 75 mg*h/L.   
Doses and schedule for anti-seizure prophylaxis should follow local institutional 
guidelines.  
Refer to Appendix F, ‘Drug Labels’, for risks and toxicities of Busulfan administration. 


 
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6.3.6. 
Dose adjustment formulas 
The following are dose adjustment formulas: 
• Ideal Body Weight (IBW) formulas: 
− Males IBW = 50 kg+2.3 kg/inch over 5 feet (or 50 kg + 0.91kg/cm over 
152.4cm)  
− Females IBW = 45.5 kg+2.3 kg/inch over 5 feet (or 45.5 kg + 0.91kg/cm 
over 152.4cm)  
• Adjusted Body Weight formula: 
− Regimen A.1/A.2: Adjusted body weight = IBW+[(0.25)x(ABW-IBW)] 
− Regimen B: Adjusted body weight = IBW+[(0.4)x(ABW-IBW)] 
6.4. 
GvHD prophylaxis medications 
All patients will receive GvHD prophylaxis with two drugs as follows: 
Calcineurin inhibitor (Tacrolimus or Cyclosporine) 
Each transplant center must commit to use the same calcineurin inhibitor (Tacrolimus or 
Cyclosporine) for all patients transplanted at their center.  In unique cases where the use 
of a different calcineurin inhibitor is deemed to be in the patient’s best interest, approval 
from the study chairs must be obtained prior to use of the different calcineurin inhibitor 
Prior to randomization, the investigator will decide and document the GvHD prophylaxis 
intended to be used for transplantation. 
Tacrolimus or Cyclosporine from day -3 to at least day +100.  
• Recommended target Tacrolimus trough blood levels of 5-15 ng/ml.  
• If administering via continuous IV infusion, it is recommended to target 
Cyclosporine trough levels of 200-400 ng/mL by TDX method (or equivalent 
level for other CSA testing methods).  For intermittent dosing, it is recommended 
to target Cyclosporine trough levels of 150-400 ng/mL by TDX method (or 
equivalent level for other CSA testing methods).   
In the event of toxicity, suspected relapse or the development/worsening of GvHD, 
dosing may be adjusted per institutional standard practice or a different drug may be 
substituted. In the absence of actual toxicity, calcineurin inhibitor taper can begin at 
day +100 at the earliest, at the discretion of the managing physician, with the goal for 
discontinuation at day 180-200.  Refer to Appendix F, ‘Drug Labels’, for risks and 
toxicities of Tacrolimus and Cyclosporine administration. 
Mycophenolate Mofetil (MMF)  
Mycophenolate Mofetil (MMF) (or Mycophenolate Sodium) will be given at a dose of 
______mg/kg TID (based upon actual body weight) with the maximum total daily dose 
not to exceed 3 grams (IV or PO rounded to the nearest capsule size) beginning day -3 to 
at least day +60. In the event of toxicity or suspected relapse, dosing may be adjusted per 


 
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institutional standard practice or a different drug may be substituted.  Refer to Appendix 
F, ‘Drug Labels’, for risks and toxicities of Mycophenolate Mofetil administration. 
6.5. 
Acute & Chronic GvHD Treatment  
Management of acute and chronic GvHD will be at the investigator's discretion and in 
accordance with the institution's guidelines.  
6.6. 
Venous Access  
Recipients will have appropriate long-term central venous access placed, per institutional 
standard practice, prior to beginning the conditioning regimen. The placement of a triple 
lumen tunneled catheter is recommended. 
6.7. 
Infusion Support 
All patients will receive the following medications 30-60 mins prior to NiCord® or 
unmanipulated CBU infusion.   
• Diphenhydramine _______mg IV or PO (or ______ mg/kg up to a maximum 
of _______mg) or Dexchlorpheniramine _______mg IV 
• Hydrocortisone ______mg IV (or ______ mg/kg up to a maximum of 
________mg) 
• Acetaminophen/Paracetamol __________mg IV or PO (or __________ mg/kg 
up to a maximum of __________mg) 
Changes to the above medications for infusion support can be allowed, but must be 
approved by the Sponsor prior to transplantation. 
Methylprednisolone should not be used in conjunction with standard delivery of NiCord® 
or unmanipulated CBU to the patient.  Management of infusion reactions during and post 
transplant is at the discretion of the managing physician. 
6.8. 
Supportive Cytokine Therapy 
G-CSF (e.g., Filgrastim, Neupogen, Granix) therapy will be started on day +1 at a dose of 
_______ µg/kg/day (rounded to nearest vial size) given IV or SC and continuing through 
the second day of ANC >1,000/µl for 2 consecutive days.  
6.9. 
Blood Products 
Thrombocytopenia: Platelet counts should be maintained at >10,000/µL after allogeneic 
transplant by transfusion of platelets. When available, single donor platelets will be used. 
Anemia: Transfusions of packed red blood cells (RBC) are indicated for the management 
of symptomatic anemia per institutional guidelines.  In the absence of symptoms, RBC 
transfusions should be considered to maintain hemoglobin > 7g/dL.   


 
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All blood products (except NiCord® or any other stem cell grafts administered) must be 
irradiated to at least 2500 cGy before administration to transplant recipients to reduce the 
risk of developing third-party graft-versus-host disease.  
6.10. 
Engraftment Syndrome 
Engraftment syndrome is a clinical diagnosis. The most frequently reported 
manifestations are transient fever, rash, and respiratory symptoms not attributable to 
infection or GvHD. The pathophysiology is poorly understood, but is thought to be 
multifactorial mediated by cellular, complement and cytokine components. 
Diagnostic criteria include fever (temperature >38.5°C) without an identifiable infectious 
cause prior to or with neutrophil recovery with or without an erythematous rash or 
capillary leak (weight gain, edema, ascites, effusions) or respiratory symptoms not 
attributable to IPS. Mild symptoms may not require therapy due to the self-limiting 
nature of this syndrome. Methylprednisolone should not be given as prophylaxis for 
engraftment syndrome prevention.  For progressive symptoms, methylprednisolone at 2 
mg/kg/day is recommended with tapering once response is achieved.  If recurrent or 
prolonged, investigation for GvHD is recommended. 
6.11. 
Infection Prophylaxis and Surveillance 
Unless otherwise specified below, institutional guidelines will be followed to provide 
prophylaxis for infections. In general, each transplant center should use the same anti-
microbial prophylaxis regimens for all patients transplanted at their center, apart from 
unique cases where the use of a different anti-microbial agent is deemed to be in the 
patient’s best interest. Strict guidelines for hygiene and care will be applied. Before 
starting the pre-transplant conditioning there should be no uncontrolled mucosal or 
cutaneous infections.  Oral candida prevention should be vigorously pursued.  
All patients must be nursed in a single room during neutropenia and should preferably be 
nursed in a single room during all admissions. All visitors must be free of active 
infections. Rigorous hand washing is crucial. 
6.11.1. 
Anti-viral Prophylaxis 
Acyclovir _______mg (or _______mg/m2) PO BID is recommended for anti-viral 
prophylaxis with conditioning through the duration of neutropenia and then at 
_______mg PO BID (or _______mg/kg/day PO divided in 2–3 doses for patients <40kg, 
up to a maximum of _______mg BID) until 1 year post transplant or until 6 months after 
immunosuppression is discontinued. If unable to tolerate PO medications, IV prophylaxis 
will be necessary.  Other anti-viral prophylaxis regimens may be administered per 
institutional guidelines, however, prophylaxis with ganciclovir or valganciclovir is 
strongly discouraged on or after day -2 until engraftment is achieved.   


 
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6.11.2. 
Anti-bacterial Prophylaxis 
Anti-bacterial prophylaxis is required.  Ciprofloxacin _______mg PO BID day 0-100 is 
recommended.  Other anti-bacterial prophylaxis regimens may be administered per 
institutional guidelines. 
6.11.3. 
PCP Prophylaxis 
Trimethoprim-sulfamethoxazole or an equivalent drug will be administered after 
engraftment.  The timing and choice of drug and dosages are at the discretion of the 
investigator.  The use of Bactrim is discouraged on or after day -2 and prior to 
engraftment as it may delay engraftment, and is reserved only for cases where it is 
assessed to be essential and superior to all alternative medications. 
6.11.4. 
Fungal Prophylaxis 
Anti-fungal prophylaxis is recommended with agents such as fluconazole, itraconazole, 
voriconazole, or posaconazole. 
6.11.5. 
Toxoplasmosis Prophylaxis 
It is recommended for patients to be screened prior to transplantation for toxoplasmosis 
exposure. Those who are IgG seropositive for toxoplasmosis are at significant risk for 
life-threatening infection, and prophylaxis is recommended. 
6.11.6. 
CMV Surveillance  
All recipients must be tested for CMV (using the PCR method) at least once during the 
conditioning period, at the weekly protocol specified visits (see protocol section 7.9.2) up 
through day 42 and then on day 56, 70 and day 100 or more frequently as clinically 
indicated. Antiviral therapy for CMV reactivation should commence preemptively if 
CMV testing reveals a high or rising viral load. If CMV reactivation occurs at or before 
engraftment, foscarnet is recommended to prevent marrow suppression.  
6.11.7. 
HHV6 Surveillance  
Quantitative HHV6 DNA assessment by PCR must be tested at weekly protocol specified 
visits after transplantation until absolute neutrophil count >500 cells/microliter.  
Treatment is strongly recommended if symptomatic or following 2 weeks of rising viral 
load or an absolute count above 10k copies/ml.  If HHV6 reactivation occurs at or before 
engraftment, treatment with foscarnet is recommended. 
6.11.8. 
EBV Surveillance  
Quantitative EBV viral load assessment by PCR must be tested at protocol specified 
visits on days 21, 56, and 100 post transplant, or more frequently as clinically indicated, 
and at protocol specified visits on days 180, 270, and 365 post transplant if the patient is 
still on immunosuppression.  Patients with a positive result (>1000 copies) should be 
treated as per institutional guidelines.  Rituximab treatment is recommended. 


 
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6.11.9. 
Adenovirus Intervention Guideline 
Testing for adenovirus infection in the blood by PCR method is recommended in the 
event of symptoms suspicious for infection such as diarrhea, hepatic dysfunction or 
respiratory symptoms. If an active systemic infection is diagnosed, therapy should be 
instituted per institutional guidelines. 
6.11.10. 
Intravenous Immune Globulin 
Intravenous immune globulin may be administered according to institutional practice 
guidelines.  
6.11.11. 
Identification of Infectious Agents – Recommendations 
6.11.11.1. Blood Cultures 
Blood cultures should be taken at the presentation of fever prior to initiating antibiotics.  
In the event of clinical deterioration, suspicion of line infection, or chills following 
initiation of broad-spectrum antibiotics, additional cultures should be taken.  Repeat 
cultures for subsequent episodes of fever or persistent fever unresponsive to antibiotics. 
6.11.11.2. Blood Culture Procedure 
It is recommended that blood cultures be sampled twice per procedure. Each sample 
should be tested for both aerobic and anaerobic organisms. One sample should come 
from the peripheral blood and one sample from the central line (or a second sample from 
the peripheral blood if the central line is no longer in use). If a peripheral blood draw is 
not successful and the patient has a central line with multiple lumens, then draw one 
sample from each lumen. 
6.11.11.3. Additional Identification Procedures 
The following procedures are recommended in patients with suspected infection: 
• Chest X-ray  
• Sinus CT in patients with suspected sinusitis  
• Diarrhea: Clostridium difficile toxin PCR to be determined once in patients 
with clinical suspicion. Viral diagnostics (rotavirus, adenovirus, norovirus, 
astrovirus) in patients with clinical suspicion of infectious cause.  
• Urine culture in patients with suspected infection of indwelling catheter  
• CSF culture in patients with suspected meningitis  
• Skin lesions: biopsy or aspirate, for culture, Gram stain, GMS and cytology. 
• Pulmonary source of infection: sputum culture in patients with productive 
cough. Consider viral diagnostics using viral throat swab, especially in season: 
Influenza A and B, RSV, Coronavirus, Rhinovirus, Bocavirus, Para-influenza, 
Human metapneumovirus and mycoplasm. BAL in patients with chest HRCT 
abnormalities.  


 
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6.11.12. 
 Treatment of Infections 
Patients undergoing the conditioning treatment outlined in this study are expected to 
develop immunodeficiency. Therefore, the approach to the diagnosis and treatment of 
fever in such patients should be an aggressive one. If any infections occur, they will be 
treated per institutional practice and will be recorded in the source documents and in the 
e-CRF.  As standard treatment practices differ between institutions, will evolve over 
time, and vary by patient circumstances, we do not prescribe a specific approach to 
treatment.  Rather, it is the responsibility of the treating physician to manage infections 
according to their institutional best practices.    
6.11.13. 
 Discharge Instructions and Follow-up 
Patients and their treating physicians should be provided clear instructions at discharge 
that emphasize the importance of continued follow-up as per study protocol, including 
early reporting of infectious symptoms, medical treatments received and any other 
medical events to their clinical center.  The transplant center should attempt weekly 
contact with patients through day 70 to ask about infectious symptoms and any other 
medical events or treatments.  Transplant centers will continue with monthly contact 
from day 70 to the completion of follow-up (day 365). 
6.12. 
Nutrition  
All patients will be candidates for total parenteral nutrition; length of use is at the 
attending physician’s discretion.   
6.13. 
Guidelines for Infusing a Second Stem Cell Product  
A second transplant should not be considered unless the patient has impending or actual 
graft failure. In the event of impending or actual graft failure then the patient may be 
treated per institutional guidelines.  As standard treatment practices differ between 
institutions, will evolve over time, and vary by patient circumstances, we do not prescribe 
a specific approach to treatment.  Rather, it is the responsibility of the treating physician 
to manage graft failure according to their institutional best practices. 
6.14. 
Investigational Agents 
Unless approved by the Sponsor, investigational agents should not be administered from 
30 days prior to randomization until the end of study follow-up for all patients 
randomized. 
For patients enrolled in the post-randomization follow-up segment (see section 7.5) the 
Sponsor approval is not required.  
6.15. 
Other Medications  
Patients should receive full supportive care according to institutions’ practice patterns 
and clinical guidance as described above, including transfusions of blood and platelets, 
antibiotics, anti-emetics, or any other supportive care according to clinical judgment.  


 
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All concomitant medications and blood products administered, from time of signature on 
the IC until the end of the study, will be recorded in the source documents.  The reason 
for administration should be clearly stated and, as applicable, also documented as 
contributing to an SAE.  Concomitant medication reporting on the eCRF will follow the 
guidelines detailed in the Data Management Handbook.   
Rescue equipment (oxygen) and drugs such as hydrocortisone, epinephrine (other 
inotropic agents), and antihistamines should be available at the transplantation unit and 
will be administered at the investigator’s discretion. 


 
 
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Table 4: 
Evaluations and examinations flow sheet 
 
Schedule of Assessments Summary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Schedule of Assessments Summary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Schedule of Assessments Summary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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1   
_________________________________________________________________________________________________________________________
_______________________________________________   
2   Before signing informed consent and according to CBUs matching criteria as detailed in section 5.3 of the protocol.  After consent, the CBU documents for the CBU selected for expansion (treatment 
CBU #1) must be redacted and uploaded to ____________________ 
 prior to randomization.  
3    Signed consent is required prior to performing any protocol specific tests or procedures that are not part of the standard site practice. The ICF signature can be obtained earlier than _______ weeks 
prior to randomization. 
4    All eligibility criteria must be met prior to randomization.  Unless otherwise indicated, screening and eligibility testing must be performed and resulted within _______weeks prior to randomization. 
5 Infectious disease markers must include: HIV I/II Ab, HTLV I/II Ab, HBsAg, HBcAb, HCV Ab, VZV Ab, syphilis Ab (such as RPR), EBV Ab, and CMV screen (IgG or Total). 
6   Tests performed within 4 weeks prior to randomization are acceptable.  
7   Test results from within 9 weeks prior to randomization are acceptable. Chest X-ray is not mandatory if a chest CT or MRI was performed  
8 Verification typing (confirmatory typing) must be performed and resulted prior to CBU shipment to the Production site.  Extended high resolution typing at HLA -A, -B, -C, -DRB1 is also 
required for the patient and CBU#1 but (with the exception of -DRB1) can be performed after randomization unless anti-HLA antibody testing reveals a positive result (MFI>3000) at HLA A, 
B, C, or DRB1. If assigned to the control arm and treatment CBU #2 is selected, then HLA -A, -B, -C, -DRB1 high resolution typing is also required for treatment CBU #2; ABO and Rh 
typing is also required for the patient, CBU#1 and CBU#2 (if applicable) 
9 Baseline disease assessment should be as close as possible to randomization to minimize findings of relapse during CBU expansion.  Specific requirements for the timing of this assessment are provided 
in section 7.2.2 . ________________________________________________________________________     
10  Temperature, blood pressure and pulse at all visits; Weight through day 100 visit Respiratory rate through day 1 post-transplant. 
11  Including height, weight, and BSA. 
12 CBC performed at screening, daily from Day 0 until neutrophil engraftment, and at all study visits post transplant. Starting on transplant day, differentials required if WBC ≥0.5.  Blood chemistries 
must include (at a minimum): serum creatinine, total bilirubin, alkaline phosphatase, AST, ALT, and magnesium (at screening, day -1 (creatinine only), day 0 and then at least twice weekly until Day 
28, and weekly after Day 28 until 10 weeks post-transplant; at 100 days, 6 months, 9 months, and 1 year post-transplant). 
13   All concomitant medications and blood products administered, including total number of RBC and platelet units transfused, from time of signature on the IC until the end of the study, will be recorded 
in the source documents and the reason for administration should be clearly stated.  Concomitant medications will also be recorded in the e-CRF as detailed in the Data Management Handbook.   
14 Including standard of care cardiac and pulmonary monitoring 
15 On days 28, 70, 100, 180, and 365, site will perform a basic lymphocyte subset analysis (CD3, CD4, CD8, CD19, CD56/16) locally.  Additional assessments requested (but not required) are: CD123+ 
(dendritic lymphocytes), CD11c+ (dendritic myeloid cells), CD3+CD56+CD16+ (NKT cells), CD45RA+/CD62L+(RTE), CD25+/CD62L+(T-Reg), Total CD25+, CD57+/CD28+(CTL), HLA-
DR+(Activated), and quantitative immunoglobulins (In case quantitative immunoglobulins are assessed, a record of the most recent IVIG administrations is required).  
16 
_________________________________________________________________________________________________________________________
_____________________________________________________________________________ 
17 Measured by molecular methods, in whole blood or myeloid at day 21 or day 28 and at days 42, 100, 180, and 365.  Bone marrow chimerism is an acceptable alternative.   
18 Day 7 GvHD assessment must be done on day 7 post transplant. All the other Day 7 assessments can be done until day 10 post-transplant included 
19 All recipients must be tested for CMV (using the PCR method) at least once during the conditioning period (see section 6.11.6). 
20 Not required if patient no longer on immunosuppression 


 
 
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21 Beginning after the Day 100 visit, the site will continue at least monthly contact with the subject until day 365 visit.  If there is no hospital or clinic visit scheduled at the transplant center for 
more than 30 days, then a member of the study team will contact the subject via phone or email within 35 days from the last contact to inquire about adverse events, hospitalizations, 
infections, and medication changes (including transfusions).  This contact will be documented in the subject’s medical or research record.  
22 The patient survival and relapse status should be assessed at 15 months or later post-randomization 
23 Samples to be shipped to a central laboratory for analysis. See details in section 7.9.2 
24 Serum or urine beta HCG can be collected up to 4 weeks before randomization 
25  HRQoL not required if a survey is not available in the patient’s primary language.  Refer to protocol section 7.9.3 for details on HRQoL administration. 
26 Flow cytometry on BM or PB sample if judged necessary by the treating physician 
27 It is not mandatory to repeat molecular markers tests that were negative at diagnosis 
28  If positive: BM aspirate with morphology, cytogenetics and quantitative RT-PCR BCR/ABL 
29 Serum or urine beta HCG can be collected up to 2 weeks before randomization 


 
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Table 5: 
Follow-Up Assessments for Patients Who Do Not Receive a 
Transplant within 90 Days of Randomization 
Post Randomization Follow Up Forms Submission Schedule 
Forms 
Visit Days post Randomization 
090  
130  
210  
365  
457# 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
#   15-month assessment of survival and relapse must be on or after 15 months post randomization 
* HRQoL Questionnaires are requested if possible, but not mandatory 
 


 
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7. 
DETAILED STUDY PLAN 
7.1. 
Pre-screening activities search for matching CBUs 
Potential candidates for CBT for whom a search yielded eligible CBUs, as described 
below, will be identified as screen candidates for the study.  
Treatment CBU#1 
Patients must have a partially HLA-matched CBU: the unit must be HLA-matched at 4-
6/6 HLA class I (HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high resolution) 
loci with the patient.  There must be at least one allele match at DRB1. The CBU must 
have a pre-cryopreserved (post processing) total CD34+ cell count of _______ as well as 
a pre-cryopreserved (post processing) total nucleated cell count of _________ and total 
nucleated cell dose _________TNC/kg.  The CBU will have undergone volume reduction 
(both plasma and red blood cell depletion) prior to cryopreservation.     
Treatment CBU #2 (to be used for the control arm in case of double cord 
transplantation) 
• In case treatment CBU #1 is HLA-matched at 5-6/6 and contains a pre-
cryopreserved (post processing) total nucleated cell dose of _________TNC/kg, 
OR a pre-cryopreserved (post processing) CD34+ cell dose of _________CD34+ 
cells/kg, a second CBU must be added for the control arm, as a double CBT.  
• In case treatment CBU #1 is HLA-matched at 4/6 and contains a pre-
cryopreserved (post processing) total nucleated cell dose of _________TNC/kg, 
OR a pre-cryopreserved (post processing) CD34+ cell dose of _________ CD34+ 
cells/kg, a second CBU must be added for the control arm, as a double CBT. 
The determination of using a single or double cord in the control arm must be made by 
the investigator prior to randomization. 
Treatment CBU #2, if selected, must be HLA-matched at 4-6/6 HLA class I (HLA-A & 
HLA-B, low resolution) and II (HLA-DRB1, high resolution) loci with the patient. There 
must be at least one allele match at DRB1. Treatment CBUs #1 and #2 must have a 
combined pre-cryopreserved (post processing) total nucleated cell dose of ≥_____ 
TNC/kg. 
Backup CBUs  
Patients who will be starting conditioning prior to NiCord release for infusion must have 
an additional partially HLA-matched CBU reserved as a backup to the NiCord arm (in 
case of NiCord production failure). The backup CBU must be HLA-matched at 4-6/6 
HLA class I (HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high resolution) 
loci with the patient. A second back-up CBU is recommended to be added in the below 
cases: 
• If the back-up CBU is HLA-matched at 5 or 6/6 and contains a pre-cryopreserved 
(post processing) total nucleated cell dose of <______TNC/kg, OR a pre-
cryopreserved (post processing) CD34+ cell dose of <______ CD34+ cells/kg.   


 
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• If the back-up CBU is HLA-matched at 4/6 and contains a pre-cryopreserved 
(post processing) total nucleated cell dose of <______TNC/kg, OR a pre-
cryopreserved (post processing) CD34+ cell dose of <______ CD34+ cells/kg.  
In case of two back-up CBUs, the second back-up CBU must also be HLA-matched at 4-
6/6 HLA class I (HLA-A & HLA-B, low resolution) and II (HLA-DRB1, high resolution) 
loci with the patient. The back-up CBUs are recommended to have a combined pre-
cryopreserved (post processing) total nucleated cell dose of at least ______ TNC/kg. 
Treatment CBU #2 (to be used for the control arm in case of double cord transplantation) 
can be used also as a backup CBU for the NiCord arm, if it meets the above 
requirements. 
In case NiCord® fails to meet its required specifications, and patient conditioning has 
already started, the backup CBU/s or a different backup source of stem cells will be 
transplanted as detailed in section 8.3. 
It is strongly recommended to consider all necessary backup graft options for the patient 
in case of any other problems that may occur during graft procurement or preparation, 
taking into account the required urgency, as deemed necessary by the patient's condition. 
All CBUs should be procured from public banks that meet national applicable 
regulations. Donors are screened and tested in accordance with the relevant regulatory 
requirements. The CBU should be tested for the applicable infectious diseases and be 
eligible. In case the CBU is ineligible, with unusual findings or doesn't comply with the 
national regulations of the clinical site, the clinical site must fill out an Urgent Medical 
Need document signed by the investigator. This document will be sent to the Sponsor's 
study logistics manager (SLM) and filed in the patient's file. 
Once matching CBUs have been found, the patient will be required to sign a written 
informed consent for cord blood access as per Institutional and National requirements. 
The CBU documents of the CBU selected for expansion (treatment CBU #1) must be 
redacted and uploaded to ____________________  prior to randomization. If the search 
results contain more than one unit that meets the minimum cell dose and HLA match 
requirements for treatment CBU #1, it is recommended that all CBU documents for 
expansion eligible units be sent to the SLM – designating the investigator’s primary and 
secondary choices.  At the request of the investigator, the SLM can send the CBU 
documents to the study chairs for further discussion on the best available unit.     
7.2. 
Screening Assessments  
7.2.1. 
Informed Consent and Registration 
A conference will be held with the patient and family to discuss this study and alternative 
treatments available for the treatment of the underlying disease.  The conference will be 
conducted by the principal investigator or other designated qualified person (according to 
local regulations) who has been delegated to do so.  
Standard of care workup for transplant may be done prior to patient study consent.  Prior 
to performing any study activities/evaluations that are not part of the site’s routine 


 
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clinical practices, the patient must be thoroughly informed about all aspects of the study, 
including scheduled study visits and activities, and must sign the written informed 
consent. In particular, the timelines from randomization to transplant should be discussed, 
taking into account the period of 3 weeks for manufacturing on the research arm, as 
compared to standard timelines to transplant. Informed consent from the patient and/or 
his/her legal guardian will be obtained using a form approved by the Institutional Review 
Board or Ethics Committee of the institution enrolling the patient.  A signed copy of the 
written informed consent should be given to the patient and/or his/her legal guardian. 
Patients will be registered using the ____________________ system: Within three 
business days of consent, an authorized user at the transplant center enters the patient 
demographics and enrollment information in ____________________.  The Screening 
Enrollment Form includes a question confirming the patient (or legal guardian) signed the 
informed consent. Each patient will be assigned a study number by the 
____________________  system. 
Since the study is an open label study, Gamida Cell (GC) took upon themselves a level of 
blinding as appropriate measures to minimize bias. Therefore, the sites should not contact 
GC with any patient specific questions other than to the SLM concerning HLA typing 
and CBU selection. 
7.2.2. 
Eligibility and Baseline Assessments (_________weeks prior 
to randomization) 
Unless otherwise specified, eligibility and baseline assessments must be scheduled within 
(_________ weeks prior to randomization. Tests performed during the pre-screening 
period according to the Centers’ routine evaluation of candidates for stem cell 
transplantation need not be repeated, provided they were performed recently enough, as 
detailed below.  
Patient’s eligibility for the study will be assessed. The activities will be performed as 
detailed in Table 4  and will include:  
• Baseline evaluation: 
− Medical history including primary and concomitant diseases.  
− Primary disease characteristics including subtype, status, and cytogenetics 
− Concomitant medications will be recorded in the patient’s medical record. 
− Patients’ performance score by Karnofsky or Lansky scale  
− Health-Related Quality of Life patient self-report questionnaires (See 
section 7.9.3 for further details) 
− Physical examination and vital signs (including height, weight and BSA) 
− Laboratory: CBC 
− Blood chemistry (serum creatinine, total bilirubin, alkaline phosphatase, 
AST, ALT, and magnesium at a minimum)  


 
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− Serum or urine beta HCG (females) (tests from within 2 weeks prior to 
randomization are acceptable)  
− Complete urinalysis including microscopic examination 
− Anti-HLA antibody testing at HLA A, B, C, and DRB1 must be performed 
(tests from 4 weeks prior to randomization are acceptable) and donor 
cords with cross-reactive alleles (MFI>3000) at these loci must be 
avoided.  DQ and DP antibody testing is also recommended and donor 
cords with cross-reactive alleles at these two loci should also be avoided.   
− Chest X-ray (results from within 9 weeks prior to randomization are 
acceptable; A chest X-ray is not mandatory if a chest CT or MRI was 
performed).   
− Disease Assessment 
o Prior to Randomization:  
 For Lymphoma patients: CT scan or PET-CT chest, abdomen, 
pelvis (tests from within 9 weeks prior to randomization are 
acceptable) 
 Peripheral blood and bone marrow morphology. The bone 
marrow assessment for screening should generally be 
performed following recovery from prior chemotherapy, 
reflected by a neutrophil recovery of at least ANC>500. 
• For MDS and CML patients, aspiration is required. If 
the screening aspiration sample from a patient with 
MDS or CML is without evaluable spicules, then a 
bone marrow assessment must be performed with a 
biopsy to rule out the possibility of severe fibrosis 
Biopsy is also required at screening if at any point since 
diagnosis fibrosis was noted on a prior biopsy 
• For ALL, AML and other leukemia (not including 
MDS and CML) patients, an aspiration is sufficient (a 
biopsy is not mandatory).  
• For Lymphoma - when clinically indicated: aspiration 
and/or biopsy 
 To minimize findings of relapse during CBU expansion, bone 
marrow must be assessed within the following timelines 
(excursions up to seven days from the required window are 
acceptable in cases where randomization is delayed): 
• For the following patients, bone marrow morphology 
must be assessed within ___weeks prior to 
randomization:   
o MDS patients_____________________,  


 
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o CML patients ________________________ 
• For all other MDS and leukemia patients, bone marrow 
morphology must be assessed within (_________ 
weeks prior to randomization  
BM FACS analysis/flow cytometry for AML, ALL, and other 
leukemia (not including MDS and CML) patients. 
 Assessment of CNS disease is per institutional practice. 
___________________________________________________
___________________________________________________
___________________________________________________
___________________________________________________
_____________________ 
o Prior to Conditioning:  
 BM FACS analysis/flow cytometry for MDS and CML patients 
if sample available; - no need to repeat BM procedure. 
  Cytogenetics and molecular markers for MDS/Leukemia 
patients (it is not mandatory to repeat any molecular markers 
tests that were negative at diagnosis). 
− Serologic infectious disease markers for HIV I/II Ab, HTLV I/II Ab, 
HBsAg, HBcAb, HCV Ab, VZV Ab, Syphilis Ab (such as RPR), EBV 
Ab, and CMV Screen (IgG or Total) 
− Physiologic reserves assessment:  
o Pulmonary Function Tests 
_________________________________________________________
_________________________________________________________
_____________________________________________ 
o 12 lead EKG _________________________________ 
o Echocardiography or MUGA ______________________________ 
− (optional for patients who consented to the Immune reconstitution sub-
study: collect blood samples for T-cell receptor analysis see separate 
paragraph under section 7.9.2) 
• CBU requirements: 
− Treatment CBU #1 must be typed twice (i.e., initial typing and verification 
typing). Verification typing (confirmatory typing) should be performed in 
a lab that is ASHI/EFI accredited and must come from an attached 
segment; the results must be reported to the center before shipment to the 
production site 


 
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− Treatment CBU #1 must be reserved by the site prior to randomization and 
fully tested (all tests required for CBU eligibility including verification 
typing) before shipment to the production site. 
− Patient and CBU ABO and Rh typing 
− Extended typing of patient and CBUs HLA class I (A, B, and C) & II 
(DRB1) at high resolution.  Note that although the matching requirement 
per protocol only requires low resolution A and B matching, extended 
high resolution, DNA-based typing is required for loci A, B, and C, as 
well as DRB1.  DQ and DP typing is also recommended.  High resolution 
typing (with the exception of DRB1) does not need to be completed prior 
to randomization unless anti-HLA antibody testing reveals a potential 
donor-specific positive result (MFI>3000) at HLA A, B, C, or DRB1. 
− Peripheral blood baseline sample for chimerism (anytime during the 
screening period or post randomization prior to conditioning) 
 
Once all eligibility testing has been completed, an authorized user at the transplant center 
enters the patient eligibility information in ____________________ 
.   
The investigator (or designee) must document in the source documents and in 
____________________  the following information: 
• Disease characteristics including subtype, status, and cytogenetics  
• Screening results from flow cytometry test for minimal residual disease (ALL, 
AML, and other leukemia (not including MDS and CML) patients only) 
• The primary unit to be used for either expansion or as the unmanipulated 
CBU.   
• Intended use of single or double cord in the event the patient is randomized to 
the unmanipulated CBU arm 
o If the investigator chooses to perform a double cord transplant in the 
event of randomization to the unmanipulated CBU arm, then the 
additional unit should also be identified and CBU documents uploaded 
to ____________________ . 
• Confirmation of back-up CBU(s) reservation, if applicable 
• Intended conditioning regimen (regimen A1, regimen A2, or regimen B) and 
GvHD prophylaxis (cyclosporine or tacrolimus). 
The decisions to use single or double cord for the unmanipulated CBU arm, the 
conditioning regimen and the GvHD prophylaxis are binding and cannot be modified 
according to the treatment allocation. 
Unless otherwise noted, all above mentioned activities must be completed, and entered 
into ____________________  prior to randomization.  


 
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7.3. 
Randomization 
Before randomization, the PI or physician designee must confirm that the patient is 
eligible to randomize per protocol requirements, by signing off the eligibility checklist or 
documenting the patient eligibility in the patient’s medical records.  
When all eligibility information is entered, the PI (or designee) signs the confirmation of 
eligibility in ____________________ 
, which confirms that all eligibility information 
entered is accurate and complete, and the patient is eligible to randomize per protocol 
requirements. Then, the system generates the treatment assignment for the registered 
patient and an email confirmation is sent; this assignment page or email confirmation 
must be printed and saved in the Patient Study Binder. The treatment assignment is 
immediately displayed to the individual entering the information and an email is 
immediately sent to the site, the Sponsor and Emmes. 
7.4. 
CBU shipment and receipt 
7.4.1. 
NiCord® arm – CBU shipment and receipt at the production 
site 
Following randomization to the NiCord® arm, SLM review of all CBU documentation 
uploaded into ____________________  and SLM approval of the Treatment CBU#1 for 
production, the clinical site will immediately discuss shipment and production timelines 
with the SLM, and alert the CBB/Registry to immediately send the selected CBU for 
NiCord® expansion to the production site. The limit for CBU arrival to the production 
site is two working days before the start of production. Qualified personnel at the 
production site will ensure that this is the requested CBU to be manipulated for the 
patient according to communication with the SLM and based on the CBU accompanying 
documentation (according to the relevant Manufacturer's SOP). 
7.4.2. 
NiCord® arm – post production release and shipping  
Upon completion of the manufacturing process, final Quality Control tests of NiCord® 
CF, NF and infusion solution are initiated (according to the relevant Manufacturer's 
SOP), and NiCord® is labeled according to the relevant Manufacturer's SOP. The results 
of the Quality Control tests should meet predefined specifications.  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________ 
NiCord® CF, NiCord® NF with all available CBU segments/samples, and the infusion 
solution are either shipped immediately following manufacturing or stored at the 
manufacturing facility until they are shipped to the clinical site.  
NiCord® CF and NF will be shipped cryopreserved under quarantine status in a 
cryoshipper equipped with a calibrated data logger.  


 
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The infusion solution, used to thaw and dilute the CF and the NF, will be shipped in a 
dedicated 2-8°C shipping container equipped with a calibrated data logger in parallel to 
the shipment of the NiCord® CF and NF.  
The shipment of NiCord® will be controlled by the Sponsor in order to assure that 
shipment conditions were maintained as described in the Sponsor’s procedures. The 
checks performed will be documented in a special form according to the relevant 
Manufacturer's SOP. When a shipment is received, the consignee will acknowledge 
receipt.  
Upon arrival at clinical sites or local CBBs, NiCord® CF and NF should be kept in a 
controlled Liquid Nitrogen central storage (≤ -150°C) and the Infusion solution bags 
should be kept in a 2-8°C refrigerator until transplantation.  
7.4.3. 
Unmanipulated CBU arm – CBU shipment and receipt at 
the clinical site 
Following randomization to the Unmanipulated CBU arm, the clinical site will alert the 
CBB(s) to send the selected CBU(s) to their site.  Receipt and storage of the CBU(s) will 
be according to site standard practice. 
7.5. 
Post Randomization Follow-Up  
In the event of a failure to transplant the patient (with any stem cell source) within 90 
days post randomization, the following assessments are required at (±21) 90, 130, 210, 
and 365 days post randomization: 
• Survival status  
• Infection history (Grade 2 & 3 infections through Day 130 and Grade 3 viral 
infections through Day 365) 
• Relapse history  
• Optional (whenever possible): Health-Related QoL patient self-report 
questionnaires (See section 7.9.3 for further details) 
• Disease assessment for patients who did not relapse after randomization, 
including the following as clinically indicated.  
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_______________________________________________________________
_____________________________________________ 
CML patients: 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________


 
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__________________________________________________________________
__________________ 
Lymphoma patients: 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________ 
In addition, the patient survival and relapse status should be assessed at 15 months or 
later post-randomization. 
7.6. 
Transplant Suitability Confirmation: (within 24 hours prior to 
start of conditioning)  
Confirm that the patient is still suitable for transplant according to standard site practice.  
The primary investigator, or designee, must sign a statement within 24 hours prior to the 
start of conditioning indicating that the patient remains suitable for transplant.  Patients 
no longer suitable for transplant will be treated according to investigator’s discretion and 
will be followed for one year post randomization, as per section 7.5.   
History of grade 2/3 infections from randomization to the start of conditioning will be 
assessed and recorded in the study CRF. 
Additional viral screening is suggested prior to administration of the conditioning 
regimen to confirm absence of infection.  At the investigator’s discretion, patients with 
fever or suspected minor infection should await resolution of symptoms before starting 
the conditioning regimen.  
7.7. 
Myeloablative Conditioning  
The conditioning regimen will be administered as detailed in section 6.3.  GvHD 
prophylaxis will be administered as detailed in section 6.4.  Safety monitoring as detailed 
in section 9 will be performed.  Patient monitoring during the conditioning phase will be 
conducted per site practice with a mandatory assessment at day -1 (assessments from as 
early as day -3 are acceptable) to include: 
• Physical examination 
• Vital signs 
• CBC and blood chemistry (serum creatinine at a minimum) 
• All recipients must be tested for CMV (using the PCR method) at least once 
during the conditioning period (see section 6.11.6) 
• Documentation of historical and concomitant medications 


 
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7.8. 
Transplantation Day (Day 0) 
Safety Assessment  
Prior to the transplantation of NiCord® or the unmanipulated CBU(s), the patient will be 
evaluated by the investigator or designee including: 
• Physical Examination  
• CBC with WBC differential (differential not required if WBC<0.5) and blood 
chemistry (serum creatinine, total bilirubin, alkaline phosphatase, AST, ALT 
and magnesium, at a minimum). These lab tests should be resulted before the 
study product infusion. 
• Vital Signs: weight, temperature, blood pressure, pulse, and respiratory rate  
• Concomitant medication including RBC and platelet transfusions 
7.8.1. 
Preparation and Infusion of NiCord® or the Unmanipulated 
CBU(s) 
7.8.1.1. 
Preparation and Infusion of the Unmanipulated CBU(s)  
Patients assigned to the Unmanipulated CBU arm will receive a transplant of treatment 
CBU#1 (and treatment CBU #2 if applicable) according to institutional best practice.  
The unmanipulated CBU(s) should be thawed and diluted by trained personnel using 
institutional procedures. 
Post-thawing data: 
If the Unmanipulated CBU(s) has/have been tested for TNC count, Percent viability, 
Total CD34+ cell count, Total CD3+ cell count and Total number of colonies in product 
(CFU-GM + CFU-GEMM + BFU-E), this should be reported into 
____________________ . 
The unmanipulated CBU(s) should not be irradiated under any circumstances.   
Pre-medication prior to cord blood infusion should be administered according to 
section 6.7 (hydration should be administered per institutional procedure). The 
immediate pre-transplant evaluation will be carried out according to the operating 
procedures of the participating institutions and should be in keeping with the data 
reporting requirements of this study.  
The unmanipulated CBU(s) should be infused via the patient's central venous catheter as 
per site practice. It is recommended that the infusion should target a rate of 5 cc/kg/hr 
with a maximal rate of 10 cc/kg/hr. The unmanipulated CBU(s) should be infused as soon 
as possible after thaw. If the patient develops chest tightness or other symptoms, a brief 
rest (1-2 minutes) may be required before proceeding with the remainder of the infusion.  
A physician or physician extender (NP or PA) must be present on the patient care unit 
during the infusions and for 1 hour afterwards. Rescue equipment (oxygen) and drugs 
such as hydrocortisone, epinephrine and Diphenhydramine, should be available at the 


 
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bedside for emergency use if infusion reactions occur. Furosemide (0.5-1.0 mg/kg/dose) 
may be given if volume overload or decreased urine output occurs. 
7.8.1.2. 
Thawing and Infusion of NiCord® on Day 0 
NiCord® should not be irradiated under any circumstances.   
In case stored at a local CBB until the transplant day, NiCord® will be shipped on the 
transplant day to the clinical site in a cryoshipper and the infusion solutions will be 
shipped in a 2-8°C container, both equipped with a data logger, accompanied by the 
relevant Manufacturer’s Form.  
Prior to its infusion, NiCord® must be identified at the Clinical Site according to the 
relevant Manufacturer's SOP and Form.  The Clinical Site should check the product 
labels as well as the CoAs and QP release certificate for infusion, when applicable, and 
will make sure that all NiCord® fractions and the Infusion Solutions were shipped in 
appropriate conditions, their specifications met and are within their shelf life time.  The 
Drug Accountability form must be completed and signed/dated to document this review. 
Thawing and dilution of the NiCord® CF and NiCord® NF by the clinical site's personnel 
will be performed according to the relevant Manufacturer's SOP immediately prior to its 
infusion.  
The final volume of NiCord® CF after thawing and reconstitution is ___ml. 
The final volume of NiCord® NF after thawing and reconstitution is ___ml. 
Pre-medication prior to cord blood infusion should be administered according to 
section 6.7 (hydration should be administered per institutional procedure). The 
immediate pre-transplant evaluation will be carried out according to the operating 
procedures of the participating institutions and should be in keeping with the data 
reporting requirements of this study.  
NiCord® CF will be infused first, followed immediately ____________by the infusion of 
NiCord® NF.  
NiCord® CF and NiCord® NF should be infused via the patient's central venous catheter 
as per site practice. NiCord is intended to be given by gravity without additional support 
taking into account the overall time of infusion and the minimal infusion time according 
to the endotoxin limit. Infusion of NiCord® CF and NiCord® NF should target a rate of 5 
cc/kg/hr with a maximal rate of 10 cc/kg/hr. NiCord® CF and NiCord® NF should be 
infused as soon as possible after thaw.  
• Total duration of NiCord® CF infusion will target _____________________ 
from end of thaw to end of infusion, while considering the minimal infusion 
time specified in the product's CoA.  
• Total duration of NiCord® NF infusion will not exceed ______from end of 
thaw to end of infusion, while considering the minimal infusion time specified 
in the product's CoA.  


 
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The minimal infusion time is calculated based on the actual endotoxin test result and the 
endotoxin limit of 5 EU/Kg weight/60 minutes. 
If the patient develops chest tightness or other symptoms, a brief rest (1-2 minutes) may 
be required before proceeding with the remainder of the infusion.  
A physician or physician extender (NP or PA) must be present on the patient care unit 
during the infusions and for 1 hour afterwards. Rescue equipment (oxygen) and drugs 
such as hydrocortisone, epinephrine and diphenhydramine, should be available at the 
bedside for emergency use if infusion reactions occur. Furosemide (0.5-1.0 mg/kg/dose) 
may be given if volume overload or decreased urine output occurs.  
7.8.2. 
Evaluation and Treatment of IPQC/FPQC Safety Tests 
Failure 
The following safety quality control test results may not be available at the time the 
patient is transplanted: 
________________________________________________________________________
________________________________________________________________________ 
In the event that one of these tests proves positive, the transplant site will be notified and 
the following steps will be implemented:  
1. Blood cultures will be drawn 
2. Antibiotic coverage will be modified such that the known isolate will be 
adequately covered  
3. Antibiotic coverage will be discontinued if blood cultures prove negative and 
antibiotic cessation is clinically indicated 
The transplant site will get a final CoA containing all test results. 
7.8.3. 
Post Transplantation Follow-Up (_______________)  
The following assessments are mandatory: 
• Vital signs: weight, temperature, blood pressure, pulse, and respiratory rate 
• Toxicity assessment 24 hours post transplant.  
o For the NiCord® arm: from the start of NiCord® CF infusion up to 24 
hours after end of NiCord® NF infusion.  
o For the Control arm: from the start of the unmanipulated CBU infusion 
up to 24 hours after the end of the infusion (or end of CBU#2 infusion, 
if applicable)  
• G-CSF administered as specified in section 6.8 


 
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7.9. 
Scheduled treatment visits Post Transplant (as detailed in 
Table 4: Evaluations and examinations flow sheet) 
7.9.1. 
Scheduled Daily Assessments Post Transplant up to ANC 
Engraftment or Primary Graft Failure 
The following assessments are mandatory: 
• AEs and concomitant medications including RBC and platelet transfusions 
• Vital Signs – Weight, temperature, blood pressure and pulse; additional 
measurements per institutional practice 
• CBC with WBC differential (differential not required if WBC<0.5)  
• Infection prophylaxis and surveillance as specified in section 6.11  
• G-CSF administered as specified in section 6.8  
• GvHD prophylaxis as specified in section 6.4  
7.9.2. 
 Scheduled Visits Post Transplant on days 
___________________________________________________
___________________________________________________
__________________ 
__________________visit: All the assessments can be done until Day _______post-
transplant included, except for the acute GvHD assessment that must be performed at 
Day____________) 
The following assessments are mandatory: 
• Information about AEs, hospitalizations, infections, and concomitant 
medications (including RBC and platelet transfusions) will be recorded in the 
patient’s medical record. Concomitant medications will also be recorded in 
the eCRF as detailed in the Data Management Handbook. 
• Health-Related Quality of Life self-report questionnaires 
(days______________________________) (See section 7.9.3 for further 
details) 
• Vital signs: 
o Temperature, blood pressure and pulse at each scheduled post-
transplant visit 
o Weight at each scheduled post transplant visit through day 100 
(Additional measurements per institutional practice) 
• Physical examination: days______________________________ including 
standard of care cardiac and pulmonary monitoring 
• Patients’ performance score by Karnofsky or Lansky scale: _____________ 


 
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• CBC with WBC differential (differential not required if WBC<0.5)  
• Blood chemistry (serum creatinine, total bilirubin, alkaline phosphatase, AST, 
ALT and magnesium, at a minimum) - at least twice weekly until Day_____, 
and weekly after Day ___ until 10 weeks post-transplant; at days 
______________________________ post-transplant 
• Disease assessment: 
Disease assessment must be done on days ________________________ post 
transplant as follows.  Further tests as clinically indicated should be performed 
to assess for disease relapse on days_____________________.  Additional 
assessments may be performed according to the treating physician’s best 
judgment.  
o Leukemia and MDS patients: 
• Clinical evaluation for relapse per physician’s judgement 
(Days________________________) 
• CBC with differential (Days_________) 
• Bone marrow morphology (Days _________) 
• Flow cytometry on BM or PB sample if judged necessary by the 
treating physician (Days____________) 
• Cytogenetics and molecular markers as appropriate; It is not 
mandatory to repeat molecular makers tests that were negative at 
diagnosis (Days____________) 
o CML patients: 
• Clinical evaluation for relapse per physician’s judgement 
(Days_____________________) 
• Quantitative RT-PCR BCR/ABL in peripheral blood. If positive, 
BM morphology, cytogenetics, and quantitative RT-PCR 
BCR/ABL (Days__________________) 
o Lymphoma patients: 
• Clinical evaluation for relapse per physician’s judgement 
(Days__________________) 
• CT scan or PET-CT (Days____________) 
• When clinically indicated: BM morphology (Day___) 
• CMV PCR: at the weekly protocol specified visits __________________and 
then on day _________and day ___or more frequently as clinically indicated. 
• EBV PCR: at protocol specified visits  _________ (or more frequently as 
clinically indicated) and at days __________________ (if patient is on 
immunosuppression).    


 
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• HHV6 DNA assessment by PCR at each weekly protocol specified visit after 
transplantation until ANC >500 or until visit at day ______.   
• Peripheral blood collection for whole blood or myeloid donor/host chimerism 
(at day ___________________________and at days __________________ 
only).  Bone marrow chimerism is an acceptable alternative to peripheral 
blood.    
• Lymphocyte subsets (CD3, CD4, CD8, CD19, CD56/16) on 
days_____________________________________________.  
o Additional assessments requested (but not required) are: CD123+ 
(dendritic lymphocytes), CD11c+ (dendritic myeloid cells), 
CD3+CD56+CD16+ (NKT cells), CD45RA+/CD62L+(RTE), 
CD25+/CD62L+(T-Reg), Total CD25+, CD57+/CD28+(CTL), HLA-
DR+(Activated), and quantitative immunoglobulins (in case 
quantitative immunoglobulins are assessed, a record of the most recent 
IVIG administrations is required).  
• GvHD assessment:  
o Acute: At every visit up to day 180 post transplant, or more frequently 
as clinically indicated, Acute GvHD will be assessed according to the 
Consensus Conference on Acute GvHD grading (Appendix B).  Day 
_________ GvHD assessment must be done on day _________. 
o Chronic: on the day of diagnosis, as well as on days 
____________________________________post transplant or more 
frequently as clinically indicated. Chronic GvHD will be assessed and 
classified mild, moderate, or severe, according to the 2014 National 
Institute of Health consensus grading criteria (Appendix B).  
A record of the organ specific scoring must be kept on file at the 
clinical center.  See cGvHD scoring worksheet in the Data 
Management Handbook; Unless approved by the sponsor, either the 
provided worksheet or an equivalent EMR adaptation of the form 
approved by the sponsor must be used to document chronic GvHD. 
• GvHD prophylaxis as specified in section 6.4  
• G-CSF administered as specified in section 6.8  
• Infection prophylaxis as specified in section 6.11  
• Beginning after the Day 100 visit, the site will continue at least monthly 
contact with the subject until the day _________visit.  If there is no hospital 
or clinic visit scheduled at the transplant center for more than 30 days, then a 
member of the study team will contact the subject via phone or email within 
35 days from the last contact to inquire about adverse events, hospitalizations, 
infections, and medication changes (including transfusions).  This contact will 
be documented in the subject’s medical or research record. 


 
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• The patient survival and relapse status should be assessed at 15 months or 
later post-randomization. 
Optional supplemental immune reconstitution sub-study 
An optional supplemental immune reconstitution sub-study will explore immune 
biomarkers potentially predicting clinical outcomes such as relapse, engraftment 
and viral reactivation/disease. Blood samples for exploratory research of immune 
reconstitution will be collected from the patients who consent to this sub-study for 
immunophenotyping and MultiPlex analyses (on days 
__________________________________________________________________
______ visits) as well as for T cell receptor analysis (at screening and on days 
__________________visits). These samples will be sent to a central laboratory 
for analysis as detailed in a separate research study plan.  
7.9.3. 
Administration of Health-Related Quality of Life Measures 
The self-report questionnaires and patient declaration page will be completed prior to 
randomization and subsequently at ___________________________days from 
transplantation or until death or discontinuation from the study. For patients who were 
not transplanted within 90 days post randomization, or for those who relapsed or had 
graft failure, the completion of these questionnaires is requested if possible, but not 
mandatory; the FACT-BMT can be completed from home via a computer if needed (the 
URL will be provided by the site). Surveys are completed by participants using self-
completed instruments made available during routine scheduled clinic visits. The method 
of survey completion, the date, and the language will be recorded in the database. 
Surveys may not be completed by surrogates. It is recommended to complete the surveys 
prior to any other physical testing required at the visit. 
Only patients able to read and speak one of the languages available in the developer-
approved translations are eligible to participate in the HQL component of this trial. 
Likewise, if the paper version of the EQ-5D questionnaire is not available in the 
developer-approved translation at the patient’s transplant center, and the self-completed 
instrument cannot be made available, the patient will not be required to complete these 
questionnaires.  
 
 


 
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Table 6: 
Required Patient-reported Outcomes Data Collectiona 
Instrument 
 
 
 
 
 
 
FACT-BMT 
 
 
 
 
 
 
EQ-5D 
 
 
 
 
 
 
TOTAL  
 
 
 
 
 
 
ANTICIPATED 
TIME 
 
25-30 min 
25-30 min 
25-30 min 
25-30 min 
25-30 min 
a For patients who were not transplanted within _________days post randomization these assessments are 
requested (but not required) at __________________days post randomization. The completion of the 
questionnaires is also requested, but not mandatory for the following:  1) after relapse post transplant 2) 
after the _________questionnaire for patients who did not have primary engraftment, 3) after secondary 
graft failure. 
* For patients <18 years old, number of items = 43  
7.9.4. 
Assessment of Medical Resource Utilization (MRU) 
MRU will be captured throughout the study by recording units of medical resources 
consumed during the trial period on study case report forms to examine potential 
differences between treatment groups in drivers of MRU that are not driven by protocol.  
The types of MRU data that will be recorded include hospital resources (hospitalizations 
by setting), specialty procedures, drugs and supportive care, and complications. 
7.9.5. 
Evaluation and Treatment of Graft Failure 
Evaluation of Graft Failure: Should a patient suffer primary or secondary graft failure, an 
attempt will be made to determine the cause of failure. Evaluation will include: 
• Bone marrow aspiration/biopsy for morphologic analysis as well as 
cytogenetics;  
• Chimerism studies;  
• Viral/bacterial cultures including serology and PCR analysis for Herpes 
viruses (including fun and HHV6); and  
• Anti-HLA antibody measurements.   
For primary graft failure, the assessments listed above are recommended on day 21 if 
WBC is <= 0.1 x109/L. 
Treatment of Graft Failure: If the patient has less than 100 PMN at day +28 and most 
recent BM shows decreased marrow cellularity and paucity of donor cells (less than 20%) 
by chimerism analysis the patient will be treated at the discretion of the treating 
physician. 
In patients experiencing delayed engraftment, serologic assessment of HHV6 and CMV 
will be performed. 


 
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7.9.6. 
Early Withdrawal from Follow-up  
Reasons for withdrawal of the patient prior to end of study must be stated in the CRF and 
in the site source documentation for all study patients who were enrolled in the study. 
This includes patients who were screened and assigned a screening number but were not 
randomized. Patients will be defined as screening failures when withdrawn from the 
study before randomization. Reason for screening failures will be outlined in the study 
reports. 
Patients who were randomized but do not receive a stem cell transplant within 90 days 
post randomization are part of the intent to treat analysis and should be followed for 
Grade 2 and 3 infections, survival status, relapse, and HQL at 
___________________________days post randomization with an additional assessment 
of survival and relapse status at 15 months post randomization, according to section 7.5.  
All other assessments are not required for these patients unless they receive a stem cell 
transplant within 90 days post randomization, at which point they would be followed 
according to section 7.9.  For early withdrawal patients who withdraw or are withdrawn 
from the study post transplant, any assessments due at the time of withdrawal (according 
to Table 4) are requested.                                           
Patients who experience graft failure or relapse post transplant will continue to be 
followed according to the study visit schedule for hospitalizations, grade 2 and 3 
infections, relapse (except patients with prior post-transplant relapse), graft failure 
(except patients with prior post-transplant graft failure), survival status, and HQL.  For 
these patients, all SAEs will be reported until at least 30 days post transplant.  After day 
30 post transplant and following date of relapse or graft failure only SAEs resulting in 
death or with suspected causal relationship to the infused product will be reported.  No 
other study related assessments are required for these subjects after the date of graft 
failure or relapse.   
7.9.7. 
Criteria for Early Withdrawal 
Patients who are prematurely discontinued or withdrawn from the study should be 
followed and treated by the investigator according to institutional guidelines. Patients 
who join the study will be asked for permission that their clinical investigator be allowed 
to transmit information to the trial center on the clinical outcomes as assessed during the 
usual clinical management of their disease over the study period. This will allow us to 
continue to gather clinical information on patients who subsequently discontinue active 
participation and did not withdraw informed consent, and to include them in the analyses 
of all clinical endpoints.  
A patient may withdraw or be withdrawn from the study for the following reasons: 
• Patient withdrew consent 
• Sponsor requested patient to be withdrawn 
• Request of primary care physician or investigator 


 
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7.10. 
Optional Long term follow-up  
For patients enrolled in the optional long term follow-up sub-study, information on the 
following, performed as per the standard of care at individual institutions, will be 
collected: 
• Vital signs and physical examination 
• Donor/host chimerism and secondary graft failure 
• Lab analysis: CBC and Immunophenotyping (lymphocytes subsets and 
additional Immunophenotyping as per site practice) 
• Karnofsky/Lansky performance status score 
• GvHD assessment 
• Survival and disease status (progression/relapse, new malignancy, non-relapse 
mortality, primary and contributing cause of death) 
Data may be obtained by review of medical records from the transplant center, through 
the patient’s primary care physician, and/or contact by phone at the time points 2 years, 3 
years, 4 years and 5 years post-transplantation. 
7.11. 
Data reporting 
7.11.1. 
Criteria for Forms Submission 
Criteria for timeliness of submission for all study forms are detailed in the Data 
Management Handbook and ____________________  User’s Guide.  Forms not 
entered into ____________________ within the specified time will be considered 
delinquent.  A missing form will continue to be requested either until the form is entered 
into ____________________  and integrated into the Data Coordinating Center’s (DCC) 
master database or until a form exception is granted and entered into the missing form 
exception file, as detailed in the Data Management Handbook. Adverse Events will be 
reported as outlined in section 9 of this protocol. 


 
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8. 
STUDY MEDICATION 
8.1. 
Description 
8.1.1. 
NiCord® 
NiCord® is a cryopreserved cell-based product of allogeneic, ex vivo expanded, umbilical 
cord blood-derived, hematopoietic CD34+ progenitor cells (NiCord® CF) and the non-
expanded cell fraction of the same cord blood unit (NiCord® NF) consisting of mature 
myeloid and lymphoid cells. See further details on the cell expansion process in section 
3.4. 
Briefly, production of NiCord® involves ex vivo culture of purified CD133+ cells derived 
from a single CBU for 21 (±2) days in the presence of the cytokines 
_____________________________________________.  
On day 21 (±2) the cells are washed twice and cryopreserved in CryoStor®CS10. On the 
day of transplantation, the cells are thawed and reconstituted by a 1:5 dilution with the 
infusion solution. Harvest can be carried out from day 19 and up to day 23 if the patient’s 
clinical condition or logistical considerations require an earlier transplantation date or a 
delay. 
8.2. 
CBU Supply  
All CBUs should be procured from public banks that meet national applicable 
regulations. If the optimal unit(s) for the patient was determined ineligible or with 
unusual findings (e.g., incomplete) as per local regulations, the unit may be used under 
the urgent medical need provision and in consultation with the Sponsor.  
8.3. 
Manufacturing  
NiCord® CF, NF and infusion solution manufacturing will be performed by central 
manufacturing sites that have been trained and qualified by the Sponsor according to the 
Sponsor's SOPs  
NiCord® is manufactured in a production site, inside a laminar flow hood (class 100, ISO 
5) within a room that has been qualified as a Class 10,000 (ISO 7), in compliance with 
the production instructions and procedures as provided by the Sponsor. 
Quality control (QC) tests are performed throughout the course of the manufacturing and 
on the final product and their results are documented. The testing includes in-process 
quality controls (IPQC) and final process quality controls (FPQC) performed according 
to the relevant Manufacturer's SOP. The IPQC and FPQC tests are performed according 
to written analytical methods either by QC employees or by trained outsourcing testing 
labs.  
IPQC samples from NiCord® are taken at different identified stages during the process.  
FPQC samples from NiCord® NF are taken prior to cryopreservation on day 0 of 
production.  FPQC samples from NiCord® CF are taken prior to cryopreservation on the 


 
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harvest day. FPQC samples from infusion solution are taken at the end of the 
manufacturing day. 
FPQC tests include both bioassays (_________________________) and safety 
tests(________________________________________________). 
All safety and some of the IPQC and FPQC bioassay tests have specifications and the 
results should be within the provided specifications. Some of the IPQC and FPQC 
bioassays do not have specifications and results are only collected and documented. 
The results of the final process quality control tests for NiCord®  and the infusion solution 
will be provided  by Gamida Cell in the certificate of analysis sent for each batch of 
product 
Upon the release of NiCord® CF, some of the quality control tests results may not be 
available. Hence, two certificates of analysis will be issued for each clinical batch 
according to the relevant Manufacturer's SOP - a preliminary certificate and a final 
certificate.  
NiCord® NF will be released with a final CoA specifying quality control test results.   
The infusion solutions, used to thaw and dilute the NiCord® CF and NF, will be released 
with a final CoA specifying quality control test results. 
8.3.1. 
Out of Specification Results  
In a case an Out of Specification (OOS) result is found, a deviation report will be filled 
out, an investigation will be conducted and completed in a timely manner and any 
corrective action suggested will be implemented promptly to avoid recurrence of the 
incident.  
_____________________________________________________ 
If the result is confirmed, the clinical site as well as the site CRA, the QP when 
applicable and the Sponsor are notified immediately. The Sponsor will report to the local 
regulatory entity as required. 
8.3.1.1. 
NiCord® CF OOS 
• IPQC OOS:   
If NiCord® CF does not meet the specification of one of the quality control tests and the 
test result is confirmed by investigation, results are reported to the clinical site and 
production is stopped. In case no further investigation on the product is required both 
fractions (NiCord® CF and NiCord® NF) will be discarded by the production site, and 
will not be transplanted under any circumstances. A backup graft will be transplanted if 
patient conditioning has already started. Otherwise, a replacement CBU can be 
considered for NiCord production. 
• FPQC OOS: 
− ____________________________________________________________
____________________________________________________________


 
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____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
____________________________________________________________
_____________________________________ 
− If the OOS result is either CF sterility and/or mycoplasma FPQC test, the 
microorganism is identified, and the clinical site is notified. In the event of 
an OOS result in the CF obtained after transplantation, the following steps 
will be implemented by the investigator:  
o Blood cultures will be drawn 
o Antibiotic coverage will be modified such that the known isolate will 
be adequately covered 
o Antibiotic coverage will be discontinued if blood cultures prove 
negative and antibiotic cessation is clinically indicated 
8.3.1.2. 
NiCord® NF OOS 
If NiCord® NF does not meet the specifications of one of the quality control tests, and the 
test result is confirmed by investigation, it will be discarded at the production site prior to 
its shipment and will not be transplanted under any circumstances. In such an event, the 
production of the NiCord® CF will be stopped and the investigator will immediately be 
informed.  
A backup graft will be transplanted if patient conditioning has already started. Otherwise, 
a replacement CBU can be considered for NiCord production. 
8.4. 
Handling of NiCord®  
Labeling of NiCord® CF, NiCord® NF and the infusion solutions will be performed 
according to the relevant Manufacturer's SOP. 
Packaging of NiCord® CF, NiCord® NF and the infusion solutions will be performed 
according to the Sponsor’s procedures. 
8.5. 
Shipment  
NiCord® CF and NF will be shipped to the clinical site/local CBB under quarantine status 
with all available CBU segments/samples in a cryoshipper equipped with a calibrated 
data logger and with all necessary documentations.  The infusion solutions for NiCord® 
CF and NF will be shipped to the clinical site/local CBB in parallel in a 2-8°C package 
equipped with a calibrated data logger.  


 
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The shipment of NiCord® will be controlled by the Sponsor in order to assure that 
shipment conditions were maintained as described in the Sponsor’s procedures. The 
checks performed will be documented in a special form according to the relevant 
Manufacturer's SOP. When a shipment is received, the consignee will acknowledge 
receipt.  
 


 
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9. 
SAFETY MONITORING 
9.1. 
Definitions 
9.1.1. 
Adverse Event (AE) 
Adverse event means any untoward medical occurrence associated with the use of the 
investigational product, whether or not considered related to the investigational product.  
Treatment-emergent AEs are any AEs that occur or worsen (i.e., increase in grade) during 
or after the infusion of the study product. 
9.1.2. 
Infusion Reaction 
Any adverse event that begins or worsens (i.e., increases in grade) between the start of 
the graft infusion and 24 hours after the end of the graft infusion.   
9.1.3. 
Serious Adverse Event (SAE) 
An adverse event or suspected adverse reaction (see section 9.1.4) is considered “serious” 
if, in the view of either the investigator or Sponsor, it results in one of the following 
outcomes:  
• Death  
• A life-threatening adverse event 
NOTE: An event is considered "life-threatening" if, in the view of either the 
investigator or Sponsor, its occurrence places the patient or subject at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death.  CTCAE 
grade four events are not automatically defined as life threatening for SAE 
determination.  ___________________________________________________. 
• Inpatient hospitalization or prolongation of existing hospitalization 
NOTE:  Complications that occur during hospitalization are AEs.  If a 
complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious.  Elective or previously scheduled hospitalizations for pre-existing 
conditions which have not worsened after initiation of treatment should not be 
classified as SAEs.  Any hospitalization regardless of duration will be considered 
serious unless the hospitalization was for social or convenience reasons during 
which no untoward medical occurrence occurred.  
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
NOTE:  This definition is not intended to include experiences of relatively minor 
medical significance, such as uncomplicated headache, nausea, vomiting, 
diarrhea, influenza, or accidental trauma (i.e., sprained ankle) that may interfere 
or prevent everyday life functions but do not constitute a substantial disruption.  
• A congenital anomaly/birth defect  


 
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Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.   
For this study, primary and secondary graft failure events should be reported as SAEs; 
Disease progression/relapse should be reported as an SAE. 
Serious adverse events require reporting (see section 9.2) within 24 hours of the study 
team’s knowledge of the event.  A detailed summary of the events above are required 
from the investigator within 2 working days of knowledge of the event. 
9.1.4. 
Suspected Adverse Reaction 
A suspected adverse reaction is considered as any adverse event for which there is a 
reasonable possibility that the study product caused the event.  “Reasonable possibility” 
means there is evidence to suggest a causal relationship between the study product and 
adverse event. 
The investigator must make the determination of relationship to the study product for 
each grade 3-5 AE and for any SAE.  Alternative causes, such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the study product, will be considered and investigated. The 
investigator will also consult the Clinical Investigator’s Brochure (IB) and/or Product 
Information for marketed products in the determination of his/her assessment. 
9.1.5. 
Causality 
The following question will be used when assessing causality of an adverse event to the 
study product:  Is there a reasonable possibility that the study product caused the event?   
An affirmative answer designates the event as a suspected adverse reaction.   
9.1.6. 
Expectedness 
Unexpected: An event is considered “unexpected” when it is not listed on the specified 
list of expected events in the IB or it is not listed at the specificity and severity that has 
been observed. It also refers to adverse events or suspected adverse reactions that are 
mentioned in the investigator’s brochure but are not specifically mentioned as occurring 
with the particular study product under investigation. 
The determination of the expectedness is the Sponsor’s responsibility. 
9.1.7. 
Toxicity Grading 
GvHD symptoms will be graded according to the Consensus Conference on Acute GvHD 
grading for acute GvHD60 and National Institute of Health consensus grading criteria for 
chronic GvHD (Appendix B). 
Infections will be graded according to the grading scale provided in Appendix G. 


 
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All other AEs will be graded using NCI’s Common Terminology Criteria for Adverse 
Events (CTCAE) Version 4.03.  The categories for grade 1 and 2 events will be 
combined such that events will be assigned a grade of either ‘1 or 2’, ‘3’, ‘4’, or ‘5’.   
An AE that is assessed as CTCAE grade three (often described as “severe”) should not be 
confused with an SAE.  Severity is a category used for rating the intensity of an event; 
both AEs and SAEs can be assessed as grades 1-4. An event is described as ‘serious’ 
when it fulfils one or more of the criteria described in section 9.1.3. 
9.1.8. 
Expedited Reporting 
The following events meet the criteria for expedited reporting and require reporting by 
the investigator or delegated study personnel (see section 9.2) within 24 hours of 
knowledge of the event (note that all SAEs require reporting within 24 hours of 
knowledge of the event, although not all SAEs will require expedited reporting to 
regulatory authorities).  
• All serious, unexpected, suspected adverse reactions (SUSARs) as defined in 
21 CFR312.32 and Directive 2001/20/EC 
The Sponsor is required to report SUSARs in the NiCord arm only to regulatory 
authorities within statutory deadlines. In these cases, for reporting purposes, the Sponsor 
is unblinded with respect to the treatment arm.   
A detailed summary of the events above are required from the investigator within 2 
working days of knowledge of the event.  The summary will include date of onset, peak 
grade, potential causes, resolution date (if applicable), past medical history, concomitant 
medications, an event narrative, and actions taken.  A discharge summary or hospital 
notes with supporting labs and radiologic reports should be attached as well.   
Other Adverse Events that do not meet the criteria for expedited reporting should be 
recorded in the database as outlined in Appendix C.  Clinical centers are expected to 
report AEs to their IRB/EC according to their own institutional guidelines. 
An expedited report will also be submitted if an aggregate analysis indicates that serious 
expected suspected adverse reactions are occurring more frequently or at a higher 
severity than what was previously expected. 
9.2. 
Observation, Detection and Recording of AEs and SAEs 
The investigator and/or study personnel will enquire about the occurrence of AEs at 
every visit, after the subject has had the opportunity to spontaneously mention any 
problems.  Because of their underlying disease and toxic preparative therapy, a wide 
range of adverse events is anticipated.   
All AEs will be recorded in the source documents with sufficient detail to allow for 
grading per CTCAE v4.03, and reported on the appropriate CRF page.  The majority of 
this section outlines requirements for patients who receive a transplant within 90 days of 
randomization (see also Table 12).  For patients who do not receive a transplant within 90 
days of randomization see Table 13 for an outline of safety reporting requirements.  
Below is a broad overview of data entry requirements:  


 
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• Treated grade 1 infections after the start of the conditioning regimen and all 
grade 2 or 3 infections post randomization will be reported on the Infection 
Summary form.   
• Graft versus Host Disease (GvHD) will be reported on GvHD forms.   
• Common events post transplant (which are summarized in Appendix D) will 
be reported on a Transplant Toxicity Summary form.  For these common 
events, the highest grade over a given interval will be recorded on a Toxicity 
form, with the exception of some GvHD symptoms which will be recorded on 
the GvHD forms.  
• Non-serious uncommon events post transplant will be reported on an Adverse 
Event Log. 
• Serious Adverse Events post signing of consent will be reported on SAE 
forms set until at least 30 days post transplant and then up until the earlier of 
end of patient’s final study visit, date of relapse, or date of graft failure. 
_______________________________________________________________
_______________________________________________________________
____________________________________________. 
• For patients who do not undergo transplant within 90 days following 
randomization and are enrolled in the post-randomization follow-up (section 
7.5): only SAEs resulting in death will be reported after Day 90.  
• Hospital Admission reporting is due from time of the start of the conditioning 
regimen until end of study; this is reported on the Hospital Admission 
Summary form. 
Common Events Post Transplant 
Common events post transplant are summarized in Appendix D  and will be reported on 
the Transplant Toxicity Summary form.  The intervals for reporting common events on 
the Toxicity form are: during conditioning up to UCBU/NiCord® transplant, during and 
24 hours post UCBU/NiCord® transplant, from 24 hours post UCBU/NiCord® transplant 
to day 7, then at weekly intervals up to day 42 post transplant.  For grade 3-5 events, any 
suspected relationship of the event to UCBU/NiCord® will also be collected on the 
Toxicity form. Common events that also meet SAE criteria will be reported on SAE 
summary forms at all times post transplant until the end of the study unless otherwise 
noted. 
Non-serious Uncommon Events Post Transplant 
Non-serious uncommon events occurring or worsening post transplant through day 42 
will be reported on an Adverse Event Log form.  Information to be collected on the 
Adverse Event Log form includes the name, dates of onset and resolution (if applicable), 
intensity, and causality of the event.   
After day 42 post transplant grade 1 and 2 non-serious adverse events will not be 
reported, with the exception of certain infections and symptoms of GvHD which will 
continue to be reported on their respective forms.  After day 42, all grade 3 and 4 non-


 
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serious events will be reported on the Adverse Event Log form, regardless of whether or 
not they are common events, with the exception of infections and symptoms of GvHD 
which will continue to be reported on their respective forms.   
Serious Adverse Events 
At all times after the signing of consent, SAEs, relapse and graft failure will be reported 
on SAE summary forms.  These events may require reporting on other forms as well 
(e.g., Death form when applicable), however they should not be reported on the Adverse 
Event Log form.  SAEs must be reported within 24hrs of the study team’s knowledge 
of the event.   
• Reporting should be done by completing and submitting a Serious Adverse Event 
Form in ____________________ . 
• If initial SAE reporting via ____________________ 
is not possible within 24 
hours then the site must send an email to _________________ including the 
patient study ID and a brief description of the event including the PI’s assessment 
of causality 
Where possible, a diagnosis rather than a list of symptoms should be recorded. The 
investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as 
the AE/SAE and not the individual signs/symptoms. If a diagnosis has not been made 
then each symptom should be listed individually. 
For transplanted patients, every SAE that occurs between the time of patient consent and 
the participant’s final study visit, the investigator is responsible for reviewing all 
documentation (e.g., hospital progress notes, laboratory test results, and diagnostic 
reports) relating to the event.  Except as noted above for some events that are post relapse 
or graft failure, the investigator or designee will then record all relevant information 
about an SAE onto the appropriate page of the CRF.  The investigator must review, sign, 
and date an SAE summary report form to confirm the accuracy of the recorded 
information.  The signed report will be maintained in the site’s study files.  It is not 
acceptable for the investigator to send photocopies of the subject’s medical records in 
lieu of completion of the appropriate CRF pages.  Unless otherwise requested, transfer of 
subjects’ medical records with the CRF should be restricted to hospital admission and 
progress notes, laboratory and radiology reports, discharge summaries and autopsy 
reports, if available.  When uploading medical records to ____________________ 
, all 
subject identifiers (i.e., name, date of birth, medical record number) must be obliterated 
prior to uploading the documents to ____________________. 
9.3. 
Follow-up of AEs and SAEs 
All reported AEs and SAEs will be followed and recorded until resolution with or 
without sequelae (the patient’s health has returned to baseline status or all variables have 
returned to normal), until the condition stabilizes (the investigator does not expect any 
further improvement or worsening of the event), until an outcome is reached or the event 
is otherwise explained, or until there is agreement between the investigator and Sponsor 


 
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that additional follow-up is not warranted. The investigator will ensure that follow-up 
includes any supplemental investigations as may be indicated to elucidate the nature 
and/or causality of the AE/SAE.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care 
professionals. Where appropriate, medical tests and examinations will be performed to 
document resolution of the event(s).  Additional follow-up information, if required, or 
available, must be reported in the same timelines as initial information.  New or updated 
information will be recorded on the originally completed CRF, with all changes to SAEs 
signed and dated by the investigator on a source document and maintained in the site’s 
study files. 
9.4. 
Medical Monitor Review 
Both the Emmes Medical Monitor (MM) and the Sponsor will be alerted via email at the 
time any serious adverse event is submitted to ____________________. 
The MM is responsible for initial review of these events within 1 business day of email 
notification.  The MM review will be documented in ____________________.  If the 
MM requires additional information to make an assessment, the transplant center will 
have 2 calendar days to respond to the request.  As noted above, most information is due 
within 2 working days of the site’s knowledge of the event.   
9.5. 
Clinical Laboratory Evaluations 
All laboratory measurements will be evaluated for abnormalities.  An abnormal 
laboratory value should be interpreted primarily in the context of the disease or the 
condition leading to it. The latter (instead of the laboratory abnormality itself) should be 
reported as the adverse event and graded, whenever possible. A laboratory adverse event 
(i.e., a laboratory abnormality not associated with any particular clinical findings (e.g., 
symptoms, signs)) will be reported when judged clinically significant by the investigator. 
An abnormal laboratory finding is not by itself considered to be an AE or SAE unless the 
investigator considers the abnormal finding to be of clinical significance.  The abnormal 
laboratory finding does not have to be associated with the use of NiCord® to be 
considered clinically significant.  If a laboratory adverse event is reported, it will be 
graded using the CTCAE toxicity grading scale version 4.03. A laboratory adverse event 
with a value falling within the specified CTCAE grade 4 boundaries will only be 
considered life-threatening from a regulatory perspective if it results in an actual life-
threatening consequence i.e., its occurrence places the subject at immediate risk of death. 
Grade 4 laboratory adverse events that are not life-threatening should not be reported as 
serious adverse events unless they meet other seriousness regulatory criteria. 
9.6. 
Pregnancy 
Pregnancy will not be considered an AE. Any report of pregnancy recorded for any 
female study participant, or a female partner of a male study participant should be 
reported immediately within 24 hours to the Sponsor. 


 
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The investigator will follow the pregnant woman until completion of the pregnancy and 
must notify the Sponsor of the outcome within 24 hours of the investigator’s knowledge 
of the pregnancy outcome.  This notification includes pregnancies resulting in live, 
“normal” births. 
If the pregnant subject experiences an SAE during pregnancy, or the outcome of the 
pregnancy meets the criteria for classification as an SAE, the investigator should follow 
the procedures for reporting SAEs (i.e., report the event to the Sponsor within 24 hours of 
the investigator’s knowledge of the event). 
All neonatal deaths and congenital anomalies that occur within 30 days of birth 
(regardless of causality) should be reported as SAEs to the Sponsor.  In addition, any 
infant death or congenital anomaly occurring after 8 weeks that the investigator suspects 
is related to the in utero exposure to the study drug should also be reported to the 
Sponsor. 
9.7. 
Patient Withdrawal from Study Procedures due to Adverse 
Events 
Any patient may be removed from the study at any time if in the judgment of the 
investigator further study procedures are not in the best interests of the patient. Patients 
may also withdraw themselves from the study at any time and for any reason.  
9.8. 
DMC Reporting 
In addition to the DMC reporting procedures outlined in section 10.2 of this protocol, any 
concerns regarding the type or frequency of an adverse event will be communicated to 
the DMC Chair by the Sponsor.  The DMC Chair will review the adverse event materials, 
determine if the information is complete, determine if additional DMC review is required 
and make recommendations to the Sponsor concerning continuation or modification of 
the study. 
9.9. 
Regulatory Authorities and IRB/ECs 
The Sponsor shall notify the concerned Regulatory Authorities of Suspected Unexpected 
Serious Adverse Reactions (SUSARs) for the IMP, or other AEs as per local 
requirements. In accordance with Directive 2001/20/EC and Chapter II of Volume 10 of 
the Rules Governing Medicinal Products in the European Community, the Sponsor will 
also report SUSARs to the EudraVigilance Clinical Trial Module (EVCTM).  
 The Sponsor is required to report SUSARs in the NiCord arm only to regulatory 
authorities within statutory deadlines. In these cases, for reporting purposes, the Sponsor 
is unblinded with respect to the treatment arm.   
The Sponsor is responsible for reporting all unexpected fatal or life-threatening suspected 
adverse reactions to regulatory authorities, as per the concerned authorities’ requirements 
no later than seven calendar days after knowledge of the event.  All other serious, 
unexpected, suspected adverse reactions will be reported to the regulatory authorities by 
the Sponsor within 15 calendar days of receipt of the information.   


 
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The Sponsor or designee shall notify the Ethics Committees (EC) of SUSARs or 
significant risks to subjects, per country requirements. 
The Sponsor or designee shall notify the investigator of potential serious risks from 
clinical trials or any other sources, including the following: 
• Suspected adverse reaction that is both serious and unexpected. 
• Any findings from other studies that suggest a significant risk in humans 
exposed to the drug. 
• Any finding from animal or in vitro testing that suggest a significant risk to 
humans exposed to the drug, such as mutagenicity, teratogenicity, or 
carcinogenicity; or report of significant organ toxicity at or near the expected 
human exposure. 
It is the responsibility of the Principal Investigator (PI) to notify the IRB/EC of all SAEs 
that occur at his or her site. Each site is also responsible for notifying their IRB/EC of 
additional safety reports or other safety concerns communicated by the Sponsor. The 
investigator must keep copies of all AE information, including correspondence with the 
Sponsor or Local Ethics Committees on file. 


 
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10. 
STATISTICAL METHODOLOGY 
10.1. 
Study Design and Objectives  
The study is designed as an open-label, controlled, multicenter, Phase III, randomized 
study of transplantation of NiCord® versus unmanipulated cord blood in patients with 
hematological malignancies. 
10.1.1. 
Accrual  
The study will enroll 120 eligible patients, randomized in a 1:1 ratio to the NiCord® and 
control arms. The study accrual will be managed so that no single site will provide an 
unusually large fraction of patients. 
________________________________________________________________________
________________________________________________________________________
__________________________ 
10.1.2. 
Randomization  
The study will use a form of randomization known as minimization that is designed to 
ensure that the treatment groups are well balanced with respect to selected factors of 
prognostic importance. Such forced balance is an important advantage in a small trial 
such as this one (see section 10.1.5). The factors included in the minimization algorithm 
will include: treatment center, disease risk group, age group, and intent to perform single 
vs double cord transplant in the control arm.  
Approximately ______ treatment centers are expected. The disease risk group definition, 
which is based on the “refined DRI” described by Armand et al.61 will have three levels: 
low risk, moderate risk, and high/very high risk. The risk group will be assigned by 
applying the criteria of Armand et al for DRI assignment and will be further adjusted to 
include in high/very high risk group any AML, ALL and other leukemia (not including 
MDS and CML) patient with any level of Minimal Residual Disease detected by flow 
cytometry.  For patients with rare disease types who are not classified by Armand et al, 
the disease risk will be assigned by the site investigator. The age group factor will have 
three levels (__________________________________). Although age and disease/stage 
may not strongly influence the primary endpoint, time to engraftment, there is an 
advantage in keeping them well balanced across the treatment groups for the purposes of 
comparing other important endpoints, including overall mortality and non-relapse 
mortality. 
Minimization will be implemented as follows: a measure of treatment group imbalance 
(to be defined in a separate document) will be calculated for each new patient and the 
allocation that minimizes this imbalance will be chosen with a pre-selected probability. 
Whenever the imbalance measures are equal under the two allocations, 1:1 randomization 
will be used. 


 
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10.1.3. 
Primary Endpoint  
The primary objective is to compare time from transplant to neutrophil engraftment 
between patients allocated to receive NiCord® transplantation and those allocated to 
receive unmanipulated cord blood transplantation. 
Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) 
greater than or equal to 0.5 x 109/L on 3 consecutive measurements on different days with 
subsequent donor chimerism 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
___________________________________. 
10.1.4. 
Primary Hypothesis  
The primary null hypothesis of the study is that there is no difference between the time to 
engraftment for patients allocated NiCord® and those allocated unmanipulated cord 
blood. 
10.1.5. 
Sample Size and Power Considerations 
The primary endpoint will be time from transplant to neutrophil engraftment. The 
primary analysis for comparing time to engraftment between the two treatment groups 
will be based on the Mann-Whitney test statistic (refer to the Statistical Analysis Plan 
(SAP) for details on the test statistic to be used). Although the test will be based on the 
re-randomization distribution, rather than the usual permutation distribution or its normal 
approximation, little or no statistical power is lost thereby, as confirmed by simulations. 
The primary sample size calculations were therefore based on the usual methods 
associated with the Mann-Whitney test. Noether’s formula was used to calculate the 
sample size.62  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____________________________________________.  
Based on these datasets and factoring in adjustments assuming 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________ See Appendix I for 
details of these calculations.  
Noether’s formula 
________________________________________________________________________


 
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________________________________________________________________________
__________________________.  
Although the formal sample size calculation for the primary endpoint provided above 
yields a size between _______ and  _______, the study will be larger for the following 
reasons:  
a. in order to provide a more extensive safety database for NiCord®; 
b. to ensure that statistical significance on the primary endpoint will be very 
strong and highly convincing; and 
c. to reduce the chance of seeing higher mortality in the NiCord® group than 
in the control group even if NiCord® truly has a beneficial effect on 
mortality (see 10.1.6 below) 
For these reasons and in consideration of the orphan indications, a total sample size of 
120 patients will be entered, with approximately 60 randomized to NiCord® and 60 to 
control. With 120 patients statistical power for the primary endpoint is estimated to be 
greater than 0.99. 
10.1.6. 
Overall mortality and “reverse” results 
Overall mortality remains an important endpoint in evaluating results following cord 
blood transplant.  However, it is not possible to design the study in a way that ensures 
with high probability that the observed difference will be in the direction of benefit to 
NiCord®, even if NiCord® truly does reduce the mortality rate. This is demonstrated in 
Table 7. 
Table 7: 
Probabilities of observing that the 180-day overall mortality is higher 
in the NiCord® group under different scenarios when total sample size 
is 120 
Relative Reduction 
in Treatment-
Related Mortality 
(%) 
Overall 180-day 
mortality rate in 
NiCord® group (%)* 
Overall 180-day 
mortality rate in 
control group (%) 
Probability of a 
higher 180-day 
mortality observed 
in NiCord® group 
0 
 
 
 
10 
 
 
 
20 
 
 
 
30 
 
 
 
40 
 
 
 
* ____________________________________________________________________ 
10.2. 
Interim Analysis and Stopping Guidelines  
10.2.1. 
Data Monitoring Committee 
This trial will be reviewed periodically by a Data Monitoring Committee (DMC).  
Policies and composition of the DMC are described in the DMC Charter.  Information 
provided to the DMC will be limited to descriptive statistics, data listings, and safety 


 
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monitoring analyses.  No formal hypothesis testing of endpoints will be performed unless 
specifically requested by a majority of the DMC or specified below. 
In addition to data provided for periodic reviews, the DMC will be provided with 
information regarding 130-day mortality on a monthly basis, starting the first month after 
the first randomization.  The monitoring guideline described in section 10.2.2  below 
serves as a reference for expected mortality rates on this study based on historical reports 
of overall survival of UCBU recipients;12 it is not a formal “stopping rule” that would 
mandate automatic closure of study enrollment.  Along with the monthly mortality report, 
full data information may be provided to the DMC for complete understanding of the 
fatalities reported (e.g., adverse events, GvHD, toxicity). The medical monitor will also 
view the mortality and other safety data and may make recommendations about 
approaching the DMC between the monthly mortality updates if they have any concern 
about the number or type of events or any other concerns about the safety of participants 
on the trial. 
10.2.2. 
Guidelines for Safety Monitoring 
The key safety endpoint to be monitored is the overall mortality at Day 130 post-
randomization.  Monitoring will occur within each treatment arm according to the 
randomized treatment assignment. An extension of the sequential probability ratio test 
(SPRT) for censored exponential data will be provided for reference, as described in 
greater detail below.  Although the SPRT will be provided for participants in each 
treatment arm separately, the results for both arms will be provided at the same time to 
the DMC along with other supporting documentation of the deaths including the 
individual causes of death and a comparison of the proportion of deaths between arms. 
This sequential testing procedure conserves type I error at ______% across all of the 
monthly examinations for a treatment arm.  The SPRT can be represented graphically.  At 
each monthly interim analysis, the total time on study is plotted against the total number 
of endpoints.  The continuation region of the SPRT is defined by two parallel lines.  Only 
the upper boundary will be used for monitoring to protect against excessive Day 130 
mortality.  If the graph crosses the upper boundary, the SPRT rejects the null hypothesis, 
and concludes that there are more events than predicted by the observed time on study.  
Otherwise, the SPRT continues for each arm until enrollment reaches the maximum of 
_____ patients and all patients have had at least 130 days of follow-up post 
randomization. 
This procedure assumes a censored exponential distribution for time to mortality, and 
censors follow-up time after 130 days post-randomization.  Note that only deaths that 
occur on or before the patient has been followed for 130 days are counted.  Total time on 
study within each treatment group is computed as time from randomization until death, or 
130 days, whichever comes first, summed for all randomized patients allocated that 
treatment.   
The usual measures of performance of an SPRT are the error probabilities α and β of 
rejecting H0 when θ = θ0 and of accepting H1 when θ = θ1, respectively, and the expected 


 
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sample size E(N|θi).  The tests to be used in this protocol were developed from the 
following SPRT: 
A SPRT contrasting _______% versus _______% for 130-day mortality results in 
decision boundaries with a common slope of 0.82 and an upper intercept of 2.62, with 
nominal type I and II errors of 10% and 10%, respectively. 
The actual operating characteristics of the truncated test, shown in Table 8, were 
determined in a simulation study that assumed uniform accrual of 60 individuals over a 
36 month time period, exponential time to failure after randomization and 41 months of 
monitoring.  It is expected that the 130-day post randomization mortality rate may be 
______-______%, however, a null rate of _______% was selected for the safety 
monitoring for 130 day post randomization in order to have high power for rejecting if 
the rate is _______%; the DMC will be reminded of the operating characteristics when 
provided with the monitoring data. 
 Table 8: 
Operating characteristics of sequential testing procedure for 130 Day 
Mortality from a simulation study with 100,000 replications 
True 130-Day Rate 
 
 
 
 
 
Probability of Rejecting Null 
 
 
 
 
 
Mean Month of Crossing 
Boundary 
 
 
 
 
 
Mean # Events 
 
 
 
 
 
Mean # Patients Randomized 
 
 
 
 
 
 
For example, 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_____________________. 
10.2.1. 
Interim Analysis for Efficacy and Futility 
There will be no interim analyses for efficacy or futility but there will be pre-specified 
interim safety monitoring as described above.  Timing of final analyses is specified in 
section 10.4.1 below. 
10.3. 
Analysis Populations 
The screened population consists of all subjects who signed informed consent. 
Intent-to-Treat (ITT) population includes all patients who are randomized into the trial, 
classified in the treatment groups to which they were allocated. Analysis of the ITT 
population provides the primary analysis of the primary endpoint, and also the primary 


 
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analyses of the secondary endpoints, tertiary endpoint, and the analyses of the exploratory 
endpoints unless otherwise stated. 
Transplanted (TP) population includes all patients randomized who received a cord blood 
transplant within 90 days following randomization.  Patients are, in assigned to the 
treatment groups to which they were allocated. Analysis of the TP population provides 
the analyses for the exploratory endpoints that depend on transplant, such as graft versus 
host disease.   
As treated (AT) population includes all patients randomized who received a cord blood 
transplant within 90 days following randomization, grouped by treatment actually 
performed. Analysis of the AT population is for supportive purposes. 
ANC engrafted population (AEP) includes all subjects who received a cord blood 
transplant within 90 days following randomization and achieved ANC engraftment; 
analysis is focused on the treatment actually performed. Analysis of the AEP population 
is for supportive purposes. 
Platelets-engrafted population (PEP) includes all subjects who received a cord blood 
transplant within 90 days following randomization and achieved platelet engraftment; 
analysis is focused on the treatment actually performed. Analysis of the PEP population 
is for supportive purposes. 
Safety population (SP) is identical with to the AT population defined above. 
10.3.1. 
Demographics and Baseline Characteristics  
Demographics and relevant baseline information (e.g., medical history, HCT-specific 
comorbidity index,63 center, disease, disease risk group, intended treatment (single or 
double CBT)) will be presented and summarized with appropriate descriptive statistics. 
The comparability of the baseline factors between the treatment groups will be assessed.  
These summaries will be based on the ITT population. 
10.4. 
Analysis Plan 
10.4.1. 
Timing of final analyses and statistical significance levels 
The final analysis of the primary endpoint will be conducted after all randomized patients 
have completed follow-up to 45 days post-transplant (or 90 days post randomization if 
the patient does not receive a transplant). The final analysis of the secondary and tertiary 
endpoints and all exploratory endpoints will be conducted after all randomized patients 
have completed follow-up to the later of 210 days post-randomization or 180 days post 
transplant. An additional analysis of 15-month post randomization and 1-year post 
transplant endpoints will be performed when all study patients have completed their study 
follow-up. Follow-up on the long-term follow-up sub-study will be ongoing after the last 
patient completes their last core study assessment (at the latest 15 months post 
randomization).  However, the core study database will be cleaned, locked, and analyzed 
at the time the last patient completes their last core study visit and will not remain open 
during the additional long term follow-up period.  A separate study database will be used 


 
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to capture data on the long term follow-up sub-study and a separate SAP will be 
developed to describe the planned analyses for that sub-study. 
All statistical tests will be conducted against a two-sided alternative hypothesis, 
employing a significance level of 0.05. For the secondary endpoints, p-values will be 
adjusted for multiple testing using Hommel’s method that controls the family-wise error 
rate.64 The results of the tertiary and exploratory endpoints will be assessed to provide a 
broad picture of the efficacy and safety of NiCord® in comparison with un-manipulated 
CB transplant; the p-values will be presented but the family-wise error rate for these 
endpoints will not be controlled. 
Some of the outcomes (survival and relapse) are more naturally measured in relation to 
time from randomization, and other transplant-related outcomes (hospitalization, 
engraftment, infections, graft versus host disease, immune reconstitution) in relation to 
time from transplantation. When time from transplantation is used then it has been 
traditional in this field to consider survival or disease events up to 100 days or 180 days 
post-transplant. Since there is approximately a 30-day gap between randomization and 
transplantation, when using time from randomization, we use 130 days or 210 days 
instead. 
The primary endpoint, time to neutrophil engraftment, and the secondary endpoints will 
be evaluated from transplantation, although they will take into account events occurring 
between randomization and transplant. See the subsections below for details.  
In the remainder of section 10.4, whenever the protocol mentions relapse, if the relapse 
occurs after randomization but before transplant, and the transplant is carried out within 
90 days of randomization, then the relapse will not be counted as a primary event or 
competing risk event. However, in addition, secondary analyses will also be provided 
where the relapse occurring before transplant will be treated as a relapse and applied to 
the analysis of the primary, secondary, and tertiary endpoints. (See the SAP for more 
details.) 
10.4.2. 
Analysis of the Primary Endpoint  
The study will compare the distribution of times to engraftment in the NiCord® vs 
Control groups. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
___________. 


 
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________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
__________________The implementation will be described in more detail in the 
Statistical Analysis Plan.  
10.4.2.1. Secondary Analysis of Time to Neutrophil Engraftment 
Three secondary analyses of the time from transplant to engraftment will be conducted. 
Statistical methods analogous to those described above will be used but on different 
populations. The first will be based on the as-treated (AT) population and will exclude 
patients who do not receive a transplant within 90 days following randomization. The 
second will in addition exclude patients who do not achieve ANC engraftment, forming 
the ANC-engrafted population (AEP). The third will compare time to neutrophil 
engraftment using a logrank test statistic for the ITT population.  These secondary 
analyses (a) provide information supportive of the primary analysis, and (b) the first and 
second provide estimates of median time from transplant to engraftment that are 
commonly used in the literature.  
Analyses of the primary and secondary endpoints in the following subgroups will also be 
conducted: (a) disease risk group; (b) age group; (c) intention to perform single vs double 
CB transplant; (d) disease (ALL, AML, CML, MDS, and lymphoma); (e) HCT-specific 
Comorbidity Index (0, 1-2 and 3+).; (f) gender; (g) race/ethnicity; (h) geographical 
region. See section 10.4.6 for more details. 
10.4.3. 
Analysis of Secondary Endpoints 
The secondary endpoints are those that will be subjected to formal statistical testing with 
adjustment for multiple testing. In this subsection, we list the statistical analyses of those 
secondary endpoints. All statistical tests comparing NiCord® to unmanipulated cord 


 
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blood will be based on the re-randomization distribution. Confidence intervals for the test 
statistics will be provided in all cases. The method for computing confidence intervals 
will be described in the Statistical Analysis Plan. The following outlines the primary 
analyses that will be performed. Details of secondary analyses are fully described in the 
SAP. 
10.4.3.1. Incidence of bacterial infection grades 2-3 or invasive 
fungal infection by 100 days following transplantation 
This analysis will be performed on the ITT population. 
The proportion of patients suffering a grade 2-3 bacterial infection or invasive fungal 
infection between randomization and 100 days following transplantation will be 
estimated in each treatment group in the following manner. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_____________________________________________. 
Secondary analyses will be performed on the TP and AT populations, as specified in the 
SAP.  
10.4.3.2. Days alive and out of hospital in the first 100 days following 
transplantation 
The primary analysis will be performed on the ITT population.  
The number of days that the patient is alive and out of hospital in the first 100 days post-
transplant, will be counted. Patients who are lost to follow-up during the first 100 days, 
but have not relapsed or had graft failure, will have their value imputed as follows:  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
______________________________________________________________.  


 
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________________________________________________________________________
________________________________________________________________.   
Secondary analyses will be performed on the TP and AT populations, as specified in the 
SAP.   
10.4.3.3. Platelet engraftment by 42 days following transplantation 
This analysis will be conducted on the ITT population. The proportion of patients with 
platelet engraftment by day 42 post-transplant in each group will be estimated for each 
treatment group from the cumulative incidence curve, with competing risks as follows: 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____________________________________________________ 
Secondary analyses will be conducted on the TP and AT populations, as specified in the 
SAP.  
10.4.4. 
Analysis of Tertiary Endpoint 
10.4.4.1. Non-relapse mortality by 210 days following randomization 
The primary analysis will be performed on the ITT population.  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
__________________. A secondary analysis conducted on the ITT population will be 
performed as described in the SAP. 
10.4.5. 
Analysis of Exploratory Endpoints 
10.4.5.1. Neutrophil engraftment by 16 days following 
transplantation 
This analysis will be conducted on the ITT population. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_________________________________________________________________. 
10.4.5.2. Time from transplantation to platelet engraftment 
The primary analysis of this endpoint will be conducted on the PEP (platelet engrafted 
population) and will estimate the distribution and median of time to platelets engraftment 


 
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among the platelet engrafters. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_____________________________________________. A secondary analysis conducted 
on the ITT population will be performed as described in the SAP.  
10.4.5.3. Duration of primary hospitalization 
The primary analysis will be performed on the transplanted (TP) population.  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
______________________________________________________________________.  
A secondary analysis conducted on the AT population will be performed as described in 
the SAP. 
10.4.5.4. Non-relapse mortality by 130 days following randomization 
The primary analysis will be performed as described in section 10.4.4.1 except that the 
time-period will be limited to 130 days. A secondary analysis conducted on the ITT 
population will be performed as described in the SAP. 
10.4.5.5. Non-relapse mortality by 15 months following 
randomization 
The primary analysis will be performed as described in section 10.4.4.1, except that the 
time-period will be extended to15 months. A secondary analysis conducted on the ITT 
population will be performed as described in the SAP. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_______________________________________.   


 
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10.4.5.6. Overall survival at 210 days following randomization 
The primary analysis will be performed on the ITT population. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_____. A secondary analysis conducted on the ITT population will be performed as 
described in the SAP. 
10.4.5.7. Overall survival by 15 months following randomization 
The analysis will be performed as described in section 10.4.5.6 except that the time-
period will be extended to15 months post randomization for the primary analysis.  
10.4.5.8. Disease-free survival by 15 months following 
randomization 
This analysis will be performed on the ITT population.  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____________________. 
10.4.5.9. Neutrophil engraftment by 42 days following 
transplantation 
The primary analysis will be conducted on the ITT population. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________


 
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________________________. A secondary analysis conducted on the TP population will 
be performed as described in the SAP. 
10.4.5.10.  Acute GvHD grade II-IV by 100 days following 
transplantation 
This analysis will be conducted on the transplanted population (TP). 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________. A 
secondary analysis, based on the cumulative incidence curve, will be described in the 
SAP.  
10.4.5.11.  Acute GvHD grade III-IV by 100 days following 
transplantation 
The analyses will be performed as described in section 10.4.5.10, except that the time to 
the event will be the first time to aGvHD grade III-IV, instead of grade II-IV. A 
secondary analysis, based on the cumulative incidence curve, is described in the SAP. 
10.4.5.12.  Chronic GvHD (mild/moderate/severe) by 180 days 
following transplantation 
This analysis will be conducted on the transplanted population (TP).  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________


 
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_________________________________________________________. A secondary 
analysis will be based on the cumulative incidence curve as described in the SAP.  The 
reason for performing both primary and secondary analyses of this endpoint is given at 
the end of section 10.4.5.10. 
10.4.5.13.  Chronic GvHD (mild/moderate/severe) by 1 year following 
transplantation  
The analysis will be performed as described in section 10.4.5.12, except that the time-
period will be extended to 365 days. A secondary analysis will be based on the 
cumulative incidence curve as described in the SAP.   
10.4.5.14.  Secondary graft failure by 1 year following transplantation 
This analysis will be conducted on the transplanted population (TP).  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________. A secondary 
analysis will be based on the Kaplan-Meier curve as described in the SAP.   
10.4.5.15.  Grade 3 viral infections by 180 days following 
transplantation  
________________________________________________________________________
________________________________________________________________________
____________________________________________________________. Secondary 
analyses will be performed on the TP and AT populations, as specified in the SAP. 
10.4.5.16.  Grade 3 viral infections by 1 year following 
transplantation  
The analysis will be conducted as described in section 10.4.3.1. Secondary analyses will 
be performed on the TP and AT populations, as specified in the SAP. 
10.4.5.17.  Relapse by 15 months following randomization 
This analysis will be conducted on the ITT population.  
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____________________________________. 


 
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________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_______________________________________. A secondary analysis will be based on 
the cumulative incidence curve as described in the SAP.   
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_________________________________________________________________.  
10.4.5.18. Relapse mortality by 15 months following randomization 
This analysis will be conducted on the ITT population.  
The same approach as in section 10.4.5.17 will be used to overcome possible biases 
arising from the timing of the BM assessment. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_____________________________________________________________________. A 
secondary analysis will be based on the cumulative incidence curve as described in the 
SAP.   
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________.   
10.4.5.19.  Immune Reconstitution 
Summary statistics of the numbers and proportions of different lymphocyte 
subpopulations at days 28, 70, 100, 180 and 365 post-transplant (mean, standard 
deviation, median and quartiles) will be presented for each treatment group. This will be 
performed on the AEP population. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_______________________________________. 
10.4.5.20.  Health-Related Quality of Life 
Patient-reported health-related quality of life outcomes will be assessed on the ITT 
population using two standardized measures including the FACT BMT and the EuroQol 
EQ-5D. The self-report questionnaires will be completed prior to transplantation and 
subsequently at 42, 100, 180 and 365 days from transplantation or until death or 


 
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discontinuation from the study. Questionnaires are requested but not required after failure 
to transplant by Day 90, graft failure, or relapse. The instruments will be scored 
according to the recommendations of the developers. 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_________________________________________________. 
10.4.6. 
Subgroup Analysis 
Descriptive statistics calculated based on the primary analyses of the primary and 
secondary endpoints will be provided for the following subgroups:  
1. Disease risk group as defined in section 10.1.2  (low, moderate and high/very high 
risk). 
2. Age group as defined in section 10.1.2  
(__________________________________).  
3. Intention to perform single vs. double CB transplant  
4. Disease (ALL, AML, CML, MDS and lymphoma)  
5. HCT-specific Comorbidity Index (0, 1-2 and 3+) 
6.  Gender 
7. Race/ethnicity 
8. Geographical region 
These data are intended to serve as supportive analyses. P-values for comparing the 
treatment groups within subgroups will not be provided, since in a trial with limited 
sample size they can be misleading. The subgroup results will be presented as forest 
plots. 
10.5. 
Missing data 
Sections 10.4.2 and 10.4.3 have included details regarding the handling of missing data 
that can occur because 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
______________________.  In addition, survival analyses of time-related endpoints 
specify that loss-to-follow up will be regarded as a censoring event and the usual survival 
analysis assumptions will be applied in those cases. In what follows we describe our 


 
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approach________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________. 
10.5.1. 
Loss to follow-up in the primary analysis of the primary 
endpoint 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
_________________________________________________. 
10.5.2. 
Loss to follow-up in the primary analyses of the secondary 
endpoints 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________


 
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________________________________________________________________________
_______________________________. 
10.5.3. 
Sensitivity analyses for missing data   
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____________________. 
10.6. 
 Safety and Tolerability of NiCord® transplantation   
This analysis will be conducted on the safety population (SP). 
The analysis of adverse events, serious adverse events, and toxicities will be primarily 
descriptive. Formal comparisons between treatment groups will be performed to assess 
whether there is strong evidence of a differential safety signal. 
____________________________________________________________________.  
Adverse events (AEs) and serious adverse events (SAEs) are collected as described in 
section 9. Toxicities, adverse events, and serious adverse events are not unexpected in the 
setting of stem cell transplantation. As such, events can be broken into several categories: 
infusion reactions, common events post-transplant, uncommon adverse events. 
Infusion reactions: 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
__________. 
Common events post-transplant: 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
____________________________________________________.  


 
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Uncommon events post-transplant: 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________. 
Pregnancies on study will be followed until outcome and described. Clinical laboratory 
evaluations will not be analyzed per se, but rather clinically significant abnormal values 
will be reported as adverse events and analyzed as referenced above. 
10.7. 
Analysis Plan Deviations  
Deviations from the final statistical analysis plan will be reported in the final study 
report. 
10.8. 
 Statistical Software  
SAS® version 9.1 or higher software and R version 2.10.0 or higher will be used for 
statistical analysis and data presentation of the information collected in this study. 
10.9. 
Long-term Follow-up (optional) 
For patients who received transplantation and agreed to enroll in the observational long 
term follow-up sub-study, long-term outcomes will be collected at 2 years, 3 years, 4 
years and 5 years post transplantation.  
The overall research goals for this sub-study are: 
 Describe long term sustained donor chimerism 
 Describe survival and disease free survival 
 Describe characteristics of patients with secondary graft failure or disease relapse 
 Describe long term immune reconstitution  
 Describe incidence of chronic GvHD 
Details of the statistical analysis plan are provided in Appendix J. 
 


 
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11. 
CLINICAL DATA MANAGEMENT 
11.1. 
Data Quality Assurance  
This study will be organized, performed, and reported in compliance with the 
Sponsor/CRO’s SOPs, protocols and working practice documents, and the requirements 
of the Declaration of Helsinki and ICH/GCP guidelines. Compliance will be achieved 
through a combination of study specific audits of investigative sites and audits at regular 
intervals of the Sponsor/CRO’s systems for data handling, analysis, and reporting. 
A quality assurance audit of this trial may be conducted by the Sponsor or Sponsor’s 
designees. The quality assurance auditor will have access to all medical records, the 
investigator’s trial-related files and correspondence, and the informed consent 
documentation that is relevant to this clinical trial. 
11.2. 
Data Collection  
Investigators or designees will enter the information required by the protocol onto the 
CRFs. Each investigative site will be visited as frequently as documented in the 
monitoring plan by the CRO on behalf of the Sponsor to review the CRFs for 
completeness and accuracy. The CRO representative will highlight any discrepancies 
found between source documents and the completed CRFs, and will ensure that 
appropriate site personnel address the discrepancies. When a discrepancy results in 
corrected CRF data, the correction will be reviewed again against the correct source 
documentation. Uniform procedures will be discussed at the Site Initiation Visit. 
11.3. 
Source Documents  
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. All clinical data entered onto the CRF must be supported 
by source documentation maintained at the clinical site.  Data entered in the CRFs that 
are transcribed from source documents must be consistent with the source documents or 
the discrepancies must be explained. The investigator may need to request previous 
medical records or transfer records, depending on the trial; also, current medical records 
must be available.  
Direct access to source data - documents 
• The investigator / institution will permit trial-related monitoring, audits, IRB / 
IEC review and regulatory inspection, providing direct access to all related 
source data / documents. 
• CRFs and all source documents, including progress notes and copies of 
laboratory and medical test results must be available at all times for review by 
the Sponsor’s clinical trial monitor and inspection by health authorities (e.g., 
MS CA/EMA). The Clinical Research Associate (CRA) / on site monitor may 
review all CRFs, and written informed consents. The accuracy of the data will 
be verified by reviewing the documents. 


 
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11.4. 
Staff Training  
Prior to enrollment, all clinical study personnel will be trained to ensure adherence to the 
protocol and assure the highest possible data quality.  Training will be led by CRO and 
the Sponsor at a central location.  Training presentations will address informed consent 
procedures, study operations and protocol requirements, data collection procedures, 
maintenance of source documentation, CRF completion and review, routine reporting 
requirements, data entry and management, and policies and procedures. 
11.5. 
Data Monitoring  
CRAs will be responsible for monitoring CRFs and source documents for accuracy, 
protocol compliance, subject safety, and adherence to guidelines in the Site Operations 
Manuals. 
At each site visit, the CRA will review recruitment guidelines and study eligibility 
criteria.  As the study progresses, completed data forms may be reviewed during site 
visits and compared to source documentation (medical or site records) to confirm 
accuracy. 


 
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APPENDIX A. SCREENING SCHEDULE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
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APPENDIX B. GVHD CLASSIFICATION 
Acute GvHD Definition 
Acute GvHD will be assessed at every visit from transplantation (day 0) until day 180 or 
more frequently as clinically indicated. GvHD will be classified according to the 
Consensus Conference on Acute GvHD grading.60 
Table 9: 
GvHD classification 
Overall Grade 
Skin 
Liver 
Gut 
I 
Stage 1-2 
None 
None 
II 
Stage 3 or 
Stage 1 or 
Stage 1 
III 
 
Stage 2-3 or 
Stage 2-4 
IV 
Stage 4 or 
Stage 4 
 
*See following table for individual organ staging. The overall grade of GvHD, however, 
reflects the actual extent of disease. For each overall grade, an assessment of skin disease 
plus liver and/or gut involvement is required. 
 
Acute GvHD may be documented after day 99 (“late acute”) if according to clinical 
judgment the investigator feels it should be classified as acute rather than chronic. 
Table 10: 
Clinical manifestations and staging of acute graft versus host disease 
Organ 
Clinical Manifestations 
Staginge 
Skina 
Erythematous, maculopapular rash 
involving palms and soles; may 
become confluent 
Severe disease: bullae. 
Stage 1: <25% rash 
Stage 2: 25-50% rash 
Stage 3: generalized erythroderma 
Stage 4: bullae 
Liverb 
Painless jaundice with conjugated 
hyperbilirubinemia and increased 
alkaline phosphatase. 
Stage 1: bilirubin 2-3 mg/dL 
Stage 2: bilirubin 3.1-6 mg/dL 
Stage 3: bilirubin 6.1-15 mg/dL 
Stage 4: bilirubin >15 mg/dL 
Gastrointestinal tractc 
Upper: nausea, vomiting, anorexia. 
Lower: diarrhea, abdominal cramps, 
distention, ileus, bleeding. 
Stage 1: diarrhea >500 ml/day or 
persistent nausea, vomiting, or anorexia d 
Stage 2: diarrhea >1000 ml/day 
Stage 3: diarrhea >1500 ml/day 
Stage 4: large volume diarrhea and 
severe abdominal pain +/- ileus 
a Use ‘Rule of Nines’ or burn chart to determine extent of rash 
b  Range given as total bilirubin.  Downgrade one stage if a cause of elevated bilirubin other than GvHD 
has been documented. 
c  Downgrade one stage if a cause of diarrhea other than GvHD has been documented. 
d Downgrade upper GI one stage if biopsy result is negative, or if no biopsy done and GvHD is not an 
etiology, or if the biopsy is equivocal and GvHD is not an etiology. 


 
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e Although GvHD will be assessed at every protocol-specified visit, GvHD will only be analyzed if it 
occurs after primary neutrophil engraftment.  If GvHD is not an etiology for any organ, then GvHD is 
downgraded to stage 0. 
 
Chronic GvHD Definition 
Chronic GvHD will be assessed at the time of diagnosis and at every visit from day 100 
until day 365 or more frequently as clinically indicated.  
 
Chronic GvHD will be classified as mild, moderate, or severe, according to the National 
Institute of Health consensus grading criteria65 summarized below: 
Table 11: 
NIH Global Severity of chronic GvHD 
Global 
Severity 
Criteria 
Mild 
1-2 organs involved with a max organ severity score of 1  
AND 
Lung score=0 
Moderate 
≥3 organs involved with a max organ severity score of 1 
OR 
Any organ (except lung) with a severity score of 2 
OR 
Lung score=1 
Severe 
Any organ with a severity score of 3 
OR 
Lung score ≥2 
Notes for global severity scoring: 
Clinical centers must reference the 2014 consensus criteria for organ specific severity 
grading.65 A record of the organ specific scoring must be kept on file at the clinical 
center. See cGVHD scoring worksheet in the Data Management Handbook; either the 
provided worksheet or an equivalent EMR adaptation of the form (approved by the 
sponsor) must be used to document chronic GvHD. 
In skin: higher of the 2 scores to be used for calculating global severity. 
In lung: FEV1 is used instead of clinical score for calculating global severity. 
If the entire abnormality in an organ is noted to be unequivocally explained by a non-
GvHD documented cause, that organ is not included for calculation of the global severity. 


 
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If the abnormality in an organ is attributed to multifactorial causes (GvHD plus other 
causes) the scored organ will be used for calculation of the global severity regardless of 
the contributing causes (no downgrading of organ severity score). 
 


 
 
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APPENDIX C. SAFETY DATA REPORTING 
Table 12: 
Safety Data Reporting for transplanted patients 
From the 
time of 
Consent 
From the time of 
Randomization 
During Conditioning 
up to Start of NiCord® 
or CBU Infusion 
During NiCord® or CBU 
Infusion through 24 hours 
Post NiCord® or CBU 
Infusion 
 
> 24 hours Post NiCord® or 
CBU Infusion through Day 
42 
Day 43 through Day 365a 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
* See Appendix D for a list of common adverse events 
# With the exception of infections and GvHD symptoms which are reported on the Infection form and GvHD forms respectively. 
a An additional assessment of survival and relapse status is required on or after month 15 post randomization.  Death and or Relapse forms are required during this time period as 
applicable.  In the event of death, SAE forms are also required.   
b After day 30 post transplant and following date of relapse or graft failure only SAEs resulting in death or suspected to be related to the infused product will be reported. 


 
 
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Table 13: 
Safety Data Reporting for Post Randomization Patients Who Do Not Receive a Transplant Within 90 Days 
following Randomization 
From the time of 
Consent 
From the time of 
Randomization through Day 
90 post Randomization 
Day 91 through Day 365 post 
Randomization 
Day 366 post Randomization 
through Month 15 post 
Randomization 
 
 
 
 
 
 
 
 


 
 
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APPENDIX D. COMMON ADVERSE EVENTS 
Cardiac 
Cardiac Arrhythmias 
 
Gastrointestinal 
Abdominal distension 
Nausea/Anorexia 
Vomiting 
Constipation 
Diarrhea 
Dyspepsia 
Dysphagia 
Mucositis 
 
General Disorders 
Allergic reaction 
Chills 
Edema 
Fatigue/Malaise/Lethargy 
Fever 
Pain  
 
Injury/Poisoning/Procedural Complications 
Bruising 
Hemorrhage 
Vascular access complications 
 
Investigations 
Elevated alkaline phosphatase  
Elevated creatinine 
Elevated liver transaminases (ALT, AST) 
Elevated triglycerides 
Weight loss 
 
Metabolism and Nutrition 
Abnormal sodium  
Dehydration 
Hyperglycemia 
Hypocalcemia 
Hypokalemia 
Hypomagnesemia 
Hypophosphatemia 
Hypoalbuminemia 


 
 
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Musculoskeletal 
Generalized muscle weakness 
 
Neurologic 
Dizziness 
Dysgeusia 
Somnolence 
Syncope  
Tremors  
 
Ocular 
Dry eyes 
Blurry vision 
 
Psychiatric 
Anxiety 
Depression 
Insomnia 
 
Renal 
Non-infectious cystitis 
 
Respiratory 
Cough 
Dyspnea  
Epistaxis 
Hypoxia 
 
Skin 
Dry skin 
Pruritis 
Skin hyperpigmentation  
Skin ulceration 
 
Vascular 
Hypertension  
Hypotension 
 


 
 
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APPENDIX E. COMMON TERMINOLOGY CRITERA FOR ADVERSE 
EVENTS V4.03 (CTCAE) 
(U.S.DEPARTMENT_OF_HEALTH_AND_HUMAN_SERVIC
ES 2009)66 
Document available upon request (for site personnel, document available on the Gamida 
Cell Studies Coordinating Center website _________________) 
 
 


 
 
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APPENDIX F. DRUG LABELS 
Documents available upon request (for site personnel, documents available on the 
Gamida Cell Studies Coordinating Center website _________________) 


 
 
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APPENDIX G.  INFECTION GRADING 
Type of infection/ severity 
grade 
Grade 1 
Grade 2 
Grade 3 
Bacterial infections 
 
Bacterial focus NOS 
requiring no more than 14 
days of therapy for 
treatment (e.g., urinary 
tract infection)  
 
 
Coag Neg Staph (S. epi), 
Corynebacterium, or 
Proprioniobacterium 
bacteremia 
 
 
Cellulitis responding to 
initial therapy within 14 
days 
 
 
 
 
 
 
 
 
 
 
 
 
C. Difficile toxin positive 
stool with diarrhea < 
1L without abdominal pain 
(child < 20 mL/kg) 
 
Bacteremia (except CoNS) 
without severe sepsis  
 
 
 
 
 
Bacterial focus with persistent 
signs, symptoms or persistent 
positive cultures requiring 
greater than 14 days of therapy  
 
 
Cellulitis requiring a change in 
therapy d/t progression 
Localized or diffuse infections 
requiring incision with or 
without drain placement  
 
 
Any pneumonia documented or 
presumed to be bacterial 
 
 
 
 
 
 
C. Difficile toxin positive stool 
with diarrhea ≥ 1L (child ≥ 20 
mL/kg) or with abdominal 
pain   
 
Bacteremia with deep organ 
involvement (e.g., with new 
or worsening pulmonary 
infiltrates; endocarditis) 
 
 
 
Severe sepsis with 
bacteremia 
 
 
 
 
Fasciitis requiring 
debridement  
 
 
 
 
 
Pneumonia requiring 
intubation 
 
 
 
Brain abscess or meningitis 
without bacteremia 
 
C. Difficile toxin positive 
stool with toxic dilatation or 
renal insufficiency 
with/without diarrhea 
 
Fungal infections 
 
Superficial candida 
infection (e.g., oral thrush, 
vaginal candidiasis) 
 
Candida esophagitis (biopsy 
proven). 
 
 
Proven or probable fungal 
sinusitis confirmed 
radiologically without orbital, 
brain or bone involvement. 
 
Fungemia including 
Candidemia 
 
 
Proven or probable invasive 
fungal infections (e.g., 
Aspergillus, Mucor, 
Fusarium, Scedosporium). 
 
 
Disseminated infections 
(defined as multifocal 
pneumonia, presence of 
urinary or blood antigen, 
and/or CNS involvement) 
with Histoplasmosis, 


 
 
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Type of infection/ severity 
grade 
Grade 1 
Grade 2 
Grade 3 
Blastomycosis, 
Coccidiomycosis, or 
Cryptococcus. 
 
 
Pneumocystis jiroveci 
pneumonia (regardless of 
PaO2 level) 
Viral infections 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Viral infections continued 
 
Mucous HSV infection 
 
 
Dermatomal Zoster with 2 
or fewer dermatomes 
 
 
Asymptomatic CMV 
viremia untreated or a 
CMV viremia with viral 
load decline by at least 2/3 
of the baseline value after 
2 weeks of therapy 
 
 
 
EBV reactivation not 
treated with rituximab 
 
 
Adenoviral conjunctivitis 
asymptomatic viruria, 
asymptomatic stool 
shedding and viremia not 
requiring treatment   
 
Asymptomatic HHV-6 
viremia untreated or an 
HHV-6 viremia with a 
viral load decline by at 
least 0.5 log after 2 weeks 
of therapy 
 
BK viremia or viruria with 
cystitis not requiring 
intervention 
 
 
 
 
 
 
 
 
 
 
VZV infection with 3 or more 
dermatomes  
 
 
Clinically active CMV 
infection (e.g., symptoms, 
cytopenias) 
or CMV Viremia not 
decreasing by at least 2/3 of the 
baseline value after 2 weeks of 
therapy 
 
 
EBV reactivation requiring 
institution of therapy with 
rituximab 
 
Adenoviral upper respiratory 
infection, or symptomatic 
viruria requiring treatment 
 
 
 
HHV-6 viremia without viral 
load decline 0.5 log after 2 
weeks of therapy 
 
 
 
 
BK viremia or viruria with 
clinical consequence requiring 
prolonged therapy and/or 
surgical intervention 
 
Enterocolitis with enteric 
viruses  
Symptomatic upper tract 
respiratory virus 
 
 
 
 
Severe VZV infection 
(coagulopathy or organ 
involvement) 
 
CMV end-organ involvement 
(pneumonitis, enteritis, 
retinitis) 
 
 
 
 
 
 
EBV PTLD 
 
 
 
Adenovirus with end-organ 
involvement (except 
conjunctivitis and upper 
respiratory tract) 
 
 
Clinically active HHV-6 
infection (e.g., symptoms, 
cytopenias) 
 
 
 
 
 
 
 
 
 
 
 
Lower tract respiratory 
viruses 
 


 
 
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Type of infection/ severity 
grade 
Grade 1 
Grade 2 
Grade 3 
 
Viremia (virus not 
otherwise specified) not 
requiring therapy 
 
Any viremia (virus not 
otherwise specified) requiring 
therapy  
 
Any viral encephalitis or 
meningitis 
 
Protozoal/Parasitic 
infections 
 
Infection (not including 
toxoplasmosis or 
strongyloides) not 
requiring therapy 
Infection (not including 
toxoplasmosis or strongyloides) 
requiring therapy 
Infection causing severe 
sepsis 
 
CNS or other organ 
toxoplasmosis 
 
Strongyloides hyperinfection 
Nonmicrobiologically 
defined infections 
 
Uncomplicated fever with 
negative cultures 
responding within 14 days 
 
Clinically documented 
infection not requiring 
inpatient management 
 
 
 
 
Pneumonia or 
bronchopneumonia not 
requiring mechanical 
ventilation 
 
Typhlitis 
 
 
 
 
Any acute pneumonia 
requiring mechanical 
ventilation  
 
 
Severe sepsis without an 
identified organism 
*Concomitant or multimicrobial infections are graded according to the grade of the infection with the higher grade of 
severity. 
**Therapy includes both PO and IV formulations 
 
 


 
 
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Definition of Severe Sepsis    
 
Adults: 
Hypotension  
• 
A systolic blood pressure of <90 mm Hg or a reduction of >40 mm hg from baseline 
in the absence of other causes for hypotension 
Multiple Organ Dysfunction Syndrome 
• 
2 or more of the following: Renal failure requiring dialysis, respiratory failure 
requiring bipap or intubation, heart failure requiring pressors, liver failure 
 
Pediatrics: 
Pediatric SIRS definition and suspected or proven infection and cardiovascular dysfunction or 
ARDS or TWO or MORE other organ dysfunctions.  
Pediatric SIRS definition: 
Two or more of the following, one of which must be abnormal temperature or leukocyte 
count 
1) Core temperature >38.5C or < 36C 
2) Tachycardia, otherwise unexplained persistent in absence of external stimulus, 
chronic drugs or painful stimuli. or bradycardia, in < 1 year old, otherwise 
unexplained persistent. 
3) Tachypnea or mechanical ventilation for an acute process not related to underlying 
neuromuscular disease or general anesthesia 
4) Leukocytosis or leukopenia for age (not secondary to chemotherapy) or >10% bands 
Pediatric Organ dysfunction criteria: 
Cardiovascular: despite administration of fluid bolus >40 ml/kg in 1 hour: 
• 
Hypotension <5th percentile for age (or per Table 1)  
• 
Pressors at any dose  
• 
Two of the following:  
o Capillary refill > 5 secs  
o Core to peripheral temperature gap > 3oC  
o Urine output < 0.5 mL/kg/hr  
o Unexplained metabolic acidosis (Base deficit > 5.0 mEq/L)  
o Blood lactate > 2 x ULN  
Respiratory: 
• 
ARDS or  
• 
Intubated or  
• 
>50% FiO2 to maintain SaO2 > 92%  
Neurological: 
• 
Glasgow Coma Score < 11 or  
• 
Acute change in mental status with a decrease in GSC >3 pts from abnormal 
baseline  
Renal: 
• 
Serum creatinine > 2 x ULN for age or 2-fold increase in baseline creatinine  
Hepatic: 
• 
Total bilirubin >4 mg/dL or  
• 
ALT >2 x ULN for age  
Table 1: Four age groups relevant to HCT: 


 
 
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Age 
Tachycardia 
(bpm) 
Bradycardia 
(bpm) 
Tachypnea 
(breaths/min) 
Leukocytosis / 
Leukopenia 
(WBC) 
Hypotension 
Systolic BP 
mmHg 
1 mo to 1 yr 
>180 
<90 
>34 
>17.5 to <5.0 
<100 
2 yr to 5 yr 
>140 
NA 
>22 
>15.5 to <6.0 
<94 
6 yr to 12 yr 
>130 
NA 
>18 
>13.5 to <4.5 
<105 
13 yr to < 18 yr 
>110 
NA 
>14 
>11 to <4.5 
<117 
 
Disseminated Infections:  
• 
Two or more non-contiguous sites with the SAME organism 
• 
A disseminated infection can occur at any level of severity, but most will be grade 
2 or 3. 
Recurrence Intervals to Determine Whether an Infection is the Same or New: 
• 
CMV, HSV, EBV, HHV6: _________________ 
• 
VZV, HZV: _________________ 
• 
Bacterial, non-C. difficile: _________________ 
• 
Bacterial, C. difficile: _________________ 
• 
Yeast: __________________________________ 
• 
Molds: __________________________________ 
• 
Helicobacter: _________________ 
• 
Adenovirus, 
Enterovirus, 
Influenza, 
RSV, 
Parainfluenza, 
Rhinovirus: 
_________________ 
• 
Polyomavirus (BK virus): _________________ 
 
For infections coded as “Disseminated” per the Infection Form, any previous infection with the 
same organism but different site within the recurrence interval for that organism will be counted 
as part of the disseminated infection. 
 
 
 


 
 
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Definitions of Invasive Fungal Infections in Patients with Cancer and Recipients of 
Hematopoietic Stem Cell Transplants  
Category, Type of Infection 
Description 
Proven invasive fungal 
infections 
  
Deep Tissue Infections 
Mouldsa 
 
 
 
 
 
 
Yeastsa 
 
Histopathologic or cytopathologic examination showing hyphae from 
needle aspiration or biopsy specimen with evidence of associated tissue 
damage (either microscopically or unequivocally by imaging); or positive 
culture result for a sample obtained by sterile procedure from normally 
sterile and clinically or radiologically abnormal site consistent with 
infection, excluding urine and mucous membranes 
 
Histopathologic or cytopathologic examination showing yeast cells 
(Candida species may also show pseudohyphae or true hyphae) from 
specimens of needle aspiration or biopsy excluding mucous membranes; or 
positive culture result on sample obtained by sterile procedure from 
normally sterile and clinically or radiologically abnormal site consistent 
with infection, excluding urine, sinuses, and mucous membranes; or 
microscopy (India ink, mucicarmine stain) or antigen positivityb for 
Cryptococcus species in CSF 
Fungemia  
Mouldsa  
 
 
 
 
Yeastsa 
 
 
Blood culture that yields fungi, excluding aspergillus species and 
Penicillium species other than Penicillium marneffei, accompanied by 
temporally related clinical signs and symptoms compatible with relevant 
organism 
 
Blood culture that yields Candida species and other yeasts in patients with 
temporally related clinical signs and symptoms compatible with relevant 
organism  
Endemic fungal infectionsc 
Systemic or confined to 
lungs 
 
 
 
 
 
 
Disseminated 
 
Must be proven by culture from site affected, in host with symptoms 
attributed to fungal infection; if culture results are negative or unattainable, 
histopathologic or direct microscopic demonstration of appropriate 
morphological forms is considered adequate for dimorphic fungi 
(Blastomyces, Coccidioides and Paracoccidiodes species) having truly 
distinctive appearance; Histoplasma capsulatum variant capsulatum may 
resemble Candida glabrata 
 
May be established by positive blood culture result or positive for urine or 
serum antigen by means of RIA 
Probable invasive fungal 
infections 
At least 1 host factor criterion; and 1 microbiological criterion; and either a) 
1 major (or 2 minor) clinical criteria from abnormal site consistent with 
infection for sites other than lower respiratory tract, or b) one of the clinical 
criteria for lower respiratory tract site 


 
 
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Category, Type of Infection 
Description 
Presumptive invasive 
fungal infection 
• 
At least 1 host factor criterion and 1 clinical criterion for lower 
respiratory tract infection as listed below.  A microbiological criterion 
is NOT required.  The clinical criterion for lower respiratory tract 
infection must be consistent with the microbiological findings, if any, 
temporally related to current episode and other potential causes must 
have been eliminated, along with: 
­ The presence of one of the following “specific” imaging signs on 
CT: (1) Halo sign, (2) wedge-shaped infiltrate, (3) air crescent 
sign, OR 
­ The presence of a new non-specific focal infiltrate, PLUS at 
least one of the following: pleural rub, pleural pain, or 
haemoptysis, AND no evidence of other etiology demonstrated 
by bronchoscopic examination 
• 
Or if lacking a host criterion, but otherwise meets the microbiological 
and clinical criteria for a presumptive, probable or proven invasive 
fungal infection.  The clinical criterion for lower respiratory tract 
infection must be consistent with the microbiological findings, if any, 
temporally related to current episode and other potential causes must 
have been eliminated, along with: 
­ The presence of one of the following “specific” imaging signs on 
CT: (1) well-defined nodule with or without a halo sign, (2) halo 
sign, (3) wedge-shaped infiltrate, (4) air crescent sign, (5) cavity 
within area of consolidation OR 
­ The presence of a new non-specific focal infiltrate, PLUS at 
least one of the following: pleural rub, pleural pain, or 
haemoptysis AND no evidence of other etiology demonstrated 
by bronchoscopic examination 
Possibled invasive fungal 
infections 
At least 1 host factor criterion; and 1 microbiological criterion; or either a) 
1 major (or 2 minor) clinical criteria from abnormal site consistent with 
infection for sites other than lower respiratory tract, or b) one of the clinical 
criteria for lower respiratory tract site 
a  Append identification at genus or species level from culture, if available. 
b  False-positive cryptococcal antigen reactions due to infection with Trichosporan beigelli (1), infection with 
Stomatococcus mucilaginosis (2), circulating rheumatoid factor (3), and concomitant malignancy (4) may 
occur and should be eliminated if positive antigen test is only positive result in this category. 
c  Histoplasmosis, blastomycosis, coccidioidomycosis, and paracoccidioidomycosis. 
d  This category is not recommended for use in clinical trials of antifungal agents but might be considered for 
studies of empirical treatment, epidemiological studies, and studies of health economics 
 
 
 


 
 
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Host Factor, Microbiological, and Clinical Criteria for Invasive Fungal Infections in 
Patients with Cancer and Recipients of Hematopoietic Stem Cell Transplants  
Type of Criteria 
Criteria 
Host factors 
• Neutropenia (<500 neutrophils/mm3 for > 10 days) 
• Persistent fever (≥ 38°C) for > 96 h refractory to appropriate broad-spectrum 
antibacterial treatment in high-risk patients 
• Body temperature either > 38oC or < 36oC and any of the following 
predisposing conditions: prolonged neutropenia (> 10 days) in previous 60 
days, recent or current use of significant immunosuppressive agents in 
previous 30 days, proven or probable invasive fungal infection during previous 
episode of neutropenia, or coexistence of symptomatic AIDS 
• Signs and symptoms indicating graft-versus-host disease, particularly severe 
(Grade>2) or extensive chronic disease 
• Prolonged (>3 weeks) use of corticosteroids in previous 60 days 
Microbiological 
• Positive result of culture for mould (including aspergillus, Fusaruim, or 
Scedosporium species or Zygomycetes) or Cryptococcus neoformans or an 
endemic fungal pathogena from sputum or bronchoalveolar lavage fluid 
samples 
• Positive result of culture or findings of cytologic/direct microscopic evaluation 
for mould from sinus aspirate specimen 
• Positive findings of cytologic/direct microscopic evaluation for mould or 
Cryptococcus species from sputum or bronchoalveolar lavage fluid samples 
• Positive result for aspergillus antigen in blood samplesb  
• Positive result for aspergillus antigen in specimens of bronchoalveolar lavage 
fluid or CSF 
• Positive result for cryptococcal antigen in blood samplec 
• Positive findings of cytologic or direct microscopic examination for fungal 
elements in sterile body fluid samples (e.g., Cryptococcus species in CSF) 
• Positive result for Histoplasma capsulatum antigen in blood, urine, or CSF 
specimens  
• Two positive results of culture of urine samples for yeasts in absence of 
urinary catheter 
• Candida casts in urine in absence of urinary catheter 
• Positive result of blood culture for Candida species 
Clinical 
Must be related to site of microbiological criteria and temporally related to 
current episode 
Lower respiratory tract 
infection 
 
• The presence of one of the following “specific” imaging signs on CT: (1) well 
defined nodule(s) of at least 1 cm in diameter with or without a halo sign, (2) 
wedge-shaped infiltrate, (3) air crescent sign, or (4) cavity within area of 
consolidationd, OR 
• The presence of a new non-specific focal infiltrate, PLUS at least one of the 
following: pleural rub, pleural pain or hemoptysis 


 
 
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Type of Criteria 
Criteria 
Sinonasal infection 
Major 
 
 
 
Minor  
 
Suggestive radiological evidence of invasive infection in sinuses (i.e., erosion of 
sinus walls or extension of infection to neighboring structures, extensive skull 
base destruction) 
 
Upper respiratory symptoms (e.g., nasal discharge, stuffiness); nose ulceration or 
eschar of nasal mucosa or epistaxis; periorbital swelling; maxillary tenderness; 
black necrotic lesions or perforation of hard palate 
CNS infection  
Major  
 
 
 
Minor 
 
Radiological evidence suggesting CNS infection (e.g., mastoiditis or other 
parameningeal foci, extradural empyema, intraparenchymal brain or spinal cord 
mass lesion) 
 
Focal neurological symptoms and signs (including focal seizures, hemiparesis, 
and cranial nerve palsies); mental changes; meningeal irritation findings; 
abnormalities in CSF biochemistry and cell count (provided that CSF is negative 
for other pathogens by culture or microscopy and negative for malignant cells) 
Disseminated fungal infection 
Papular or nodular skin lesions without any other explanation; intraocular 
findings suggestive of hematogenous fungal chorioretinitis or endophthalmitis 
Chronic disseminated 
candidiasis 
Small, peripheral, target-like abscesses (bull’s-eye lesions) in liver and/or spleen 
demonstrated by CT, MRI, or ultrasound, as well as elevated serum alkaline 
phosphatase level; supporting microbiological criteria are not required for 
probable category 
Candidemia 
Clinical criteria are not required for probable candidemia; there is no definition 
for possible candidemia 
a  H. capsulatum variant capsulatum, Blastomyces dermatitidis, Coccidioides immitis, or Paracoccidioides brasiliensis. 
b  Galactomannan Positivity: A positive galactomannan assay is defined as two positives on the same specimen or two consecutive 
positives on different specimens, i.e., a repeat test on the first specimen was not performed.  Sera with an index less than 0.5 are 
considered to be negative.  Sera with an index greater than or equal to 0.5 are considered to be initially positive. 
Whenever a sample has an index ≥ 0.5, positivity must be confirmed by re-testing the sample, including repeating the heat treatment on a 
new aliquot, and by testing another sample obtained from the patient.  This confirmation is necessary in order to eliminate any false-
positive results due to contamination of the sample after collection.   
c False-positive cryptococcal antigen reactions due to infection with Trichosporan beigelli (1), infection with Stomatococcus mucilaginosis 
(2), circulating rheumatoid factor (3), and concomitant malignancy (4) may occur and should be eliminated if positive antigen test is only 
positive result in this category. 
d In absence of infection by organisms that may lead to similar radiological findings including cavitation, such as Mycobacterium, 
Legionella, and Nocardia species. 


 
 
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APPENDIX H. EUROPEAN LEUKEMIANET GUIDELINES 
The following table summarizes the criteria for response as outlined in the European 
LeukemiaNet Guidelines.67   
Table 14: 
CML Response Criteria 
 
Optimal response 
Suboptimal response 
Failure 
Month 3 
CHR and at least 
minor CyR 
No CyR (>95% Ph+ 
cells) 
No CHR 
Month 6 
At least pCyR 
Less than pCyR 
No CyR (>95% Ph+ cells) 
Month 12 
cCyR 
Less than cCyR 
Less than pCyR 
Month 18 
MMR 
Less than MMR 
Less than cCyR 
At any 
time  
Stable or improving 
MMR 
Loss of MMR, BCR-
ABL mutation 
Loss of CHR, loss of cCyR, Clonal 
evolution 
Definitions: 
Complete Hematologic response (CHR)= normalized peripheral blood counts, white 
blood cell count below 10×109/L, platelets below 450×109/L, immature cells absent or 
normalized differential, no signs and symptoms of disease  
Cytogenetic response: 
Cytogenetic response (CyR) = 0-95% Ph+ cells 
Complete Cytogenetic response (cCyR) = absence of Ph+ cells 
Partial Cytogenetic response (pCyR) = 1–35% Ph+ cells 
Minor Cytogenetic response (mCyR) = 35-65% Ph+ cells 
Molecular response:  
Complete Molecular Response (CMR)= complete absence of BCR-ABL gene 
transcripts  
Major Molecular Response (MMR)= a 3-log decrease or a reduction to 0.1% 
compared with the baseline level of BCR-ABL transcripts 


 
 
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APPENDIX I. STATISTICAL ANNEX 
Further Details on Sample Size Calculation (Appendix to section 10.1.5 in the Protocol) 
The primary endpoint will be time from transplant to neutrophil engraftment. 
________________________________________________________________________
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Page 150 
APPENDIX J. LONG TERM FOLLOW-UP OBSERVATIONAL 
STUDY STATISTIC PLAN 
All analyses mentioned below will be conducted separately within each randomized 
treatment. Estimated quantities will be provided together with their standard errors or 
95% confidence intervals. 
Chimerism 
Peripheral blood chimerism will be assessed. Descriptive statistics (e.g., min, q1, median, 
q3, max) will be provided for chimerism at 2, 3, 4, and 5 years post transplant.  Patients 
who have progressed/relapsed, had autologous recovery, had graft failure, or who die 
before target day (2, 3, 4, and 5 years) will be excluded from this analysis after that event. 
 
Overall Survival  
The proportion of patients alive at 2, 3, 4, and 5 years post transplant will be estimated 
using the Kaplan-Meier method. 
 
Disease Free Survival  
The proportion of patients alive and without progression/relapse or autologous recovery 
at 2, 3, 4, and 5 years post transplant will be estimated using the Kaplan-Meier method. 
 
Secondary Graft Failure and Disease Relapse    
The cumulative incidence of patients with secondary graft failure and with disease 
relapse will be estimated.  For secondary graft failure, death, relapse, and primary 
engraftment failure will be considered competing events.  For relapse, death without 
relapse will be considered a competing event.   Characteristics of patients with secondary 
graft failure will be described separately from those patients without secondary graft 
failure. Similarly, characteristics of patients with disease progression/relapse or 
autologous recovery will be described separately from those who remain disease free. 
 
Immune Reconstitution 
The distributions of the numbers and proportions of different lymphocyte subpopulations 
at 2, 3, 4, and 5 years (mean, standard deviation, median, quartiles) will also be 
estimated.  Patients who have progressed/relapsed or experienced autologous recovery, 
had graft failure, or who die before target day (2, 3, 4, and 5 years) will be excluded from 
this analysis after that event. 
 
Chronic GvHD 
The cumulative incidence of patients who experience chronic GvHD will be computed at 
2, 3, 4, and 5 years post transplant. Death and second transplant will be considered as a 
competing risk in the estimation. 
 


 
 
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APPENDIX K. PROTOCOL AMENDMENT SUMMARY 
Table 15: 
Protocol Amendment Summary 
Protocol Version 
Main Reason(s) for Amendment 
Original 
N/A 
Amendment I 
 
Amendment II 
 
Amendment III 
 
Amendment IV 
 
Amendment IV.1 
 
Amendment IV.2 
 
Amendment V 
 
Amendment V.1 
 
Amendment VI 
 


 
 
 
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REFERENCES 
 
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Soc Hematol Educ Program: 419-437. 
2 Grewal, S. S., J. N. Barker, et al. (2003). "Unrelated donor hematopoietic cell 
transplantation: marrow or umbilical cord blood?" Blood 101(11): 4233-4244. 
3 Barker, J. N., T. P. Krepski, et al. (2002). "Searching for unrelated donor hematopoietic 
stem cells: availability and speed of umbilical cord blood versus bone marrow." 
Biol Blood Marrow Transplant 8(5): 257-260. 
4 Eapen, M. and J. E. Wagner (2010). "Transplant outcomes in acute leukemia. I." Semin 
Hematol 47(1): 46-50. 
5 Ballen, K. K., J. Koreth, et al. (2012). "Selection of optimal alternative graft source: 
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6 Iori, A. P., V. Valle, et al. (2012). "Concurrent search for unrelated cord and volunteer 
donor in high-risk acute lymphoblastic leukemia." Ann Hematol 91(6): 941-948. 
7 Solh, M. (2014). "Haploidentical vs cord blood transplantation for adults with acute 
myelogenous leukemia." World J Stem Cells 6(4): 371-379. 
8 Wagner, J. E. (2009). "Should double cord blood transplants be the preferred choice 
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9 Aljitawi, O. S. (2012). "Ex vivo expansion of umbilical cord blood: where are we?" Int 
J Hematol 95(4): 371-379. 
10 Brunstein, C. G., J. A. Gutman, et al. (2010). "Allogeneic hematopoietic cell 
transplantation for hematological malignancy: relative risks and benefits of 
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11 Eapen, M., V. Rocha, et al. (2010). "Effect of graft source on unrelated donor 
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12 Barker, J. N., M. Fei, et al. (2014). "Results of a prospective multicentre myeloablative 
double-unit cord blood transplantation trial in adult patients with acute leukaemia 
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13 Ruggeri, A., M. Labopin, et al. (2014). "Engraftment kinetics and graft failure after 
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regimen." Haematologica 99(9): 1509-1515. 
 


 
 
 
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14 Wagner, J. E., J. N. Barker, et al. (2002). "Transplantation of unrelated donor umbilical 
cord blood in 102 patients with malignant and nonmalignant diseases: influence 
of CD34 cell dose and HLA disparity on treatment-related mortality and 
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15 Yamazaki, R., M. Kuwana, et al. (2006). "Prolonged thrombocytopenia after allogeneic 
hematopoietic stem cell transplantation: associations with impaired platelet 
production and increased platelet turnover." Bone Marrow Transplant 38(5): 377-
384. 
16 Barker, J. N., A. Scaradavou, et al. (2010). "Combined effect of total nucleated cell 
dose and HLA match on transplantation outcome in 1061 cord blood recipients 
with hematologic malignancies." Blood 115(9): 1843-1849. 
17 Eapen, M., J. P. Klein, et al. (2014). "Impact of allele-level HLA matching on 
outcomes after myeloablative single unit umbilical cord blood transplantation for 
hematologic malignancy." Blood 123(1): 133-140. 
18 Purtill, D., K. Smith, et al. (2014). "Dominant unit CD34+ cell dose predicts 
engraftment after double-unit cord blood transplantation and is influenced by 
bank practice." Blood 124(19): 2905-2912. 
19 MacMillan, M. L., D. J. Weisdorf, et al. (2009). "Acute graft-versus-host disease after 
unrelated donor umbilical cord blood transplantation: analysis of risk factors." 
Blood 113(11): 2410-2415. 
20 Ramirez, P., C. G. Brunstein, et al. (2010). "Delayed platelet recovery after allogeneic 
transplantation: a predictor of increased treatment-related mortality and poorer 
survival." Bone Marrow Transplant. 
21 Stanevsky, A., A. Shimoni, et al. (2010). "Double umbilical cord blood transplant: 
more than a cell dose?" Leuk Lymphoma. 
22 Wagner, J. E., Jr., M. Eapen, et al. (2014). "One-unit versus two-unit cord-blood 
transplantation for hematologic cancers." N Engl J Med 371(18): 1685-1694. 
23 Glimm, H., W. Eisterer, et al. (2001). "Previously undetected human hematopoietic cell 
populations with short-term repopulating activity selectively engraft NOD/SCID-
beta2 microglobulin-null mice." J Clin Invest 107(2): 199-206. 
24 Tse, W. W., S. L. Zang, et al. (2008). "Umbilical cord blood transplantation in adult 
myeloid leukemia." Bone Marrow Transplant 41(5): 465-472. 
25 Cheung, A. M., D. Leung, et al. (2012). "Distinct but phenotypically heterogeneous 
human cell populations produce rapid recovery of platelets and neutrophils after 
transplantation." Blood 119(15): 3431-3439. 
26 De Lima, M., S. Robinson, et al. (2010). "Mesenchymal Stem Cell (MSC) Based Cord 
Blood (CB) Expansion (Exp) Leads to Rapid Engraftment of Platelets and 
Neutrophils." ASH Annual Meeting Abstracts 116(21): 362-. 
 


 
 
 
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27 Delaney, C., S. Heimfeld, et al. (2010). "Notch-mediated expansion of human cord 
blood progenitor cells capable of rapid myeloid reconstitution." Nat Med 16(2): 
232-236. 
28 de Lima, M., McNiece, I., Robinson, S.N., Munsell, M., Eapen, M., Horowitz, M., 
Alousi, A., Saliba, R., McMannis, J.D., Kaur, I., Kebriaei, P., Parmar, S., Popat, 
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Andersson, B.S., Shah, N., Oran, B., Cooper, L.J.N., Worth, L., Qazilbash, M.H., 
Korbling, M., Rondon, G., Ciurea, S., Bosque, D., Maewal, I., Simmons, P.J., and 
Shpall, E.J. (2012). "Cord-Blood Engraftment with Ex Vivo Mesenchymal-Cell 
Coculture." N Engl J Med 367(24): 2305-2315. 
29 Srour, E. F., R. Abonour, et al. (1999). "Ex vivo expansion of hematopoietic stem and 
progenitor cells: are we there yet?" J Hematother 8(2): 93-102. 
30 Ando, K., T. Yahata, et al. (2006). "Direct evidence for ex vivo expansion of human 
hematopoietic stem cells." Blood 107(8): 3371-3377. 
31 Drake, A. C., M. Khoury, et al. (2011). "Human CD34+ CD133+ hematopoietic stem 
cells cultured with growth factors including Angptl5 efficiently engraft adult 
NOD-SCID Il2rgamma-/- (NSG) mice." PLoS One 6(4): e18382. 
32 Holmes, T., F. Yan, et al. (2012). "Ex vivo expansion of cord blood progenitors 
impairs their short-term and long-term repopulating activity associated with 
transcriptional dysregulation of signalling networks." Cell Prolif 45(3): 266-278. 
33 Horwitz, M. E., N. J. Chao, et al. (2014). "Umbilical cord blood expansion with 
nicotinamide provides long-term multilineage engraftment." J Clin Invest 124(7): 
3121-3128. 
34 Xu, R. and J. A. Reems (2001). "Umbilical cord blood progeny cells that retain a 
CD34+ phenotype after ex vivo expansion have less engraftment potential than 
unexpanded CD34+ cells." Transfusion 41(2): 213-218. 
35 Szilvassy, S. J., Bass, M. J., Van Zant, G., Grimes, B. (1999). "Organ-selective homing 
defines engraftment kinetics of murine hematopoietic stem cells and is 
compromised by Ex vivo expansion." Blood 93(5): 1557-1566. 
36 Takatoku, M., S. Sellers, et al. (2001). "Avoidance of stimulation improves 
engraftment of cultured and retrovirally transduced hematopoietic cells in 
primates." J Clin Invest 108(3): 447-455. 
37 Ahmed, F., S. J. Ings, et al. (2004). "Impaired bone marrow homing of cytokine-
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38 Hofmeister, C. C., Zhang, J., Knight, K. L., Le, P., Stiff, P. J. (2007). "Ex vivo 
expansion of umbilical cord blood stem cells for transplantation: growing 
knowledge from the hematopoietic niche." Bone Marrow Transplant 39(1): 11-23. 
 


 
 
 
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39 Laughlin, M. J., J. Barker, et al. (2001). "Hematopoietic engraftment and survival in 
adult recipients of umbilical-cord blood from unrelated donors." N Engl J Med 
344(24): 1815-1822. 
40 Rocha, V., M. Labopin, et al. (2004). "Transplants of Umbilical-Cord Blood or Bone 
Marrow from Unrelated Donors in Adults with Acute Leukemia." N Engl J Med 
351(22): 2276-2285. 
41 Barker, J. N., D. J. Weisdorf, et al. (2005). "Transplantation of 2 partially HLA-
matched umbilical cord blood units to enhance engraftment in adults with 
hematologic malignancy." Blood 105(3): 1343-1347. 
42 Schoemans, H., K. Theunissen, et al. (2006). "Adult umbilical cord blood 
transplantation: a comprehensive review." Bone Marrow Transplant. 
43 Rodrigues, C. A., G. Sanz, et al. (2009). "Analysis of risk factors for outcomes after 
unrelated cord blood transplantation in adults with lymphoid malignancies: a 
study by the Eurocord-Netcord and lymphoma working party of the European 
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44 The 2012 revised edition of the EBMT-ESH Handbook on Haematopoietic Stem Cell 
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45 Kim, D. H., S. K. Sohn, et al. (2006). "Clinical significance of platelet count at day +60 
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46 Hamza, N. S., M. Lisgaris, et al. (2004). "Kinetics of myeloid and lymphocyte 
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47 Parody, R., R. Martino, et al. (2006). "Severe infections after unrelated donor 
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48 Engels, E. A., C. A. Ellis, et al. (1999). "Early infection in bone marrow 
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49 Vydra, J., R. M. Shanley, et al. (2012). "Enterococcal bacteremia is associated with 
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50 Yazaki, M., Y. Atsuta, et al. (2009). "Incidence and risk factors of early bacterial 
infections after unrelated cord blood transplantation." Biol Blood Marrow 
Transplant 15(4): 439-446. 
 


 
 
 
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55 Storek, J., M. A. Dawson, et al. (2001). "Immune reconstitution after allogeneic 
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SAP_001.pdf: 
 
CLIENT CONFIDENTIAL 
NCT02730299 
STATISTICAL ANALYSIS PLAN 
For 
Study Title:  A Multicenter, Randomized, Phase III Registration Trial of 
Transplantation of NiCord®, Ex Vivo Expanded, Umbilical Cord Blood-derived, 
Stem and Progenitor Cells, versus Unmanipulated Umbilical Cord Blood for 
Patients with Hematological Malignancies 
 
Version 5.0 
 
March 8, 2020 
 
Study Chairs 
________________________________ 
_______________________________ 
 
 
 
 
 
 
Distributed by: 
_____________ 
This communication is privileged and confidential. 


Statistical Analysis Plan 
 
Version 5.0 
PROTOCOL GC P#05.01.020 
 
March 8, 2020 
 
CLIENT CONFIDENTIAL 
2 
 
STUDY TITLE: A Multicenter, Randomized, Phase III Registration Trial of Transplantation of NiCord®, 
Ex Vivo Expanded, Umbilical Cord Blood-derived, Stem and Progenitor Cells, versus Unmanipulated 
Umbilical Cord Blood for Patients with Hematological Malignancies 
Short Title: 
Transplantation of NiCord® vs Unmanipulated 
Umbilical Cord Blood Cells for Patients with 
Hematological Malignancies 
Development Phase:  
Phase III, Registration 
Products:  
NiCord® 
IND Number: 
14459 
EudraCT Number: 
2016-000704-28  
Form/Route:  
Single ex-vivo expanded cord blood unit 
transplantation 
Indication Studied:  
Hematological malignancies 
Sponsor:  
Gamida Cell Ltd 
Jerusalem, Israel 
Protocol Chairs:  
_____________________________________
_____________________________________
_____________________________________ 
DCC Medical Monitor:  
_____________________________________
_____________________________________
_____________________________________ 
Clinical Trial Initiation Date:  
December 20, 2016 
Clinical Trial Completion Date:  
TBD 
Date of the Analysis Plan:  
March 8, 2020 
SAP Version Number:  
5.0 
This study will be performed in compliance with Good Clinical Practice. 
 


Statistical Analysis Plan 
 
Version 5.0 
PROTOCOL GC P#05.01.020 
 
March 8, 2020 
 
CLIENT CONFIDENTIAL 
3 
 
SIGNATURE PAGE 
SPONSOR: 
Gamida Cell Ltd 
 
STUDY TITLE:  
A Multicenter, Randomized, Phase III Registration Trial of Transplantation of 
NiCord®, Ex Vivo Expanded, Umbilical Cord Blood-derived, Stem and Progenitor 
Cells, versus Unmanipulated Umbilical Cord Blood for Patients with 
Hematological Malignancies 
 
 
 
 
 
 
 
 
 
 
 
 
Principal Study Statistician:  
 
Signed: 
 
Date:  
 
____________________:  
 
Signed: 
 
Date:  
 
 


Statistical Analysis Plan 
 
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March 8, 2020 
 
CLIENT CONFIDENTIAL 
4 
Table of Contents 
1. 
PREFACE .............................................................................................................................................. 10 
2. 
INTRODUCTION ................................................................................................................................... 10 
3. 
STUDY OBJECTIVES AND ENDPOINTS.................................................................................................. 10 
3.1 
Study Objectives ......................................................................................................................... 10 
3.2 
Study Endpoints .......................................................................................................................... 11 
3.3 
Study Definitions and Derived Variables .................................................................................... 11 
3.3.1 
Date of randomization ............................................................................................................ 11 
3.3.2 
Date of transplant ................................................................................................................... 11 
3.3.3 
Neutrophil engraftment .......................................................................................................... 12 
3.3.4 
Platelet engraftment ............................................................................................................... 12 
3.3.5 
Grade 2/3 Bacterial Infections and Grade 3 Viral infections ................................................... 12 
3.3.6 
Invasive Fungal Infection ......................................................................................................... 12 
3.3.7 
Duration of Primary Hospitalization ........................................................................................ 13 
3.3.8 
Days Alive and out of Hospital ................................................................................................ 13 
3.3.9 
Overall Survival ........................................................................................................................ 13 
3.3.10 Disease Relapse ....................................................................................................................... 13 
3.3.11 Disease-free Survival ............................................................................................................... 14 
3.3.12 Non-relapse Mortality ............................................................................................................. 14 
3.3.13 Relapse Mortality .................................................................................................................... 15 
3.3.14 Acute GvHD ............................................................................................................................. 15 
3.3.15 Chronic GvHD .......................................................................................................................... 15 
3.3.16 Immune Reconstitution ........................................................................................................... 15 
3.3.17 Health-Related Quality of Life (HQL) ....................................................................................... 15 
3.3.17.1 FACT-BMT ......................................................................................................................... 15 
3.3.17.2 EQ-5D ................................................................................................................................ 16 
3.3.18 Safety and Tolerability of NiCord® Transplantation ................................................................. 16 
4. 
INVESTIGATIONAL PLAN ..................................................................................................................... 16 
4.1 
Overall Study Design and Plan .................................................................................................... 16 
4.2 
Discussion of Study Design, Including Choice of Control Groups ............................................... 17 
4.3 
Selection of Study Population .................................................................................................... 19 
4.4 
Inclusion Criteria ......................................................................................................................... 19 


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4.5 
Exclusion Criteria ........................................................................................................................ 21 
4.6 
Treatments ................................................................................................................................. 22 
4.6.1 
Treatments Administered ....................................................................................................... 22 
4.7 
Method of Assigning Patients to Treatment Groups .................................................................. 23 
5. 
SAMPLE SIZE CONSIDERATIONS .......................................................................................................... 24 
6. 
GENERAL STATISTICAL CONSIDERATIONS ........................................................................................... 25 
6.1 
General Principles ....................................................................................................................... 25 
6.2 
Timing of Analyses ...................................................................................................................... 26 
6.3 
Analysis Populations ................................................................................................................... 26 
6.4 
Covariates and Subgroups .......................................................................................................... 27 
6.5 
Missing Data ............................................................................................................................... 27 
6.6 
Interim Analyses and Data Monitoring ....................................................................................... 28 
6.7 
Multicenter Studies .................................................................................................................... 28 
6.8 
Multiple Comparisons/Multiplicity ............................................................................................. 28 
7. 
Study Patients ..................................................................................................................................... 28 
7.1 
Patient Disposition ...................................................................................................................... 28 
7.2 
Protocol Deviations .................................................................................................................... 29 
8. 
Efficacy evaluation .............................................................................................................................. 29 
8.1 
Demographic and other baseline characteristics ....................................................................... 29 
8.2 
Concurrent illnesses and medical conditions ............................................................................. 29 
8.3 
Prior and concurrent medications .............................................................................................. 29 
8.4 
Measurements of treatment compliance .................................................................................. 29 
8.5 
Efficacy Analyses ......................................................................................................................... 29 
8.5.1 
Primary Efficacy Analysis ......................................................................................................... 31 
8.5.1.1 
Time to neutrophil engraftment ....................................................................................... 31 
8.5.1.1.1 Test Statistic ................................................................................................................. 32 
8.5.1.1.2 Re-randomization Distribution .................................................................................... 33 
8.5.1.1.3 Confidence Intervals for P* and for the difference in median times to engraftment . 33 
8.5.1.1.4 Missing Data for the Primary Endpoint........................................................................ 34 
8.5.1.1.5 Cumulative Incidence ................................................................................................... 35 
8.5.1.2 
Secondary analyses of time to neutrophil engraftment ................................................... 35 
8.5.1.3 
Clarification with regard to relapse before transplant ..................................................... 36 


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8.5.2 
Secondary Efficacy Analyses .................................................................................................... 37 
8.5.2.1 
Incidence of grade 2/3 bacterial or invasive fungal infections by 100 days 
following transplantation ................................................................................................. 37 
8.5.2.1.1 Missing Data ................................................................................................................. 37 
8.5.2.1.2 Secondary analyses ...................................................................................................... 38 
8.5.2.2 
Days alive and out of hospital in the first 100 days following transplantation ................ 39 
8.5.2.2.1 Missing Data ................................................................................................................. 39 
8.5.2.2.2 Secondary Analyses...................................................................................................... 40 
8.5.2.3 
Platelet engraftment by 42 days following transplantation ............................................. 40 
8.5.2.3.1 Missing Data ................................................................................................................. 41 
8.5.2.3.2 Secondary Analyses...................................................................................................... 41 
8.5.3 
Tertiary Endpoint ..................................................................................................................... 41 
8.5.3.1 
Non-relapse mortality by Day 210 post randomization ................................................... 41 
8.5.3.1.1 Missing Data ................................................................................................................. 41 
8.5.3.1.2 Secondary Analyses – Non-relapse mortality by Day 180 Post-Transplant ................. 42 
8.5.4 
Exploratory Efficacy Analyses .................................................................................................. 42 
8.5.4.1 
Neutrophil engraftment by 16 days following transplantation ........................................ 42 
8.5.4.2 
Time from transplantation to platelet engraftment ......................................................... 43 
8.5.4.3 
Duration of primary hospitalization .................................................................................. 43 
8.5.4.4 
Non-relapse mortality by 130 days following randomization .......................................... 44 
8.5.4.5 
Non-relapse mortality by 15 months following randomization ....................................... 44 
8.5.4.6 
Overall survival by 210 days following randomization ..................................................... 45 
8.5.4.7 
Overall survival by 15 months following randomization .................................................. 45 
8.5.4.8 
Disease-free survival by 15 months following randomization ......................................... 45 
8.5.4.9 
Neutrophil engraftment by 42 days following transplantation ........................................ 46 
8.5.4.10 Acute GvHD grade II-IV by 100 days following transplantation ....................................... 47 
8.5.4.11 Acute GvHD grade III-IV by 100 days following transplantation ...................................... 47 
8.5.4.12 Chronic GvHD (mild/moderate/severe) by 180 days following transplantation .............. 48 
8.5.4.13 Chronic GvHD (mild/moderate/severe) by 1 year following transplantation .................. 48 
8.5.4.14 Secondary graft failure by 1 year following transplantation ............................................ 48 
8.5.4.15 Grade 3 viral infections by 180 days following transplantation ....................................... 49 
8.5.4.16 Grade 3 viral infections by one year following transplantation ....................................... 49 
8.5.4.17 Relapse by 15 months following randomization .............................................................. 49 
8.5.4.18 Relapse mortality by 15 months following randomization............................................... 50 
8.5.4.19 Immune reconstitution at 28, 70, 100, 180, and 365 days following transplantation ..... 50 


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8.5.4.20 Health-related quality of life ............................................................................................. 50 
8.5.5 
Sub group analyses .................................................................................................................. 51 
9. 
Safety Monitoring ............................................................................................................................... 52 
10. Safety Evaluation ................................................................................................................................ 52 
10.1 
Solicited Adverse Events and Symptoms .................................................................................... 52 
10.1.1 Infusion Reactions ................................................................................................................... 52 
10.1.2 Infections ................................................................................................................................. 52 
10.1.3 Graft versus Host Disease ........................................................................................................ 52 
10.1.4 Common Events Post Transplant ............................................................................................ 52 
10.2 
Other Adverse Events ................................................................................................................. 53 
10.3 
Grade 3-5 and/or Serious Adverse Events during or post transplant ........................................ 53 
10.4 
Treatment Emergent Adverse Events ......................................................................................... 54 
10.5 
Maximum Severity of Adverse Events ........................................................................................ 54 
10.6 
Deaths ......................................................................................................................................... 54 
10.7 
Pregnancies ................................................................................................................................. 54 
10.8 
Clinical Laboratory Evaluations ................................................................................................... 54 
10.9 
Vital Signs and Physical Evaluations ........................................................................................... 55 
10.10 Concomitant Medications .......................................................................................................... 55 
11. Pharmacokinetics ................................................................................................................................ 55 
12. Other Analyses .................................................................................................................................... 55 
13. Technical Details ................................................................................................................................. 55 
14. Summary of Changes in the Conduct of the Study or Planned Analyses ............................................ 55 
15. Listing of Tables, Figures, and Data Listings ........................................................................................ 59 
16. References .......................................................................................................................................... 60 
 
 
 


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List of Abbreviations 
AE 
Adverse Event 
AEP 
ANC-Engrafted Population 
aGvHD 
Acute Graft-versus-host Disease 
ALL 
Acute Lymphoblastic Leukemia  
ALT 
Alanine Transaminase 
AML 
Acute Myelogenous Leukemia  
ANC 
Absolute Neutrophil Count 
APL 
Acute Promyelocytic Leukemia 
AST 
Aspartate Transaminase 
BM 
Bone Marrow 
BMT 
Bone Marrow Transplant 
BMTS 
Bone Marrow Transplantation Subscale 
CB 
Cord Blood 
CBB 
Cord Blood Bank 
CBU 
Cord Blood Unit 
cDLCO 
Corrected Diffusing Capacity of the Lungs for Carbon Monoxide 
CF 
Cultured Fraction 
cGvHD 
Chronic Graft-versus-host Disease 
CI 
Confidence Interval 
CIBMTR 
Center for International Blood and Marrow Transplant Research 
CML 
Chronic myeloid leukemia 
CMMoL 
Chronic myelomonocytic leukemia 
CNS 
Central Nervous System 
DCC 
Data Coordinating Center 
DLCO 
Diffusing Capacity of the Lungs for Carbon Monoxide 
DMC 
Data Monitoring Committee 
DRI 
Disease Risk Index 
EBV 
Epstein-Barr Virus 
FACT-BMT 
Functional Assessment of Cancer Therapy – Bone Marrow Transplant Module 
FACT-G 
Functional Assessment of Cancer Therapy - General  
FEV1 
Forced Expiratory Volume in One Second  
FISH 
Fluorescent In Situ Hybridization 
FVC 
Forced Vital Capacity  
FWE 
Family-wise Error Rate 
GvHD 
Graft-versus-host Disease 
HCG 
Human Chorionic Gonadotropin 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 


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HQL 
Health-related Quality of Life 
IPSS 
International Prognostic Scoring System 
ITT 
Intent to Treat 
IUD 
Intrauterine contraceptive Device 
KM 
Kaplan-Meier 
LCL 
Lower Confidence Limit 
LVEF 
Left Ventricular Ejection Fraction 
MDS 
Myelodysplastic Syndrome  
MFI 
Mean Fluorescence Intensity 
MLL  
Myeloid/Lymphoid Leukemia 
MMF 
Mycophenolate Mofetil 
MRD 
Minimal Residual Disease 
MRI 
Magnetic Resonance Imaging 
NF 
Non-cultured Fraction 
NIH 
National Institutes of Health 
PA 
Physician Assistant 
PCR 
Polymerase Chain Reaction 
PEP 
Platelet-Engrafted Population 
PT 
Preferred Term 
QOL 
Quality Of Life 
ROC 
Receiver Operating Characteristic 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SCID 
Severe Combined Immunodeficiency  
SCT 
Stem Cell Transplant 
SOC 
System Organ Class 
SP 
Safety Population 
TBI 
Total Body Irradiation 
TKI 
Tyrosine Kinase Inhibitor 
TNC 
Total Nucleated Cell 
TP 
Transplanted Population 
UCB 
Umbilical Cord Blood  
UCL 
Upper Confidence Limit 
WBC 
White Blood Cell 
 


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1. PREFACE 
The Statistical Analysis Plan (SAP) for Transplantation of NiCord® vs Unmanipulated Umbilical Cord Blood 
Cells for Patients with Hematological Malignancies provides additional detail for the statistical 
information described in the protocol.  This trial is sponsored by Gamida Cell, Ltd., and is implemented 
at multinational sites.  ____________ serves as the Data Coordinating Center (DCC) for this trial.   
The protocol itself provides details on conduct of the study and the operational aspects of clinical 
assessments.  This document provides a review of the study design, statements of general statistical 
considerations, detailed and comprehensive sections regarding the statistical analysis methods for 
efficacy and safety outcomes, and a list of proposed tables and figures.  Any deviation from this SAP will 
be described and justified in subsequent SAP amendments and/or in the Complete Study Report (CSR), 
as appropriate. 
2. INTRODUCTION 
The overall study objective is to compare the safety and efficacy of conditioning therapy followed by either 
NiCord® single ex vivo expanded cord blood unit (CBU) transplantation or unmanipulated cord blood unit 
CBU transplantation in patients with hematological malignancies for whom allogenic SCT is currently a 
recommended and potentially lifesaving treatment.  Patients will be randomized to NiCord® or 
unmanipulated CBU transplantation.  Sites may choose to use one of the protocol-specified conditioning 
regimens for all patients, or according to primary diagnosis/age group.  Patients will undergo the 
conditioning regimen, and then have the assigned transplant.  Patients are evaluated at post transplant 
study Days 1-7, 14, 21, 28, 35, 42, 56, 70, 100, 180, 270, and 365 for safety and efficacy endpoints.  
Patients are also evaluated at 15 months post randomization for survival and relapse status.  The primary 
endpoint is based on time to neutrophil engraftment with chimerism, where ANC engraftment must first 
be documented by Day 42.  Secondary endpoints include incidence of grade 2/3 bacterial or fungal 
infections by 100 days post transplant, days alive and out of hospital in the first 100 days post transplant, 
and platelet engraftment by Day 42 post transplant. Non-relapse mortality by Day 210 post randomization 
will be a tertiary endpoint.  Exploratory endpoints are described in Section 8.5.4. 
Patients may enroll in an optional long-term follow up substudy in which they will be followed for up to 
5 years post-transplantation.  The analyses for the substudy are provided in the protocol’s Appendix J. 
3. STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
The overall study objective is to compare the safety and efficacy of NiCord® single ex vivo expanded cord 
blood unit transplantation to unmanipulated cord blood unit transplantation in patients with 
hematological malignancies following conditioning therapy as follows:  
Primary Objective:  Assess the time to neutrophil engraftment following transplantation. 
Secondary Objectives:  Assess the secondary, tertiary and exploratory study endpoints. 


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3.2 
Study Endpoints 
Secondary Endpoints: 
• 
Incidence of grade 2/3 bacterial or invasive fungal infections by 100 days following 
transplantation 
• 
Days alive and out of hospital in the first 100 days following transplantation 
• 
Platelet engraftment by 42 days following transplantation 
Tertiary Endpoint: 
• 
Non-relapse mortality by 210 days following randomization 
Exploratory Endpoints: 
• 
Neutrophil engraftment by 16 days following transplantation 
• 
Time from transplantation to platelet engraftment 
• 
Duration of primary hospitalization 
• 
Non-relapse mortality by 130 days and 15 months following randomization 
• 
Overall survival by 210 days and 15 months following randomization 
• 
Disease free survival by 15 months following randomization 
• 
Neutrophil engraftment by 42 days following transplantation 
• 
Acute GvHD grade II-IV and III-IV by 100 days following transplantation 
• 
Chronic GvHD (mild/moderate/severe) by 180 days and 1 year following transplantation 
• 
Secondary graft failure by 1 year following transplantation 
• 
Grade 3 viral infections by 180 days and 1 year following transplantation 
• 
Safety and tolerability of NiCord® transplantation  
• 
Relapse by 15 months following randomization 
• 
Relapse mortality by 15 months following randomization 
• 
Immune reconstitution at 28, 70, 100, 180, and 365 days following transplantation 
• 
Supplemental immune reconstitution assessments at a central laboratory (optional) 
• 
Health-related quality of life  
• 
Long-term clinical outcomes up to 5 years following transplantation (optional) 
3.3 
Study Definitions and Derived Variables 
3.3.1 Date of randomization 
The date of randomization is defined as the date that the patient’s treatment assignment is issued. 
3.3.2 Date of transplant 
The date of transplant is defined as the first date of stem cell infusion following randomization, 
regardless of stem cell source. 


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3.3.3 Neutrophil engraftment 
Neutrophil engraftment is defined as achieving an absolute neutrophil count (ANC) ≥ 0.5 x 109/L on 3 
consecutive measurements on different days with subsequent donor chimerism (≤ 10% host cells by 
peripheral blood chimerism or bone marrow chimerism if peripheral blood chimerism is not available) 
any time on or after the day of engraftment up to the earlier of day 100 post-transplant, date of relapse, 
date of secondary graft failure, or date of death. The first day of the three ANC measurements will be 
designated the day of neutrophil engraftment and must occur on or before 42 days post transplant and 
also prior to any competing risks.  Chimerism from whole blood assessments on peripheral blood or 
bone marrow may be used, and myeloid (CD15 or CD33 lineage) may also be used to determine if the 
patient had <=10% host cells. 
Primary graft failure is defined as failure to achieve neutrophil engraftment by Day 42 as described 
above.  Infusion of a second stem cell product on or prior to day 42 will also be considered primary graft 
failure, with the following exception:  
• 
Infusion of an additional stem cell product after documented neutrophil engraftment will be 
considered secondary graft failure, even if it occurs on or prior to Day 42. 
The date of primary graft failure will be designated as Day 43 post transplant. 
Secondary graft failure consists of documented neutrophil engraftment, followed by severe neutropenia 
(<0.5 x 109/L for three or more consecutive laboratory values on separate days) with marrow cellularity 
<5%, without subsequent improvement occurring either spontaneously or after growth factor 
treatment.  Infusion of an additional stem cell product after documented neutrophil engraftment will be 
considered secondary graft failure.  The earlier of the first day of severe neutropenia, as defined above, 
or the date of first additional stem cell infusion will be designated the date of secondary graft failure.   
3.3.4 Platelet engraftment 
Platelet engraftment is defined as the first day of a minimum of 3 consecutive measurements on 
different days such that the patient has achieved a platelet count >20x109/L with no platelet 
transfusions in the preceding 7 days (count day of engraftment as one of the preceding 7 days) and no 
prior competing risks. The first day of the three measurements will be designated the day of platelet 
engraftment. 
3.3.5 Grade 2/3 Bacterial Infections and Grade 3 Viral infections 
The infection grading criteria are provided in protocol Appendix G.   
3.3.6 Invasive Fungal Infection 
Invasive fungal infection is defined as any grade 3 fungal infection.  The infection grading criteria are 
provided in the protocol Appendix G.   


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3.3.7 Duration of Primary Hospitalization 
Duration of primary hospitalization is defined as the total number of days from transplant to first 
discharge from the hospital. _____________________________________________________________ 
______________________________________ 
3.3.8 Days Alive and out of Hospital 
A day alive and out of hospital is defined as a full day (calendar day) in which the patient was alive and 
not hospitalized. Partial days alive and out of hospital, such as the day of admission, day of discharge 
and day of death, do not count as a day alive and out of hospital. The day of transplant will not count as 
a day alive and out of hospital ________________________________________________________.   
3.3.9 Overall Survival 
Overall survival is defined as the time from the date of randomization to death from any cause. 
3.3.10 Disease Relapse  
Relapse of malignancy  
Testing for recurrent malignancy in the blood, marrow or other sites will be used to assess relapse after 
transplantation. For the purpose of this study, relapse is defined by either morphological or cytogenetic 
evidence of AML, ALL, CML, MDS, or Lymphoma consistent with pre-transplant features.  For the 
purposes of the analyses, the date entered in the Disease Progression/Relapse (DPR) form as the 
progression/relapse date will be the relapse date. 
Minimal residual disease (MRD) 
MRD is defined by the sole evidence of malignant cells by flow cytometry, or fluorescent in situ 
hybridization (FISH), or Southern blot or Western blot, or polymerase chain reaction (PCR), or other 
techniques, in the absence of morphological or cytogenetic evidence of disease in blood or marrow.  
Since the frequency of testing for minimal residual disease is highly variable among centers, and the 
sensitivity is highly variable among laboratory techniques, evidence of minimal residual disease alone 
will not be sufficient to meet the definition of relapse in the context of this trial.  However, minimal 
residual disease that progresses can be considered as relapse and the date of relapse will be the date of 
detection of minimal residual disease, as described below.  
Acute Leukemia  
Relapse can be defined as any of the following.  
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________


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_____________________________________________________________________________________
_____________________________________________________________________________________
Chronic Myelogenous Leukemia (CML) 
Hematological relapse can be diagnosed when: 
_____________________________________________________________________________________
_____________________________________________________________________________________
Cytogenetic relapse can be diagnosed when:  
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
____________ 
MDS 
Relapse can be defined as any of the following.  
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
Lymphoma   
Relapse can be defined according to the criteria in protocol Table 2 and/or one or more of the following 
criteria: 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
3.3.11 Disease-free Survival 
Disease-free survival is defined as the survival without disease relapse or death from any cause, 
whichever comes first.   
3.3.12 Non-relapse Mortality 
Non-relapse mortality is defined as any death not preceded by relapse. 


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3.3.13 Relapse Mortality 
Relapse mortality is defined as any death preceded by relapse. 
3.3.14 Acute GvHD  
Acute GvHD will be staged and graded using the Consensus Conference on Acute GvHD grading 
(protocol Appendix B) at every protocol-specified scheduled visit up to day 180 post transplant. The date 
of GvHD, if applicable, will be assigned as the target visit date assigned to the first visit day post 
transplant on which the maximum symptoms in the assessment period meet the definition of acute 
GvHD. 
3.3.15 Chronic GvHD  
Chronic GvHD will be assessed on the day of diagnosis, as well as on Day 100, 180, 270 and year 1 post 
transplant and classified as mild/moderate/severe according to the 2014 NIH consensus criteria 
(protocol Appendix B). 
3.3.16 Immune Reconstitution 
Immune reconstitution will be assessed on Days 28, 70, 100, 180, and 365 post transplant. Cellular 
immune recovery will be assessed based on lymphocyte subset analysis to quantify the numbers and 
proportions of different lymphocyte subpopulations (CD3, CD4, CD8, CD19, CD56/16).  Additional 
assessments requested (but not required) are: CD123+ (dendritic lymphocytes), CD11c+ (dendritic 
myeloid cells), CD3+CD56+CD16+ (NKT cells), CD45RA+/CD62L+(RTE), CD25+/CD62L+(T-Reg), Total 
CD25+, CD57+/CD28+(CTL), HLA-DR+(Activated), and quantitative immunoglobulins (and record of IVIG 
administrations).  In patients enrolled in the optional immune reconstitution sub-study, additional 
exploratory immunologic parameters will be assessed.  The sub-study analyses are not described in 
this SAP and the specifications and analyses will be provided separately from the analyses specified 
in this SAP. 
3.3.17 Health-Related Quality of Life (HQL) 
Patient-reported health-related quality of life (HQL) outcomes will be assessed during the trial using two 
standardized measures including the Functional Assessment of Cancer Therapy –Bone Marrow 
Transplant Module (FACT BMT) and the EuroQol EQ-5D. 
3.3.17.1 
FACT-BMT 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 


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3.3.17.2 
EQ-5D 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________ 
3.3.18 Safety and Tolerability of NiCord® Transplantation 
The safety and tolerability of NiCord® transplantation will be evaluated based on infusion reactions, 
common events post-transplant, uncommon events post-transplant, infections, and hospitalizations.   
An infusion reaction is any adverse event that initiates or worsens (i.e., increases in grade above grade 
1) between the start of the graft infusion and 24 hours after the end of the graft infusion.  
Common events post-transplant are summarized in Appendix D of the protocol and reported 
___________________________________________________________________. Some 
additional events reported _____________________________ may be classified as common events 
based on a supplemental list provided prior to database closure (e.g., infections, relapse, febrile 
neutropenia, events related to GvHD).  Uncommon events are any adverse events that are not 
summarized in Appendix D and not on the supplemental list.  Non-serious uncommon events are 
reported on ________________________________________________________ and serious 
uncommon adverse events are reported on _________________________________________. 
4. INVESTIGATIONAL PLAN 
4.1 
Overall Study Design and Plan 
This study is an open-label, controlled, multicenter, international, Phase III, randomized study comparing 
transplantation of NiCord® to transplantation of one or two unmanipulated, unrelated cord blood units 
in patients with hematological malignancies for whom allogenic SCT is currently a recommended and 
potentially lifesaving treatment, all with required disease features rendering them eligible for allogeneic 
transplantation. 
Once qualifying CBUs have been identified and the patient (or legal guardian) signs the informed 
consent form (ICF), the patient will be screened for the study. 
Eligible patients will be randomized to receive either NiCord® or unmanipulated cord blood 
transplantation.  Randomization will be performed using a minimization algorithm.   
For patients randomized to the NiCord® transplantation arm, the CBU chosen for production (Treatment 
CBU #1) will be shipped from the Cord Blood Bank (CBB) to the manufacturing site. Upon release, 
NiCord® CF + NF will be shipped to the clinical site before transplantation. NiCord® CF will be thawed 
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the backup CBU(s), or a different backup source of stem cells will be transplanted as detailed in section 
8.3 of the protocol.  
For patients randomized to the unmanipulated cord blood transplantation arm, either one CBU 
(Treatment CBU #1) or two CBUs (Treatment CBU #1 and #2) chosen for transplantation will be shipped 
from the CBB to the clinical site and transplanted. 
Prior to the start of conditioning, the investigator must confirm patient suitability for transplant 
according to standard site practice. The conditioning regimen will consist of one of three options.  In 
general, each transplant center should commit to use the same conditioning regimen for all patients 
transplanted at their center, or according to primary diagnosis/age group _________________________ 
____  ________________________________________.  In any case, the determination of the choice of 
conditioning regimen must be made prior to randomization. 
The GvHD prophylaxis regimen will consist of Mycophenolate Mofetil (MMF) and a calcineurin inhibitor 
(Tacrolimus or Cyclosporine).  
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
___________________________________________________________ 
The decisions to use single or double cord for the unmanipulated CBU arm, the conditioning regimen 
and the GvHD prophylaxis are binding and cannot be modified according to the treatment allocation. 
Patients will have post-transplant study visits on Days 1-7, 14, 21, 28, 35, 42, 56, 70, 100, 180, 270, and 
365. The patient survival and relapse status should be assessed at 15 months or later post-
randomization. 
4.2 
Discussion of Study Design, Including Choice of Control Groups 
The study design was guided by the following considerations: 
Choice of control group 
The patients on the trial have hematological malignancies for which allogeneic SCT is currently a 
recommended and potentially lifesaving treatment.  For ethical reasons, the study will only enroll 
patients who do not have an adequate suitably matched and readily available stem cell donor.  
________________________________________.  This treatment has been selected as the control 
treatment for this trial.   
Blinding and randomization prior to preparation of CBU 
Treatment assignment is not blinded in this protocol because there is a delay between randomization 
and transplant due to different processing times required by the two treatments.  Randomization is 
completed prior to preparation of the NiCord® product or CBU(s) so that the randomization represents 
the clinical decision to initiate treatment with either standard of care or NiCord®.  


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Randomization method 
Patients will be randomized to treatment by NiCord® or by unmanipulated cord blood (single or double 
unit). The method of minimization will be used so as to provide balanced treatment assignment across 
selected factors of prognostic importance including: treatment center, age group, disease risk group, 
and intent to perform double or single CBU transplant.  
Conditioning Regimens 
Over the years, a number of different conditioning regimens have been established as standard of care 
for unrelated CB transplantation in adults, generally divided into TBI – based versus non-TBI.  In this 
study, the choice of conditioning regimen and GvHD prophylaxis agents is kept limited, in order to 
confirm the use of optimal patient care and to allow for clear interpretation of study results, while still 
providing the flexibility to choose between TBI-based and non-TBI regimens, and to allow for individual 
country and site accepted practices and experience. 
4.3 
Selection of Study Population 
The study will include patients with hematological malignancies for whom allogeneic SCT is currently a 
recommended and potentially lifesaving treatment. For ethical reasons, the study will only enroll 
patients who do not have an adequate suitably matched and readily available stem cell donor. 
4.4 
Inclusion Criteria 
Patients must meet all the following criteria to be eligible for study enrollment: 
1. Patients must be 12-65 years of age at the time of randomization 
2. Patients with one of the following hematological malignancies: 
• 
Acute lymphoblastic leukemia (ALL) at one of the following stages: 
• 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
__________________________________________________________ 
• 
Acute myelogenous leukemia (AML) at one of the following stages: 
• 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________ 


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• 
Chronic myelogenous leukemia (CML) at one of the following phases: 
• 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
________________________________________________________ 
• 
Myelodysplastic Syndrome (MDS) with history of one or more of the following: 
• 
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
________________________________________________ 
• 
Biphenotypic/undifferentiated/Prolymphocytic/Dendritic Cell Leukemias and Natural Killer 
Cell Malignancies________________________________________, adult T-cell 
leukemia/lymphoma ________________________________________ 
• 
Lymphoma, meeting one or more of the following criteria: 
o Burkitt’s lymphoma ________________________________________ 
OR 
o High risk lymphomas ________________________________________ 
OR 
o Chemotherapy-sensitive (defined as at least stable disease) lymphomas that have failed 
at least 1 prior regimen of multi-agent chemotherapy and are not candidates for an 
autologous transplant. 
(Patients with CLL are not eligible regardless of disease status) 
3. CBU criteria as described per protocol  
4. Patients who will be starting conditioning prior to NiCord release for infusion (i.e., NiCord arrival 
on site in adequate condition) must have an additional partially HLA-matched CBU reserved as a 
backup to the NiCord arm (in case of production failure).  
________________________________________________________________________
________________________________________________________________________
________________ 
5. ________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________________ 
6. Patient’s Performance score ≥70% by Karnofsky or Lansky 


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7. Patient has sufficient physiologic reserves including: 
• 
Cardiac 
__________________________________________________________________
______________________________________________________. 
• 
Pulmonary function tests 
__________________________________________________________________
__________________________________________________________________
__________________________________________________________________
__________________________________________.  
• 
Renal 
__________________________________________________________________
______________  
• 
Hepatic 
__________________________________________________________________
______________ 
8. Females of childbearing potential, defined 
________________________________________________________________________
________________________________________________________________________
________________________________________________________________________
________________________. 
9. Patient (or legal guardian) signs the written informed consent after being aware of the nature of 
the patient’s disease and willingly consents to the treatment program after being informed of 
alternative treatments, potential risks, benefits, and discomforts. 
 
4.5 
Exclusion Criteria 
1. MDS or CML with “marked” or “3+” fibrosis 
2. CLL 
3. Fewer than 21 days have elapsed since initiation of the patient's last chemotherapy cycle and 
the initiation of the stem cell transplant preparative regimen 
______________________________________________________________________________
__________________________________________ 
4. Persistent clinically significant toxicities 
______________________________________________________________________________
__  
5. Evidence of donor specific anti-HLA antibodies to the selected treatment CBU #1 (MFI>3000 to 
HLA A, B, C, or DRB1) 
6. Evidence of HIV infection or HIV positive serology 


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7. Evidence of active Hepatitis B, or Hepatitis C as determined by serology or PCR 
8. Pregnancy, as indicated by a positive serum or urine human chorionic gonadotrophin (HCG) test, 
or lactation 
9. Active malignancy other than that for which the UCB transplant is being performed within 12 
months of enrollment.  Fully resected cutaneous squamous cell or basal cell carcinoma or 
cervical carcinoma in situ within 12 months of enrollment will be permitted.   
10. Evidence of uncontrolled bacterial, fungal or viral infections or severe concomitant diseases, 
________________________________________ 
 
11. Patients with presence of leukemic blasts in the central nervous system (CNS)  
12. Patients with an 8/8 allele level HLA-matched and readily available related or unrelated donor 
(whose stem cells can be collected in a timely manner without jeopardizing recipient outcome). 
Patients who have haploidentical related donors or syngeneic donors will not be excluded 
13. Prior allogeneic hematopoietic stem cell transplant 
14. Allergy to bovine products, gentamicin, or to any other product that may interfere with the 
treatment  
15. Psychologically incapable 
______________________________________________________________________________
__ 
16. Enrolled in another interventional clinical trial or received an investigational treatment within 30 
days prior to the anticipated date of randomization, 
______________________________________________________________________________
_______________________________________________________________________ 
4.6 
Treatments 
4.6.1 Treatments Administered 
NiCord® is a cryopreserved cell-based product of allogeneic, ex vivo expanded, umbilical cord blood-
derived, hematopoietic CD34+ progenitor cells (NiCord® CF) and the non-expanded cell fraction of the 
same cord blood unit (NiCord® NF) consisting of mature myeloid and lymphoid cells.  
All CBUs should be procured from public banks that meet national applicable regulations. If the optimal 
unit(s) for the patient was determined ineligible or with unusual findings as per local regulations, the 
unit may be used under the urgent medical need provision and in consultation with the Sponsor.  
Prior to transplant, all patients will be treated with a conditioning regimen that is selected by the site 
from the protocol’s three options, and patients will be administered GHVD prophylaxis medications pre- 
and post-transplant. 


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4.7 
Method of Assigning Patients to Treatment Groups  
Enrolled patients will be assigned to the NiCord® or unmanipulated UCB arm based on minimization.  
This method will be used because of the limited number of patients, the potentially large number of 
participating centers, and the existence of several known important factors.  Minimization controls the 
balance of prognostic factors across the treatment groups more tightly than does stratified block 
randomization. A version of minimization will be used that includes assignment to the “optimal” group 
with a probability of 0.9, where “optimal” refers to the assignment that best balances the treatment 
groups with respect to the minimization factors.   
The minimization algorithm will be based on four factors:   
1. Treatment center  
• 
_____________________________________________________________________ 
2. Disease risk group  
• _____________________________________________________________________ 
3. Age group 
• _____________________________________________________________________  
4. Intent to perform single or double cord blood transplant 
• _____________________________________________________________________  
Although age, disease/stage, and intent to perform single or double cord blood transplant may not 
strongly influence the primary endpoint (time to neutrophil engraftment), there is an advantage in 
keeping them well balanced across the treatment groups for the purposes of comparing other important 
endpoints, including overall mortality and non-relapse mortality.   
To implement the minimization randomization, a measure of treatment group imbalance will be 
calculated for each new patient. For a given patient, the algorithm will compare the numbers of patients 
previously assigned to NiCord® at the same levels of the four factors as the current patient to the 
numbers of patients on unmanipulated UCB at the same levels of the four factors as the current patient.  
That is, 
• 
If nNicord< nUCB then assign to NiCord® with 90% probability. 
• 
If nNicord= nUCB then assign to NiCord® with 50% probability. 
• 
If nNicord> nUCB then assign to NiCord® with 10% probability. 
where  
• 
nNicord= count of those assigned to NiCord® in this patient’s disease risk group  
+ count of those assigned to NiCord® in this patient’s age group  
+ count of those assigned to NiCord® in this patient’s Center  


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+ count of those assigned to NiCord® where the intent was to perform a transplant of 
the same type (single/double) as this patient’s 
• 
nUCB= count of those assigned to unmanipulated UCB in this patient’s disease risk group  
+ count of those assigned to unmanipulated UCB in this patient’s age group  
+ count of those assigned to unmanipulated UCB in this patient’s Center  
+ count of those assigned to unmanipulated UCB where the site intended to perform a 
transplant of the same type (single/double) as this patient’s 
 
After the site completes the enrollment screening form in ______________________ and the patient 
meets all of the inclusion criteria and none of the exclusion criteria, and the site enters information 
regarding the patient’s disease risk group, age, and whether single or double cord blood transplant 
would be done, then the nNicord and nUCB scores are calculated by within the 
______________________ system.  Depending on which score is lower, the system will choose from the 
appropriate list of treatment assignments that are based on random uniform numbers.  Three lists will 
be used, so that one list will have NiCord® treatment assignments if the random number is less than or 
equal to 0.9, one will have unmanipulated UCB treatment if the random number is greater than 0.5, and 
one will have NiCord® treatment if the random number is less than or equal to 0.1. 
If a site incorrectly enters data for one or more of the minimization factors, and if it has been verified 
that change needs to be made to a minimization factor, a manual data change will be implemented.  The 
change in the factor will be incorporated into the analyses as described in section 8.5.1.1.2. 
5. SAMPLE SIZE CONSIDERATIONS 
The primary endpoint is time from transplant to neutrophil engraftment and the analysis will be based 
on the Mann Whitney test statistic if there are no losses to follow-up before Day 42.   
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_____________________________________________________________________________________
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__________________________________ 
The primary hypothesis is:  
H0:  there no difference in time to neutrophil engraftment by treatment group 
HA:  there is a difference in time to neutrophil engraftment by treatment group 
_____________________________________________________________________________________
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____________ 
The protocol targets an _______________ sample size of 120 patients for the following reasons: 
a) to provide an extensive safety database for NiCord® 
b) to determine whether a difference exists between the two groups for the primary endpoint and 
ensure that the statistical significance ______________________ 
c) ______________________________________________________________________________
________________________________ 
With the addition of a 12-17y age group in December 2017, the statistical power was recalculated, 
__________________________________________________________________ 
__________________________________________________________________ 
____________________________________________  A cap on the number of 12-17y olds to be 
entered into the trial will be set at 30.  
6. GENERAL STATISTICAL CONSIDERATIONS 
6.1 
General Principles 
Unless otherwise specified, all continuous variables will be summarized using the following statistics: n, 
mean, standard deviation (and/or median and quartiles or interquartile range (IQR), as appropriate), 
maximum, minimum.  All categorical variables will be summarized using the frequency and percentages 
of observed levels.  Statistics will be based on non-missing sample sizes unless methods for analyzing the 
missing data have been pre-specified.  Summary tables will be structured with a column or row for 
NiCord® and for Control (unmanipulated UCB) patients.   


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If a patient is lost to follow up, the day of loss to follow up is defined as the day after the date of last 
study contact. 
6.2 
Timing of Analyses 
The primary analysis and related neutrophil engraftment analyses will be conducted after all patients 
entered have completed follow-up necessary to evaluate the primary endpoint.  
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________. 
6.3 
Analysis Populations 
The screened population consists of all patients who signed informed consent. 
Intent-to-Treat (ITT) population includes all patients randomized into the trial, classified in the 
treatment groups to which they were allocated. Analysis of the ITT population provides the primary 
analysis of the primary endpoint, and also the primary analyses of the secondary endpoints, tertiary 
endpoint, and the analyses of exploratory endpoints unless otherwise stated. 
Transplanted population (TP) includes all patients randomized who received a cord blood transplant on 
or before 90 days post randomization.  Patients who received a cord blood transplant that was out of 
specifications are included in the TP.  Patients are assigned to the treatment groups to which they were 
allocated. Analysis of the TP population provides the analyses for the exploratory endpoints that depend 
on transplant, such as graft versus host disease.   
As treated (AT) population includes all patients randomized who received a cord blood transplant on or 
before 90 days post randomization, grouped by treatment actually performed.  Patients who received a 
cord blood transplant that was out of specifications are not included in the AT population.  Analysis of 
the AT population is for supportive purposes. 
ANC engrafted population (AEP) includes all patients who received a cord blood transplant on or before 
90 days post randomization and achieved neutrophil engraftment by Day 42 with subsequent 
chimerism; analysis is focused on the treatment actually performed.  Analysis of the AEP is for 
supportive purposes. 
Platelets-engrafted population (PEP) includes all patients who received a cord blood transplant on or 
before 90 days post randomization and achieved platelet engraftment; analysis is focused on the 
treatment actually performed.  Analysis of the PEP is for supportive purposes. 
Safety population (SP) is identical to the AT population defined above. 
A cord blood transplant includes a NiCord® transplant or a transplant from any cord blood unit, including 
unit(s) that differed from the unit(s) intended for transplant at the time of randomization.  All analysis 


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populations will include the patients as defined, even if the patients are later determined to have not 
met the eligibility criteria.  
6.4 
Covariates and Subgroups 
Descriptive statistics calculated based on the primary analyses of the primary and secondary endpoints 
will be provided for the following subgroups:  
1. Disease risk group as defined in section 4.7 (low, moderate and high/very high risk). 
2. Age group ____________________________________________.  
3. Intention to perform single versus double CB transplant  
4. Disease (ALL, AML, CML, MDS, Lymphoma, and other)  
5. HCT-specific co-morbidity index (0, 1-2, 3+) 
6. Gender (male, female) 
7. Race/Ethnicity (e.g., White/Hispanic or Latino, White/Not Hispanic or Latino, Black/Hispanic or 
Latino, Black/Not Hispanic or Latino, Asian/Hispanic or Latino, Asian/Not Hispanic or Latino, etc.)  
8. Geographical region 
The subgroup categories for race/ethnicity and geographical region will be added after 70% of the 
patients have been enrolled in the study. 
_____________________________________________________________________________________
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_____________________________________________________________________________________
_____________________________________________________________________________________
____________ 
6.5 
Missing Data 
If data for transplant or the primary or secondary endpoints are missing, the primary analyses of these 
endpoints will be adjusted for the missing data.  
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_____________________________________________________________________________________
_____________________________________________________________________________________
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___________________________________________________________________________ 
6.6 
Interim Analyses and Data Monitoring 
In addition, periodic data review will be conducted by the Data Monitoring Committee (DMC).  Policies 
and composition of the DMC are described in the DMC Charter.  Baseline characteristics, engraftment, 
infection, hospitalization, survival, relapse, GvHD, graft failure, toxicity, adverse events, and immune 
reconstitution will be summarized and reported to the DMC at each interim data review.  Additional 
outcomes or data may be provided to the DMC at their request.  
_____________________________________________________________________________________
_____________________________________________________________________________________
______.  No formal hypothesis testing of endpoints will be performed unless specifically requested by a 
majority of the DMC. 
____________________________________________  The procedures for monitoring these data will be 
specified in the protocol or DMC charter.   
6.7 
Multicenter Studies 
It is anticipated that up to _______ sites will participate in this study, and site is one of the factors for 
minimization randomization.  Site will not be included as an adjustment factor in the analyses but 
patient disposition, accrual, demographics, and baseline characteristics will be reported combined and 
separately by site to assess unanticipated site differences. 
6.8 
Multiple Comparisons/Multiplicity 
All statistical tests will be conducted against a two-sided alternative hypothesis, employing a significance 
level of 0.05. For the secondary endpoints, p-values will be adjusted for multiple testing using Hommel’s 
method that controls the family-wise error (FWE) rate. 1   
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________ 
7. Study Patients 
7.1 
Patient Disposition 
Patient disposition will be described in tables by site and randomized treatment group.  A CONSORT 
diagram will describe the patient disposition and loss to follow-up through the course of the study. 


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7.2 
Protocol Deviations 
Patient-specific and site-specific protocol deviations will be described.  Listings will include a description 
of the deviation and any action taken as a result.  
8. Efficacy evaluation 
8.1 
Demographic and other baseline characteristics 
Demographics and relevant baseline information (e.g., medical history, HCT-specific co-morbidity index, 
center, disease, disease risk group, intended treatment (single or double), weight) will be presented and 
summarized with appropriate descriptive statistics by site and overall. The comparability of the baseline 
factors between the treatment groups will be assessed. These summaries will be based on the ITT 
population. 
Descriptive statistics will be provided for cell doses, based on the ITT and AT population.   
8.2 
Concurrent illnesses and medical conditions 
Hospitalizations and infections will be analyzed as secondary endpoints. 
8.3 
Prior and concurrent medications 
No formal analyses or summaries of prior and concurrent medications will be completed by transplant 
group. 
8.4 
Measurements of treatment compliance 
Deviations from the conditioning regimen, infusion support, supportive cytokine therapy, transplant, 
and GvHD prophylaxis will be described based on the ITT population.  
_____________________________________________________________________________________
_____________________________________________________________________ 
8.5 
Efficacy Analyses 
The endpoints for efficacy include the primary efficacy endpoint, secondary endpoints, tertiary, and 
exploratory endpoints.   
General note on statistical testing and on confidence intervals for estimated parameters 
Because minimization is used for the treatment allocation method, we will employ re-randomization 
tests throughout (described below), for any intent-to-treat analysis to test for differences between the 
NiCord® and Control (unmanipulated UCB) groups.  
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_____________________________________________________________________________________
_____________________________________________________________________________________
____________________________________________________________________________________  
Re-randomization confidence interval 
(i) Introduction:  
_____________________________________________________________________________________
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_______________________________ 
(ii) General method:  
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(iii) Application to the primary endpoint:  
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(iv) Application to the secondary endpoint, probability of grade 2-3 bacterial/fungal infection by 100 
days post-transplant:  
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______________________________________________   
(v) Application to the other secondary endpoints:  
_____________________________________________________________________________________
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_____________________________________________________________________________________
_____________________________________________________ 
(vi) Validation of the proposed method:  
_____________________________________________________________________________________
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_______________________________________ 
8.5.1 Primary Efficacy Analysis 
8.5.1.1 
Time to neutrophil engraftment  
Tables will be included to provide descriptive statistics for time to transplant from randomization, and to 
provide reasons for not receiving a transplant by day 90 (if applicable). 
For the primary analysis of the primary endpoint of time from transplant to neutrophil engraftment 
(ANC engraftment with chimerism), the following data will be used for time to neutrophil engraftment: 
Primary Endpoint Outcome 
Assigned analysis day 
Met definition for neutrophil engraftment1 on or before 
Day 42 
First day of 3 different days of 
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Primary Endpoint Outcome 
Assigned analysis day 
x 109/L with donor chimerism < 10% of 
host cells documented as defined 
____________________________________________ 
______________________ 
____________________________________________ 
______________________ 
____________________________________________ 
______________________  
____________________________________________  
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____________________________________________  
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______________________  
____________________________________________ 
______________________ 
1 ANC recovery must occur on or before 42 days post transplant and donor chimerism must occur any time on or 
after the day of engraftment up to the earlier of day 100 post-transplant, date of relapse, date of secondary 
graft failure, or date of death. 
2_____________________________________________________________________________
____________________________________ 
3_____________________________________________________________________________
___________ 
   
8.5.1.1.1 
Test Statistic 
We will use the Mann-Whitney statistic, calculated on the engraftment times as defined in the table in 
Section 8.5.1.1. That table was formed by defining as competing risks the following events: (i) failure to 
receive a transplant within 90 days following randomization (counted as a competing risk event at 
day 0), (ii) relapse, (iii) death, and (iv) second transplant. 
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8.5.1.1.2 
Re-randomization Distribution 
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___________________________.  
8.5.1.1.3 
Confidence Intervals for P* and for the difference in 
median times to engraftment 
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_____________________________________________________________________________________
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____________ 
8.5.1.1.4 
Missing Data for the Primary Endpoint 
No Loss to Follow-up Prior to Day 42 
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Sensitivity Analysis If No Loss to Follow-up Prior to Day 42 
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Loss to Follow-up Prior to Day 42 
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_____________________________________________________________________________________
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__________________  
Sensitivity analysis for loss to follow-up 
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______ 
8.5.1.1.5 
Cumulative Incidence 
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_______________  
8.5.1.2 
Secondary analyses of time to neutrophil engraftment  
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__________________________________________. 
8.5.1.3 
Clarification with regard to relapse before transplant 
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_____________________ 
8.5.2 Secondary Efficacy Analyses 
8.5.2.1 
Incidence of grade 2/3 bacterial or invasive fungal infections by 
100 days following transplantation 
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8.5.2.1.1 
Missing Data 
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Sensitivity analysis 
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8.5.2.1.2 
Secondary analyses  
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_______________ 
8.5.2.2 
Days alive and out of hospital in the first 100 days following 
transplantation 
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8.5.2.2.1 
Missing Data 
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____________ 
Sensitivity Analysis 
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8.5.2.2.2 
Secondary Analyses 
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8.5.2.3 
Platelet engraftment by 42 days following transplantation 
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_____________________________________________________________________________________
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_________  
8.5.2.3.1 
Missing Data 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
___.   
Sensitivity Analysis 
_____________________________________________________________________________________
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________ 
8.5.2.3.2 
Secondary Analyses 
_____________________________________________________________________________________
_____________________________________________________________________________________
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___ 
8.5.3 Tertiary Endpoint 
8.5.3.1 
Non-relapse mortality by Day 210 post randomization 
The primary analysis will be performed on the ITT population.  
______________________________________________________________________________
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8.5.3.1.1 
Missing Data 
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Sensitivity Analysis 
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____________. 
8.5.3.1.2 
Secondary Analyses – Non-relapse mortality by Day 180 
Post-Transplant 
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________________________________________________________________________. 
8.5.4 Exploratory Efficacy Analyses 
8.5.4.1 
Neutrophil engraftment by 16 days following transplantation 
This analysis will be conducted on the ITT population. 
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8.5.4.2 
Time from transplantation to platelet engraftment 
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8.5.4.3 
Duration of primary hospitalization 
The primary analysis will be performed on the transplanted (TP) population.  
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____________ 
8.5.4.4 
Non-relapse mortality by 130 days following randomization 
The primary analysis will be performed on the ITT population.  
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8.5.4.5 
Non-relapse mortality by 15 months following randomization 
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_______________ 
8.5.4.6 
Overall survival by 210 days following randomization 
The primary analysis will be performed on the ITT population. 
_____________________________________________________________________________________
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_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________ 
8.5.4.7 
Overall survival by 15 months following randomization 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
__________________________________________________________________  
8.5.4.8 
Disease-free survival by 15 months following randomization 
This analysis will be performed on the ITT population.  
_____________________________________________________________________________________
_____________________________________________________________________________________


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_____________________________________________________________________________________
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_____________________________________________________________________________________
_____________________________________________________________________________________
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_____________________________________________________________________________________
_____________________________________________________________________________________
_______________ 
8.5.4.9 
Neutrophil engraftment by 42 days following transplantation 
The primary analysis will be conducted on the ITT population. 
_____________________________________________________________________________________
_____________________________________________________________________________________
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_____________________________________________________________________________________
________________________ 
8.5.4.10 
Acute GvHD grade II-IV by 100 days following transplantation 
This analysis will be conducted on the transplanted population (TP) 
_____________________________________________________________________________________
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_____________________________________________________________________________________
_____________________________________________________________________________________
__________________ 
8.5.4.11 
Acute GvHD grade III-IV by 100 days following transplantation 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
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_____________________________________________________________________________________
____________ 


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8.5.4.12 
Chronic GvHD (mild/moderate/severe) by 180 days following 
transplantation 
_____________________________________________________________________________________
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_____________________________________________________________________________________
__________________  
8.5.4.13 
Chronic GvHD (mild/moderate/severe) by 1 year following 
transplantation 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
________________ 
8.5.4.14 
Secondary graft failure by 1 year following transplantation 
This analysis will be conducted on the transplanted population (TP).  
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________


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_____________________________________________________________________________________
_____________________________________________________________________________________
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_____________________________________________________________________________________
_____________________________________________________________________________________
____________ 
8.5.4.15 
Grade 3 viral infections by 180 days following transplantation 
_____________________________________________________________________________________
_____________________________________________________________________________________
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_____________________________________________________________________________________
_____________________________________________________________________________________
_________ 
8.5.4.16 
Grade 3 viral infections by one year following transplantation 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
___ 
8.5.4.17 
Relapse by 15 months following randomization 
This analysis will be conducted on the ITT population.  
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
______________________________________________________________________________
________________________________________________________________________ 


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8.5.4.18 
Relapse mortality by 15 months following randomization 
This analysis will be conducted on the ITT population.  
_____________________________________________________________________________________
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____________ 
8.5.4.19 
Immune reconstitution at 28, 70, 100, 180, and 365 days 
following transplantation 
_____________________________________________________________________________________
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_______________ 
8.5.4.20 
Health-related quality of life  
Patient-reported health-related quality of life outcomes will be assessed on the ITT population using two 
standardized measures including the FACT BMT and the EuroQol EQ-5D. 
_____________________________________________________________________________________
_____________________________________________________________________________________


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_____________________________________________________________________________________
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_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
__________________. 
8.5.5 Sub group analyses 
Descriptive statistics calculated based on the primary analyses of the primary and secondary endpoints 
will be provided for the following subgroups:  
1. Disease risk group (low, moderate and high/very high risk). 
2. Age group __________________________________________________________.  
3. Intention to perform single vs. double CB transplant  
4. Disease (ALL, AML, CML, MDS, Lymphoma, and other)  
5. HCT-specific co-morbidity index (0, 1-2, 3+) 
6. Gender (male, female) 
7. Race/ethnicity (e.g., White/Hispanic or Latino, White/Not Hispanic or Latino, Black/Hispanic or 
Latino, Black/Not Hispanic or Latino, Asian/Hispanic or Latino, Asian/Not Hispanic or Latino, etc.) 
8. Geographical region 
_____________________________________________________________________________________
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_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_________ 


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9. Safety Monitoring 
The DMC will be provided monthly data ___________________________________________________  
10. Safety Evaluation 
The safety evaluations will be conducted on the safety population (SP). 
The analysis of adverse events, serious adverse events, and toxicities will be primarily descriptive. 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
___. 
10.1 
Solicited Adverse Events and Symptoms 
10.1.1 Infusion Reactions 
Infusion reactions will be described by nature and severity. The proportion of patients experiencing any 
infusion reaction and severe (Grade 3-5) infusion reactions at any time from start of infusion to 24 hours 
post infusion _________________________________________________________________________  
A table will be provided to summarize the maximum severity of infusion reaction reported per patient. 
The table will show maximum severity levels and the number of patients and the percentage of patients 
in that treatment group with that maximum severity level. 
10.1.2 Infections 
All grade 2 or 3 infections post randomization will be reported on an infection form.  Grade 2-3 bacterial 
infections or invasive fungal infections will be analyzed as a secondary endpoint.  Grade 3 viral infections 
will be analyzed as an exploratory endpoint.   
10.1.3 Graft versus Host Disease 
All AEs associated with GvHD will be reported on GvHD forms and used to calculate GvHD grade.  GvHD 
will be analyzed as an exploratory endpoint.  Some of the GvHD AEs may also be reported on the Serious 
Adverse Event form; these will be included in the safety evaluation analyses. 
10.1.4 Common Events Post Transplant 
Common events post transplant will be reported on the Adverse Event Form, Non Serious Adverse Event 
Log, and a Transplant Toxicity Summary form.  Common events will include those listed in protocol 
Appendix D, plus additional events in a supplemental list.  The summary of common events post 
transplant will not include symptoms from the GvHD forms unless they are also reported on the Adverse 
Event Forms, Adverse Event Logs, or Toxicity forms. 


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_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
______   
10.2 
Other Adverse Events 
• 
Non-serious uncommon events post transplant will be reported on an Adverse Event Log. 
• 
Serious Adverse Events post signing of consent will be reported on SAE forms set until at 
least 30 days post transplant and then up until the earlier of end of patient’s final study visit, 
date of post-transplant relapse, or date of graft failure.  Following date of post-transplant 
relapse or graft failure only SAEs resulting in death or with suspected causal relationship to 
the infused product will be reported.  However, SAEs must be reported on SAE summary 
forms set for at least 30 days post transplant even if post-transplant relapse or graft failure 
occur prior to that time point. 
• 
For patients who do not undergo transplant within 90 days following randomization and are 
enrolled in the post-randomization follow-up, only SAEs resulting in death will be reported 
after Day 90. Hospital admission reporting is due from time of the start of the conditioning 
regimen until end of study; this is reported on the Hospital Admission Summary form. 
Uncommon adverse events will be described by time period (Day 0-42, Day 42-365), MedDRA System 
Organ Class (SOC), Preferred Term (PT), severity, seriousness, and relationship to study product.  
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
___   
10.3 
Grade 3-5 and/or Serious Adverse Events during or post transplant 
Both common and uncommon severe grade 3-5 and/or serious adverse events will be described overall 
and pre-Day 42 and post-Day 42. 
_____________________________________________________________________________________
_____________________________________________________________________________________
_________________________________________________________________________________ 
A separate table will be provided to summarize the number of patients within each treatment group 
reporting serious adverse events by SOC/PT combination for events reported Day 0-42 and post Day 42. 


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10.4 
Treatment Emergent Adverse Events 
For this study, a treatment emergent adverse event is defined as an event that emerges during or after 
infusion having been absent pre-infusion, or worsens relative to the pre-infusion event. For events 
reported on the toxicity form, any event marked not clinically significant is considered as a grade 0 event 
for the purpose of the treatment emergent analyses.  All grade 1/2 events in categories in which the 
clinically significance question is present are analyzed as not clinically significant.  When the severity of 
an event on the toxicity form is missing or indicated as not evaluated at a visit, it is ignored when 
considering whether an event has worsened. 
An overview table of treatment emergent adverse events will be shown.  Additionally, tables by 
treatment group will summarize the number and percent of patients with treatment emergent events.  
In these tables, the number of people reporting an event within each SOC/PT combination will be 
counted for: 
• 
Grade 3-5 treatment emergent events in any SOC/PT combination that are related to study 
product  
• 
Treatment emergent events in any SOC/PT combination that are related to study product and 
that are reported as related to study product in at least 3% of the safety population 
• 
Grade 3-5 treatment emergent events in any SOC/PT combination that are reported in at least 
3% of the safety population 
10.5 
Maximum Severity of Adverse Events 
A table will be provided by treatment group that shows, on a patient level, the maximum severity of 
each SOC/PT combination reported for any adverse event or toxicity during the Day 0 – Day 42 and post 
Day 42 time periods.  Similar tables restricted to serious adverse events will be provided. 
10.6 
Deaths 
Primary cause of death will be summarized by treatment group.  
_____________________________________________________________________________________
________________________________________________________ 
10.7 
Pregnancies 
Pregnancies on study will be followed until outcome and described. 
10.8 
Clinical Laboratory Evaluations 
Clinical laboratory evaluations will not be analyzed per se, however, clinically significant abnormal values 
will be reported as adverse events and analyzed as referenced above.  A separate table summarizing the 
number of patients reporting laboratory adverse events by SOC and PT will be provided by treatment 
group.  Descriptive statistics for serum chemistry values and hepatic enzymes will also be provided by 
treatment group.  All post-randomization assessments will be used. 


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10.9 
Vital Signs and Physical Evaluations 
Vital sign and physical examination data including height and weight will not be analyzed for treatment 
group differences. A table summarizing the number of patients reporting vital sign adverse events by 
SOC and PT will be provided by treatment group.  Descriptive statistics for vital signs will also be 
provided by treatment group. All post-randomization assessments will be used. 
10.10 Concomitant Medications 
No formal statistical tests will be conducted on concomitant medication use.  A separate analysis will be 
conducted on resource utilization, including some concomitant medications.  Details will be provided in 
a separate document. 
Listings for conditioning medications, GvHD prophylaxis medications, GvHD treatment medications, 
infection treatment medications, and concomitant medications will be provided.  
11. Pharmacokinetics 
No pharmacokinetics analyses are planned in this study. 
12. Other Analyses 
The planned analyses are described above. 
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_____________________________________________________________________________________
_________ 
13. Technical Details 
SAS® version 9.4 or higher software and R version 3.1 or higher will be used for statistical analysis and 
data reporting of the information collected in this study. 
14. Summary of Changes in the Conduct of the Study or Planned Analyses 
This section will be updated as necessary at the time of analysis or amendment to the SAP.  Deviations 
from the final statistical analysis plan will be reported in the final study report. 


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Changes that do not affect the analyses or are not changes in the conduct of the study are not 
summarized. 
 
 


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Summary of SAP Changes in Conduct of Study or Planned Analyses  
(Version 1.0 to Version 5.0) 
Section Updated 
(Numbering based on 
latest SAP version) 
Summary of Update 
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Summary of Update 
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Summary of Update 
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15. Listing of Tables, Figures, and Data Listings 
The appendix contains potential table shells, figure outlines, and data listings.  Titles and structures of 
the TFL are intended to be descriptive only and not restrict designation of the publication table titles 
and structures. Further alternate data presentations may be considered as requested by investigators or 
for publication.  Additional data listings, including listings for any of the tables in the analysis, may also 
be provided. A listing for any table may also provide additional patient details (e.g., age, gender, 
diagnosis). 
 
 


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16. References 
 
1Hommel G.  A stagewise rejective multiple test procedure based on a modified Bonferroni test.  Biometrika 1988; 
75(2):383-386. 


Statistical Analysis Plan Version 5.0  
 
COVID-19 Section Version 1.0 
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August 31, 2020 
 
 
 
 
CLIENT CONFIDENTIAL 
1 
CHANGES RELATED TO COVID-19 PUBLIC HEALTH EMERGENCY 
Version 1.0 
31AUG2020 
Executive Summary 
• 
This addendum was incorporated to the SAP to document the assessment of the impact of the 
COVID-19 Public Health Emergency on the collection, analysis and interpretation of study GC 
P#05.01.020. The chapter was incorporated after the primary endpoint was analyzed and 
reported, and prior to analysis and review of any other study data, including the secondary and 
tertiary endpoints. 
• 
The potential impact was assessed by collecting and documenting all relevant changes that 
occurred in patient treatment, surveillance, and care. These changes will be reported and 
summarized in the Clinical Study Report (CSR). A detailed survey was conducted with the study 
sites to assess specifically any practice changes that may have impacted patient follow up or 
care for all study patients under the period of COVID-19 effect. 
• 
The interpretation of the information collected concludes that no specific change to the analysis 
of the study endpoints is currently warranted. 
Data Collection and Monitoring During the COVID-19 Public Health Emergency 
In response to the COVID-19 public health emergency occurring during the follow-up period of protocol 
GC P#05.01.020, several steps were undertaken to address any potential changes in data collection and 
monitoring that were required. 
Protocol Conduct Memorandum 
The trial sponsor distributed a memorandum on 24MAR2020 regarding “Protocol conduct during the 
COVID-19 pandemic” to all active sites. --------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------------------------------
------------------------------------------------------------------------------------------------------------------   
Reporting Requirements 
The electronic case report forms (eCRFs) were modified to collect information about whether 
alternative methods were used, and to consistently track those assessments that were missed due to 
the COVID-19 pandemic.  The Status Summary form was to be collected at all scheduled visits from Day 
42 to Day 365 post transplant and at Month 15 post randomization for transplanted patients and at all 
scheduled visits from Day 90 to Month 15 post randomization for non-transplanted patients; 
participants who were not transplanted by Day 90 were provided with the applicable subset of the 
questions.  Data were captured retrospectively beginning with forms version 11.01 (released on 
20MAR2020) or higher and on all new Status Summary eCRFs entered after 20MAR2020.  The questions 
include: 
• 
Was the patient seen at the original transplant center for the [XX] study visit?  (Yes/No) 
If the patient was physically seen in-person at the original transplant center, select "Yes." 


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2 
• 
Was the site's ability to perform any of the patient's study visit assessments affected by the 
restrictions implemented on patient visit/site staff/resources due to the COVID-19 pandemic? 
(Yes/No) 
• 
Were any required tests performed at a laboratory not listed on the FDA 1572 Form? (Yes/No) 
o --------------------------------------------------------------------------------------------------------------------- 
o --------------------------------------------------------------------------------------------------------------------- 
o --------------------------------------------------------------------------------------------------------------------- 
o --------------------------------------------------------------------------------------------------------------------- 
o --------------------------------------------------------------------------------------------------------------------- 
o --------------------------------------------------------------------------------------------------------------------- 
o --------------------------------------------------------------------------------------------------------------------- 
o --------------------------------------------------------------------------------------------------------------------- 
o --------------------------------------------------------------------------------------------------------------------- 
o --------------------------------------------------------------------------------------------------------------------- 
• 
Was the patient assessed by non-study team physician (or physician extender)? (Yes/No) 
o Acute and/or chronic GvHD (Yes/No) 
o Physical examination (Yes/No) 
• 
Were additional alternative methods (e.g. telemedicine) used to collect data at this study visit?   
(Yes/No) 
o If yes, specify the additional alternative methods of data collection. 
 
In addition, the following question was added to all Hospital Admission Summary eCRFs entered after 
November 27, 2019: 
• 
Was the patient’s date of discharge delayed or accelerated due to the COVID-19 pandemic?  If 
yes, provide an explanation. 
 
The study report will include data listings of these responses, including a list of patient visits conducted 
with a remote assessment, listings of hospital durations, missing forms exceptions, and patient visits, 
and protocol deviations related to the COVID-19 public health emergency.   
 
The sponsor reviewed and allowed the implementation of alternative methods for assessing patients if it 
was determined that the alternative methods did not materially change the protocol and allowed for 
continuing the study without impacting the integrity or quality of the data.  The sponsor also allowed for 
the study data to be remotely monitored through form uploads to the electronic data collection system 
and through remote viewing of the electronic medical record when permitted by the clinical site and by 
the local regulations.  Remote monitoring of the patients medical record was done through secure 
systems and in accordance with Good Clinical Practice (GCP), the Declaration of Helsinki, the provisions 
of the International Conference on Harmonization (ICH) Guidelines and all local applicable privacy laws 
and regulations. 
 
Sites Survey 
 
In addition to the data collected through the eCRF, the study monitors surveyed each site to assess 
changes in patient management, including hospitalization/discharge policies and supportive care, and 


Statistical Analysis Plan Version 5.0  
 
COVID-19 Section Version 1.0 
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August 31, 2020 
 
 
 
 
CLIENT CONFIDENTIAL 
3 
any changes to patient follow-up and the ability to detect outcome events.  Sites were surveyed to 
determine whether site practice changes affected study outcomes.  The survey questions were designed 
to capture any and all procedural changes related to the pandemic regardless of their direct relevance to 
the study endpoints.  This was meant to ensure that potentially impactful changes would not be missed 
because of a misunderstanding by site staff on what might be considered relevant.  These questions 
included: 
--------------------------------------------------------------------------------------------------------------------- 
--------------------------------------------------------------------------------------------------------------------- 
--------------------------------------------------------------------------------------------------------------------- 
--------------------------------------------------------------------------------------------------------------------- 
--------------------------------------------------------------------------------------------------------------------- 
--------------------------------------------------------------------------------------------------------------------- 
--------------------------------------------------------------------------------------------------------------------- 
--------------------------------------------------------------------------------------------------------------------- 
--------------------------------------------------------------------------------------------------------------------- 
Assessment of the Potential Impact of COVID-19 Public Health Emergency on Study 
Data 
The follow-up time extends either 42 days or 100 days post-transplant for the evaluation of the 
secondary endpoints and extends 210 days post randomization (which corresponds to minimum of 180 
days post transplant) for evaluation of the tertiary endpoint. Table 1 summarizes the number and 
percent of patients who remained under evaluation for the secondary or tertiary endpoints during the 
period when COVID-19 practices had taken effect.  According to the site survey responses, COVID-19 
related practice changes were implemented during March 2020 in most sites. Therefore, March 15, 
2020 was selected as a pivot-point for follow-up conducted before or during COVID-19 practice changes.  
Table 1.  Number of Randomized Patients with Evaluation Period Completed before March 15, 2020 
 
Randomized to 
NiCord 
(N=62) 
Randomized to 
Unmanipulated UCB 
(N=63) 
Endpoint 
Criteria Met before March 15, 
2020 
N 
% 
N 
% 
First grade 2/3 
bacterial or grade 3 
fungal infection by 
Day 100 post-
transplant 
 
 
 
 
 


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Randomized to 
NiCord 
(N=62) 
Randomized to 
Unmanipulated UCB 
(N=63) 
Endpoint 
Criteria Met before March 15, 
2020 
N 
% 
N 
% 
Number of days alive 
and out of hospital in 
the first 100 days 
post-transplant 
---------------------------------------------
------------- 
-------- 
-------- 
-------- 
-------- 
Platelet engraftment 
by Day 42 post-
transplant 
---------------------------------------------
-------                  --- 
-------- 
-------- 
-------- 
-------- 
Non-relapse mortality 
by Day 210 post-
randomization 
---------------------------------------------
-------                                                      
-------- 
-------- 
-------- 
-------- 
 
 
As shown in Table 1, approximately ------ of the study patients had completed their evaluation period for 
the secondary endpoints. Thus, only a limited number of study patients were at risk for any potential 
impact of COVID-19 on the evaluation of the study secondary endpoints. In addition, these patients 
were similarly distributed between the two study arms. 
 
-------- sites did not have any patients in follow-up during the COVID-19 public health emergency.  ---------
-------were sent the survey and --------  sites responded, representing ---------------- patients potentially 
affected by the COVID-19 public health emergency.  Written responses were followed by a conversation 
to clarify the responses as needed. Site responses did not indicate any changes that would have 
impacted the endpoints of the study.  Changes to standard practice included: 
• 
addition of COVID-19 specific testing requirements and patient education 
• 
use of telemedicine, home visits and local labs to limit potential exposure 
• 
visitor limitations and masking requirements 
• 
one site indicated some delays in getting lab results 
• 
completion of Health Related Quality of Life Questionnaires at home 
 
 
There was no indication of any changes in: 
• 
the likelihood or length of hospitalization 
• 
frequency of non-COVID infection surveillance 
• 
threshold to initiate infection work up and testing for respiratory symptoms  
• 
antimicrobial prophylaxis or treatment 
• 
platelet transfusion policies 
• 
frequency or timing of disease assessments 
• 
frequency of lab testing 


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A detailed summary of the changes in practices will be provided in the CSR. 
Based on the survey responses and the data in Table 1, the study sponsor and principal study statistician 
determined that the planned analyses for the study endpoints do not need to be changed from the pre-
determined plan described in the study’s statistical analysis plan (SAP).