Clinical trial NCT02406651
Conditions: Acute Graft vs Host Disease
Sponsor: EVIVE Biotechnology
Start date: 2016-05-12; Completion date: 2020-03-08
Enrollment: 30 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
A Phase IIa single arm open-label study to investigate the safety, tolerability, and PK of F-652 in combination with systemic corticosteroids in subjects who have undergone Hematopoietic Stem Cell Transplantation (HSCT) and have newly diagnosed grade II-IV lower GI acute Graft Verses Host Disease (aGVHD). Treatment with F-652 will be once a week for 4 weeks, with post treatment follow up visits on days 28, 56, 180 and 365.

Detailed description:
This is a Phase IIa single arm open-label study to investigate the safety, tolerability, and PK of F-652 in combination with systemic corticosteroids in subjects who have undergone HSCT and have newly diagnosed grade II-IV lower GI aGVHD. The HSCT may be derived from bone marrow, peripheral blood stem cells, or cord blood. The PK of F-652 in this subject population will be investigated. Subjects may be replaced if subject withdrawal is not related to safety or treatment response.

F-652 will be administered in conjunction with prednisone (or equivalent) at the time of the onset of clinical symptoms consistent with GI and/or liver aGVHD. Prednisone (or equivalent) will be given at a dose of 2 mg/kg/day and tapered as per protocol.

F-652 will be administered intravenously at a rate of 100 mL/hour for one hour once per week for four weeks. A total of 4 doses will be administered at a dose of 45 μg/kg each. Subjects will be followed for safety and efficacy through Day 180, and subject survival status will be collected at Day 365.

In the first stage of the trial, a total of 16 subjects will be enrolled. If six or fewer have a Day 28 treatment response, the trial will close due to a lack of efficacy. If seven or more have a response, an additional 11 subjects will be enrolled into study for a total sample size of 27. During the course of a subject's therapy, dose reduction may occur on an individual basis as per protocol.

Arms: arm 1: Subjects will be dosed once a week for four weeks with Recombinant Human Interleukin-22 IgG2-Fc (F-652). Dosing will be concurrent with systemic corticosteroids.
Interventions: intervention 1: Recombinant Human Interleukin-22 IgG2-Fc (F-652) intervention 2: Systemic Corticosteroids
Intervention descriptions: intervention 1: IV infusion of reconstitution lyophilized F-652. intervention 2: Prednisone (or equivalent) at the time of the onset of clinical symptoms consistent with GI and/or liver aGVHD, as per the standard of care. Prednisone (or equivalent) will be given at a dose of 2 mg/kg/day and tapered as needed.

Protocol documents:
Prot_000.pdf: 


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INTRODUCTORY AND CONFIDENTIALITY STATEMENT 
This protocol has been prepared according to the International Conference on 
Harmonisation (ICH) Harmonised Tripartite Guidelines for Good Clinical Practice 
issued in June 1996, with an implication date of January 17, 1997 and Food and Drug 
Administration (FDA) Good Clinical Practice (GCP) guidelines and Code of Federal 
Regulations (CFR): 21 CFR 312, 21 CFR 50, 21 CFR 56.  
This document contains confidential information of the Generon (Shanghai) 
Corporation that should not be disclosed to anyone other than the recipient study staff, 
members of the Ethics Committee, or Institutional Review Board, and Regulatory 
Authorities. This information cannot be used for any purpose other than the evaluation 
or conduct of the clinical study without the prior written consent of Generon (Shanghai) 
Corporation. 
PRINCIPAL INVESTIGATOR'S STATEMENT 
I, the undersigned, have reviewed this protocol, including appendices, and I agree to 
conduct the clinical study as described (subject to any amendments). Any changes in 
procedure will only be made if necessary to protect the safety, rights or welfare of study 
subjects. 
I agree to conduct in person or to supervise the study. I agree to ensure that all who 
assist me in the conduct of the study are aware of their obligations. 
 
Site Investigator: 
Site Number: 
 
 
…………………………………. 
……………………………………. 
Signature 
Date 


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Sponsor Approval and Medical Expert for the Trial: 
 
Tom Tang, MD,  
Regulatory and Clinical Affairs 
Building 9, 787 Kangqiao Road,  
Shanghai, PRC 201315 
Tel: 86 21-61760866 
Fax: 86 21-61760865 
 
 
 
 
…………………………………. 
……30 May 2017………………………… 
Signature 
Date 
 
 


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TABLE OF CONTENTS 
1 
INTRODUCTION ........................................................................................................................ 13 
1.1 
Acute GVHD and Current Therapy .................................................................................... 13 
1.1.1 
Recombinant Human IL-22 (F-652) and Reduction of GVHD ............................ 14 
1.1.2 
Clinical Studies and Previous Human Usage ....................................................... 16 
1.1.3 
Potential Risks and Benefits ................................................................................. 17 
2 
STUDY OBJECTIVES ................................................................................................................. 18 
2.1 
Study Objective .................................................................................................................. 18 
2.2 
Study Endpoints .................................................................................................................. 18 
Safety Endpoints ........................................................................................................................... 18 
Primary Efficacy Endpoint ............................................................................................................ 18 
Secondary Efficacy Endpoints ...................................................................................................... 18 
3 
INVESTIGATIONAL PLAN ....................................................................................................... 20 
3.1 
Overall Study Design .......................................................................................................... 20 
3.2 
Rationale for Study Design ................................................................................................. 24 
3.2.1 
F-652 Dosing ........................................................................................................ 24 
3.3 
Study Duration and Dates ................................................................................................... 24 
3.3.1 
Duration of Subject Participation ......................................................................... 24 
3.3.2 
Hold and Stop Rules ............................................................................................. 25 
3.3.2.1 
Hold and Discontinuation Rules for the Clinical Trial ........................ 25 
3.3.2.2 
Reasons for Subject Study Drug Discontinuation ................................ 25 
3.3.3 
End of Treatment and Follow-up Visits ............................................................... 25 
4 
STUDY POPULATION SELECTION ......................................................................................... 27 
4.1 
Study Population ................................................................................................................. 27 
4.2 
Inclusion Criteria ................................................................................................................ 27 
4.3 
Exclusion Criteria ............................................................................................................... 27 
5 
STUDY TREATMENTS .............................................................................................................. 29 
5.1 
Description of Treatments .................................................................................................. 29 
5.1.1 
Study Drug: F-652 (Recombinant human IL-22) ................................................. 29 
5.1.2 
Preparation 
 ............................................................................ 29 
5.2 
Treatments Administered .................................................................................................... 29 
5.2.1 
F-652 .................................................................................................................... 29 
5.2.1.1 
Pre-Treatment Criteria and Dose Modification Guidelines ................. 30 
5.2.2 
Systemic Corticosteroids ...................................................................................... 31 
5.2.3 
Prophylaxis Against Infection .............................................................................. 31 
5.2.4 
Supportive Care .................................................................................................... 31 
5.3 
 ....................................................................................... 32 
5.4 
Investigational Product at Study Site .................................................................................. 32 
5.5 
Test Article Accountability ................................................................................................. 32 
5.6 
Investigational Product at Study Site at Study Conclusion ................................................ 32 
5.7 
Selection and Timing of Dose for Each Subject ................................................................. 33 
5.8 
Method of Assigning Treatment to Subjects ...................................................................... 33 
6 
TRIAL PROCEDURES ................................................................................................................ 34 
6.1 
Measures to Avoid Bias ...................................................................................................... 34 
6.1.1 
Randomization ..................................................................................................... 34 
6.1.2 
Blinding ................................................................................................................ 34 


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6.1.3 
Simultaneous Utilization of All Arms .................................................................. 34 
6.2 
Concomitant Therapy ......................................................................................................... 34 
6.2.1 
Approved Medications ......................................................................................... 34 
6.2.2 
Change from Baseline in Medications ................................................................. 35 
6.3 
Restrictions ......................................................................................................................... 35 
6.3.1 
Medications Not Permitted ................................................................................... 35 
6.4 
Treatment Compliance ........................................................................................................ 35 
7 
STUDY PROCEDURES .............................................................................................................. 36 
7.1 
Informed Consent ............................................................................................................... 36 
7.2 
Medical History .................................................................................................................. 36 
7.3 
Physical Examination ......................................................................................................... 36 
7.4 
Vital Signs .......................................................................................................................... 36 
7.5 
Clinical Laboratory Tests ................................................................................................... 36 
7.5.1 
Laboratory Parameters ......................................................................................... 37 
7.5.1.1 
Sample Collection, Storage, and Shipping........................................... 37 
7.5.1.2 
Blood Volume ...................................................................................... 38 
7.5.2 
Urinalysis ............................................................................................................. 38 
7.5.3 
Assessment of aGVHD ........................................................................................ 38 
7.6 
Efficacy Assessments ......................................................................................................... 38 
7.6.1 
Methods and Timing for Assessing Acute Graft-Versus-Host Disease 
(aGVHD) .............................................................................................................. 38 
7.7 
Safety Assessments ............................................................................................................. 39 
7.7.1 
Standard Safety Parameters .................................................................................. 39 
7.7.2 
Adverse Events Assessments ............................................................................... 40 
7.7.2.1 
Procedures for Eliciting Reports of and Recording Adverse 
Events and Inter-current Illnesses ........................................................ 40 
7.7.2.2 
Timing and Duration of Follow-up of Subjects after Adverse 
Events Reported ................................................................................... 40 
7.7.3 
Defining, Grading, and Reporting Adverse Events .............................................. 40 
7.7.3.1 
Adverse Events .................................................................................... 40 
7.7.3.2 
Serious Adverse Events ....................................................................... 41 
7.7.3.3 
Severity and Grading ........................................................................... 42 
7.7.3.4 
Relationship ......................................................................................... 42 
7.7.3.5 
Clinical Significance ............................................................................ 43 
7.7.3.6 
Clinical Laboratory Adverse Events .................................................... 43 
7.7.3.7 
Reporting Adverse Events (Serious and Non-serious)......................... 43 
7.7.3.8 
Exposure In Utero ................................................................................ 45 
7.7.4 
Toxicity (Adverse Event) Management ............................................................... 46 
7.7.4.1 
Hematologic Toxicity .......................................................................... 46 
7.7.4.2 
Skin Toxicity ........................................................................................ 47 
7.7.4.3 
Other Toxicities ................................................................................... 47 
7.8 
Concomitant Medication Assessments ............................................................................... 48 
7.9 
Removal of Subjects from the Trial or Study Drug ............................................................ 48 
7.9.1 
Criteria for Subject Withdrawal ........................................................................... 48 
7.9.2 
Procedures for Subject Withdrawal ...................................................................... 49 
7.9.3 
Replacements for Withdrawn Subjects ................................................................ 49 
7.9.4 
Follow-Up of Withdrawn Subjects ....................................................................... 49 
7.9.5 
Documentation ..................................................................................................... 49 


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8 
QUALITY CONTROL AND ASSURANCE ............................................................................... 50 
9 
PLANNED STATISTICAL METHODS...................................................................................... 51 
9.1 
General Considerations ....................................................................................................... 51 
9.2 
Determination of Sample Size ............................................................................................ 51 
9.3 
Analysis Populations .......................................................................................................... 51 
9.3.1 
Safety Population ................................................................................................. 51 
9.3.2 
Efficacy Evaluable Population ............................................................................. 51 
9.3.3 
................................................................................. 51 
9.4 
Demographics and Baseline Characteristics ....................................................................... 52 
9.5 
Study Endpoints .................................................................................................................. 52 
9.6 
Statistical Methods.............................................................................................................. 52 
9.6.1 
Safety Analysis ..................................................................................................... 52 
9.6.2 
Primary Efficacy Analysis .................................................................................... 52 
9.6.3 
Secondary Efficacy Analysis ................................................................................ 52 
9.6.4 
 ............................................................................................ 53 
9.6.5 
 ................................................................................... 53 
9.6.6 
Criteria for Termination and Sponsor Discontinuation Criteria ........................... 53 
9.6.7 
Level of Significance............................................................................................ 53 
9.6.8 
Procedure for Accounting for Missing, Unused and Spurious Data .................... 53 
10 ADMINISTRATIVE CONSIDERATIONS ................................................................................. 54 
10.1 Investigators and Study Administrative Structure .............................................................. 54 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval ............................................................................................................................. 54 
10.3 Ethics .................................................................................................................................. 54 
10.3.1 
Treatment Considerations ..................................................................................... 54 
10.3.2 
Ethical Conduct of the Study ................................................................................ 55 
10.4 Subject Information and Consent ....................................................................................... 55 
10.5 Subject Confidentiality ....................................................................................................... 55 
10.6 Study Monitoring ................................................................................................................ 55 
10.7 Case Report Forms and Study Records .............................................................................. 55 
10.7.1 
Electronic Case Report Forms .............................................................................. 56 
10.8 Protocol Interpretation and Compliance ............................................................................. 56 
10.9 Access to Source Documentation ....................................................................................... 56 
10.10 Data Generation and Analysis ............................................................................................ 56 
10.11 Records Retention and Retention of Data ........................................................................... 57 
10.12 Financial Disclosure ........................................................................................................... 57 
10.13 Publication and Disclosure Policy ...................................................................................... 57 
11 REFERENCE LIST ...................................................................................................................... 58 
 


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LIST OF IN-TEXT TABLES 
Table 3.3.2.1. 
Stopping criteria for excessive mortality based on a Pocock boundary. ...25 
Table 5.2.1.1. 
F-652 administration schedule ...................................................................30 
Table 5.2.1.2. 
 ..............................................................................31 
Table 7.5.1.1. 
List of Laboratory Tests .............................................................................37 
Table 7.7.3.1. 
Attribution of Adverse Events ...................................................................43 
Table 7.7.4.1. 
Hematology Toxicity Management ...........................................................46 
Table 7.7.4.2. 
Skin Toxicity Management ........................................................................47 
Table 7.7.4.3. 
Other Toxicity Management ......................................................................47 
 


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LIST OF IN-TEXT FIGURES 
Figure 1. 
Post-BMT ISC Survival Curve in IL-22-Deficient Mice ..........................15 
Figure 2. 
Post-BMT Survival Curve .........................................................................16 
Figure 3. 
......................................................................22 
Figure 4. 
 ................................................................................23 
Figure 5. 
 .....................................................................32 
 


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LIST OF APPENDICES 
Appendix 1 
Trial Procedures and Study Activities .......................................................62 
Appendix 2 
Schedule of Procedures and Events ...........................................................65 
Appendix 3 
 .........................................................66 
Appendix 4 
 ......................................................................................67 
Appendix 5 
aGVHD Diagnosis and Grading Tables .....................................................69 
Appendix 6 
Criteria for Therapeutic Response/Outcome Assessment ..........................70 
Appendix 7 
List of Abbreviations and Definitions of Terms ........................................72 
 


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STUDY SYNOPSIS 
Protocol Number: 
GC-652-02 
Title: 
A Phase IIa Study of Recombinant Human Interleukin-22-IgG2-Fc (F-652) in 
Combination with Systemic Corticosteroids for the Treatment of Newly 
Diagnosed Grade II-IV Lower Gastrointestinal Acute Graft-versus-Host Disease 
in Hematopoietic Stem Cell Transplantation Recipients 
Study Phase: 
Phase IIa 
Name of Product: 
F-652 
Name of Active 
Ingredient: 
Recombinant human interleukin (IL)-22 and human immunoglobulin (Ig) 
IgG2-Fc fusion protein (rhIL-22 IgG2 Fc). 
Indication: 
Gastrointestinal (GI) Acute Graft-versus-Host Disease (aGVHD) in 
Hematopoietic Stem Cell Transplantation (HSCT) Recipients.  
Sponsor: 
Generon (Shanghai) Corporation  
Building 9, 787 Kang Qiao Road, 
Shanghai, PRC 201315 
Tel: 8621-61760866 
Fax: 8621-61760865 
Name of Sponsor 
Contact: 
Tom Tang, MD 
Generon (Shanghai) Corporation 
Name of Principal 
Investigators: 
Doris M. Ponce, M.D. 
Alan Hanash, M.D., PhD 
Juliet N. Barker, MBBS 
Memorial Sloan Kettering Cancer Center 
1275 York Avenue, 
New York, NY 10065  
Test Product, Dose, and 
Mode of Administration:  
F-652 is to be administered intravenously (IV) once a week for a total of 4 doses 
at 45 μg/kg each. Dose reduction is permitted depending on individual subject 
safety and tolerability. Reduced doses permitted in de-escalation order: 30 μg/kg 
and then 10 μg/kg. 
Concurrent Control: 
No concurrent control 
Objectives and Study 
Endpoints: 
Objective:  
The objective of the study is to assess the safety, efficacy, and pharmacokinetics 
(PK) of F-652 in combination with systemic corticosteroids for the treatment of 
newly diagnosed grade II-IV lower GI aGVHD in HSCT recipients. GVHD 
cytokines and biomarkers will be explored. 
Safety Endpoints: 
1. Adverse event (AE) reporting. 
2. Vital sign measurements 
3. Laboratory measurements 
4. Physical Examination 
Primary Efficacy Endpoint: 
To assess the lower GI aGVHD treatment response rate at Day 28. 
Secondary Efficacy Endpoints: 




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liver) will be allowed if grade II-IV lower GI aGVHD is concurrently present. 
Subjects will have an absolute neutrophil count (ANC) ≥500/mm3 and serum 
creatinine ≤3 mg/dL. A biopsy of the GI tract is required for study entry; 
However, results are not needed to initiate treatment. If GVHD is not confirmed 
histologically, treatment with F-652 will be discontinued and the subject will be 
withdrawn and replaced in the study. The severity of aGVHD will be graded 
using the International Bone Marrow Transplant Registry (IBMTR) criteria.  
Duration of Treatment: 
The duration of study treatment will be a total of approximately 4 weeks with a 
screening phase and a post treatment phase. All post treatment visits are 
scheduled after the initial F-652 treatment. 
Clinical assessments will occur during the screening period (up to 5 days), study 
entry (Day 0, first dose of F-652), and on Days 7, 14, 21, 28, 56, 180, and 365. 
Clinical visits will also occur according to the PK sampling schedule.  
PK sampling will occur on dosing Days 0, 7, 14, and 21 as follows (all post-dose 
sampling time points are after the start of the infusion): 
Day 0: 60 min pre-dose and post-dose 30 min, 1 hr, 8 hr, and 72 hrs. 
Days 7 and 14: 60 min pre-dose and post dose 30 min and 72 hrs. 
Days 21: 60 min pre-dose and post-dose 30 min, 1 hr, 8 hr, 24 hrs, 48 hrs, 
72 hrs, and 96 hrs. 
PK sampling will occur during follow-up on Days 28 and 56 as follows: 
Days 28 and 56: during the visit. 
. 
Subject Assignment: 
All eligible subjects will be given open label F-652. There will be no 
randomization in this single arm study. 
Efficacy Assessments: 
The efficacy of F-652 in combination with systemic corticosteroids for the 
treatment of grade II-IV lower GI aGVHD will be assessed by evaluating 
therapy response rate by Day 28.  
Safety Assessments: 
• 
AEs and serious adverse events (SAEs) 
• 
Vital signs 
• 
Clinical laboratory tests (to include hematology, serum chemistry, and 
urinalysis)  
• 
Physical examination 
Data Analyses: 
• 
Safety analysis will be assessed by a review of all safety parameters 
including AEs, SAEs, laboratory safety parameters, and vital signs. 
• 
Efficacy will be evaluated by treatment response along with 
immunosuppressive use and overall survival. In addition, GVHD 
biomarkers and cytokines will be explored. 
• 
Non-compartmental analysis of PK parameters, such as Cmax and AUC will 
be performed. 
Date 
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1 
INTRODUCTION 
1.1 
Acute GVHD and Current Therapy 
Acute graft versus host disease (aGVHD) is a frequent and, at times, unpredictable and severe 
complication of hematopoietic stem cell transplantation (HSCT).2-4 Organs affected in 
GVHD include the skin, liver, and/or the gastrointestinal (GI) tract, and is a common cause of 
transplant-related mortality (TRM).2,5 While calcineurin-inhibitor based GVHD prophylaxis 
has decreased the incidence and mortality associated with aGVHD, it provides inadequate 
protection since this disease commonly affects more than 50% of HSCT recipients.6,7 
Although several clinical factors have been associated with aGVHD risk, such as recipients 
of sex-mismatched HSCT, donor-recipient human leukocyte antigen-mismatch, peripheral 
blood stem cell graft and myeloablative conditioning,8,9 and omission of anti-thymocyte 
globulin (ATG) in the conditioning regimen,10 it is currently unknown which patients will 
develop this complication post-allograft. Ponce et al. demonstrated that GVHD frequently 
occurs after unmodified unrelated donor and cord blood transplantation; the incidence of 
grade II-IV aGVHD at Day 100 was found to be 56% and 55%, respectively.11 GVHD was 
the most common cause of transplant-related death in T-replete and T-cell depleted unrelated 
donor and cord blood transplant recipients. In this study and others, the GI tract was the organ 
most commonly associated with lethal GVHD.12-14 These findings support the investigation 
of new GVHD treatment strategies specifically targeting the GI tract. 
The standard treatment for grade II-IV aGVHD is systemic corticosteroids at a daily dose of 
2 mg/kg.15 However, treatment with systemic corticosteroids is non-target specific and can be 
associated with several and potential life-threatening side effects including lethal infections.16 
Approximately 50% of the patients will not achieve a sustained complete response (CR) to 
therapy with corticosteroids,6 and for those patients who fail to respond or are unable to 
maintain aGVHD control upon tapering corticosteroid therapy, escalation of 
immunosuppressive therapy is necessary.17,18 While several immunosuppressive agents can 
be added for second-line therapy, such as ATG, alemtuzumab, monoclonal antibodies against 
CD3, tumor-necrosis factor (TNF)-α inhibitor and pentostatin,19-24 they are usually associated 
with a very low durable CR rate and profound immunosuppression that may cause severe 
sequelae of infection and abrogation of graft-versus-tumor effect increasing the risk of 
disease relapse or progression.25,26 If clinical response is achieved to these agents, duration of 
remission is typically short. Therefore, survival is poor in corticosteroid-resistant aGVHD 
and approximately only 15% of the patients will be alive after 2 years.27 Thus, the ideal 
treatment of aGVHD is one that can preserve overall immunity and have low risk of infection 
complications while maintaining graft-versus-tumor effect to preserve the protection against 
malignant relapse. 
Better understanding of the mechanisms involved in the development of aGVHD could 
potentially reveal a targeted-specific therapy. Acute GVHD is caused by the allorecognition 
of host antigens by donor lymphocytes. The affected host organs may initially undergo injury 
from the direct toxicity of the conditioning regimen, which also leads to local entry of 
microbial products such as endotoxin or bacterial DNA. This injury and the subsequent 
signals generated by cytokines and microbial products could be the initial trigger for the 
production of further inflammatory cytokines which induce more efficient antigen processing 
and presentation by local dendritic cells (DC). This consequently leads to recruitment and 
activation of alloreactive naïve donor T-cells in secondary lymphoid tissues and proliferation. 
End-organ damage to targeted tissue (GI tract, skin, and liver) is subsequently mediated by 
the direct cytotoxic actions of activated donor effector T-cells as well as the actions of local 
cytokines. In animal models, cytokines up-regulation or down-regulation have been identified 


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as a manifestation of aGVHD.12,28-30 In the GI tract specifically, inflammatory cytokines can 
promote tissue injury causing an alteration of the intestinal stem cell (ISC) and progenitor cell 
niche that may result in gut GVHD.31,32 However, there is currently no treatment available to 
promote the recovery of the epithelial tissue that has been damaged by GVHD. 
GVHD involves complex interactions between innate and adaptive immunity, culminating in 
tissue damage by inflammatory mediators and cellular effectors. Acute GVHD is a 
proinflammatory process mediated in part by donor T-cells. Cytokines and chemokines 
influence T-cell differentiation pathways and trafficking to GVHD target organs and also 
mediate direct tissue damage. Notably, in murine studies, proinflammatory cytokines 
expressed in GVHD have been reported to regulate homing molecule expression on 
alloreactive donor activated T-cells.33-35 At Memorial Sloan Kettering Cancer Center 
(MSKCC), Hanash et al evaluated the effects of interleukin (IL)-21 signaling in donor T-cells 
in a murine model of bone marrow transplant.31 Using IL-21 receptor deficient donor T-cells 
they demonstrated that abrogation of IL-21 signaling led to decreased GVHD mortality and 
GI GVHD pathology. IL-21 receptor deficient T-cells showed decreased gut infiltration and 
reduction in inflammatory cytokine production within the mesenteric lymph nodes. IL-23 has 
similarly been implicated in experimental GI GVHD. This cytokine is produced by antigen 
presenting cells post-bone marrow treatment (BMT),35 and has been reported as a major 
regulator of IL-22 production.36-38 Donor bone marrow deficient in IL-23 reduced GI GVHD 
compared with animals receiving wild-type grafts. In DCs purified from the colon, levels of 
IL-23 and its receptor were elevated, but not at other GVHD target sites. Increased interferon 
(IFN)-γ CD4+ T-cells appear to mediate these inflammatory effects.35 
New insights into the roles played by cytokines in GVHD biology may provide novel targets 
for the prevention and treatment of aGVHD. 
1.1.1 
Recombinant Human IL-22 (F-652) and Reduction of GVHD 
IL-22 is an IL-10-family cytokine produced by innate lymphoid cells (ILCs) and T-cells.39,40 
The IL-22 receptor is present in many epithelial tissues and expression of IL-22 reduces the 
severity of multiple experimental injury models including colitis, hepatitis, and thymic 
radiation injury.41-43 Murine models of allogeneic HSCT have provided clinically relevant 
experimental systems for assessing mechanisms of immune-mediated intestinal damage and 
regeneration.44-46 Hanash et al studied the role of IL-22 in murine gut GVHD.32 They showed 
that intestinal IL-22 can be produced by intestinal lamina propia ILCs post-BMT, but that GI 
GVHD leads to loss of gut ILCs and impaired IL-22 production due to the elimination of 
IL-22 producing cells by the donor immune system. Deficiency of IL-22 led to increased 
GVHD in HSCT recipients (Figure 1). Additionally, mice deficient for IL-22 demonstrated 
increased gut pathology due to GVHD including intestinal crypt apoptosis, depletion of ISCs 
in the small intestine, and loss of epithelial integrity. 










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Pharmacokinetic Endpoints 
• Total exposure (AUC) 
• Cmax 
• Other parameters, such as CL, Vd, and λz maybe estimated. 


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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design  
This Phase IIa open label single arm study will enroll up to 27 subjects to investigate the 
safety, efficacy, and PK of F-652 (recombinant human IL-22) in combination with systemic 
corticosteroids for the treatment of newly diagnosed grade II-IV lower GI aGVHD in HSCT 
recipients. Acute GVHD will be initially diagnosed clinically and staged accordingly.1 
Grading of aGVHD will be based on International Bone Marrow Transplant Registry 
(IBMTR) criteria52. This clinical trial will investigate if the use of F-652 enhances the 
recovery of the GI tract after aGVHD mediated-injury. The safety endpoints of this study are 
to assess the incidence of AEs and SAEs, along with other safety. The primary efficacy 
endpoint is to assess F-652 treatment response at Day 28 in subjects with lower GI aGVHD. 
Candidates for this trial will include subjects ≥18 years and ≤80 years of age who are 
recipients of allogeneic HSCT using bone marrow, peripheral blood stem cells, or umbilical 
cord blood. Subjects must have stage 1-4 aGVHD of the lower GI tract at screening which 
will be determined by the maximum stool output in the preceding 3 days. Subjects with 
concurrent involvement of liver or skin aGVHD will be allowed but not as the sole organ 
affected. Biopsy of the GI tract is required for GVHD confirmation; however, results are not 
needed to initiate treatment. If GVHD is not confirmed histologically, treatment with F-652 
will be discontinued and the subject will be replaced. 
Eligible subjects will be consented and enter the study screening period. During this period, 
screening samples and tests will be obtained. A GI biopsy will be performed (if not done 
prior to study entry) for aGVHD disease histologic confirmation. The first dose of F-652 is to 
occur within 5 days after the subject’s initial administration of systemic corticosteroids. 
The expected duration of treatment for each subject is 4 weeks. F-652 weekly will be 
administered once a week for a total of 4 doses. Study enrollment will begin with 16 subjects 
dosed at 45 μg/kg of F-652. These subjects will be evaluated for treatment response at 
Day 28. If ≤6 of the first 16 subjects demonstrate a treatment response (i.e., response ≥PR), 
the clinical trial will be closed due to a lack of efficacy. If 7 or more subjects of the first 16 
subjects have a treatment response, an additional 11 subjects will be required to complete 
enrollment into the study for a total sample size of 27 patients (Figure 3). 
All subjects will be followed for efficacy through Day 56, safety through Day 180, and 
subject survival status will be collected at Day 365 (1 year from the date of initial dosing of 
F-652). 
Prior to each dosing of F-652, subjects are required to meet the following criteria: ANC 
≥500/mm3, serum creatinine ≤3.0 mg/dl, and all non-hematologic toxicity (except alopecia) 
attributed to the study drug as probable or greater to resolved to ≤ Grade 1 or returned to the 
subject’s baseline condition. Failure to meet these criteria will result in treatment delay, dose 
reduction, or withdrawal from the study, as outlined in Section 3.3.2 (Hold and Stop Rules). 
A review of excess subject mortality at Day 56 will occur for every 6 subjects accrued into 
the study. 
During the course of the study, systemic corticosteroids (prednisone or methylprednisolone 
equivalent) will be administered concurrently with F-652. Tapering of corticosteroids is 
permitted as outlined in Section 5.2 (Treatment Administrations); however, tapering should 
result in no less than 0.25 mg/kg/day of prednisone (or IV equivalent) by Day 28, after which 
tapering may be according to local institutional guidelines. 


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All subjects should be treated to the institutional allogeneic BMT standard of care guidelines 
for prophylaxis against infection. This includes, Pneumocystis carinii, Herpes simplex, 
Herpes Zoster, and fungal infections. Subjects will be closely monitored for cytomegalovirus 
(CMV) reactivation according to the each local center standard practice. 
The study drug will be administered on an inpatient or outpatient basis, depending on the 
subject’s clinical condition. The route of administration of F-652 is IV and will be 
administered once a week on Days 0, 7, 14, and 21. Following infusion of F-652, vital signs 
will be obtained and nursing assessment will be performed according to the BMT 
institutional standard of care. PK sampling will occur as per the schedule listed in Appendix 3 
and serum samples to test the immunogenicity of F-652 will be taken. Subjects will be 
evaluated for grade 3-4 toxicities, graded by the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE). A complete description of the study 
procedures for each clinical visit is presented in Appendix 1. 
GVHD biomarkers will be assessed at baseline and post-treatment. Baseline assessment of 
GVHD markers in the peripheral blood and GI tissue will be performed at the time of GVHD 
diagnosis, pending specimen availability. Due to the extensive processing of the peripheral 
blood for the assessment of GVHD cytokine markers, cytokine samples are optional for 
subjects participating in this study.  The biomarker panel will include ST2 and REG3α 
whereas the cytokine panel will include IL-21, IL-22, and IL-23 levels. A stool sample will 
be collected for intestinal microbiota analysis and GVHD biology, including histology and 
epithelial gene expression, will also be analyzed in biopsy samples from the GI tract as the 
specimen allows. Post-treatment evaluation of GVHD biomarkers/cytokines in the peripheral 
blood, stool sample for intestinal microbiota, and GI tract biopsies will be performed 
approximately 28 days after study drug initiation or at least 3 days after receiving last dose of 
study drug (subject and sample availability permitting). Sampling may be withheld in patients 
who are critically ill. 
A study visit schematic is provided in Figure 4 and a complete schedule of study procedures 
and events are presented in Appendix 2 (Schedule of Procedures and Events). 
 






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3.2 
Rationale for Study Design 
Acute GVHD is a frequent complication following HSCT and a leading cause of TRM. The 
mainstay of treatment of aGVHD is corticosteroids. Although effective for some, the overall 
initial response rate is only 50% which decreases to 42% when the GI tract is affected. GI 
aGVHD produces direct epithelial tissue injury causing intestinal damage and inflammation. 
Murine models have shown that GI aGVHD particularly targets the ISC compartment and 
results in the loss of ILCs. These ILCs produce cytokine IL-22, which mediates a variety of 
protective effects including maintenance of tissue homeostasis, epithelial barrier integrity, 
and inducer of antimicrobial peptides in the GI tract. However, with the loss of ILCs in GI 
aGVHD, the production of IL-22 is impaired. While there is no current approved therapy that 
enhances the recovery of the human intestinal damage caused by aGVHD, treatment with 
IL-22 in vivo has emerged as a novel therapy in murine GI aGVHD. These studies have 
demonstrated that IL-22 administration promoted healing of the GI tract through its trophic 
effects on the intestinal epithelium and increased the ISC recovery. 
This study is designed to determine the efficacy, safety, tolerability, and PK of F-652 in 
subjects with lower GI grade II-IV aGVHD. Based on the safety profile of F-652 observed in 
the Phase I trial and the lack of serious side effects and toxicity observed, this trial has been 
designed for the treatment of lower GI aGVHD with F-652 at a dose of 45 μg/kg in 
combination with systemic corticosteroids. 
All subjects will be dosed with single administration of 45 μg/kg of F-652 weekly for a total 
of 4 doses. Safety of the subjects will be m nitored throughout the study. An assessment of a 
subject’s ability to continue treatment before each dosing of F-652 will be made, with a dose 
reduction permitted (Section 5.2.1.1), as determined by the treating physician. The potential 
benefits of F-652 for the treatment of aGVHD in a clinical setting are to be evaluated in order 
to determine if expansion of F-652 in a clinical program is warranted. The design of this 
study ensures an incremental evaluation of subjects with aGVHD to ensure subject safety. 
3.2.1 
F-652 Dosing  
The dose chosen, 45 μg/kg, was the highest dose of F-652 tested in healthy male subjects 
with a demonstrated tolerable safety profile. The most common TEAEs identified were dry 
skin and eye pruritus. The PK results from the previous study indicated a once a week 
treatment regimen administered for 4 weeks, is appropriate. Study drug preparation is 
detailed in Appendix 4. 
3.3 
Study Duration and Dates 
3.3.1 
Duration of Subject Participation  
The duration of the study participation consists of an initial screening period, followed by 4 
weeks of treatment, and  4 post-treatment clinical visits (Days 28, 56, 180, and Day 365). 
Prior to study admission, there is a screening period of up to 5 days for the completion of the 
study consent form, the collection of medical history, signs and symptoms, laboratory tests, 
and biopsy sampling. After completion of therapy, subsequent evaluations will consist of a 
physical exam, blood tests, aGVHD assessment, and a post-treatment GI biopsy (as permitted 
by subject). 
Subjects will be required to provide samples for the PK and immunogenicity evaluation of 
F-652. PK sampling will occur as per the schedule listed in Appendix 3. 


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3.3.2 
Hold and Stop Rules 
3.3.2.1 
Hold and Discontinuation Rules for the Clinical Trial  
Subjects will be closely monitored for clinical deterioration (i.e., disease progression) by the 
study Investigators, the study Medical Monitor, and the Sponsor’s medical expert. In addition 
to standard toxicities such as alterations in blood chemistries or hematology, this monitoring 
will also include disease progression and treatment efficacy. 
Clinical Trial Termination: 
The study includes stopping criteria in the event that excessive Day 56 TRM is observed. The 
historical rate of TRM deaths is approximately 15-20%.53 A TRM of 40% at Day 56 would 
be considered unexpected and an unacceptable number of excess deaths. TRM is defined as 
death at any time from the commencement of pre-transplant conditioning due to any cause 
other than disease relapse with the exception of automobile or other accidents. 
In this study, there will be an ongoing review for excessive TRM. The study will be stopped 
for interim evaluation if the number of deaths is 3 or more in the first 5 subjects treated, 4 or 
more in the first 9 subjects treated, etc. as per Table 3.3.2.1. This evaluation will occur for the 
subject’s Day 56 visit (post their initial F-652 dosing). Subjects removed from the study due 
to negative biopsy for aGVHD will not be accountable for the mortality rate rule analysis. 
Table 3.3.2.1. Stopping criteria for excessive mortality based on a Pocock boundary. 
Failure Type 
Mortality Rate Rule for 
Study Termination 
Death rate in the 
population 
Probability boundary 
is crossed  
Transplant-Related 
Mortality (day +56)   
3 deaths in the first 5 
subjects treated 
0.15 
0.10 
4 deaths in the first 9 
subjects treated 
5 deaths in the first 13 
subjects treated 
0.40 
0.93 
6 deaths in the first 18 
subjects treated 
7 deaths in the first 23 
subjects treated 
8 deaths at any point   
From Ivanova A, Qaqish BF and Schell MJ (2005).54 
 
3.3.2.2 
Reasons for Subject Study Drug Discontinuation 
A subject may withdraw from the trial at any time at his/her own request, or he/she may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, behavioral, 
or administrative reasons. The list of reasons for subject withdrawal is provided in 
Section 7.9.1.  
3.3.3 
End of Treatment and Follow-up Visits 
All subjects will receive an End of Treatment assessment on Day 28. Subjects withdrawing 
from the study early will have their End of Treatment assessment visit and will be asked to 


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participate in a follow-up phone call. All AEs and concomitant medications will be recorded 
through 28 days after the last dose of study drug (Study Day 56) and only related SAEs (and 
associated concomitant medications)will be recorded through its stabilization, resolution, or 
the end of the study.   
For subjects completing treatment, follow up visits will occur on Days 56, 180, and 365 from 
the first dose of F-652. The 365-day follow up visit will evaluate the subject’s general health 
and aGVHD status. Subjects will be discharged from the study following the Day 365 
Follow-up Visit. 


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4 
STUDY POPULATION SELECTION 
4.1 
Study Population 
The study population will consist of adult male and female subjects aged ≥18 to ≤80 years of 
age with newly diagnosed stage I-IV lower GI aGVHD1 following allogeneic HSCT.  
Eligible subjects must meet all entry criteria prior to receiving study medication, except for 
histologic confirmation of disease, as outlined below. If lower GI aGVHD is not confirmed 
histologically, the subject will be withdrawn from the study and replaced. 
4.2 
Inclusion Criteria 
Each subject must meet the following criteria to be enrolled in this study: 
1. Age ≥18 years and ≤80.  
2. Newly diagnosed stage 1-4 lower GI aGVHD1 with a minimum stool volume 
>500 mL/day (determined by the maximum stool output in the preceding 3 days) 
following allogeneic HSCT using bone marrow or peripheral blood stem cells, or cord 
blood. 
3. Subjects are willing to undergo a biopsy to confirm lower GI aGVHD. Biopsy results are 
not needed to initiate treatment. However, if aGVHD is not confirmed histologically, 
treatment with F-652 will be discontinued. 
4. Female subjects of childbearing potential who: agree to practice 2 effective methods of 
contraception at the same time from the time of signing the informed consent form (ICF) 
through 90 days after the last dose of study drug, OR are postmenopausal for at least 1 
year before the screening visit, OR are surgically sterile, OR agree to practice true 
abstinence when this is in line with the preferred and usual lifestyle of the subject 
(periodic abstinence and withdrawal are not acceptable methods of contraception). 
5. Male subjects, even if surgically sterilized (i.e. status post-vasectomy) must agree to one of 
the following: agree to practice effective barrier contraception during the entire study 
treatment period and through 90 days after the last dose of study drug, OR agree to 
practice true abstinence when this is in line with the preferred and usual lifestyle of the 
subject (periodic abstinence and withdrawal are not acceptable methods of contraception). 
6. Have adequate renal function (Serum creatinine <3 mg/dL). 
7. ANC >500/mm3. 
8. Show evidence of a personally signed and dated informed consent document indicating 
that the subject (or legally acceptable representative) has been informed of all pertinent 
aspects of the trial.  
4.3 
Exclusion Criteria 
Subjects who meet any of the following criteria will be excluded from the study. 
1. Evidence of relapse or progression of hematologic malignancy at the time of study 
enrollment. 
2. Active uncontrolled infection. Subjects with a controlled infection receiving definitive 
therapy for 48 hours prior to enrollment are eligible. 
3. Subjects requiring vasopressors or mechanical ventilation. 
4. Subjects who have received previous systemic corticosteroids for the treatment of acute 
GI GVHD for longer than 5 days. Subjects who were treated with systemic 
corticosteroids for aGVHD for a prior allogeneic HSCT >12 months ago are eligible. 


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5. Subjects who received any corticosteroid therapy (for non-GVHD) at doses 
>0.5 mg/kg/day prednisone (or IV equivalent) within 7 days prior to the onset of GVHD 
therapy. 
6. Subjects who developed aGVHD after unplanned donor lymphocyte infusion. 
7. Subjects with chronic GVHD features (i.e., acute/chronic GVHD overlap syndrome or 
classical chronic GVHD). 
8. History of psoriasis. 
9. History of epithelial malignancies including melanoma or any carcinomas. 
10. History or diagnosis of mantle cell lymphoma or anaplastic large cell lymphoma. 
11. Subject is pregnant or breast-feeding. 
12. Evidence of current uncontrolled cardiovascular conditions, including uncontrolled 
hypertension, uncontrolled cardiac arrhythmias, symptomatic congestive heart failure, 
unstable angina, or myocardial infarction within the past 6 months. 
13. The subject or guardian is unable to give informed consent or unable to comply with the 
treatment protocol including appropriate supportive care, follow-up, and research tests. 
14. The subject has tested positive for the Clostridium difficile toxin within 7 days of study 
entry. 
15. Cytotoxic, biologic, or investigational agents are not permitted throughout the study. 
These include, but are not limited to, antithymocyte globulin, alemtuzumab, rituximab, 
photopheresis, and thalidomide. Subjects who participated in any other investigational 
drug trial or had exposure to any other investigational agent, device or procedure, within 
4 weeks prior to screening and throughout the entire trial, except for trials of 
investigational drugs administered prophylactically for GVHD or CMV post allogeneic 
HSCT. In this exception, the other investigational drug must be discontinued upon 
enrolling (i.e., screening/sign ICF) into this study. 
16. Any serious medical or psychiatric illness that could, in the Investigator’s opinion, 
potentially interfere with the completion of treatment according to this protocol. 










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action being taken with study medication after the study is completed, the Investigator will 
contact the Sponsor or the contracted research organization for approval of such action. 
5.7 
Selection and Timing of Dose for Each Subject 
Once a subject has met the eligibility criteria, dosing will commence as specified in 
Section 5.2.  
5.8 
Method of Assigning Treatment to Subjects  
Study site personnel will assign the investigational drug to each subject via IWRS. The IWRS 
system will identify which study drug vial is to be used for reconstitution and administered to 
a subject using its unique identification number. 




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6.2.2 
Change from Baseline in Medications  
Systemic corticosteroid therapy may be tapered, as indicated in Section 5.2.2. No tapering of 
systemic immunosuppression will be allowed sooner than Study Day 3. Taper after Study 
Day 3 is allowed at the discretion of the treating physician. The treating physician may adjust 
tacrolimus, CSA, MMF, and sirolimus medications, as necessary. 
6.3 
Restrictions 
6.3.1 
Medications Not Permitted 
Besides those medications specified in the exclusion criteria (see Section 4.3), addition of 
other systemic immunosuppression agents would result in subject withdrawal from the study. 
Cytotoxic, biologic, or investigational agents are not permitted throughout the study. 
6.4 
Treatment Compliance 
Subject compliance will be monitored by obtaining the study medication accountability 
inventory and a record of any delayed doses, along with a list of concomitant medications 
according to the institutional policy, at each visit. 


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7 
STUDY PROCEDURES 
7.1 
Informed Consent 
The Investigator will obtain and document an ICF for each subject screened in this study. 
Prior to the initiation of any study procedures, all subjects will be informed in writing of the 
nature of the protocol and investigational therapy, its possible hazards, and their right to 
withdraw at any time, and will sign a form indicating their consent to participate. The 
subject’s medical records should contain written documentation indicating that informed 
consent was obtained. The ICF must be reviewed and approved by the Investigator’s 
designated Institutional Review Board (IRB)/Independent Ethics Committee (IEC) and by the 
Sponsor. The ICF should include all the elements as outlined in Section 4.8.10 of the ICH 
guideline for GCP (E6). 
7.2 
Medical History 
Medical history will be collected at screening evaluation and clinical symptomatology will be 
assessed by subject interview at each scheduled visit post-initial dose of F-652 therapy. 
Concomitant medications, dose of corticosteroids, illnesses, AEs, and participation in other 
investigational drug studies will also be recorded. If other unscheduled activities are 
performed up to Study Day 56, such as physical examination or laboratory studies, the results 
should be recorded in the subject’s eCRF. 
7.3 
Physical Examination 
Physical examination including height and body weight will be performed at screening. 
Height will be recorded at screening only; if it is not possible to measure height at screening, 
a historical record of height may be used (e.g., height as measured at hospital admission). 
Physical exam will be done on visit Days 0, 28, 56, 180, and 365 post-initial dose of F-652 
therapy. Any change from baseline will be evaluated and assessed by the Investigator. Any 
clinically significant findings from an abbreviated physical exam for any unscheduled visit up 
to Study Day 56, as deemed necessary by medical staff must be included in the eCRFs.  
7.4 
Vital Signs 
Blood pressure, heart rate, body temperature, and respiratory rate will be measured according 
to Appendix 2 (Schedule of Procedures and Events) or following early termination of the 
study.  If multiple vital signs measurements are taken for a subject on the day of a study visit, 
the results of the first vital signs measurement of the day will be recorded on the CRFs. Vital 
signs are to be taken 15 minutes after the start of infusion, at the completion of infusion, and 
1 hour after the end of the infusion for each dose of F-652. 
7.5 
Clinical Laboratory Tests 
Blood will be collected to assess hematology and serum chemistry profiles at screening and 
on Days 0, 7, 14, 21, 28, and 56 as per Appendix 2 (Schedule of Procedures and Events). For 
each subject, all clinical laboratory assessments will be reported in the eCRF. 
Immunogenicity serum samples will be taken on Days 0, 7, 14, 21, 28, and 56, pre-dosing of 
F-652, where applicable. All immunogenicity samples will be shipped to the Sponsor or its 
agent, as directed in the study laboratory manual.  




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7.5.1.2 
Blood Volume 
Total blood volume for all research tests will be approximately 200 mL. 
7.5.2 
Urinalysis 
Urinalysis parameters for clinical laboratory tests will be obtained at screening and Day 28 
and will include the following assessments: 
appearance 
occult blood 
bilirubin 
pH 
glucose 
protein 
ketones 
specific gravity 
leukocyte esterase 
urobilinogen 
7.5.3 
Assessment of aGVHD 
A complete assessment of aGVHD will be conducted at Screening (baseline) and at Study 
Visit Days 7, 14, 21, 28, 56, 180, and 365 post-initial dose of F-652 therapy.  
7.6 
Efficacy Assessments 
The aim of this study is to assess the safety, efficacy, and PK of F-652 in combination with 
systemic corticosteroids for the treatment of newly diagnosed grade II-IV lower GI aGVHD 
in allogeneic HSCT recipients. The efficacy primary endpoint is to assess the lower GI 
aGVHD response rate at Day 28. 
7.6.1 
Methods and Timing for Assessing Acute Graft-Versus-Host Disease (aGVHD) 
Acute GVHD will be diagnosed clinically and staged according to modified Keystone criteria 
(Appendix 5). Grading of aGVHD will be based on IBMTR criteria52 (Appendix 5). Biopsy 
samples will be obtained prior to therapy initiation for confirmation of clinical diagnosis. 
Acute GVHD assessments will be obtained at Screening (baseline) and on Days 7, 14, 21, 28, 
56, 180, and 365 post-initial dose of F-652 therapy.  
Responses to aGVHD therapy will be determined using published definitions6 of GVHD 
response and will be assessed on Days 14, 28, and 56. 
Acute lower GI GVHD Response Criteria: 
Scoring of CR, VGPR, PR, progression, and NR will be in comparison to the participant’s 
lower GI aGVHD stage prior to treatment with F-652. Response will be based on the 
following response definitions: 
• CR: stage of 0 for all aGVHD symptomatology in the lower GI tract with no 
additional intervening aGVHD therapy. 
• VGPR: tolerating food or enteral feeding, predominantly formed stools, no overt GI 
bleeding or abnormal cramping. 
• PR: improvement by at least 1 stage in lower GI aGVHD symptomatology with no 
additional intervening therapy for their GVHD. 
• Progression: deterioration in lower GI tract aGVHD. 
• NR/stable: absence of any improvement in aGVHD stage. Subjects receiving 
secondary therapy (including need to re-escalate corticosteroid dose to 


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≥2.5 mg/kg/day of prednisone (or methylprednisolone equivalent) will be classified 
as non-responders. 
Response for All Organs Involved with aGVHD: 
Treatment response defined as CR, VGPR, PR, MR, progression, and NR will be in 
comparison to the subject’s aGVHD stage prior to treatment with F-652. Response will be 
based on the following response definitions: 
• CR: stage of 0 of all aGVHD symptomatology in all GVHD target organs with no 
additional intervening GVHD therapy. 
• VGPR: tolerating food or enteral feeding, predominantly formed stools, no overt GI 
bleeding or abnormal cramping, no more than occasional nausea or vomiting. 
• PR: improvement in aGVHD stage in all initial GVHD target organs without 
complete resolution and without worsening in any other GVHD target organs 
• MR: improvement in 1 or more GVHD target organs with deterioration in another 
organ manifesting symptoms of aGVHD or development of symptoms of aGVHD 
in a new organ. 
• Progression: worsening of GVHD in at least 1 organ without any improvement in 
others. 
• NR/stable: absence of any improvement in aGVHD stage.  Subjects receiving 
secondary therapy (including need to re-escalate corticosteroid dose to 
≥2.5 mg/kg/day of prednisone [or methylprednisolone equivalent of 2 mg/kg/day]) 
will be classified as non-responders. 
Treatment Failure: 
The following will be considered as treatment failures: 
• NR/stable after 14 days of therapy. 
• Progression after 7 days of therapy. 
• Administration of additional systemic therapy for aGVHD (or re-escalation of 
corticosteroids dose to ≥ 2.5 mg/kg/day of prednisone (or methylprednisolone 
equivalent) 
• TRM 
7.7 
Safety Assessments 
7.7.1 
Standard Safety Parameters 
Standard safety parameters include hematology, blood chemistry, urinalysis, vital signs, 
physical examination, and symptom/toxicity assessment as outlined in Section 7 and 
according to the schedule of events presented in Appendix 2 (Schedule of Procedures and 
Events).  
The NCI CTCAE will be used to grade potential AEs (see Section 7.7.3.3).  


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7.7.2 
Adverse Events Assessments 
7.7.2.1 
Procedures for Eliciting Reports of and Recording Adverse Events and 
Inter-current Illnesses 
The Investigator is to document  on the eCRFall directly observed AEs and all AEs 
spontaneously reported by the trial subject through Study Day 56 (or approximately 28 days 
after last dose of study drug). After Study Day 56, only SAEs deemed possibly, probably, or 
definitely related to the investigational product are required to be recorded through to the end 
of the study (Day 365).   
Each trial subject will be questioned about AEs at each clinic visit. AEs can be discovered by 
observing the subject, questioning the subject objectively, and/or receiving an unsolicited 
complaint from the subject. For all study visits, up to and including a subject’s Day 56 study 
visit,, a history of any AEs occurring since the last visit are to be recorded in the study the 
eCRF pages.  Only SAEs deemed possibly, probably, or definitely related to the 
investigational product are required to be recorded from study Day 56 through to the end of 
the study (Day 365).  Specimens are to be collected for specified laboratory tests as needed 
and results will be reviewed. Physical examinations will be performed as appropriate. 
7.7.2.2 
Timing and Duration of Follow-up of Subjects after Adverse Events 
Reported 
The subject is routinely followed up for 4 weeks after termination of drug dosing for 
identification of potential AEs. Any Grade 3 or 4 AEs or SAE is to be followed until it has 
resolved or stabilized. Sponsor must be advised of all Grade 3 or 4 AEs within one week of 
their identification and of all SAEs within 24 hours of identification. Subjects will be 
followed until the AE resolves or stabilizes. 
7.7.3 
Defining, Grading, and Reporting Adverse Events 
7.7.3.1 
Adverse Events 
All AEs, whether observed by researchers or reported by subjects, regardless of treatment 
group or suspected causal relationship to the investigational product(s), will be documented 
on the AE page(s) of the eCRF up to and including Study Day 56.  After Day 56,  SAEs 
deemed possibly, probably, or definitely related to the investigational product are required to 
be recorded through to the end of the study (Day 365).   
For all AEs, the Investigator must obtain information adequate to determine the cause and 
outcome of the AE and to assess whether it meets the criteria for classification as an SAE, 
which require immediate notification to Sponsor and its designated representative (see 
Section 7.7.3.7). The Investigator is required to assess causality and record that assessment 
on the eCRF. Follow-up of the AE after the date of therapy discontinuation is required if the 
AE or its sequelae persist. Follow-up is required until the event or its sequelae is resolved 
and/or stabilized at a level acceptable to the Investigator and the Sponsor clinician and safety 
officer. 
DEFINITION 
An AE is any occurrence or worsening (from baseline) of an undesirable or unintended sign, 
symptom (including an abnormal laboratory finding), or disease temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal product. 
Worsening of underlying disease will not be considered to be an AE, since it will be 


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classified as a treatment failure. Pregnancy will not be considered to be an AE, but will be 
collected separately. However if the resultant child has a birth defect, this will be considered 
to be an SAE. 
Throughout the study, the Investigator must record all AEs on the eCRF through Study Day 
56, regardless of the severity or relationship to study medication or procedure. The 
Investigator should treat subjects with AEs appropriately and observe them at suitable 
intervals until the events resolve or stabilize. 
AEs will be regarded as ‘pre-treatment’ if they occur between the Screening Visit (signing of 
ICF) and the time of administration of the first dose of study medication. All events reported 
following the first study medication administration will be recorded as treatment emergent 
AEs (TEAE). AEs that are unresolved at the time of study termination will be followed until 
they resolve or stabilize. 
7.7.3.2 
Serious Adverse Events 
An SAE is defined by federal regulation as any AE occurring at any dose that results in any 
of the following outcomes: 
• Death: A death occurring during the study or which comes to the attention of the 
Investigator during the protocol-defined follow-up after the completion of therapy, 
whether or not considered treatment-related, must be reported. 
• Life-threatening: Any adverse therapy experience that places the subject, in the 
view of the Investigator, at immediate risk of death from the reaction as it occurred. 
• Inpatient hospitalization (i.e. the event required at least a 24-hour hospitalization or 
prolonged hospitalization beyond the expected length of stay). Hospitalization 
admissions and/or surgical operations scheduled to occur during the study period, 
but planned prior to study entry are not considered SAEs if the illness or disease 
existed before the person was enrolled in the trial, provided that it did not 
deteriorate in an unexpected manner during the trial. 
• Persistent or significant disability/incapacity. 
• Congenital anomaly/birth defect. 
 
Additionally, any AEs occurring at any dose that suggests a significant hazard, 
contraindication, side effect, or precaution may be considered an SAE. This includes, but 
may not be limited to any of the following events:  
• Spontaneous abortion or death of the infant within 1 month of birth. 
• An event that required intervention to prevent permanent impairment or damage. 
 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, 
it may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed above. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependency or drug abuse. 
Pregnancy is NOT considered an SAE (see Section 7.7.3.8). 


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SAEs will be collected from the time of study entry until 30 days after completion of the trial 
or 30 days after premature withdrawal of a subject from the trial. 
If an event meets any of the criteria listed above, it must be reported on the eCRFs as an SAE 
regardless of its presumed relationship to the study drug. However, after Study Day 56, only 
SAEs deemed possibly, probably, or definitely related to the investigational product are 
required to be reported through to the end of the study (Day 365). 
7.7.3.3 
Severity and Grading 
Toxicity grades are assigned by the study site to indicate the severity of AEs occurring in 
study participants. To do this, the NCI CTCAE grading system will be used in AE reporting. 
The purpose of using the CTCAE system is to provide a standard language to describe 
toxicities, to facilitate tabulation and analysis of the data, and to facilitate the assessment of 
the clinical significance of all AEs. AEs should be recorded and graded 1 to 5 according to 
the CTCAE grades provided below: 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL)*. 
Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
ADL**. 
Grade 4: Life-threatening consequences; urgent intervention indicated. 
Grade 5: Death related to AE. 
*Activities of Daily Living (ADL):  
*Instrumental ADL refer to preparing meals, shopping for groceries or clothes, using the telephone, managing money, 
etc. 
**Self-care ADL refer to bathing, dressing and undressing, feeding self, using the toilet, taking medications, and not 
bedridden. 
If an AE term cannot be found in the CTCAE, the AE should be graded based on the verbiage 
provided for the grades above. 
7.7.3.4 
Relationship 
The relationship between an AE and an investigational product is determined by the site 
Investigator and recorded on the appropriate eCRF and/or SAE Report Form. The CTCAE 
provides the following descriptors and definitions. (See Table 7.7.3.1.) 
The Investigator’s determination of drug-relatedness (attribution) for each AE should be 
recorded in the source documentation.  
For additional information, please consult the CTCAE and the Common Toxicity Criteria 
Document at the following URL: http://ctep.cancer.gov/reporting/ctc.html. 




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If an SAE occurs, the Generon Safety Officer and/or his/her agent are to be notified within 
24 hours of awareness of the event by the Investigator. In particular, if the SAE is fatal or 
life-threatening, notification must be made to the Generon Safety Officer or his/her agent 
immediately, irrespective of the extent of available AE information. This time frame also 
applies to additional new information (follow-up) on previously forwarded SAE reports. 
In the rare event that the Investigator does not become aware of the occurrence of an SAE 
immediately (e.g., if an outpatient trial subject initially seeks treatment elsewhere), the 
Investigator is to report the event within 24 hours after learning of it and document the time 
of his/her first awareness of the AE. 
For all SAEs, the Investigator is obligated to provide information to the Generon Safety 
Officer and his/her agent in accordance with the time frames for reporting specified above. In 
addition, Generon study clinician or the Generon Safety Officer may request an Investigator 
to obtain specific follow-up information in an expedited fashion. This information may be 
more detailed than that captured on the AE eCRF. This will include a description of the AE in 
sufficient detail to allow for a complete medical assessment of the case and independent 
determination of possible causality. Information on other possible causes of the event, such as 
concomitant medications and illnesses must be provided. In the case of a subject death, a 
summary of available autopsy findings must be submitted as soon as possible to Generon 
Safety Officer and his/her designated representative. 
The Investigator’s causality assessment must be included in all reports of SAEs. An 
Investigator’s causality assessment is the determination of whether there exists a reasonable 
possibility that the investigational product caused or contributed to an AE. If the 
Investigator’s final determination is that causality is unknown and the Investigator cannot 
determine whether the event is related to study drug, then the event will be handled as 
“related to study drug” for reporting purposes. If the Investigator's causality assessment is 
"unknown but not related to study drug", this should be clearly documented on study records. 
In addition, if the Investigator determines the AE is associated with trial procedures, the 
Investigator must record this causal relationship in the source documents and eCRF, as 
appropriate and report such an assessment in accordance with the SAE reporting 
requirements. 
 
It should be noted that the form for collection of SAE information is not the same as the AE 
eCRF. Where the same data are collected, the forms must be completed in a consistent 
manner. For example, the same AE term should be used on both forms. AEs should be 
reported using concise medical terminology on the eCRFs as well as on the form for 
collection of SAE information. 
If a subject begins a new therapy (i.e., is discontinued from the study and completes the end 
of study assessment), the AE reporting period will end at the time of the new treatment is 
started. Death must be reported if it occurs within 30 days after the date of last dose of 
investigational product, irrespective of any intervening treatment. 
Since the study population (patients with aGVHD) is expected to have a relatively high 
background of AEs, anticipated AEs that are serious will not be reported in an expedited 
manner to the FDA, as they are anticipated to occur at a frequency independent of drug 
exposure. Examples include events related to the disease/condition under study (e.g., 
symptoms, disease progression), events unlikely to be related to the underlying disease or 
condition under investigation but common in the study population independent of drug 


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therapy, and events anticipated from any background treatment. These events do not warrant 
expedited reporting as individual cases because it is not possible, based on a single case, to 
determine that there is a reasonable possibility that the drug caused the event. An IND safety 
report will be submitted only if an aggregate analysis indicates that such events are occurring 
more frequently than expected in the drug treatment group. 
7.7.3.8 
Exposure In Utero 
For investigational products within clinical trials and for marketed products, an exposure 
in-utero (EIU) occurs if a female becomes, or is found to be pregnant either while receiving 
or having been exposed to (e.g., environmental toxin) an investigational medication or 
product, or the female becomes or is found to be pregnant after discontinuing and/or being 
exposed to the investigational medication or product. 
If any trial subject becomes or is found to be pregnant while receiving an investigational 
medication/product, the Investigator must submit this information to the Generon Safety 
Officer or sponsor designee (using the SAE reporting contact fax number) on a Pregnancy 
Report Form. This must be done irrespective of whether an AE has occurred, and within 
24 hours of awareness of the pregnancy. 
The information submitted should include the anticipated date of delivery (see below for 
information related to induced termination of pregnancy). 
The Investigator will follow the subject until completion of the pregnancy or until pregnancy 
termination (i.e., induced abortion) and then notify Generon (Shanghai) Corporation Medical 
Officer or Sponsor’s designee of the outcome.  
The Investigator will provide this information as a follow up to the initial Pregnancy Report 
Form. The reason(s) for an induced abortion should be specified. A pregnancy report is not 
created when an ectopic pregnancy report is received since this pregnancy is not usually 
viable. Rather, an SAE is to be submitted with the event of ectopic pregnancy. 
If the outcome of the pregnancy meets the criteria for immediate classification as a SAE (i.e., 
spontaneous abortion, stillbirth, neonatal death, or congenital anomaly [including that in an 
aborted fetus, stillbirth or neonatal death]), the Investigator should follow the procedures for 
reporting SAEs. 
In the case of a live birth, the “normality” of the newborn can be assessed at the time of birth 
(i.e., no minimum follow-up period of a presumably normal infant is required before a 
Pregnancy Report Form can be completed). The “normality” of an aborted fetus can be 
assessed by gross visual inspection, unless pre-abortion test findings are suggestive of a 
congenital anomaly. 
Additional information about pregnancy outcomes that are classified as SAEs follows: 
• “Spontaneous abortion” includes miscarriage and missed abortion. 
• All neonatal deaths that occur within 1 month of birth should be reported, without 
regard to causality, as SAEs. In addition, any infant death after 1 month that the 
Investigator assesses as possibly related to the in utero exposure to the investigational 
medication should be reported. 


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7.7.4 
Toxicity (Adverse Event) Management 
Subjects should receive full supportive care per institutional guidelines including blood 
products, antibiotics, and antiemetics at the discretion of the provider. Suggested guidelines 
for potential toxicities are detailed in the subsections below, including when and how long 
study drug should be withheld and when subjects should be discontinued from the study.  
Re-initiation of the study drug that was withheld cannot occur until drug-related toxicity 
(probably or definitely related) decreases to ≤grade 1 or baseline condition. Subjects who 
require >14 days recovering from a potential drug-related toxicity will be taken off study 
treatment. Dose modification or delay may occur in the setting of lower grade toxicity if the 
Investigator believes that is in the interest of a subject safety. In the event of a grade 1-2 toxic 
event, re-treatment with F-652 is permitted in the presence of the toxicity. 
If a probably related or definitely related AE occurs again after resumption of study drug, 
subject will hold drug until resolution to ≤grade 1 or baseline condition and then resume 
study drug at a reduce dose as outlined in Table 7.7.4.3Error! Reference source not found.. 
If resolution of an initial AE takes >7 days but <14 days and has no other explanation, then 
the study drug will be restarted at a reduced dose upon resolution ≤grade 1 or baseline 
condition. If resolution of an initial AE takes >7 days and has an alternative explanation not 
related to study, F-652 may be restarted at the original dose at the discretion of the 
Investigator. If resolution of an initial AE takes >14 days and has no other explanation, then 
the subject will be removed from the study treatment.  
Study drug will be held immediately at the identification of a study-related SAE. If an SAE 
resolves to CTCAE ≤grade 1 or baseline in <7 days, then a subject may resume study drug at 
the original dose. If an SAE does not resolve but is determined to be unrelated to study drug, 
treatment can be restarted at the original dose at the discretion of the Investigator.  
7.7.4.1 
Hematologic Toxicity 
Blood counts should be checked at each treatment visit. Granulocyte colony stimulating 
factor (G-CSF) is not routinely included in the care of these subjects but can be used at the 
discretion of the Investigator. G-CSF treatment is strongly recommended if ANC 
<1000 mm3.  
No primary prophylactic use of white blood cell growth factor support is recommended, but 
may be used as secondary prophylaxis at the discretion of the Investigator. 
Hematology toxicity related to F-652 treatment should be managed as outlined in 
Table 7.7.4.1Error! Reference source not found.. 
Table 7.7.4.1. Hematology Toxicity Management 
Blood Counts (ANC/mm3) 
Administer % of Full Dose 
>500 
100% 
<500 and subject afebrile (temp <38.0ºC) 
Hold F-652 and give G-CSF support. Give 100% of dose 
once ANC >500 mm3. 
<500 and subject febrile (>38ºC) 
Hold F-652. Treatment of neutropenic fever per institutional 
guidelines. Restart at full dose after 1 week if ANC 
>500 mm3 (G-CSF support is allowed). 
 


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7.7.4.2 
Skin Toxicity 
Skin dryness was the most common side effect reported with F-652 use. Skin erythema was 
also observed, but was less common. Baseline skin findings including rash should be 
documented prior to initiation of each treatment dose. Given that the differential diagnosis 
also includes skin aGVHD, histologic evaluation is recommended for assessment of etiology 
at any grade of presentation. Skin toxicity related to F-652 treatment is to be managed as 
outlined in Table 7.7.4.2Error! Reference source not found.. 
Table 7.7.4.2. Skin Toxicity Management 
Skin Rash 
Administer % of Full DoseF-652 dose 
Comments 
Grade 1 
100% 
Obtain skin biopsy, start topical 
corticosteroids and/or moisturizer 
Grade 2 
Scattered but not 
generalized erythema  
100% 
Obtain skin biopsy, start topical 
corticosteroids and/or moisturizer 
Grade 3 
Generalized 
erythroderma, ulcerative 
dermatitis or skin 
changes with pain 
interfering with function  
Withhold dose until toxicity is <Grade 1 
or has returned to baseline. If subject has 
a second grade 3 toxicity or if resolution 
of the first takes >7 days, withhold dose 
until toxicity is <grade 1, then reduce dose 
by one dose level and resume treatment. 
Obtain skin biopsy. 
If a 3rd Grade 3 event occurs, 
subjects will be discontinued from 
the study. 
Grade 4 
Life-threatening, 
disabling 
Withhold dose until toxicity is <grade 1, 
then reduce dose by one dose level and 
resume treatment, or discontinue at the 
discretion of the PI after discussion with 
treating physician. 
Obtain skin biopsy.  
If a 2nd Grade 4 event occurs, 
subjects will be discontinued from 
the study. 
 
7.7.4.3 
Other Toxicities 
All other Grade 3-4 toxicities (except hematologic and skin) considered probably or 
definitely related to F-652 should be managed as outlined in Table 7.7.4.3Error! Reference 
source not found.. 
Table 7.7.4.3. Other Toxicity Management 
Toxicity 
Administer % of Full DoseF-652 dose 
Comments 
Grade 1 
100% 
 
Grade 2 
100% 
 
Grade 3 
Withhold dose until toxicity is <grade 1 or has returned 
to baseline. If subject has a second grade 3 toxicity or 
if resolution of the first takes >7 days, withhold dose 
until toxicity grade is <1, then reduce dose by one dose 
level and resume treatment. 
If a 3rd Grade 3 event occurs, 
subjects will be discontinued 
from the study. 
Grade 4 
Withhold dose until toxicity is <grade 1 or has returned 
to baseline, then reduce dose by one dose level and 
resume treatment, or discontinue at the discretion of the 
PI after discussion with treating physician. 
If a 2nd Grade 4 event occurs, 
subjects will be discontinued 
from the study. 
 


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7.8 
Concomitant Medication Assessments 
All concomitant medications (over the counter or prescribed) taken by subjects during the 
screening period and throughout the duration of the study will be documented in the patient’s 
medical/source records. Concomitant medications are to be recorded in the eCRFs as 
described below, up to Study Day 56. Common medications typical for treatment of aGVHD 
and/or transplant are to be documented on the “Common aGVHD/Transplant Medications” 
eCRF and will include the medication name and start/stop date of the medication regardless 
of dose changes. All other medications not common to aGVHD/transplant therapy are to be 
documented on the “Concomitant Medication” eCRF page and must include medication 
name, indication (reason for use), start/stop date, dose, route, and frequency. 
After Study Day 56, only concomitant medications related to a SAE will be documented on 
the eCRFs. 
7.9 
Removal of Subjects from the Trial or Study Drug 
A subject may withdraw from the trial at any time at his/her own request, or he/she may be 
withdrawn at any time at the discretion of the Investigator or Sponsor for safety, behavioral, 
or administrative reasons. The Investigator will document the reason for a subject’s 
withdrawal from the study. 
7.9.1 
Criteria for Subject Withdrawal 
The following are criteria for subject discontinuation from the study: 
1. Subject withdraws study consent.  
2. Subject is found to be ineligible for the protocol as per the Inclusion/Exclusion criteria. 
3. Subject’s lower GI acute GVHD is not confirmed histologically. 
4. Subject has aGVHD progression after 7 days of therapy (dose 2) or at any subsequent 
point or NR/stable aGVHD after 14 days of therapy (dose 3). The Investigator may 
withdraw the subject from the study and treat the subject per the standard of care.  
5. Subject requires more than 2 investigational drug (F-652) dose reductions. 
6. Failure of the subject to comply with protocol requirements. 
7. Subject is initiated on protocol-prohibited medications. 
8. Exhibition of unacceptable toxicity (adverse event), which would make it difficult or 
dangerous to comply with further protocol requirements such as study visits, blood draws, 
etc. 
9. Subject experiences an acute infection that is either not identified or controlled by the 
next scheduled infusion. 
10. Subject develops serious infusion reaction (such as bronchospasm with wheezing or 
requires ventilatory support) or serum sickness-like reactions manifesting 1 to 14 days 
after drug administration. 
11. Subject experiences a recurrent Grade 4 AE related to study treatment. 
12. Subject develops malignancy, including skin cancer or relapse of the disease for which 
the allogeneic HSCT was performed. 
13. Subject requires tapering of systemic corticosteroids (<2 mg/kg/day) before Study Day 3. 
14. Subject requires an increase in their current immunosuppression therapy or the addition of 
systemic immunosuppression therapies due to active aGVHD. 
15. There are changes in medical status of the subject such that the Investigator believes that 
subject safety will be compromised or that it would be in the best interest of the subject to 
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16. Death of the subject. 
17. Subjects with a test consistent with pregnancy such as a positive beta-hCG. 
18. Subject is lost to follow-up. 
7.9.2 
Procedures for Subject Withdrawal 
At the time of study withdrawal, subjects, if capable, will be asked to complete all of the 
procedures that would normally be performed at the Day 28 (End of Treatment) assessment. 
Collection of research/exploratory samples is at the discretion of the Investigator. If the End 
of Treatment Visit for early withdrawal overlaps with another study visit (within 1-2 days), 
only one set of laboratory and research samples will be collected during the visit. If the End 
of Treatment Visit occurs between regularly planned study visits, a 1-2 day window is 
allowed for the visit and sample collection relative to the withdrawal date. All assessments 
for the visit must be completed and samples collected prior to the subject starting a new 
treatment. Withdrawn subjects will have a 30-day follow-up phone call after their last clinical 
assessment. 
7.9.3 
Replacements for Withdrawn Subjects 
Subjects withdrawn from the study due to a failure of aGVHD histologic confirmation will be 
replaced. 
7.9.4 
Follow-Up of Withdrawn Subjects 
At the time of withdrawal from study, the reasons for the withdrawal should be ascertained 
and recorded. If it is for a medical procedure, the outcome should be recorded. 
If the subject withdraws consent to continue in the study, the subject will be requested at a 
minimum to participate in a post-treatment follow-up phone call (30 days after the last dose). 
If the subject declines, no further evaluations are to be performed and no attempts should be 
made to contact the subject or collect additional data. If the subject is withdrawn from the 
study prior to initiation of the study drug, no follow-up will be conducted. 
If a subject does not return for scheduled visits, every effort should be made to re-establish 
contact. Attempts made to reach the subject should be clearly documented. If the subject 
cannot be contacted, every effort should be made to document subject outcome as far as 
possible.  
7.9.5 
Documentation 
For any subject who withdraws, the date and the reason for the withdrawal must be recorded 
on the appropriate eCRF. 


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8 
QUALITY CONTROL AND ASSURANCE 
During trial conduct, Generon or its agents will conduct periodic monitoring visits to ensure 
that the protocol and GCP are being followed. The monitors may review source documents to 
confirm that the data recorded on eCRFs are accurate. The investigators and institutions will 
allow Generon’s monitors or its agents and appropriate regulatory authorities direct access to 
source documents to perform this verification. 
The trial sites may be subject to review by the IRB/IEC, quality assurance audits performed 
by Generon, and/or inspection by appropriate regulatory authorities from the US or other 
countries. 
Investigators and their relevant personnel must be available during the monitoring visits and 
audits or inspections. Sufficient time must be devoted to these inspections. 
The Investigator is required to keep accurate records to ensure the conduct of the study is 
fully documented. The Investigator is required to ensure that all eCRFs are complete and 
accurate for every subject entered in the trial. 
The Sponsor is responsible for regular inspection of the conduct of the trial, for verifying 
adherence to the protocol, and for confirming the completeness, consistency, and accuracy of 
all documented data. 


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9 
PLANNED STATISTICAL METHODS 
9.1 
General Considerations 
Detailed methodology for summary and statistical analyses of the data collected in this trial 
will be documented in a Statistical Analysis Plan (SAP), which will be signed and maintained 
by the Sponsor. This document will expand upon and may modify the plans outlined in the 
protocol; however, any major modifications of the primary endpoint definition and/or its 
analysis will also be reflected in a protocol amendment. In this exploratory Phase IIa study, 
all statistical tests will be two-sided with no adjustment for multiplicity.  
Descriptive summaries of variables will be provided where appropriate. For continuous 
variables, the number of non-missing values (n) and the median, mean, standard deviation, 
minimum, and maximum will be summarized. For categorical variables, the number and 
percent of each variable will be summarized. All collected data will be presented in listings. 
9.2 
Determination of Sample Size 
As described in Section 9.6.1, this study is designed to distinguish between an unpromising 
Day+28 treatment response rate of 35% and a promising treatment response rate of 60% 
using a Simon’s two-stage optimal design. With a maximum sample of 27 patients, this study 
has a type I error of 0.10 and a type II error of 0.10. 
9.3 
Analysis Populations  
Three study populations are defined for the study: a Safety Population, an Efficacy Evaluable 
Population, and a PK Population. Additional study populations may be defined to further 
explore study data. Any additional study populations will be defined in either the SAP or in 
the final clinical study report. 
9.3.1 
Safety Population 
All enrolled subjects receiving any study treatment will be included in the Safety analysis set, 
which will be used for all safety analyses. 
9.3.2 
Efficacy Evaluable Population  
All subjects who receive study treatment and provide at least one post-treatment assessment 
for aGVHD treatment response will be included in the Efficacy Evaluable Population, which 
will be used for all efficacy analyses. Missing aGVHD treatment response will be imputed as 
non-response for this analysis. 
9.3.3 
Pharmacokinetic Population 
All subjects who receive study treatment and provide sufficient samples for PK parameter 
estimation will be included in the PK Population, which will be used for all PK analyses. 
Subjects who have reported protocol deviations, which may have a significant impact on the 
estimation of the PK parameters, will be removed from the PK population. Subjects with 
partial serum concentration data will be evaluated to determine whether sufficient data is 
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9.4 
Demographics and Baseline Characteristics 
All baseline subject characteristics and demographic data (including age, height, weight, race, 
ethnicity), medical history, physical examination (abnormalities only), and prior/concomitant 
medications will be listed for all subjects. Demographic data will be summarized and 
tabulated. 
9.5 
Study Endpoints 
Study endpoints are provided in Section 2.2. 
9.6 
Statistical Methods  
9.6.1 
Safety Analysis 
Safety will be assessed based on AE reporting, physical examination, vital sign measurement, 
and clinical laboratory test results.  
AEs will be tabulated by body system and preferred term according to a standardized 
thesaurus (Medical Dictionary for Regulatory Activities [MedDRA]). The severity of AEs 
will be classified using the NCI-CTCAE toxicity scale as detailed in Section 7.7.3.3. 
Summaries will be provided in separate tables for SAEs, treatment-related AEs, and AEs 
leading to study discontinuation. AEs will also be summarized by maximum severity and 
relationship to the study drug for each treatment group and overall.  
Concomitant medications including baseline medications will be tabulated by subject with 
drug category and preferred term. 
Physical examination findings will be provided as subject listings. Descriptive statistics for 
vital sign measurements, by treatment and time (after dose) will be provided. Hematological 
data and blood chemistry will be graded according to NCI CTCAE severity grade. Shift 
tables from the screening visit to the end of study visit will be presented for clinical 
laboratory measurements (serum chemistry, hematology, and urinalysis). 
9.6.2 
Primary Efficacy Analysis 
The primary endpoint of aGHVD treatment response rate 28 days following the initiation of 
therapy will be reported as the proportion of subjects who provide a response as defined in 
Appendix 6. 
9.6.3 
Secondary Efficacy Analysis 
Secondary efficacy endpoints will be analyzed as follows: 
1. Response to therapy will be explored by examining the proportion of subjects with a 
CR, VGPR, PR or have NR/stable or progression of lower GI aGVHD 
symptomatology at 14 and 56 days post treatment initiation. 
2. Overall aGVHD response to therapy will be explored by examining the proportion of 
subjects with a CR, VGPR, PR, MR, NR/stable or who have progression of aGVHD at 
Days 14, 28, and 56 post-treatment initiation. 
3. The proportion of subjects who have stopped immunosuppressive medication at 
Day 180 and 1 year will be estimated. 
4. Immune recovery will be evaluated through the B and T lymphocytes recovery and 
will be measured on Study Days 0 and 28 post-initial dose of F-652. Graphical and 
summary measures will be used to describe the CD3+CD4+, CD3+CD8+, and CD19+ 
populations. 




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10 ADMINISTRATIVE CONSIDERATIONS 
10.1 Investigators and Study Administrative Structure 
The PI and study staff has the responsibility of maintaining a comprehensive and centralized 
filing system containing all study-related documentation. These files must be available for 
inspection by the sponsor, representatives of the sponsor, the IRB/IEC, and regulatory 
authorities (i.e., FDA or international regulatory authorities) at any time, and should consist 
of the following elements: 
• Subject files, supporting source documentation from the medical record including 
laboratory data and the ICF. 
• Regulatory files, containing the protocol with all amendments and Investigator signature 
pages, copies of all other regulatory documentation, and all correspondence between the 
site and the IRB/IEC and Sponsor; and drug accountability files, including a complete 
account of the receipt and disposition of the study medication (test article). 
Records are to be available for 2 years after marketing application approval, or if the 
application is not approved or never submitted, 2 years after the last shipment and delivery of 
the material and the appropriate competent regulatory authorities are notified. The Sponsor 
will provide written notification when it is appropriate for the Investigator to discard the 
study-specific documents referenced above. 
10.2 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
Approval 
It is the responsibility of the Investigator to obtain prior approval of the trial protocol, 
protocol amendments, ICFs, and other relevant documents (e.g., advertisements) if 
applicable, from the IRB/IEC. All correspondence with the IRB/IEC should be retained in the 
Investigator File. Copies of IRB/IEC approvals should be forwarded to Generon or its 
designees. 
The only circumstance in which an amendment may be initiated prior to IRB/IEC approval is 
where the change is necessary to eliminate apparent immediate hazards to the subjects. In that 
event, the Investigator must notify the IRB/IEC and Generon or its designees in writing 
within 5 working days after the implementation. 
10.3 Ethics 
10.3.1 
Treatment Considerations 
The final study protocol, including the final version of the ICF, must be approved or given a 
favorable opinion in writing by an IRB or IEC as appropriate. The Investigator must submit 
written approval to the Sponsor or its designee before he or she can enroll any subject into the 
study. 
The PI is responsible for informing the IRB or IEC of any amendment to the protocol in 
accordance with local requirements. In addition, the IRB or IEC must approve all advertising 
used to recruit subjects for the study. The protocol must be re-approved by the IRB or IEC 
upon receipt of amendments and annually, as local regulations require. 


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The PI is also responsible for providing the IRB/IEC with reports of any reportable serious 
adverse drug reactions from any other study conducted with the investigational product. The 
Sponsor or its designee will provide this information to the PI. 
Progress reports and notifications of serious adverse drug reactions will be provided to the 
IRB or IEC according to local regulations and guidelines. 
10.3.2 
Ethical Conduct of the Study 
The trial will be performed in accordance with the protocol, International Conference on 
Harmonisation (ICH) GCP guidelines, and applicable local regulatory requirements and laws. 
10.4 Subject Information and Consent 
The ICF must be agreed to by Generon and the IRB/IEC and must be in compliance with 
ICH-GCP, local regulatory requirements, and legal requirements. 
The Investigator must ensure that each trial subject, or his/her legally acceptable 
representative, is fully informed about the nature and objectives of the trial and possible risks 
associated with participation. The Investigator will obtain written ICF each subject or the 
subject's legally acceptable representative before any study-specific activity is performed. 
The ICF used in this trial, and any changes made to it during the course of the trial, must be 
approved by both the IRB/IEC and Sponsor before use. The Investigator will retain a copy of 
each subject's signed consent form. 
A Sponsor recommended sample informed consent form will be provided to the 
investigational site as a separate document. Modifications to the consent required by ethics 
committee/IRB should be reviewed by the Sponsor. 
10.5 Subject Confidentiality 
All information obtained during the conduct of the study with respect to the subjects’ state of 
health will be regarded as confidential. This is detailed in the written information provided to 
the subject. An agreement for disclosure of any such information will be obtained in writing 
and is included in both copies of the ICF signed by the subject. The study data shall not be 
disclosed to a third party without the written consent of the sponsor. 
10.6 Study Monitoring 
The Sponsor or a sponsor representative will visit the study center periodically to monitor 
adherence to the protocol, compliance with ICH guidelines, adherence to applicable 
regulations, and the maintenance of adequate and accurate clinical records. eCRFs will be 
reviewed to ensure that key safety and efficacy data are collected and recorded as specified 
by the protocol. The monitor will be permitted to access subjects’ complete medical records, 
laboratory data, and other source documentation as needed to monitor the trial appropriately. 
10.7 Case Report Forms and Study Records 
Each site is responsible for collecting and maintaining the source documentation describing 
the clinical information.  
eCRFs are required and should be completed in a timely manner for each included subject. 
The completed original eCRFs are the sole property of Generon and should not be made 


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available in any form to third parties, except for authorized representatives of Generon or 
appropriate regulatory authorities, without written permission from Generon. 
It is the Investigator's responsibility to ensure completion and to review and approve all 
eCRFs. eCRFs must be signed by the Investigator or by an authorized staff member. These 
signatures serve to attest that the information contained on the eCRFs is correct and 
complete. At all times, the Investigator has final personal responsibility for the accuracy and 
authenticity of all clinical and laboratory data entered on the eCRFs. Subject source 
documents are the physician's subject records maintained at the trial sites. In most cases, the 
source documents will be the hospital's or the physician's charts. In cases where the source 
documents are the hospital or the physician's charts, the information collected on the eCRFs 
must match those charts. 
All information recorded in the electronic Case Report Forms must be documented in the 
source document. To leave as is implies that the Investigator may document directly into the 
eCRF and not record in the clinic record. If a policy or standard operating procedure requires 
the present language, it must be specified what information can be documented directly into 
the eCRF. 
10.7.1 
Electronic Case Report Forms 
eCRFs are to be completed using the iDataFax electronic data capture system. Sites will 
receive training and guidelines for appropriate eCRF completion.  
All eCRFs should be completed by designated, trained, data entry personnel or the study 
coordinator as appropriate. The eCRF should be reviewed and electronically signed and dated 
by the Investigator. 
In addition, at the end of the study, the Investigator will receive subject data for his or her site 
in a read-only format on a compact disc that must be kept with the study records. 
10.8 Protocol Interpretation and Compliance 
To ensure accurate interpretation and implementation of the study, the procedures and 
endpoints defined in the protocol will be carefully reviewed by the PI and his or her staff 
prior to the time of study initiation. The Sponsor and PI will follow all reasonable means to 
resolve any differences of opinion of matters of eligibility, toxicity and other endpoints. In 
the event that a resolution cannot be reached then one or both parties may seek to terminate 
the study following the provisions outlined in the Clinical Trials Agreement. 
10.9 Access to Source Documentation 
The PI and the Investigator’s institution must permit trial-related monitoring, audits, IRB/IEC 
review, and regulatory inspections by providing direct access to source data/documents. 
10.10 Data Generation and Analysis 
The eCRF data will be verified by a series of computerized edit checks, and all relevant data 
queries will be resolved on an ongoing basis. When the eCRFs are complete, they will be 
reviewed and signed by the Investigator. All elements of data entry (i.e., time, date, verbatim 
text, and the person performing the data entry) are recorded in an electronic audit trail to 
allow all data changes in the database to be monitored and maintained in accordance with 
federal regulations. 


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10.11 Records Retention and Retention of Data 
To enable evaluations and/or audits from regulatory authorities or Generon, the Investigator 
agrees to keep complete records, including the identity of all participating subjects (sufficient 
information to link records, e.g., eCRFs and hospital records), all original signed ICFs, copies 
of all eCRFs, source documents, and detailed records of treatment disposition. The records 
must be retained by the Investigator according to ICH and local regulations as well as the 
Clinical Trials Agreement. 
If the Investigator relocates, retires, or for any reason withdraws from the trial, Generon 
should be notified in advance. The trial records must be transferred to an acceptable designee, 
such as another Investigator, another agreed-upon institution, or to Generon. The Investigator 
must obtain written permission from Generon before disposing of any records, even if 
retention requirements have been met. 
10.12 Financial Disclosure 
The Sponsor, Generon, will provide adequate insurance for trial conduct.  
10.13 Publication and Disclosure Policy 
Publication of study results is discussed in the Clinical Trials Agreement. All publications to 
be submitted to scientific journals or presentations to be given at scientific meetings must be 
submitted to the Generon (Shanghai) Corporation at least one month prior to submission. 
Planned presentations must include all slides. This includes presentations given at the 
presenter’s own institution (such as Grand Rounds). However, presentations given to the 
study team are not required to be approved in advance. 


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17. Deeg HJ. How I treat refractory acute GVHD. Blood. 2007;109(10):4119-4126. 
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19. Macmillan ML, Couriel D, Weisdorf DJ, et al. A phase 2/3 multicenter randomized 
clinical trial of ABX-CBL versus ATG as secondary therapy for steroid-resistant acute 
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20. Van Lint MT, Milone G, Leotta S, et al. Treatment of acute graft-versus-host disease with 
prednisolone: significant survival advantage for day +5 responders and no advantage for 
nonresponders receiving anti-thymocyte globulin. Blood. 2006;107(10):4177-4181. 
21. Gomez-Almaguer D, Ruiz-Arguelles GJ, del Carmen Tarin-Arzaga L, et al. 
Alemtuzumab for the treatment of steroid-refractory acute graft-versus-host disease. Biol 
Blood Marrow Transplant. 2008;14(1):10-15. 
22. Anasetti C, Martin PJ, Storb R, et al. Treatment of acute graft-versus-host disease with a 
nonmitogenic anti-CD3 monoclonal antibody. Transplantation. 1992;54(5):844-851. 
23. Busca A, Locatelli F, Marmont F, Ceretto C, Falda M. Recombinant human soluble tumor 
necrosis factor receptor fusion protein as treatment for steroid refractory graft-versus-host 
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2007;82(1):45-52. 
24. Alam N, Atenafu EG, Tse G, et al. Limited benefit of pentostatin salvage therapy for 
steroid-refractory grade III-IV acute graft-versus-host disease. Clin Transplant. 
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25. Martin PJ, Schoch G, Fisher L, et al. A retrospective analysis of therapy for acute graft-
versus-host disease: secondary treatment. Blood. 1991;77(8):1821-1828. 
26. Soiffer RJ, Lerademacher J, Ho V, et al. Impact of immune modulation with anti-T-cell 
antibodies on the outcome of reduced-intensity allogeneic hematopoietic stem cell 
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27. Westin JR, Saliba RM, De Lima M, et al. Steroid-Refractory Acute GVHD: Predictors 
and Outcomes. Adv Hematol. 2011;2011:601953. 
28. Hill GR, Crawford JM, Cooke KR, Brinson YS, Pan L, Ferrara JL. Total body irradiation 
and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory 
cytokines. Blood. 1997;90(8):3204-3213. 
29. Reddy P, Negrin R, Hill GR. Mouse models of bone marrow transplantation. Biol Blood 
Marrow Transplant. 2008;14(1 Suppl 1):129-135. 
30. Robb RJ, Hill GR. The interferon-dependent orchestration of innate and adaptive 
immunity after transplantation. Blood. 2012;119(23):5351-5358. 
31. Hanash AM, Kappel LW, Yim NL, et al. Abrogation of donor T-cell IL-21 signaling 
leads to tissue-specific modulation of immunity and separation of GVHD from GVL. 
Blood. 2011;118(2):446-455. 
32. Hanash AM, Dudakov JA, Hua G, et al. Interleukin-22 Protects Intestinal Stem Cells 
from Immune-Mediated Tissue Damage and Regulates Sensitivity to Graft versus Host 
Disease. Immunity. 2012;37(2):339-350. 
33. Schmaltz C, Alpdogan O, Muriglan SJ, et al. Donor T cell-derived TNF is required for 
graft-versus-host disease and graft-versus-tumor activity after bone marrow 
transplantation. Blood. 2003;101(6):2440-2445. 
34. Kappel LW, Goldberg GL, King CG, et al. IL-17 contributes to CD4-mediated graft-
versus-host disease. Blood. 2009;113(4):945-952. 
35. Das R, Chen X, Komorowski R, Hessner MJ, Drobyski WR. Interleukin-23 secretion by 
donor antigen-presenting cells is critical for organ-specific pathology in graft-versus-host 
disease. Blood. 2009;113(10):2352-2362. 
36. Zheng Y, Danilenko DM, Valdez P, et al. Interleukin-22, a T(H)17 cytokine, mediates IL-
23-induced dermal inflammation and acanthosis. Nature. 2007;445(7128):648-651. 
37. Kreymborg K, Etzensperger R, Dumoutier L, et al. IL-22 is expressed by Th17 cells in an 
IL-23-dependent fashion, but not required for the development of autoimmune 
encephalomyelitis. J Immunol. 2007;179(12):8098-8104. 
38. Cella M, Fuchs A, Vermi W, et al. A human natural killer cell subset provides an innate 
source of IL-22 for mucosal immunity. Nature. 2009;457(7230):722-725. 
39. Sonnenberg GF, Fouser LA, Artis D. Border patrol: regulation of immunity, 
inflammation and tissue homeostasis at barrier surfaces by IL-22. Nat Immunol. 
2011;12(5):383-390. 
40. Sanos SL, Diefenbach A. Innate lymphoid cells: from border protection to the initiation 
of inflammatory diseases. Immunol Cell Biol. 2013;91(3):215-224. 
41. Zheng Y, Valdez PA, Danilenko DM, et al. Interleukin-22 mediates early host defense 
against attaching and effacing bacterial pathogens. Nat Med. 2008;14(3):282-289. 


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42. Sawa S, Lochner M, Satoh-Takayama N, et al. RORgammat+ innate lymphoid cells 
regulate intestinal homeostasis by integrating negative signals from the symbiotic 
microbiota. Nat Immunol. 2011;12(4):320-326. 
43. Sabat R, Ouyang W, Wolk K. Therapeutic opportunities of the IL-22-IL-22R1 system. 
Nat Rev Drug Discov. 2014;13(1):21-38. 
44. Shlomchik WD. Graft-versus-host disease. Nat Rev Immunol. 2007;7(5):340-352. 
45. Ferrara JL, Levine JE, Reddy P, Holler E. Graft-versus-host disease. Lancet. 
2009;373(9674):1550-1561. 
46. Blazar BR, Murphy WJ, Abedi M. Advances in graft-versus-host disease biology and 
therapy. Nat Rev Immunol. 2012;12(6):443-458. 
47. Lindemans CA, Mertelsmann AM, O’Connor MH, et al. Interleukin-22 Is an Intestinal 
Stem Cell Growth Factor, and IL-22 Administration in Vivo Reduces Morbidity and 
Mortality in Murine GVHD. Blood. 2015; 124(21):651a. 
48. Takashima S, Kadowaki M, Aoyama K, et al. The Wnt agonist R-spondin1 regulates 
systemic graft-versus-host disease by protecting intestinal stem cells. J Exp Med. 
2011;208(2):285-294. 
49. Jenq RR, Ubeda C, Taur Y, et al. Regulation of intestinal inflammation by microbiota 
following allogeneic bone marrow transplantation. J Exp Med. 2012;209(5):903-911. 
50. Eriguchi Y, Takashima S, Oka H, et al. Graft-versus-host disease disrupts intestinal 
microbial ecology by inhibiting Paneth cell production of alpha-defensins. Blood. 
2012;120(1):223-231. 
51. Barker N, van Oudenaarden A, Clevers H. Identifying the stem cell of the intestinal crypt: 
strategies and pitfalls. Cell Stem Cell. 2012;11(4):452-460. 
52. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index for grading acute 
graft-versus-host disease: retrospective comparison with Glucksberg grade. British 
Journal of Haematology. 1997;97(4):855-864. 
53. Levine JE, Logan B, Wu J, et al. Graft-versus-host disease treatment: predictors of 
survival. Biol Blood Marrow Transplant. 2010;16(12):1693-1699 
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Appendix 1 
Trial Procedures and Study Activities 
Screening (begins with consent): 
• Informed Consent is signed 
• Registration of Subject into the IWRS system 
• Relevant Medical history 
• Listing of all treatments and current therapies over the past 1 month and any 
chemotherapy regimens in the past 1 year from the date of informed consent 
• Concomitant medications 
• Physical examination 
• Height and body weight 
• Vital Signs (BP and heart rate, respiratory rate, body temperature) 
• Complete blood count (CBC) with Differential  
• Blood chemistry (Sodium, Potassium, BUN, Serum Creatinine, Chloride, Carbon 
Dioxide, Calcium, Phosphorus, Glucose, Bilirubin total and direct, ALT, AST, ALP, 
CRP, LDH, Albumin, Fibrinogen, Total Protein, Total Cholesterol, Triglycerides) 
• Urinalysis  
• ECG-12 lead 
• Stool sample for C. diff testing (if not tested in the last 7 days) 
• Stool sample for microbiota testing 
• aGVHD baseline scoring and grading (by IBMTR scoring system) 
• GI evaluation and biopsy*: flexible sigmoidoscopy (preferred) or colonoscopy and 
upper endoscopy, according to local center practice. 
• Skin biopsy for evaluation of rash, optional in the absence of rash 
• Collection of adverse events (AEs) 
• Serum pregnancy test as appropriate  
* If no biopsy for GI aGVHD confirmation has been performed before study entry. GI 
evaluation to be done within 5 days of initial systemic corticosteroid administration 
Study Day 0, Initial Dose of F-652 (to be within 5 days of initial systemic corticosteroid 
administration): 
• Body weight 
• Physical examination  
• Vital Signs (BP and heart rate, respiratory rate, body temperature). Vital signs are 
to be taken 15 min. after the start of F-652 infusion, at the completion, and 1 hour 
after the end of the initial infusion. 
• Serum sample for F-652 antibody testing (prior to administration of F-652) 
• PK testing samples 
• Collection of AEs and toxicity assessments 
• Concomitant medications  
• Administration of F-652 
• aGVHD blood research samples (cytokine samples optional) 
 
Study Days 7*, 14*, and 21*:  
• Body weight 


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• Collect vital signs (BP and heart rate, respiratory rate, body temperature). Vital 
signs are to be taken 15 min. after the start of F-652 infusion, at the completion, 
and 1 hour after the end of the initial infusion. 
• CBC with Differentials 
• Blood chemistry (Sodium, Potassium, BUN, Serum Creatinine, Chloride, Carbon 
Dioxide, Calcium, Phosphorus, Glucose, Bilirubin total and direct, ALT, AST, ALP, 
CRP, LDH, Albumin, Fibrinogen, Total Protein, Total Cholesterol, Triglycerides) 
• Serum sample for F-652 antibody testing (prior to administration of F-652) 
• PK testing samples (see schedule for Day 21+ sampling) 
• Collection of AEs and toxicity assessments 
• Concomitant medications  
• Administration of F-652 
• aGVHD scoring and grading (by IBMTR scoring system) 
• Skin biopsy if rash develops during treatment, optional in the absence of rash 
(Day 14) 
• aGVHD treatment response (only for visit Day 14)  
*Actual study day may vary as per the allowed window for visit due to each subject’s 
individual schedule. 
Study Day 28* (End of Treatment Visit): 
• Body weight 
• Physical examination  
• Collect vital signs (BP and heart rate, respiratory rate, body temperature) 
• CBC with Differential 
• Blood chemistry (Sodium, Potassium, BUN, Serum Creatinine, Chloride, Carbon 
Dioxide, Calcium, Phosphorus, Glucose, Bilirubin total and direct, ALT, AST, ALP, 
CRP, LDH, Albumin, Fibrinogen, Total Protein, Total Cholesterol, Triglycerides) 
• Serum sample for F-652 antibody testing 
• Urinalysis 
• PK testing samples 
• Collection of AEs and toxicity assessments 
• Concomitant medications  
• aGVHD scoring and grading (by IBMTR scoring system) 
• aGVHD treatment response 
• aGVHD blood research samples (cytokine samples optional) 
• Stool sample for microbiota testing 
• Skin biopsy if rash develops during treatment, optional in the absence of rash  
• ECG-12 lead 
• GI evaluation and biopsy*: flexible sigmoidoscopy (preferred) or colonoscopy and 
upper endoscopy with biopsy according to local center practice. (1 sample 
required, subject permitting, 4 others collected). 
*Actual study day may vary as per the allowed window for visit due to each subject’s 
individual schedule. 
Study Follow up Day 56*: 


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• Relevant medical history 
• Body weight 
• Physical examination  
• Collect vital signs (BP and heart rate, respiratory rate and body temperature) 
• CBC with Differential 
• Blood chemistry (Sodium, Potassium, BUN, Serum Creatinine, Chloride, Carbon 
Dioxide, Calcium, Phosphorus, Glucose, Bilirubin total and direct, ALT, AST, ALP, 
CRP, LDH, Albumin, Fibrinogen, Total Protein, Total Cholesterol, Triglycerides) 
• Serum sample for F-652 antibody testing 
• Current therapy and concomitant medications  
• Collection of AEs and toxicity assessments 
• aGVHD scoring and grading (by IBMTR scoring system) 
• aGVHD treatment response 
• PK testing sample 
*Actual study day may vary as per the allowed window for visit due to each subject’s 
individual schedule. 
Study Follow up Days 180 and 365*: 
• Relevant medical history 
• Body weight 
• Physical examination  
• Collect vital signs (BP, heart rate, respiratory rate, body temperature) 
• aGVHD scoring and grading (by IBMTR scoring system) 
• SAEs (possibly, probably, or definitely related to the investigational drug) 
• Current therapy and concomitant medications (only for subjects with SAEs reported 
after Day 56) 
 
*Actual study day may vary as per the allowed window for visit due to each subject’s 
individual schedule. 


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Appendix 2 
Schedule of Procedures and Events 
Assessments 
Screening 
Day 0 
Day 7 
Day 14 
Day 21 
Day 28* 
Day 56 
Day 180 
Day 365 
Window for visit (days) 
(5) days 
  
(±) 2 
(±) 2 
(±) 2  
(±) 4 
(±) 14 
(±) 30 
(±) 30 
Signing of Informed Consent 
X 
 
 
 
 
 
 
 
 
Relevant Medical History 
X 
 
 
 
 
 
X 
X 
X 
Body Temperature, Weight, Vital Signs (BP, heart rate, respiratory rate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
X 
X 
X 
X 
CBC1 
X 
  
X 
X 
X 
X 
X 
 
 
Blood chemistry1 
X 
  
X 
X 
X 
X 
X 
 
 
Urinalysis  
X 
 
 
 
 
X 
 
 
 
Immune recovery (per institutional standard)2 
 
X 
 
 
 
X 
 
 
 
Serum for F-652 antibody testing (pre dosing of F-652)  
 
X 
X 
X 
X 
X 
X 
 
 
ECG 
X 
 
 
 
 
X 
 
 
 
Stool C. Difficile testing (if not done within 7 days) 
X 
 
 
 
 
 
 
 
 
Stool microbiota test 
X 
 
 
 
 
X 
 
 
 
Pregnancy test3 
X 
 
 
 
 
 
 
 
 
Current therapy and concomitant medications4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GI Biopsy5 
X 
 
 
    
 
X 
 
 
 
PK Testing6 (see additional schedule) 
 
X 
X 
X 
X 
X 
X 
 
 
Administration of F-6527 (within 5 days of consent)  
 
X 
X 
X 
X 
 
 
 
 
Collection of AEs and toxicity assessment8 
X 
X 
X 
X 
X 
X 
X 
 
 
aGVHD blood research samples ( cytokine samples optional) 
 
X 
 
 
 
X 
 
 
 
Skin biopsy, subject permitting or if skin rash develops during treatment 
X 
 
 
X 
 
X 
 
 
 
GVHD treatment response 
 
 
 
X 
 
X 
X 
 
 
aGVHD evaluation  
X 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: aGVHD = acute graft-versus-host disease; BP = blood pressure; ECG = electrocardiogram; GVHD = graft-versus-host disease; PK = pharmacokinetics.* End of treatment visit 
1 Blood samples are taken predose at Screening and Days 7, 14, 21, 28, and 56, and at 72 hours post-dose for CRP determination only at Screening and Days 7, 14, and 21. 
2 Immune recovery assessed on Day 0 as baseline and Days 28, post initial dose of F-652. Testing can be withheld if the patient has very low circulating white blood cells. 
3 For females with reproductive potential, serum test. 
4 Concomitant medications will be collected at each visit, scheduled or unscheduled. Collection of concomitant medications after Day 56 is required only for subjects with reported SAEs. 
5 Screening: for those subjects where no previous biopsy sample has been taken for GVHD confirmation. Day 28 Biopsy: subject permitting.  
6 See schedule for details (Appendix 3).  
7 Intravenous (IV) solution prepared per protocol.  
8 Collected at each scheduled or unscheduled visit. All AEs will be collected and documented on the study eCRF page through Study Day 56 (28 days after last dosing of F-652). After Study 
Day 56, only SAEs deemed possibly, probably, or definitely related to the investigational product are recorded through to the end of the study (Day 365). 








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Appendix 5 
aGVHD Diagnosis and Grading Tables 
Appendix Table 2. 
Modified Keystone Criteria 
 
Stage 0 
Stage 1 
Stage 2 
Stage 3 
Stage 4 
Skin 
No Rash 
Rash <25% BSA 
25-50% BSA 
>50% BSA 
Generalized 
erythroderma with 
bullae and/ or 
desquamation  
GI Tract* 
<500 ml/day 
stool volume 
501-1000 ml/day 
stool volume 
1001-1500 
ml/day stool 
volume 
>1500 
ml/day stool 
volume 
Severe abdominal 
pain +/- ileus, with or 
without 
hematochezia 
Upper GI 
 
Severe nausea, 
vomiting, or 
anorexia 
 
 
 
Liver 
Total 
bilirubin 
<2.0 mg/dL 
2.1-3 mg/dl 
3.1-6 mg/dl 
6.1-15 
mg/dl 
>15 mg/dl 
Abbreviations: BSA = body surface area; GI = gastrointestinal 
* If stool sample is not quantified in mL, each episode of diarrhea will be estimated to be a volume of 200 mL. 
 
Appendix Table 3. 
IBMTR Severity Index for Grading aGVHD 
 
Skin 
Liver 
GI 
I 
Stage 1 
0 
0 
II 
Stage 2 
Stage 1-2 
Stage 1-2 
III 
Stage 3  
Stage 3  
Stage 3 
IV 
Stage 4  
Stage 4 
Stage 4 
 


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Appendix 6 
Criteria for Therapeutic Response/Outcome Assessment 
Acute lower GI GVHD Response Criteria: 
• Complete Response (CR): stage of 0 of all aGVHD symptomatology in the lower GI tract 
with no additional intervening GVHD therapy. 
• Very good partial response (VGPR): tolerating food or enteral feeding, predominantly 
formed stools, no overt GI bleeding or abnormal cramping. 
• Partial Response (PR): improvement by at least 1 stage in lower GI GVHD 
symptomatology with no additional intervening therapy for their GVHD. 
• No Response (NR)/stable: absence of any improvement in GVHD stage. Subjects 
receiving secondary therapy (including need to re-escalate corticosteroid dose to 
≥2.5 mg/kg/day of prednisone (or methylprednisolone equivalent) will be classified as 
non-responders.  
• Progression: deterioration in lower GI tract. 
 
Response for All Organs Involved with Acute GVHD: 
• Complete Response (CR): stage of 0 of all aGVHD symptomatology in all GVHD target 
organs with no additional intervening GVHD therapy. 
• Very good partial response (VGPR): tolerating food or enteral feeding, predominantly 
formed stools, no overt GI bleeding or abnormal cramping, no more than occasional 
nausea or vomiting. 
• Partial response (PR): improvement in GVHD stage in all initial GVHD target organs 
without complete resolution and without worsening in any other GVHD target organs.  
• Mixed response (MR): improvement in 1 or more GVHD target organs with deterioration 
in another organ manifesting symptoms of GVHD or development of symptoms of 
GVHD in a new organ. 
• No response (NR)/stable: absence of any improvement in GVHD stage. Subjects 
receiving secondary therapy (including need to re-escalate corticosteroid dose to 
≥2.5 mg/kg/day of prednisone or methylprednisolone equivalent) will be classified as 
non-responders.  
• Progression: deterioration in at least 1 organ without any improvement in others.  
 
Treatment Failure: 
The following will be considered as treatment failures: 
• NR/stable after 14 days of therapy. 
• Progression after 7 days of therapy. 
• Administration of additional systemic therapy for GVHD (or re-escalation of 
corticosteroid dose to ≥2.5 mg/kg/day of prednisone (or methylprednisolone equivalent) 
• Transplant-related mortality (TRM) 
 


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Discontinuation of Immunosuppressive Medications. 
• Discontinuation of immunosuppression will be assessed over time. The date of 
discontinuation of corticosteroids will be recorded. In addition, dates for discontinuation 
of all other systemic immunosuppressive medications (including CSA, tacrolimus, 
sirolimus, etc.) for treatment or prevention of aGVHD will be assessed.  
 
Transplant related mortality (TRM) 
• TRM is defined as death at any time from the commencement of pre-transplant 
conditioning due to any cause other than disease relapse with the exception of automobile 
or other accidents. The incidence of TRM at Day 56 is the primary safety endpoint. 


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Protocol: GC-652-02 
 
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Appendix 7 
List of Abbreviations and Definitions of Terms 
z 
Elimination half-life 
ADL 
Activities of daily living 
AE 
Adverse event 
aGVHD 
Acute Graft-versus-Host Disease 
ALP 
Alkaline Phosphatase 
ALT (SGOT) 
Alanine aminotransferase 
ANC 
Absolute neutrophil counts 
AST (AGPT) 
Aspartate aminotransferase 
ATG 
Anti-thymocyte globulin 
AUC 
Area under the plasma concentration vs. time curve 
BMT 
Bone marrow transplant 
BUN 
Blood Urea Nitrogen 
Cmax 
Concentration Maximum 
CBC 
Complete Blood Count 
CFR 
Code of Federal Regulations 
CL 
Clearance 
CMV 
Cytomegalovirus 
CR 
Complete response 
CRP 
C-reactive Protein  
CSA 
Cyclosporine 
CTCAE 
Common Terminology Criteria for Adverse Events 
D5W 
5% dextrose in water 
DC 
Dendritic cell 
DP 
Drug product 
DS 
Drug substance 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EIU 
Exposure in utero 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GMP 
Good Manufacturing Practices 


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hCG 
Human chorionic gonadotropin 
Hgb 
Hemoglobin 
HSCT 
Hematopoietic stem cell transplantation 
IBMTR 
International Bone Marrow Transplant Registry 
ICF 
Informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IL 
Interleukin 
ILC 
Innate lymphoid cell 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISC 
Intestinal stem cell 
IV 
Intravenous 
IWRS 
Interactive web based response system 
MedDRA 
Medical Dictionary for Regulatory Activities 
MHC 
Major histocompatibility complex 
MMF 
Mycophenolate mofetil 
MR 
Mixed response 
NCI 
National Cancer Institute 
NR 
No response 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PR 
Partial response 
rh 
Recombinant human 
rm 
Recombinant murine 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
t1/2 
Half-life 
tmax 
Maximum concentration (of a drug in bloodstream) 
TEAE 
Treatment-emergent adverse event 
TRM 
Transplant-related mortality 
Vd 
Volume of distribution 
VGPR 
Very Good Partial Response 
 

SAP_001.pdf: 
 
 
 
 
16.1.9 
Documentation of Statistical Methods 
16.1.9.1 
Statistical Analysis Plan (Version 1.1, Dated 19 March 2020) ................................................... 2 
16.1.9.2 
Statistical Analysis Plan (Version 1.0, Dated 07 October 2019) ............................................ 147 
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Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN 
 
 
 
Trial Sponsor: 
Generon (Shanghai) Corporation Ltd. 
Protocol Number: 
GC-652-02 
IND Number: 
 
Investigational Drug: F-652 
Indication: 
Gastrointestinal Graft versus Host Disease 
Dosage Form/Strength F-652, 45 μg/kg IV 
 
Protocol Title: A Phase IIa Study of Recombinant Human Interleukin-22 IgG2-Fc (F-652) in 
Combination with Systemic Corticosteroids for the Treatment of Newly Diagnosed Grade II-IV 
Lower Gastrointestinal Acute Graft-versus-Host Disease (aGVHD) in Hematopoietic Stem Cell 
Transplantation Recipients 
 
 
Last Revision Date: 
19 March 2020 
Version: 
1.1  
Final Sign-off Date: 
 
Archive Date: 
 
 
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Change Log for Changes Made after the Initial Approval 
Revision 
Date** 
Section(s)M
odified 
Brief Description of Revision(s) or Reason(s) 
for Revision 
Modifications 
Reviewed and 
Approved by* 
Sponsor, Everest 
17MAR2020 
6.2.4 
Added details on the stopping date for the definition of 
treatment emergent AEs 
K Dreyer, F Tang 
17MAR2020 
6.3.3 and 7.5.2 
Clarified Immune recovery analysis will performed 
separately. 
K Dreyer, F Tang 
17MAR2020 
6.4 and 7.7 
Clarified PK analysis will performed separately. 
K Dreyer, F Tang 
17MAR2020 
7.4.4 
Added details on how to handle special laborotory values 
(">" or "<")   
K Dreyer, F Tang 
*   Provide person’s initial and last name. 
** Update the Last Revision Dates on the cover page and the document header. 
 
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
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TABLE OF CONTENTS 
APPROVAL SIGNATURES ........................................................................................................................ 2 
GLOSSARY OF ABBREVIATIONS .......................................................................................................... 6 
1. 
INTRODUCTION ................................................................................................................................ 8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................................ 8 
2.1 
Study Objective .......................................................................................................................... 8 
2.2 
Safety Endpoints ......................................................................................................................... 8 
2.3 
Primary Efficacy Endpoint ......................................................................................................... 8 
2.4 
Secondary Efficacy Endpoints .................................................................................................... 8 
2.5 
 ................................................................................................................ 9 
2.6 
 ........................................................................................................ 9 
3. 
STUDY DESIGN .................................................................................................................................. 9 
3.1 
Study Design ............................................................................................................................... 9 
3.2 
Schedule of Procedures and Events .......................................................................................... 13 
3.3 
Randomization .......................................................................................................................... 15 
3.4 
Hypothesis Testing ................................................................................................................... 15 
3.5 
Interim Analysis ....................................................................................................................... 15 
3.5.1 
Hold and Discontinuation Rules for the Clinical Trial ............................................... 15 
3.6 
Sample Size .............................................................................................................................. 16 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE .................................................................. 16 
5. 
ANALYSIS POPULATIONS ............................................................................................................. 16 
5.1 
Safety Population ...................................................................................................................... 16 
5.2 
Efficacy Evaluable Population ................................................................................................. 16 
5.3 
 ..................................................................................................... 16 
6. 
SPECIFICATION OF ENDPOINTS AND VARIABLES ................................................................. 16 
6.1 
Demographic and Baseline Characteristics .............................................................................. 17 
6.1.1 
Demographics and Baseline Characteristics .............................................................. 17 
6.1.2 
Medical and Surgery History, Prior Chemotherapy ................................................... 17 
6.2 
Safety ........................................................................................................................................ 18 
6.2.1 
Safety Baseline and Study Day .................................................................................. 18 
6.2.2 
Extent of Exposure to Study Medication.................................................................... 18 
6.2.3 
Prior and Concomitant Medication ............................................................................ 18 
6.2.4 
Adverse Events ........................................................................................................... 19 
6.2.5 
Laboratory Data .......................................................................................................... 21 
6.2.6 
Vital Signs .................................................................................................................. 22 
6.2.7 
Electrocardiogram ...................................................................................................... 22 
6.2.8 
Other Safety Assessments .......................................................................................... 22 
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6.3 
Efficacy ..................................................................................................................................... 23 
6.3.1 
Study Day ................................................................................................................... 23 
6.3.2 
Primary Efficacy Variables ........................................................................................ 23 
6.3.3 
Secondary Efficacy Variables .................................................................................... 23 
6.3.4 
................................................................................................. 24 
6.4 
 ....................................................................................................... 24 
7. 
STATISTICAL ANALYSIS ............................................................................................................... 24 
7.1 
General Data Handling Rules and Definitions ......................................................................... 24 
7.1.1 
Missing Data and Imputation ..................................................................................... 24 
7.1.2 
Analysis Visit and Visit Window Definitions ............................................................ 25 
7.2 
Subject Disposition ................................................................................................................... 25 
7.3 
Demographic and Baseline Characteristics .............................................................................. 25 
7.4 
Safety Analyses ........................................................................................................................ 26 
7.4.1 
Extent of Exposure to Study Medication.................................................................... 26 
7.4.2 
Concomitant Medications........................................................................................... 26 
7.4.3 
Adverse Events ........................................................................................................... 26 
7.4.3.1 
Incidence of Adverse Events ..................................................................... 27 
7.4.4 
Laboratory Data .......................................................................................................... 27 
7.4.5 
Vital Signs .................................................................................................................. 27 
7.4.6 
Electrocardiogram ...................................................................................................... 27 
7.4.7 
Other Safety Assessments .......................................................................................... 27 
7.5 
Efficacy Analyses ..................................................................................................................... 28 
7.5.1 
Primary Efficacy ........................................................................................................ 28 
7.5.1.1 
Sensitivity Analyses ................................................................................... 28 
7.5.2 
Secondary Efficacy..................................................................................................... 28 
7.6 
................................................................................................................ 28 
7.7 
 ...................................................................................................... 29 
8. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................. 29 
9. 
STATISTICAL SOFTWARE ............................................................................................................. 29 
10. REFERENCES .................................................................................................................................... 29 
APPENDIX 1 
 DATA HANDLING RULES .................................................................................... 30 
APPENDIX 2 
 SAS CODE FOR STATISTICAL ANALYSES ....................................................... 30 
APPENDIX 3 
 MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) ..................................... 31 
 
 
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GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
aGVHD 
Acute Graft-versus-Host Disease 
AE 
Adverse event 
ANC 
Absolute neutrophil count 
AUC 
Area under the curve 
BLOQ 
Below the limit of quantitation 
BMI 
Body mass index 
BMT 
Bone marrow transplant 
BPM 
Beats per minute 
BSA 
Body surface area 
Cmax  
Concentration Maximum  
CBC 
Complete Blood Count 
CI 
Confidence interval 
CL 
Clearance 
CMV 
Cytomegalovirus 
CR 
Complete response 
eCRF 
Electronic Case Report Form 
CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
ECG 
Electrocardiogram 
GI 
Gastrointestinal 
HSCT 
Hematopoietic Stem Cell Transplantation 
IBMTR 
International Bone Marrow Transplant Registry 
IV 
Intravenous 
IWRS 
Interactive Web-based Response System 
λz 
Elimination half-life 
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Abbreviation 
Term 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Mixed response 
NCA 
Non-compartmental analysis 
NCI 
National Cancer Institute 
NR 
No response 
OTC 
Over-the-counter 
PE 
Physical examination 
PK  
Pharmacokinetics  
PR 
Partial response 
PT 
Preferred term 
QA 
Quality assurance 
QC 
Quality control 
QTcF 
Fridericia corrected QT interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SI units 
International System of Units 
SOC 
System organ class 
SOP 
Standard operating procedure 
TEAE 
Treatment Emergent Adverse Event 
TRM 
Transplant-related mortality 
Vd 
Volume of distribution 
VGPR 
Very good partial response 
VS 
Vital signs 
WHO-DD 
World Health Organization Drug Dictionary 
 
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
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1. INTRODUCTION 
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and analysis 
of data collected within the scope of Generon (Shanghai) Corporation Ltd. protocol GC-652-02, Protocol 
Amendment 4.0 dated May 30, 2017. The purpose of this plan is to provide general guidelines from 
which the analysis will proceed. Nevertheless, deviations from these guidelines must be substantiated by a 
sound statistical rationale. 
The SAP should be read in conjunction with the study protocol and the Case Report Forms (CRFs). This 
version of the SAP has been developed using the final version of the protocol mentioned above and the 
study CRFs, Version 4.  
This is a Phase IIa open label single arm study to investigate the safety, efficacy, and pharmacokinetics 
(PK) of F-652 (recombinant human IL-22), administered as an intravenous (IV) infusion once a week for 
a total of 4 doses at 45 μg/kg, in combination with systemic corticosteroids for the treatment of newly 
diagnosed grade II-IV lower gastrointestinal (GI) acute graft-versus-host disease (aGVHD) in 
Hematopoietic Stem Cell Transplantation (HSCT) recipients. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objective 
The objective of the study is to assess the safety, efficacy and PK of F 652 in combination with systemic 
corticosteroids for the treatment of newly diagnosed grade II-IV lower GI aGVHD in HSCT recipients. 
GVHD cytokines and biomarkers will be explored. 
2.2 
Safety Endpoints 
The safety endpoints of this study are the following:  
 
Adverse event (AE) reporting 
 
Vital sign (VS) measurements 
 
Laboratory measurements 
 
Physical Examination (PE) 
2.3 
Primary Efficacy Endpoint 
 
To assess the lower GI aGVHD treatment response rate at Day 28.  
2.4 
Secondary Efficacy Endpoints 
 
Lower GI aGVHD treatment response at Days 14 and 56 categorized by complete response (CR), 
very good partial response (VGPR), partial response (PR), no response (NR)/stable, and progression. 
 
Overall aGVHD treatment response at Days 14, 28, and 56 categorized by CR, VGPR, PR, mixed 
response (MR), NR, and progression. 
 
Discontinuation of immunosuppressive medication at Day 180 and 1 year post initial dosing of F-652. 
 
Characteristics of immune reconstitution after F-652 treatment. 
 
Overall survival at 1 year after first infusion of F-652. 
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efficacy. If 7 or more subjects of the first 16 subjects have a treatment response, an additional 11 subjects 
will be required to complete enrollment into the study for a total sample size of 27 subjects (Figure 1). 
All subjects will be followed for efficacy through Day 56, safety through Day 180, and subject survival 
status will be collected at Day 365 (1 year from the date of initial dosing of F-652). 
Prior to each dosing of F-652, subjects are required to meet the following criteria: absolute neutrophil 
count (ANC) ≥500/mm3, serum creatinine ≤3.0 mg/dl, and all non-hematologic toxicity (except alopecia) 
attributed to the study drug as probable or greater to resolved to ≤ Grade 1 or returned to the subject’s 
baseline condition. Failure to meet these criteria will result in treatment delay, dose reduction, or 
withdrawal from the study, as outlined in Protocol Section 3.3.2 (Hold and Stop Rules). A review of 
excess subject mortality at Day 56 will occur for every 6 subjects accrued into the study. 
During the course of the study, systemic corticosteroids (prednisone or methylprednisolone equivalent) 
will be administered concurrently with F-652. Tapering of corticosteroids is permitted as outlined in 
Protocol Section 5.2 (Treatment Administrations); however, tapering should result in no less than 0.25 
mg/kg/day of prednisone (or IV equivalent) by Day 28, after which tapering may be according to local 
institutional guidelines. 
All subjects should be treated to the institutional allogeneic bone marrow transplant (BMT) standard of 
care guidelines for prophylaxis against infection. This includes, Pneumocystis carinii, Herpes simplex, 
Herpes Zoster, and fungal infections. Subjects will be closely monitored for cytomegalovirus (CMV) 
reactivation according to the each local center standard practice. 
The study drug will be administered on an inpatient or outpatient basis, depending on the subject’s 
clinical condition. The route of administration of F-652 is IV and will be administered once a week on 
Days 0, 7, 14, and 21. Following infusion of F-652, vital signs will be obtained and nursing assessment 
will be performed according to the BMT institutional standard of care. PK sampling will occur as per the 
schedule listed in the Protocol in Appendix 3 and serum samples to test the immunogenicity of F-652 will 
be taken. Subjects will be evaluated for grade 3-4 toxicities, graded by the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE). A complete description of the study 
procedures for each clinical visit is presented in the Protocol in Appendix 1. 
GVHD biomarkers will be assessed at baseline and post-treatment. Baseline assessment of GVHD 
markers in the peripheral blood and GI tissue will be performed at the time of GVHD diagnosis, pending 
specimen availability. Due to the extensive processing of the peripheral blood for the assessment of 
GVHD cytokine markers, cytokine samples are optional for subjects participating in this study.  The 
biomarker panel will include ST2 and REG3α whereas the cytokine panel will include IL-21, IL-22, and 
IL-23 levels. A stool sample will be collected for intestinal microbiota analysis and GVHD biology, 
including histology and epithelial gene expression, will also be analyzed in biopsy samples from the GI 
tract as the specimen allows. Post-treatment evaluation of GVHD biomarkers/cytokines in the peripheral 
blood, stool sample for intestinal microbiota, and GI tract biopsies will be performed approximately 28 
days after study drug initiation or at least 3 days after receiving last dose of study drug (subject and 
sample availability permitting). Sampling may be withheld in subjects who are critically ill. 
A study visit schematic is provided in Figure 2 and a complete schedule of study procedures and events 
are presented in Section 1.1 (Schedule of Procedures and Events). 
 
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3.2 
Schedule of Procedures and Events 
Table 1 Schedule of Assessments 
Assessments 
Screening Day 0 
Day 7 
Day 14 
Day 21 
Day 28* 
Day 56 
Day 180 Day 365 
Window for visit (days) 
(5) days 
  
(±) 2 
(±) 2 
(±) 2  
(±) 4 
(±) 14 
(±) 30 
(±) 30 
Signing of Informed Consent 
X 
 
 
 
 
 
 
 
 
Relevant Medical History 
X 
 
 
 
 
 
X 
X 
X 
Body Temperature, Weight, Vital Signs (BP, heart rate, respiratory 
rate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
X 
X 
X 
X 
CBC1 
X 
  
X 
X 
X 
X 
X 
 
 
Blood chemistry1 
X 
  
X 
X 
X 
X 
X 
 
 
Urinalysis  
X 
 
 
 
 
X 
 
 
 
Immune recovery (per institutional standard)2 
 
X 
 
 
 
X 
 
 
 
Serum for F-652 antibody testing (pre dosing of F-652)  
 
X 
X 
X 
X 
X 
X 
 
 
ECG 
X 
 
 
 
 
X 
 
 
 
Stool C. Difficile testing (if not done within 7 days) 
X 
 
 
 
 
 
 
 
 
Stool microbiota test 
X 
 
 
 
 
X 
 
 
 
Pregnancy test3 
X 
 
 
 
 
 
 
 
 
Current therapy and concomitant medications4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GI Biopsy5 
X 
 
 
    
 
X 
 
 
 
 (see additional schedule) 
 
X 
X 
X 
X 
X 
X 
 
 
Administration of F-6527 (within 5 days of consent)  
 
X 
X 
X 
X 
 
 
 
 
Collection of AEs and toxicity assessment8 
X 
X 
X 
X 
X 
X 
X 
 
 
aGVHD blood research samples ( cytokine samples optional) 
 
X 
 
 
 
X 
 
 
 
Skin biopsy, subject permitting or if skin rash develops during 
treatment 
X 
 
 
X 
 
X 
 
 
 
GVHD treatment response 
 
 
 
X 
 
X 
X 
 
 
aGVHD evaluation  
X 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE = adverse event; aGVHD = acute graft-versus-host disease; BP = blood pressure; CBC = complete blood count; ECG = electrocardiogram; F-652 = 
recombinant human interleukin-22-IgG2-Fc; GI = gastrointestinal; GVHD = graft-versus-host disease; PK = pharmacokinetics.* End of treatment visit 
1 Blood samples are taken predose at Screening and Days 7, 14, 21, 28, and 56, and at 72 hours post-dose for CRP determination only at Screening and Days 7, 14, and 21. 
2 Immune recovery assessed on Day 0 as baseline and Days 28, post initial dose of F-652. Testing can be withheld if the subject has very low circulating white blood cells. 
3 For females with reproductive potential, serum test. 
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3.3 
Randomization 
There is no randomization as this is a single arm study. An Interactive Web-based Response System 
(IWRS) with a 24-hour live support help desk will be used to assign subject numbers and to assign study 
drug. Authorized study site personnel will access the web-based system using a user ID and password. 
Prior training and a user’s manual will be provided to all the study participating sites. 
3.4 
Hypothesis Testing 
In this exploratory Phase IIa study, all statistical tests will be two-sided with no adjustment for 
multiplicity.  All statistical tests and confidence intervals (CI) will use a Type I error rate of 10%. No 
adjustment will be made for multiple testing. 
3.5 
Interim Analysis 
No interim analysis is planned for this study.   
3.5.1 
Hold and Discontinuation Rules for the Clinical Trial 
Subjects will be closely monitored for clinical deterioration (i.e., disease progression) by the study 
Investigators, the study Medical Monitor, and the Sponsor’s medical expert. In addition to standard 
toxicities such as alterations in blood chemistries or hematology, this monitoring will also include disease 
progression and treatment efficacy. 
Clinical Trial Termination: 
The study includes stopping criteria in the event that excessive Day 56 TRM is observed. The historical 
rate of TRM deaths is approximately 15-20%.3 A TRM of 40% at Day 56 would be considered 
unexpected and an unacceptable number of excess deaths. TRM is defined as death at any time from the 
commencement of pre-transplant conditioning due to any cause other than disease relapse with the 
exception of automobile or other accidents. 
In this study, there will be an ongoing review for excessive TRM. The study will be stopped for interim 
evaluation if the number of deaths is 3 or more in the first 5 subjects treated, 4 or more in the first 9 
subjects treated, etc. as per Table 3. This evaluation will occur for the subject’s Day 56 visit (post their 
initial F-652 dosing). Subjects removed from the study due to negative biopsy for aGVHD will not be 
accountable for the mortality rate rule analysis. 
Table 3 Stopping criteria for excessive mortality based on a Pocock boundary 
Failure Type 
Mortality Rate Rule for 
Study Termination 
Death rate in the 
population 
Probability boundary 
is crossed  
Transplant-Related 
Mortality (day +56)   
3 deaths in the first 5 
subjects treated 
0.15 
0.10 
4 deaths in the first 9 
subjects treated 
5 deaths in the first 13 
subjects treated 
0.40 
0.93 
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Statistical Analysis Plan 
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6.1 
Demographic and Baseline Characteristics 
6.1.1 
Demographics and Baseline Characteristics 
Demographic parameters collected include:  
 
Age 
 
Sex 
 
Race 
 
Ethnicity 
 
Reproductive status 
Baseline characteristics include: 
 
Weight (kg) 
 
Height (cm) 
 
Body mass index (BMI) in kg/m2 
 
Body surface area (BSA) in m2 
 
Days since clinical lower GI aGVHD diagnosis 
 
Screening aGVHD stage for each target organ (Skin, Lower GI Tract, Upper GI Tract, and Liver) 
using the modified keystone criteria 
 
IBMTR Severity Grade 
 
Type of HSCT (Blood, Bone Marrow, Cord, or Haploidentical) 
 
CMG IgG serostatus (Positive, Negative, or Equivocal) 
 
CMG IgM serostatus (Positive, Negative, or Equivocal) 
 
Physical examination clinically significant abnormalities (Yes or No) 
 
Age, BMI, BSA, and days since clinical lower GI aGVHD diagnosis will be computed as: 
Table 4 Data Handling Rules for Demographic Data 
Description 
Data Handling Rule 
Age (years) 
Age = integer((date of screening-date of birth)/365.25)   
BMI 
BMI = Weight (kg) / [Height (cm)/100]2 
BSA 
BSA =( [Height (cm) x Weight (kg) ]/ 3600 )1/2 
Days since clinical lower 
GI aGVHD diagnosis 
Days since clinical lower GI aGVHD diagnosis = Date of screening – 
Date of Clinical Lower GI aGVHD diagnosis 
 
6.1.2 
Medical and Surgery History, Prior Chemotherapy 
Medical and surgical history and prior chemotherapy will be collected. 
General medical and surgical history will include a description of the diagnosis or procedures, start and 
end date, and if the condition is still ongoing. 
Prior chemotherapy agent name, number of cycles, and date of last dose will be recorded on the eCRF.   
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6.2 
Safety 
 
AE reporting 
 
VS measurements 
 
Laboratory measurements (hematology, serum chemistry, and urinalysis) 
 
Electrocardiogram (ECG) measurements 
 
PE 
Standard safety parameters include hematology, blood chemistry and urinalysis parameters, vital signs, 
physical examination, and toxicity management. The National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) v 4.03 will be used to grade potential AEs. 
6.2.1 
Safety Baseline and Study Day  
The baseline of safety measures are the last measure before first dose of F-652. 
Study day will be computed from Day 0 as:   
Study day = (Date of interest) – (Date of Day 0) + 1 
6.2.2 
Extent of Exposure to Study Medication 
Extent of exposure to study drug (F-652) will be assessed using the following variables: 
Table 5 Data Handling Rules for Extent of Exposure to Study Medication Data 
Description 
Definition/ Data Handling Rule 
Number of Treatments 
Number of infusions started, regardless of the completion status. 
Treatment duration 
Treatment duration (days) = Date of last dose of F-652– Date of first 
dose of F-652 + 1 
Total F-652 Received 
(mg) 
The total dosage of F-652 received. The starting dose is 45 μg/kg.  
Subsequent doses may be reduced, as determined by the Investigator, to 
30 μg/kg or 10 μg/kg.   
The drug administered is at a concentration of 5 mg/mL.  Dose infused 
(mg) can be calculated as (Volume infused (mL) * 5 mg/mL). 
Number of Subjects with 
Doses Interrupted or 
Discontinued Prematurely 
(Overall and for each 
dose) 
Number of subjects administered study drug but who had the infusion 
interrupted or discontinued prematurely. 
 
6.2.3 
Prior and Concomitant Medication 
Prior and concomitant medications, including BMT/GVHD and systemic corticosteroid medications, will 
be recorded at screening and during the study. Prior medication is defined as any medication taken before 
the first dose of F-652. Concomitant medication is defined as any medication taken during the study 
between the date of the first dose of F-652 and the last study date of the subject, up to the Day 56 visit.  
Any medications started after the last study date of the subject will not be considered concomitant 
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medications. After Day 56, only concomitant medications related to a SAE will be documented on the 
eCRFs and will be considered as post-dose medications. 
Any medication which cannot be identified as prior or concomitant will be considered as being in both of 
the categories that are possible from the available information. 
All relevant information, including reason for use, dose, unit, frequency and route, will be recorded for 
any medication administered or received prior and during the study. 
Summaries of all concomitant medications taken during the course of the study will be presented in 
tabular form using Anatomical Therapeutic Chemical 4 classification codes and preferred drug name via 
the World Health Organization Drug Dictionary (WHO-DD) with latest version to be specified in the 
Clinical Study Report. For the summary tables, if a subject has taken a concomitant medication more than 
once, the subject will be counted only once for the medication. 
For medications with incomplete dates, imputation will be used to convert to a complete date. Imputed 
dates will be used to determine the study day. 
Partial medication start dates will be imputed as follows:  
1. Only the year is reported: If the subject started receiving study treatment in the year reported, 
then the date of the first dose of study treatment will be used as the starting date of the 
medication. Otherwise, January 1 will be used as the start of the medication. 
2. The month and year is reported: If the subject started receiving study treatment during the month 
and year reported, then the date of first dose of study treatment will be used as the starting date of 
the medication. Otherwise, the first day of the month will be used as the start of the medication. 
Partial medication end dates will be imputed for non-ongoing medications as follows:  
1. Only the year is reported: If the subject stopped receiving study treatment in the year reported, 
then the date of the last dose of study treatment will be used as the end date of the medication. 
Otherwise, December 31 will be used as the end of the medication.  
2. The month and year is reported: If the subject stopped receiving study treatment during the month 
and year reported, then the date of last dose of study treatment will be used as the end date of the 
medication. Otherwise, the last day of the month will be used as the end of the medication. 
The above rules are subject to logical sense, for example, imputed start date should be on or prior to 
imputed end date. 
6.2.4 
Adverse Events 
Adverse events (AEs) will be collected and coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Analysis of adverse events will be carried out on the Safety 
Population. 
All AEs from the time of randomization, regardless of suspected causal relationship to the investigational 
product, will be documented on the AE page(s) of the eCRF up to and including Study Day 56.  After 
Day 56,  SAEs deemed possibly, probably, or definitely related to the investigational product are required 
to be recorded through to the end of the study (Day 365). 
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A treatment-emergent adverse event (TEAE) is any adverse event that begins on or after first dose of F-
652, or is a worsening of a pre-existing medical condition, up to study follow-up Day 56 (or 28 days after 
last dosing of F-652 if the subject does not have follow-up Day 56). SAEs that start after Day 56 will be 
considered post-treatment.  Incidence of TEAE will be presented overall for all subjects.  
The severity of each AE will be classified using the NCI-CTCAE toxicity scale as follows: 
 
Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL) 
 
Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL 
 
Grade 4 = Life-threatening consequences; urgent intervention indicated.  
 
Grade 5 = Death related to AE. 
The relationship of each AE will be assessed by the investigator and assigned to  1 of the following 
categories: 
 
Unrelated 
 
Unlikely 
 
Possible 
 
Probable 
 
Definite 
An AE will be considered “related” to study drug if the relationship is “possible”, “probable” or 
“definite”. 
Serious adverse events (SAE) are defined as any adverse events occurring at any dose that suggests a 
significant hazard, contraindication, side effect, or precaution. SAEs will be collected from the time of 
study entry until 30 days after completion of the trial or 30 days after premature withdrawal of a subject 
from the trial. 
If the death of a subject is reported at any point during the study, the date of death, autopsy performed 
(yes/no), and any clarifying information should be collected. The event causing death will be reported as a 
SAE. 
Adverse Events Counting Rules: 
1. In the analyses, a subject having the same event (AE preferred term) more than once during the study 
will be counted only once for that event type.  
2. A subject with more than one different adverse event in a particular system organ class (SOC) will be 
counted only once in the total of subjects experiencing adverse events in that particular SOC. 
3. If an event changes in intensity or in seriousness during the study, it will be counted only once with 
the worst grade and seriousness respectively. 
4. If the causal relationship to the study drug is assessed differently, it will be counted only once by 
considering the “Worst” documented degree of relationship. 
Missing values will be treated as missing except for relationship, grade and seriousness of an AE, at 
which occurrence a “worst case” approach will be taken. Thus, if relationship is missing the AE will be 
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regarded as related to the study drug, if the grade is missing the grade of the AE will be regarded as 
severe (Grade 3), if seriousness is missing the AE will be regarded as an SAE. 
Events with Irregular Start Dates: All treatment-emergent adverse events will be included in the 
tabulations regardless the completeness of the onset dates. Partial dates may be imputed when 
appropriate, as discussed below. 
If a partial date is reported for the start of an adverse event, a complete date will be estimated by the 
following algorithm: 
1. Only the year is reported: If the subject started receiving study medication in the prior year, then 
January 1 will be used as the starting date of the event. If the subject started receiving study 
medication in the year reported, then the date of the first dose of study medication will be used as the 
start of the event.  
2. The month and year are reported: If the subject started receiving study medication prior to the month 
and year reported, then the first day of the month will be used as the starting date of the event. If the 
subject started receiving medication during the month and year reported, then the date of the first dose 
of study medication will be used as the start of the event.  
If a partial date is reported for the end of an adverse event and the adverse event is not continuing, a 
complete date will be estimated by the following algorithm:  
1. Only the year is reported: If the subject started receiving study medication in the prior year, then the 
date of final study contact with the subject will be used as the end of the adverse event. If the subject 
started receiving study medication in the year reported, the earlier of December 31 or the date of final 
study contact with the subject will be used as the end of the adverse event.  
2. The month and year are reported: The earlier of the last day of the month or the date of final contact 
with the subject will be used as the end of the adverse event.  
Before the database lock, uncoded events will be assigned the string “UNCODED” as the body system, 
and the verbatim term will be used as the preferred term, so they can be included in the summary tables. 
In the final dataset, all the adverse events should have been coded.  
6.2.5 
Laboratory Data 
This study will be conducted in up to 4 clinical centers in North America.  Blood samples for hematology, 
serum chemistry, and serum hCG, as well as stool samples for C. difficile will be collected and analyzed 
by a local laboratory.  Blood samples collected for PK will be analyzed by a central laboratory.   
Conversion to the International System of Units 
All laboratory data will be stored in the database with the units in which they are originally reported. 
Laboratory data in summary tables and subject data listings will be presented in the International System 
of Units (SI units). Laboratory data not reported in SI units will be converted to SI units before further 
processing or data analysis. 
Hematology and blood chemistry data will be graded according to NCI-CTCAE severity grade.  
Baseline laboratory parameters (blood chemistry, hematology, and urinalysis) are defined as the subject’s 
last assessment prior to the first dose of F-652.    
Change in laboratory parameters post baseline can be computed as: 
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Change from baseline = Current Value – Baseline Value 
Missing laboratory values will not be imputed for the safety analysis. In case of repeated measurements at 
a given visit, the latest value will be used for analysis.   
6.2.6 
Vital Signs 
Vital signs are collected at Screening, Days 0, 7, 14, 21, 28, 56, 180, and 365, and include the following 
parameters: 
 
Height (cm) (Screening only) 
 
Weight (kg) 
 
Temperature (oC) 
 
Heart rate (beats per minute [BPM]) 
 
Diastolic and systolic blood pressure (mmHg) 
 
Respiratory rate (beats/minute) 
Weight at Days 0, 7, 14, and 21 will be measured once.  Temperature, heart rate, blood pressure, and 
respiratory rate at Days 0, 7, 14, and 21 will be measured 15 minutes after the start of infusion, at the 
completion of infusion, and 1 hour after the end of infusion.  All parameters will be collected one time 
each at Screening and on Days 28, 56, 180, and 365.     
Baseline and change from baseline are defined similarly as in Section 6.2.5.  
6.2.7 
Electrocardiogram 
Standard 12-lead ECG will be measured at screening and Day 28. The following parameters are included:  
 
PR Interval 
 
QRS Duration 
 
QT Interval 
 
RR Interval 
 
Heart Rate 
 
QTc Fridericia Interval (QTcF) 
QTcF will be calculated as:  𝑄𝑇√𝑅𝑅
3
⁄
.   
Another version of QTc was also collected from the CRF and will only be listed.  
6.2.8 
Other Safety Assessments 
Other safety assessments include: 
 
Serum pregnancy test 
 
Urine pregnancy test  
 
Physical examination 
Any clinically significant abnormalities from physical examination will be reported as medical history if 
observed at Screening, or as an AE if observed after enrollment. 
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6.3 
Efficacy 
The Efficacy Evaluable Population will be used for the efficacy analyses.  
Missing aGVHD treatment response will be imputed as non-response for this analysis. Handling of 
missing values is covered in section 7.1.1. 
6.3.1 
Study Day 
The date of the first dose of F-652 represents Study Day 1. 
Study day will be computed from day 1 as:   
Study day = (date of interest) – (date of Study Day 1) + 1 
6.3.2 
Primary Efficacy Variables 
 
The lower GI aGVHD treatment response rate 28 days following the initiation of therapy will be 
assessed by examining the proportion of subjects with a CR, VGPR, PR or have NR/stable or 
progression of lower GI aGVHD symptomatology.  Treatment Response will be defined as CR, 
VGPR, or PR.  No Treatment Response will be defined as NR/stable or progression. 
6.3.3 
Secondary Efficacy Variables 
 
The lower GI aGVHD treatment response rate at Days 14 and 56 will be assessed by examining the 
proportion of subjects with a CR, VGPR, PR or have NR/stable or progression of lower GI aGVHD 
symptomatology.  Treatment Response will be defined as CR, VGPR, or PR.  No Treatment 
Response will be defined as NR/stable or progression. 
 
The overall aGVHD treatment response rate at Days 14, 28, and 56 will be assessed by examining the 
proportion of subjects with a CR, VGPR, PR, MR, or have NR/stable or progression of overall 
aGVHD symptomatology.  Treatment Response will be defined as CR, VGPR, PR, or MR.  No 
Treatment Response will be defined as NR/stable or progression. 
 
Discontinuation of immunosuppressive medication at Day 180 and 1 year post initial dosing of F-652 
will be assessed by estimating the proportion of subjects who have stopped immunosuppressive 
medication at Day 180 and 1 year.  Immunosuppresive medications will be identified as those 
collected on the BMT/GVHD Medications CRF and categorized as Immunosuppressants.  Subjects 
who discontinue at Day 180 and at 1 year will be defined as those who have stopped all 
immunosuppressant medications that were being taken at or after the first dose of F-652.   
 
Overall survival from the time of the first infusion of F-652 will be calculated as the number of days 
from the date of the first infusion to the date of death (Date of death – Date of first infusion +1) for 
subjects who die.  Survival time for subjects who do not die will be based on the subject’s study 
completion or discontinuation date (Date of completion/discontinuation – Date of first infusion +1).  
 
Characteristics of immune reconstitution after F-652 treatment will be evaluated through the B and T 
lymphocytes recovery and will be measured on Study Days 0 and 28 post-initial dose of F-652.  They 
will be detailed in a separate analysis plan. 
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All medical history, acute graft-versus-host disease (aGVHD) diagnosis, prior chemotherapy, physical 
examination (abnormalities only), prior/concomitant medications, BMT/GVHD medications, and 
systemic corticosteroid administration data collected on the eCRF will be presented in listings. 
7.4 
Safety Analyses 
All safety analysis will be performed on the Safety Population. Safety will be assessed based on AE 
reporting, physical examination, vital sign measurement, and clinical laboratory test results.  Summaries 
of safety parameters will be presented for all treated subjects.  
Wherever applicable for a safety parameter, the last assessment made before the first dose of F-652 will 
be used as the baseline for all analyses of that safety parameter.  
In case of repeated measurements at a given timepoint, the latest value will be used for analysis. 
Measurements at unscheduled visits will only be listed, unless it is actually a repeat of the scheduled 
measurement.  
7.4.1 
Extent of Exposure to Study Medication 
Descriptive statistics will be presented for the number of treatments, treatment duration (days), total F-
652 received (mg), and number of incompleted doses.  Study drug dose, date and time, and volume will 
be provided in listings. 
7.4.2 
Concomitant Medications 
The number and percent of subjects with concomitant medications will be tabulated by ATC class and 
preferred term.  Other details, including medication verbatim and coding, will be provided in listings.  
The number and percent of subjects with BMT/GVHD medications will be tabulated by category and 
drug name, as defined in the CRF.  Other details will be provided in listings.  The number and percent of 
subjects with systemic corticosteroid medications will be tabulated by corticosteroid name (Prednisone, 
Methylprednisolone, and Other).  Other details, including other specified corticosteroid names, will be 
provided in listings.   
7.4.3 
Adverse Events 
Analysis of adverse events will be carried out on the Safety Population. All adverse events will be 
included in the analyses, summaries, and individual subject data listings.  
A TEAE overview summary table will be provided for all treated subjects including the number and 
percentage of subjects reporting at least one TEAE and the number of TEAEs reported for the following 
categories: 
 
Any TEAEs 
 
Serious TEAEs  
 
Deaths  
 
TEAE leading to study drug interruption 
 
TEAE leading to discontinuation of study drug 
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7.4.3.1 
Incidence of Adverse Events 
TEAEs will be summarized by SOC and preferred term (PT). The summary tables will display the total 
number and percentage of subjects reporting a specific TEAE, and the number of TEAE reported. TEAEs 
will be presented by SOC sorted alphabetically and PT sorted in decreasing frequency of occurrence. 
Summary tables will be prepared for: 
 
Summary of TEAEs 
 
All TEAEs 
 
Serious TEAEs 
 
Treatment-related TEAEs 
 
TEAE leading to study drug discontinuation 
 
TEAEs by maximum severity 
 
TEAEs by relationship to study drug 
 
Common TEAEs with > 5% incidence rate 
 
Post-treatment SAE's 
Supporting data listings will be provided, including: 
 
All adverse events (including any AEs reported in the study)  
 
Serious adverse events  
 
Deaths 
 
Adverse events for subjects who discontinued the study due to AE 
 
Glossaries of Preferred terms to verbatim by System Organ Class (SOC) 
Infusion related reactions details will also be listed.   
7.4.4 
Laboratory Data 
Laboratory values of ‘>=x’ or ‘<=x’ will be taken as the value of x in the analyses. If a laboratory value is 
prefixed with ‘>’: the available original value +0.001 will be used for table summaries; if a laboratory 
value is prefixed with ‘<’, then the original value –0.001 will be used in table summaries. 
Shift tables from screening visit to the worst post-baseline value will be presented for clinical laboratory 
measurements (serum chemistry and hematology) for all treated subjects.  
All data will be all displayed in subject data listings for all safety subjects. 
7.4.5 
Vital Signs 
Descriptive statistics will be prepared for vital sign measurements, by visit and time (after dose), for 
actual values and changes from baseline.  All data will be all displayed in subject data listings for all 
safety subjects. 
7.4.6 
Electrocardiogram 
All ECG parameters will be listed. 
7.4.7 
Other Safety Assessments 
Physical examination and pregnancy test results will be presented in listings for all Safety subjects.   
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APPENDIX 1 DATA HANDLING RULES 
Category 
Description 
Data Handling Rules 
Demographics 
Age (years) 
Age = integer((date of screening-date of 
birth)/365.25)   
Demographic 
BMI 
BMI = Weight(kg) / [Height(cm)/100]2 
Demographic 
BSA 
BSA = ( [Height(cm) x Weight(kg)]/ 3600 )1/2 
Demographic 
Days since clinical lower GI 
aGVHD diagnosis 
Days since clinical lower GI aGVHD diagnosis = 
Date of screening – Date of Clinical Lower GI 
aGVHD diagnosis 
Medical History 
Any Medical history 
flags are none, but data are present, change the flag 
to “Yes” 
Efficacy 
Stop day of 
immunosuppresive 
medication 
= Stop date of immunosuppresive medication – Date 
of first dose of F-652 + 1 
Efficacy 
Overall survival time 
= Date of completion/discontinuation – Date of first 
infusion + 1 
Extent of Exposure to 
Study Medication 
Actual volume infused 
Collected on the CRF in mL, rounded to 1 decimal 
place. 
Safety Lab 
Assessment day 
Assessment day = (Date of assessment) – (Date of 
first dose) + 1. 
Safety Lab 
Change from baseline 
Change from baseline = Current Value – Value at 
last assessment prior to dose 1 treatment. 
APPENDIX 2 SAS CODE FOR STATISTICAL ANALYSES 
The SAS code for the efficacy endpoint analyses are given below.   
Proportion of Subjects 
with Response- Primary 
Efficacy Endpoint 
proc freq; 
   tables aval/binomial(exact) alpha=0.1; 
run; 
 
Note:  Use for Primary Efficacy endpoint, lower GI aGHVD response at day 28. 
Proportion of Subjects 
with Response- 
Secondary Efficacy 
Endpoints 
proc freq; 
   tables aval/binomial(exact) alpha=0.1; 
   by avisitn; 
run; 
 
Note:  Use for Secondary Efficacy endpoints, lower GI aGHVD 
response at days 14 and 56, overall aGVHD response at days 14, 28, 
and 56, and proportion of subjects who have stopped 
immunosuppressive medication at days 180 and 365. 
Kaplan Meier Survival 
Estimate- Secondary 
proc lifetest; 
   time survdays*censor(1); 
run; 
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Efficacy Endpoint 
Overall Survival 
   
APPENDIX 3 MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) 
Mockup tables, listings, and graphs are presented in a separate document prior to the final signoff of this 
SAP. 
 
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Statistical Analysis Plan 
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 (Page 2 of 114) 
 
 
 
 
General Instructions for End-of-Text TFLs 
 
Following are the specifications for end of text standard tables, listings, and figures 
(TFLs). 
 
Header 
 
The following header should appear at the very top of each page of a table, a listing, or a 
figure (TLF): 
 
Generon (Shanghai) Corporation Ltd 
 
 
 
 
                 F-652         
Protocol GC-652-02 
 
 
 
 
 
 
 
   Page n of N 
 
Footer 
 
The following footer should appear at the bottom of each page of a TLF generated in SAS: 
 
Report generated by program:/sasdir/PGNAME.sas  Version yyyy-mm-dd hh:mm 
 
where: PGNAME = SAS program name. Version will be replaced by “Draft” or “Final”. 
 
Title 
 
At least three (3) lines should be reserved for the whole title. The first line is for the TLF 
number (i.e., title index #); the second line is for the actual title (title); and the third line is 
reserved for the analysis population descriptor (population). All titles should be centered, 
as shown in the following example: 
 
Table 3.1 
Demographics 
Safety Population 
 
Footnotes 
 
 
In general, a footnote serves as a brief explanation/clarification/definition/concept of 
a flag symbol or a character, an abbreviation, a terminology, etc., that appears in or 
related directly to the displayed content of a TLF. Detailed/technical elaboration of, 
for example, a mathematical/statistical formula, a statistical term/test, or an algorithm 
for deriving a parameter value, should be addressed in the text of the statistical 
analysis plan (SAP). 
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 
All footnotes should follow immediately after a horizontal solid line. There should be 
one and only one space between the last footnote and the footer.  
 
When an abbreviation (e.g. TEAE, SAE, etc.) appears first time in the whole set of 
TLFs for a study, a footnote should be provided at least once; and it is up to the Study 
Biostatistician, Pharmacokinetic (PK) Scientist, and Study Programmer to decide 
whether there is a need to repeat the same footnote for the rest of TLFs (if 
applicable).  
 
Each line of a complete footnote should end with a period. When a footnote needs 
more than 1 line, one (1) period is needed. 
 
Footnotes should be in the format shown in the following example:   
 
N = number of subjects in the Safety Population. 
n = number of subjects in the specific category. 
% = 100 x (n/N). 
Baseline is defined as the last assessment before the first dose of the 
investigational product. 
        
Page Layout  
 
 
All output should be in landscape orientation. A margin of 1.5, 1, 1, and 1 inch should 
be on the top, right, left, and bottom, respectively.  
 
All efforts should be made to present all treatment groups in one page. 
 
When 3 or more treatment groups are designed for a study and if it is not possible to 
fit all of them in one page, the 4th, 5th and 6th treatment groups should be displayed on 
the 2nd page, etc. The Study Biostatistician will pre-determine the order for the 
display of the treatment groups.  
 
Page Format 
 
 
There should be a solid line at the top of the tables and listings just below the title. 
 
There should be a solid line just below the column headings that runs completely 
across the width of the tables and listings. 
 
There should be a solid line at the bottom of the tables and listings just above the 
footnote(s) on every page. 
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Protocol No: GC-652-02
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Statistical Analysis Plan 
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 (Page 4 of 114) 
 
 
 
Font 
 
 
The default font to be used in the actual study tables/listings should be Courier New 8 
point which is approximately equivalent to the acceptable font size of Times New 
Roman 9-10 in accordance with the FDA’s guidance on Electronic Common 
Technical Document Specification.  
 
The use of Courier New 7 point is optional for some tables/listings and will be 
determined at the study level by the Study Biostatistician and Study Programmer. 
However, it is recommended that this option be used primarily for data listings. 
 
Descriptive Statistics 
 
By default, descriptive statistics in this template covers: n, Mean, Median, Standard 
Deviation (SD), Minimum (Min), and Maximum (Max). Unless otherwise specified in the 
actual table shells, the mean and median should be displayed to one more decimal place 
than the original data, the standard deviation, standard error of the mean should be 
displayed to two more decimal place than the original data. 
 
Rounding for Percentage 
 
Unless specified in the actual table shells for a study, all percentages will be rounded to 1 
decimal place in all TLFs. 
 
Unless specified in the actual table shells for a study, p-values will be presented with 4 
decimal places. 
 
Alignment of Decimals 
 
 
It is recommended that all the decimal places be aligned in summary tables, as shown 
in the following example: 
 
Decimal Align 
Mean 
xx.xx 
SD 
xx.xxx 
Median 
xx.xx 
Min, Max 
xx.x, xx.x 
n 
xxx 
 When numbers with decimal points are included in brackets (e.g., percentages), have 
the brackets aligned to the right and then padded to allow for all possible percentages 
and then the left brackets will also be aligned. For example: 
 
Generon (Shanghai) Corporation, F-652 
Protocol No: GC-652-02
Clinical Study Report 
CSR Final, 12 Feb 2021
 
 
 
 
 
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 (Page 5 of 114) 
 
 
 
Brackets Align 
(99.9%) 
(xx.x) 
( 9.9%) 
( x.x%) 
  
 It is recommended that all column entries in a summary tables and listings are aligned 
to the center. 
 Columns for text fields are all left justified. Columns with whole numbers are all right 
justified. 
 For graphs, the lines are distinguishable and that the symbols for each line are 
appropriate. Legend is consistent across output for treatment names and abbreviations. 
  
Use of N Versus n 
 
 N = total number of subjects in the defined Population. 
 n = total number of subjects in the specific category. 
 If N is specified in the column heading then any reference to the number of 
patients in the body should be small n, as shown in the following example:  
 
Demographic Parameter 
Treatment 
Group A 
(N=XXX) 
Treatment 
Group B 
(N=XXX) 
Total 
(N=XXX) 
 
 
 
 
Age (years) 
 
 
 
Mean 
xx.x 
xx.x 
xx.x 
SD 
  x.x 
  x.x 
  x.x 
Median 
xx.x 
xx.x 
xx.x 
Min, Max   
 xx, xx 
 xx, xx 
 xx, xx 
n 
 xxx 
 xxx 
 xxx 
 
 
A Note for Subject Data Listings 
 
 Observed Dates/AE Intensity/Relationship to investigational product are used in 
subject data listings. 
 Observed values or raw assessment scores are used in data listings along with their 
derived values used in analyses, e.g., raw assessment scores and derived total scores. 
 
 
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Protocol No: GC-652-02
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 (Page 6 of 114) 
 
 
 
TABLE OF CONTENTS  
  
APPENDIX 3 SPECIFICATION OF END OF TEXT STANDARD OUTPUT TABLES, LISTINGS, 
AND FIGURES (TLFs) .................................................................................................................................. 1 
TABLE OF CONTENTS ............................................................................................................................... 6 
1. 
SUBJECT DISPOSITION ............................................................................................................. 16 
Table 1.1.1 ....................................................................................................................................... 17 
Subject Disposition 
All Screened Subjects 
Listing 1.1 ........................................................................................................................................ 19 
Listing of Screen Failures and Reason for Failure 
All Screened Subjects 
Listing 1.2 ........................................................................................................................................ 20 
Subjects Who Prematurely Discontinued the Study 
All Enrolled Subjects 
Listing 1.3 ........................................................................................................................................ 21 
Subject Disposition Information 
All Screened Subjects 
Listing 1.4 ........................................................................................................................................ 22 
GI Biopsy 
All Screened Subjects 
Listing 1.5 ........................................................................................................................................ 23 
Subjects Excluded From Efficacy Evaluable Population 
2. 
DEMOGRAPHICS, BASELINE CHARACTERISTICS AND OTHER SUMMARIES ........ 25 
Table 2.1.1 ....................................................................................................................................... 26 
Demographics and Baseline Characteristics 
Safety Population 
Table 2.1.2 ....................................................................................................................................... 30 
Demographics and Baseline Characteristics 
Efficacy Evaluable Population 
Table 2.1.3 ....................................................................................................................................... 30 
Demographics and Baseline Characteristics 
Listing 2.1 ........................................................................................................................................ 31 
Demographics 
Safety Population 
Listing 2.2 ........................................................................................................................................ 32 
Baseline Characteristics 
Safety Population 
Listing 2.3 ........................................................................................................................................ 33 
Acute Graft-Versus-Host Disease (aGVHD) Diagnosis 
Safety Population 
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Protocol No: GC-652-02
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Statistical Analysis Plan 
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Listing 2.4 ........................................................................................................................................ 34 
Medical and Surgical History (Excluding aGVHD and HSCT) 
Safety Population 
Listing 2.5 ........................................................................................................................................ 35 
Prior Chemotherapy 
Safety Population 
Listing 2.6 ........................................................................................................................................ 36 
Prior and Concomitant Medications 
Safety Population 
Listing 2.7 ........................................................................................................................................ 37 
BMT/GVHD Medications 
Safety Population 
Listing 2.8 ........................................................................................................................................ 38 
Systemic Corticosteroid Administration 
Safety Population 
Listing 2.9 ........................................................................................................................................ 39 
Glossary of Medication Classes, Preferred Terms, and Verbatim Terms for Medications 
Safety Population 
3. 
SAFETY ANALYSIS ..................................................................................................................... 40 
3.1. 
EXTENT OF EXPOSURE TO STUDY DRUG ........................................................................... 40 
Table 3.1.1 ....................................................................................................................................... 41 
Exposure to Study Drug 
Safety Population 
Listing 3.1.1 ..................................................................................................................................... 42 
Study Drug Administration 
Safety Population 
3.2. 
CONCOMITANT MEDICATIONS ............................................................................................. 43 
Table 3.2.1 ....................................................................................................................................... 43 
Concomitant Medications 
Safety Population 
Table 3.2.2 ....................................................................................................................................... 44 
Concomitant BMT/GVHD Medications 
Safety Population 
Table 3.2.3 ....................................................................................................................................... 45 
Concomitant Systemic Corticosteroid Administration 
Safety Population 
3.3. 
ADVERSE EVENT ........................................................................................................................ 46 
Table 3.3.1 ....................................................................................................................................... 47 
Overall Summary of Treatment Emergent Adverse Events 
Safety Population 
Table 3.3.2 ....................................................................................................................................... 48 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
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Protocol No: GC-652-02
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 (Page 8 of 114) 
 
 
 
Safety Population 
Table 3.3.3 ....................................................................................................................................... 49 
Treatment Emergent Serious Adverse Events by System Organ Class and Preferred Term 
Safety Population 
Table 3.3.4 ....................................................................................................................................... 50 
Treatment Related Treatment Emergent Adverse Events by System Organ Class and Preferred 
Term 
Safety Population 
Table 3.3.5 ....................................................................................................................................... 51 
Treatment Emergent Adverse Events Leading to Study Drug Discontinuation by System Organ 
Class and Preferred Term 
Safety Population 
Table 3.3.6 ....................................................................................................................................... 52 
Treatment Emergent Adverse Events by Maximum NCI-CTCAE Grade 
Safety Population 
Table 3.3.7 ....................................................................................................................................... 53 
Treatment Emergent Adverse Events by Relationship to Study Drug 
Safety Population 
Table 3.3.8 ....................................................................................................................................... 54 
Common Treatment Emergent Adverse Events > 5% Incidence Rate by System Organ Class and 
Preferred Term 
Safety Population 
Table 3.3.9 ....................................................................................................................................... 55 
Post-Treatment Serious Adverse Events by System Organ Class and Preferred Term 
Safety Population 
Listing 3.3.1 ..................................................................................................................................... 56 
Adverse Events 
Safety Population 
Listing 3.3.2 ..................................................................................................................................... 57 
Serious Adverse Events 
Safety Population 
Listing 3.3.3 ..................................................................................................................................... 59 
Deaths 
Safety Population 
Listing 3.3.4 ..................................................................................................................................... 60 
Adverse Events for Subjects Who Discontinued the Study Due to AE 
Safety Population 
Listing 3.3.5 ..................................................................................................................................... 61 
Adverse Events of Special Interest: Toxicity 
Safety Population 
Listing 3.3.6 ..................................................................................................................................... 62 
Glossary of System Organ Class, Preferred Term and Verbatim Term for Adverse Event 
Safety Population 
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Protocol No: GC-652-02
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3.4. 
CLINICAL LABORATORY MEASUREMENTS ...................................................................... 63 
Table 3.4.1 ....................................................................................................................................... 64 
Shifts from Baseline to Post-baseline Laboratory Abnormality for Hematology Parameters 
Safety Population 
Post-hoc Table 3.4.1a ...................................................................................................................... 65 
Shifts from Baseline to Post-baseline Laboratory Abnormality for Platelet Count 
Safety Population 
Table 3.4.2 ....................................................................................................................................... 65 
Shifts from Baseline to Post-baseline Laboratory Abnormality for Chemistry Parameters 
Safety Population 
Post-hoc Table 3.4.3 ........................................................................................................................ 65 
Hematology Parameters of Special Interest: Platelet by Weight Subgroup 
Safety Population 
Post-hoc Figure 3.4.4 ...................................................................................................................... 66 
Hematology Parameters of Special Interest: Platelet Count by Visit for Subjects with AE Platelet 
Count Decreased 
Safety Population 
Listing 3.4.1 ..................................................................................................................................... 67 
Laboratory Parameters – Hematology by Visit 
Safety Population 
Listing 3.4.2 ..................................................................................................................................... 68 
Laboratory Parameters – Chemistry by Visit 
Safety Population 
Listing 3.4.3 ..................................................................................................................................... 68 
Hematology Parameters of Special Interest: Platelet for these subjects with AE Platelet count 
decreased 
Safety Population 
Post-hoc Listing 3.4.4 ..................................................................................................................... 68 
Hematology Parameters of Special Interest: Platelet Count by Visit for Subjects with AE Platelet 
Count Decreased 
Safety Population 
Figure 3.4.3 ...................................................................................................................................... 68 
Platelet for these subjects with AE Platelet count decreased – Subject xxxx 
Safety Population 
VITAL SIGNS ............................................................................................................................................... 70 
Table 3.5.1 ....................................................................................................................................... 71 
Descriptive Statistics for Vital Signs by Visit and Timepoint 
Safety Population 
Listing 3.5.1 ..................................................................................................................................... 73 
Vital Signs 
Safety Population 
3.5. 
ECG PARAMETERS .................................................................................................................... 74 
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Protocol No: GC-652-02
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Listing 3.6.1 ..................................................................................................................................... 75 
ECG Results by Visit 
Safety Population 
3.6. 
OTHER SAFETY ASSESSMENTS ............................................................................................. 76 
Listing 3.7.1 ..................................................................................................................................... 77 
Pregnancy Test 
Safety Population 
Listing 3.7.2 ..................................................................................................................................... 78 
Physical Examination 
Safety Population 
Listing 3.7.3 ..................................................................................................................................... 79 
Follow-up Telephone Call 
Safety Population 
4. 
EFFICACY ..................................................................................................................................... 80 
4.1. 
PRIMARY EFFICACY ANALYSIS ............................................................................................ 81 
Table 4.1.1 ....................................................................................................................................... 81 
Lower GI aGVHD Treatment Response Rate at Day 28 
Efficacy Evaluable Population 
Post-hoc Table 4.1.1a ...................................................................................................................... 82 
Lower GI aGVHD Treatment Response Rate at Day 28 by Risk Group 
Efficacy Evaluable Population 
Post-hoc Table 4.1.1b ..................................................................................................................... 82 
Lower GI aGVHD Treatment Response Rate at Day 28 by Risk Group and Weight Subgroup 
Efficacy Evaluable Population 
Post-hoc Figure 4.1 – Subject xxxxx ............................................................................................. 83 
Lower GI aGVHD Treatment Response over Time 
4.2. 
SECONDARY EFFICACY ANALYSIS ...................................................................................... 84 
Table 4.2.1 ....................................................................................................................................... 85 
Lower GI aGVHD Treatment Response Rate at Days 14 and 56 
Efficacy Evaluable Population 
Pos-hoc Table 4.2.1a ....................................................................................................................... 86 
Lower GI aGVHD Treatment Response Rate at Days 14 and 56 by Risk Group 
Efficacy Evaluable Population 
Pos-hoc Table 4.2.1b ....................................................................................................................... 86 
Lower GI aGVHD Treatment Response Rate at Days 14 and 56 by Risk Group and Weight 
Subgroup 
Efficacy Evaluable Population 
Table 4.2.2 ....................................................................................................................................... 86 
Overall aGVHD Treatment Response Rate at Days 14, 28, and 56 
Efficacy Evaluable Population 
Post-hoc Table 4.2.2a ...................................................................................................................... 87 
Overall aGVHD Treatment Response Rate at Days 14, 28, and 56 by Risk Group 
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Protocol No: GC-652-02
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Statistical Analysis Plan 
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 (Page 11 of 114) 
 
 
 
Efficacy Evaluable Population 
Post-hoc Table 4.2.2b ..................................................................................................................... 88 
Overall aGVHD Treatment Response Rate at Days 14, 28, and 56 by Risk Group and Weight 
Subgroup 
Efficacy Evaluable Population 
Table 4.2.3 ....................................................................................................................................... 88 
Discontinuation of Immunosuppressive Medication at Day 180 and 1 Year Post Initial Dosing of F-
652 
Efficacy Evaluable Population 
Table 4.2.4 ....................................................................................................................................... 89 
Immune Recovery 
Efficacy Evaluable Population 
Figure 4.2.1 ...................................................................................................................................... 90 
Mean Absolute Lymphocyte Count (ALC) Over Time 
Efficacy Evaluable Population 
Figure 4.2.2 ...................................................................................................................................... 91 
Median Absolute Lymphocyte Count (ALC) Over Time 
Efficacy Evaluable Population 
Figure 4.2.3 ...................................................................................................................................... 91 
Mean CD45+ Lymphocytes Over Time 
Efficacy Evaluable Population 
Figure 4.2.4 ...................................................................................................................................... 91 
Median CD45+ Lymphocytes Over Time 
Efficacy Evaluable Population 
Figure 4.2.5 ...................................................................................................................................... 91 
Mean CD3+ T cells Over Time 
Efficacy Evaluable Population 
Figure 4.2.6 ...................................................................................................................................... 91 
Median CD3+ T cells Over Time 
Efficacy Evaluable Population 
Figure 4.2.7 ...................................................................................................................................... 91 
Mean CD3+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.8 ...................................................................................................................................... 91 
Median CD3+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.9 ...................................................................................................................................... 91 
Mean CD3+4+8- T Subset Over Time 
Efficacy Evaluable Population 
Figure 4.2.10 .................................................................................................................................... 91 
Median CD3+4+8- T Subset Over Time 
Efficacy Evaluable Population 
Figure 4.2.11 .................................................................................................................................... 91 
Mean CD3+4+8- Absolute Over Time 
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Protocol No: GC-652-02
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Efficacy Evaluable Population 
Figure 4.2.12 .................................................................................................................................... 91 
Median CD3+4+8- Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.13 .................................................................................................................................... 91 
Mean CD4+45RA+ T Subset Over Time 
Efficacy Evaluable Population 
Figure 4.2.14 .................................................................................................................................... 92 
Median CD4+45RA+ T Subset Over Time 
Efficacy Evaluable Population 
Figure 4.2.15 .................................................................................................................................... 92 
Mean CD4+45RA+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.16 .................................................................................................................................... 92 
Median CD4+45RA+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.17 .................................................................................................................................... 92 
Mean CD3+4-8+ T Subset Over Time 
Efficacy Evaluable Population 
Figure 4.2.18 .................................................................................................................................... 92 
Median  
CD3+4-8+ T Subset Over Time 
Efficacy Evaluable Population 
Figure 4.2.19 .................................................................................................................................... 92 
Mean CD3+4-8+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.20 .................................................................................................................................... 92 
Median CD3+4-8+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.21 .................................................................................................................................... 92 
Mean CD3+4+8+ T Subset Over Time 
Efficacy Evaluable Population 
Figure 4.2.22 .................................................................................................................................... 92 
Median CD3+4+8+ T Subset Over Time 
Efficacy Evaluable Population 
Figure 4.2.23 .................................................................................................................................... 92 
Mean CD3+4+8+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.24 .................................................................................................................................... 92 
Median CD3+4+8+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.25 .................................................................................................................................... 93 
Mean CD3+4-8- T Subset Over Time 
Efficacy Evaluable Population 
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Protocol No: GC-652-02
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
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Figure 4.2.26 .................................................................................................................................... 93 
Median CD3+4-8- T Subset Over Time 
Efficacy Evaluable Population 
Figure 4.2.27 .................................................................................................................................... 93 
Mean CD3+4-8- Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.28 .................................................................................................................................... 93 
Median CD3+4-8- Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.29 .................................................................................................................................... 93 
Mean CD3-19+ B cells Over Time 
Efficacy Evaluable Population 
Figure 4.2.30 .................................................................................................................................... 93 
Median CD3-19+ B cells Over Time 
Efficacy Evaluable Population 
Figure 4.2.31 .................................................................................................................................... 93 
Mean CD3-19+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.32 .................................................................................................................................... 93 
Median CD3-19+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.33 .................................................................................................................................... 93 
Mean CD3-56+16+ NK cells Over Time 
Efficacy Evaluable Population 
Figure 4.2.34 .................................................................................................................................... 93 
Median CD3-56+16+ NK cells Over Time 
Efficacy Evaluable Population 
Figure 4.2.35 .................................................................................................................................... 93 
Mean CD3-56+16+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.36 .................................................................................................................................... 94 
Median CD3-56+16+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.37 .................................................................................................................................... 94 
Mean CD3+56+16+ NKT cells Over Time 
Efficacy Evaluable Population 
Figure 4.2.38 .................................................................................................................................... 94 
Median CD3+56+16+ NKT cells Over Time 
Efficacy Evaluable Population 
Figure 4.2.39 .................................................................................................................................... 94 
Mean CD3+56+16+ Absolute Over Time 
Efficacy Evaluable Population 
Figure 4.2.40 .................................................................................................................................... 94 
Median CD3+56+16+ Absolute Over Time 
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Efficacy Evaluable Population 
Figure 4.2.41 .................................................................................................................................... 94 
Mean CD3+4+8-/CD3+4-8+ Ratio Over Time 
Efficacy Evaluable Population 
Figure 4.2.42 .................................................................................................................................... 94 
Median CD3+4+8-/CD3+4-8+ Ratio Over Time 
Efficacy Evaluable Population 
Figure 4.2.43 .................................................................................................................................... 94 
Mean PHA (Phytohemagglutinin-P)Over Time 
Efficacy Evaluable Population 
Figure 4.2.44 .................................................................................................................................... 94 
Median PHA (Phytohemagglutinin-P)Over Time 
Efficacy Evaluable Population 
Table 4.2.6 ....................................................................................................................................... 95 
Overall Survival 
Efficacy Evaluable Population 
Figure 4.2.45 .................................................................................................................................... 96 
Kaplan-Meier Plot for Overall Survival 
Efficacy Evaluable Population 
Post-hoc Table 4.3.1 ........................................................................................................................ 97 
Maintenance of Lower GI aGVHD Response at Day 56 in High Risk Group 
Efficacy Evaluable Population 
Post-hoc Table 4.3.2 ........................................................................................................................ 97 
Maintenance of Lower GI aGVHD Response at Day 56 in Standard Risk Group 
Efficacy Evaluable Population 
Listing 4.2.1 ..................................................................................................................................... 99 
aGVHD Treatment Response by Visit 
Efficacy Evaluable Population 
Listing 4.2.2 ................................................................................................................................... 100 
Discontinuation of Immunosuppressive Medication 
Efficacy Evaluable Population 
Listing 4.2.3 ................................................................................................................................... 101 
Immune Recovery by Visit 
Efficacy Population 
Listing 4.2.4 ................................................................................................................................... 102 
Overall Survival 
Efficacy Evaluable Population 
Post-hoc Listing 4.2.5 ................................................................................................................... 103 
Lower GI aGVHD Response in High Risk Group 
Efficacy Evaluable Population 
Post-hoc Listing 4.2.6 ................................................................................................................... 103 
Lower GI aGVHD Response in Subjects with a Treatment Response that Subsequently Lost the 
Response 
Efficacy Evaluable Population 
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5. 
EXPLORATORY ANALYSIS .................................................................................................... 104 
6. 
PHARMACOKINETIC ANALYSIS .......................................................................................... 105 
Table 6.1 ........................................................................................................................................ 106 
Descriptive Statistics of F-652 Plasma Concentrations (Unit) by Visit and Timepoint 
PK Population 
Table 6.2 ........................................................................................................................................ 107 
Descriptive Statistics of F-652 Pharmacokinetic Parameters by Visit 
PK Population 
Figure 6.1 ....................................................................................................................................... 108 
Mean Plasma Concentration-Time Profile of F-652 (Linear-Linear Scale) 
PK Population 
Figure 6.2 ....................................................................................................................................... 108 
Mean Plasma Concentration-Time Profile of F-652 (Linear-Log Scale) 
PK Population 
Figure 6.3 ....................................................................................................................................... 108 
Individual Plasma Concentration-Time Profile of F-652 (Linear Scale), Subject <xxxxxxx> 
PK Population 
Similar to Figure 6.1 without (+/- SE). 
Figure 6.4 ....................................................................................................................................... 109 
Individual Plasma Concentration-Time Profile of F-652 (Linear-Log Scale), Subject <xxxxxxx> 
PK Population 
Similar to Figure 6.1 without (+/- SE). 
Listing 6.1 ...................................................................................................................................... 110 
Plasma Concentrations of F-652 by Subject, Visit, and Timepoint 
PK Population 
Listing 6.2 ...................................................................................................................................... 111 
Derived Pharmacokinetic Parameters for F-652 by Subject and Visit 
PK Population 
 
Shells for End-of-Text TLFs 
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Protocol No: GC-652-02
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Generon (Shanghai) Corporation Ltd. 
 
F-652 
Protocol GC-652-02 
 
Page x of y 
 
 
Report generated by program: /sasdir/xxxx.sas                                                         
Draft    YYYY-MM-DD   HH:MM
 
Page 16
 
 
1. SUBJECT DISPOSITION 
 
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Protocol No: GC-652-02
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Generon (Shanghai) Corporation Ltd. 
 
F-652 
Protocol GC-652-02 
 
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Draft    YYYY-MM-DD   HH:MM
 
Page 17
 
 
Table 1.1.1 
Subject Disposition 
All Screened Subjects 
 
 
Total 
 
(N = XX) 
 
n 
(%) 
Screened 
xx 
(xx.x) 
Screen Failed  
xx 
(xx.x) 
Dose With Study Treatment                                                                 
xx 
(xx.x) 
Histologically confirmed GVHD 
xx 
(xx.x) 
 
 
 
Started Dose 1 (Day 0) 
xx 
(xx.x) 
 
 
 
Started Dose 2 (Day 7) 
xx 
(xx.x) 
 
 
 
Started Dose 3 (Day 14) 
xx 
(xx.x) 
 
 
 
Started Dose 4 (Day 21) 
xx 
(xx.x) 
 
 
 
Completed Treatment Period (Day 28) 
xx 
(xx.x) 
 
 
 
Completed Day 56 
xx 
(xx.x) 
 
 
 
Completed Day 180 
xx 
(xx.x) 
 
 
 
Completed the Study(Day 365) 
xx 
(xx.x) 
 
 
 
Early Withdrawal before Completing Treatment Period (Day 28) 
xx 
(xx.x) 
  Reason for Discontinuation 
 
 
    Adverse Event 
xx 
(xx.x) 
Transplant-Related Mortality (TRM)  
xx 
(xx.x) 
 
Other Adverse Event  
xx 
(xx.x) 
    Withdrawal of Consent 
xx 
(xx.x) 
    Lost to Follow-up 
xx 
(xx.x) 
  Failure to Comply with Protocol Requirements 
xx 
(xx.x) 
  Protocol Specified Discontinuation Criteria 
xx 
(xx.x) 
Lower GI aGVHD Not Confirmed Histologically 
xx 
(xx.x) 
Progressive GVHD 
xx 
(xx.x) 
Lack of GVHD Treatment Response 
xx 
(xx.x) 
Requires Tapering of Corticosteroids Before Day 3 
xx 
(xx.x) 
Requires Increase Immunosuppression Therapy Due to Active aGVHD 
xx 
(xx.x) 
Requires > 2 Study Drug Dose Reductions 
xx 
(xx.x) 
  Pregnancy 
xx 
(xx.x) 
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  Investigator Decision 
xx 
(xx.x) 
  Sponsor Decision 
xx 
(xx.x) 
 
 
 
Early Withdrawal after Treatment Period (Day 28)[1] 
xx 
(xx.x) 
  Reason for Discontinuation 
 
 
    Withdrawal of Consent 
xx 
(xx.x) 
    Subject Lost-To-Follow-Up 
xx 
(xx.x) 
    Subject Deceased 
xx 
(xx.x) 
    Subject experiences relapse of primary malignancy or develops new malignancy 
xx 
(xx.x) 
    Progression of GVHD 
xx 
(xx.x) 
    Subject started new therapy 
xx 
(xx.x) 
    Other 
xx 
(xx.x) 
 
 
 
Safety Population 
xx 
(xx.x) 
Efficacy Evaluable Population 
xx 
(xx.x) 
Pharmacokinetic Population 
xx 
(xx.x) 
Safty Population includes all subjects who received any study treatment. 
Efficacy Evaluable Population includes all subjects who are eligible and have any post-treatment GVHD evaluation (not strictly limited 
to treatment response) or have disease progression before a GVHD evaluation can be performed.   
Pharmacokinetic Population includes all subjects who received any study treatment and provided sufficient samples for PK parameter 
estimation. 
[1] Subject xxxx completed the treatment period (4 doses of F-652), and discontinued on study day xxx.   
N = number of all screened subjects. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N). 
Source:  Listings 1.1, 1.2, 1.3 
 
 
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Listing 1.1 
Listing of Screen Failures and Reason for Failure 
All Screened Subjects 
 
 
Subject 
ID 
Age(yrs)[1]/Sex/Race 
 
 
 
Screen Failure? 
Date of Informed 
Consent Signed 
Protocol Version 
Criteria  
Waiver 
Granted 
by 
Sponsor 
Reason 
xxxxxx 60/M/Caucasian 
Yes 
yyyy-mm-dd 
x 
xxxxxxxx 
xxx 
xxxxxxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
This table includes all screened subjects who failed any inclusion/exclusion criteria.  
[1] Age = age at Screening. M = Male, F = Female. 
 
 
 
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Listing 1.2 
Subjects Who Prematurely Discontinued the Study 
All Enrolled Subjects 
 
Subject 
ID 
Age(yrs)/Sex/Race 
Reason for Early 
Discontinuation 
  Specified Reason  
 
Date of 
Discontinuation 
(Study Day) [1] 
Date of Last Contact 
(Study Day) [2] 
xxxxxx 
60/F/Caucasian 
Adverse Event 
Other Adverse Event 
yyyy-mm-dd (xx) 
yyyy-mm-dd (xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day = date of discontinuation – first dose date + 1. 
[2] Date of Last Contact is for the subjects lost to Follow-up. Study Day = date of last contact – first dose date + 1. 
M = Male, F = Female. 
 
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Listing 1.3 
Subject Disposition Information 
All Screened Subjects 
 
 
Subject ID 
 
Date of 
Informed 
Consent 
Date of 
Completion/Discon
tinuation/Last 
Contact (Study 
Day) [1]
Dates of 
First/Last Dose 
of Study Drug 
(Study Day) [1]
Completed Dose 
1/2/3/4? 
 
 
Safety 
Population  
Efficacy 
Evaluable 
Population 
 
Population 
 
 
 
 
 
 
 
 
xxxxxx 
yyyy-mm-dd 
yyyy-mm-dd 
   (xx) 
yyyy-mm-dd(xx)/ 
yyyy-mm-dd(xx) 
Y/Y/Y/N  
Yes 
No  
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.  
[1] Study Day = date of interest – date of dose 1 + 1. 
 
 
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Listing 1.4 
GI Biopsy 
All Screened Subjects 
 
Subject 
ID 
Date of 
Completion/Di
scontinuation
/Last Contact 
(Study Day) 
[1] 
Dates of 
First/Last Dose 
of Study Drug 
(Study Day) [1]
 
 
Safety 
Populat
ion   
Efficacy 
Evaluable 
Population 
Visit
 
 
GI Biopsy 
Performed
? 
Date of 
Biopsy 
 
 
 
Type of 
Procedure 
Performed 
 
 
aGVHD 
histologically 
confirmed? 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
yyyy-mm-dd 
   (xx) 
yyyy-mm-dd(xx)/
yyyy-mm-dd(xx) 
Yes 
No  
Screeni
ng 
Yes 
yyyy-mm-dd 
Colonscop
y 
Yes 
 
 
 
 
 
Day 28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 [1] Study Day = date of interest – date of dose 1 + 1. 
 
 
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Listing 1.5 
Subjects Excluded From Efficacy Evaluable Population 
Safety Population    
 
Subject ID 
 
Date of 
Informed 
Consent 
Date of 
Completion/Discon
tinuation/Last 
Contact (Study 
Day) [1]
Dates of 
First/Last Dose 
of Study Drug 
(Study Day) [1]
Completed Dose 
1/2/3/4? 
Efficacy 
Evaluable 
Population 
Reason For 
Exclusion 
 
 
 
 
 
 
 
 
 
xxxxxx 
yyyy-mm-dd 
yyyy-mm-dd 
   (xx) 
yyyy-mm-dd(xx)/ 
yyyy-mm-dd(xx) 
Y/Y/Y/N  
No  
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 [1] Study Day = date of interest – date of dose 1 + 1. 
 
 
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2. DEMOGRAPHICS, BASELINE CHARACTERISTICS AND OTHER SUMMARIES  
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Table 2.1.1 
Demographics and Baseline Characteristics 
Safety Population 
 
 
Total 
 
 
(N=XX) 
 
 
Age (yrs) 
 
  Mean 
xx.x  
SD 
xx.xx 
  Median 
xx.x 
  Min, Max 
xx, xx 
  n 
xxx 
 
 
Sex - n(%) 
 
  Female 
xx ( xx.x) 
    Childbearing potential[1] 
xx ( xx.x) 
    Non-childbearing potential[1]  
xx ( xx.x) 
  Male 
xx ( xx.x) 
 
 
Race - n(%) 
 
 White 
xx ( xx.x) 
 Black or African American 
xx ( xx.x) 
 Asian 
xx ( xx.x) 
 American Indian or Alaska Native 
xx ( xx.x) 
 Native Hawaiian or other Pacific Islander 
xx ( xx.x) 
 Other 
xx ( xx.x) 
 
 
 
 
Ethnicity – n(%) 
 
 Hispanic or Latino 
xx ( xx.x) 
 Not Hispanic or Latino 
xx ( xx.x) 
 
 
Weight in kg 
 
  Mean  
xx.xx 
SD 
xx.xxx 
  Median 
xx.xx 
  Min, Max 
xx, xx 
  n 
xxx 
 
 
 
 
Height in cm 
 
  Mean  
xx.xx 
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SD 
xx.xxx 
  Median 
xx.xx 
  Min, Max 
xx, xx 
  n 
xxx 
 
 
BMI in kg/m2 [2] 
 
  Mean  
xx.xx 
SD 
xx.xxx 
  Median 
xx.xx 
  Min, Max 
xx, xx 
  n 
xxx 
 
 
BSA in m2[3] 
 
  Mean  
xx.xx 
SD 
xx.xxx 
  Median 
xx.xx 
  Min, Max 
xx, xx 
  n 
xxx 
 
 
Days Since Clinical Lower GI aGVHD Diagnosis [4] 
 
  Mean  
xx.xx 
SD 
xx.xxx 
  Median 
xx.xx 
  Min, Max 
xx, xx 
  N 
xxx 
 
 
Screening aGVHD Stage for Each Target Organ [5] 
 
Skin – n(%) 
 
  Stage 0 
xx ( xx.x) 
  Stage 1 
xx ( xx.x) 
  Stage 2 
xx ( xx.x) 
  Stage 3 
xx ( xx.x) 
  Stage 4 
xx ( xx.x) 
 
 
Lower GI Tract – n(%) 
 
  Stage 0 
xx ( xx.x) 
  Stage 1 
xx ( xx.x) 
  Stage 2 
xx ( xx.x) 
  Stage 3 
xx ( xx.x) 
  Stage 4 
xx ( xx.x) 
 
 
Upper GI Tract – n(%) 
 
  Stage 0 
xx ( xx.x) 
  Stage 1 
xx ( xx.x) 
 
 
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Liver – n(%) 
 
  Stage 0 
xx ( xx.x) 
  Stage 1 
xx ( xx.x) 
  Stage 2 
xx ( xx.x) 
  Stage 3 
xx ( xx.x) 
  Stage 4 
xx ( xx.x) 
 
 
IBMTR Severity Grade – n(%) [6] 
 
I 
xx ( xx.x) 
II 
xx ( xx.x) 
III 
xx ( xx.x) 
IV 
xx ( xx.x) 
 
 
Type of HSCT – n(%) 
 
Blood 
xx ( xx.x) 
Bone Marrow 
xx ( xx.x) 
Cord 
xx ( xx.x) 
Haploidentical 
xx ( xx.x) 
 
 
 CMV IgG Serostatus – n(%) 
 
Positive 
xx ( xx.x) 
Negative 
xx ( xx.x) 
Equivocal 
xx ( xx.x) 
 
 
 CMV IgM Serostatus – n(%) 
 
Positive 
xx ( xx.x) 
Negative 
xx ( xx.x) 
Equivocal 
xx ( xx.x) 
 
 
 Physical Examination Clinically Significant Abnormalities – n(%) 
 
Yes 
xx ( xx.x) 
No 
xx ( xx.x) 
 
 
Risk Group [6] 
 
High Risk 
xx ( xx.x) 
Standard Risk 
xx ( xx.x) 
 
N = number of subjects in the Safety population.  
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N). 
[1] BMI = Weight(kg) / [(Height(cm)/100)^2]. 
[2] BSA = ( [Height(cm) x Weight(kg)]/ 3600 )^1/2. 
[3] Days since clinical lower GI aGVHD diagnosis = Date of enrollment – Date since clinical lower GI aGVHD diagnosis.  
[4] Screening aGVHD Stage for Each Target Organ: Stages defined using Modified Keystone Criteria in Protocol Appendix 5, Table 2.   
[5] IBMTR Severity Grade:  Grades defined using IBMTR Severity Index for Grading aGVHD in Protocol Appendix 5, Tables 3.   
[6] Risk group based on refined aGVHD Risk Score by MacMillan et al., 2015 April.  
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Source: Listing 2.1 to 2.3  
 
Programming Note: Add a row of Missing for any categorical variable with missing values for the baseline characteristic. 
 
 
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Table 2.1.2 
Demographics and Baseline Characteristics 
Efficacy Evaluable Population 
 
Programmer note:  This table is only needed when Efficacy Evaluable≠Safety . 
 
Table 2.1.3 
Demographics and Baseline Characteristics 
PK Population 
 
 
Programmer note:  This table is only needed when Efficacy Evaluable≠PK . 
 
 
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Listing 2.1 
Demographics 
Safety Population 
 
 
Subject 
ID 
Age(yrs)/ 
Sex/ 
Race/ 
Ethnicity 
Reproductive Status 
Weight 
(kg) 
Height 
(cm) 
BMI (kg/m^2) 
BSA (m2) 
 
  
 
 
 
 
xxxx Xx/F/ 
Caucasian/ 
Not Hispanic 
Non-childbearing potential 
xxx.x 
xxx.x 
xx.x 
xx.x 
xxxxxx Xx/M/ 
Caucasian/ 
Hispanic 
NA 
xxx.x 
xxx.x 
xx.x 
xx.x 
xxxxxx Xx/F/ 
Caucasian/ 
Not Hispanic 
Childbearing potential 
xxx.x 
xxx.x 
xx.x 
xx.x 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
BMI = Body Mass Index. BSA = Body Surface Area. M = Male, F = Female. 
 
 
 
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Listing 2.2 
Baseline Characteristics 
Safety Population 
 
 
 
 
Screening aGVHD Stage for Each 
Target Organ [2] 
 
 
 
 
 
 
Subje
ct 
ID 
Days Since 
Clinical 
Lower GI 
aGVHD 
Diagnosis [1] 
Skin 
Lower 
GI 
Tract 
Upper 
GI 
Tract 
Liver 
IBMTR 
Severity 
Grade 
[3] 
Type of 
HSCT 
CMV IgG 
Serostat
us 
CMV IgM 
Serostatu
s 
 
 
 
Risk Group 
Physical 
Examination 
Clinically 
Significant 
Abnormalities 
 
  
 
 
 
 
 
 
 
 
 
xxxx 
xxx.x 
Stage 
3 
Stage 
3 
Stage 
1 
Stage 
0 
0 
Bone 
Marrow 
Positive 
Equivocal 
High Risk 
Yes 
xxxxx
x 
xxx.x 
Stage 
2 
Stage 
4 
Stage 
0 
Stage 
4 
I 
Cord 
Negative
Negative
Low Risk 
No 
xxxxx
x 
xxx.x 
Stage 
1 
Stage 
1 
Stage 
1 
Stage 
3 
IV 
Haploide
ntical 
Equivoca
l 
Positive 
Low Risk 
No 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
GI = Gastrointestinal. aGVHD = Acute Graft-versus-Host Disease. IBMTR = International Bone Marrow Transplant Registry. HSCT = 
Hematopoietic Stem Cell Transplantation. CMG = . IgG = Immunoglobulin G. IgM = Immunoglobulin M. 
[1] Days Since Clinical Lower GI aGVHD diagnosis = Date of screening – Date of Clinical Lower GI aGVHD diagnosis. 
[2] Screening aGVHD Stage for Each Target Organ: Stages defined using Modified Keystone Criteria in Protocol Appendix 5, Table 2.   
[3] IBMTR Severity Grade:  Grades defined using IBMTR Severity Index for Grading aGVHD in Protocol Appendix 5, Tables 3.   
 
 
 
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Listing 2.3 
Acute Graft-Versus-Host Disease (aGVHD) Diagnosis 
Safety Population 
 
 
Subject 
ID 
Date of 
Hematopoietic 
Stem Cell 
Transplantation 
Type of HSCT 
Date of 
Clinical 
Lower GI 
aGVHD 
Diagnosis 
Was Pre-
Transplant 
Cytomegalovirus 
Serostatus for 
the Recipient 
Available? 
If Yes, Date of 
CMV Test 
If Yes, CMG IgG 
If Yes, CMG IgM 
 
  
 
 
 
 
 
 
 
 
xxxx yyyy-mm-dd  
Bone Marrow 
yyyy-mm-dd 
Yes 
yyyy-mm-dd  
Positive 
Equivocal 
xxxxxx yyyy-mm-dd 
Cord 
yyyy-mm-dd 
No 
 
 
 
xxxxxx yyyy-mm-dd 
Haploidentical 
yyyy-mm-dd 
Yes 
yyyy-mm-dd 
Equivocal 
Negative 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
HSCT = Hematopoietic Stem Cell Transplantation. GI = Gastrointestinal. aGVHD = Acute Graft-versus-Host Disease. CMV = Cytomegalovirus. 
CMG = . IgG = Immunoglobulin G. IgM = Immunoglobulin M. 
 
 
 
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Listing 2.4  
Medical and Surgical History (Excluding aGVHD and HSCT)  
Safety Population 
 
 
Subject 
ID 
System Organ 
Class 
Diagnosis or Procedures 
(Verbatim Term) 
Onset Date 
Is Condition 
Still Present? 
(Yes/No) 
End 
Date 
xxxxxx Drug Allergy 
 
xxxxxxxxxxxxxxxxxxxxxx 
(XXXXXXXXXXXXXXX) 
yyyy-mm 
 
No  
yyyy-mm 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
  
 
 
 
 
 
 
Note to programers: sort by subjid, SOC, onset date and diagnosis 
 
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Listing 2.5 
Prior Chemotherapy  
Safety Population 
 
 
Subject 
ID 
Any 
Chemotherapy 
in the Past 1 
Year? 
Therapy  
Code 
Agent Name
Number of 
Cycles
Date of Last Dose
Ongoing at Screening? 
xxxxxx 
Yes 
Chemo/Anthracycline
xxxxxxxxxx 
xx
 
Yes 
xxxxxx 
Yes 
Hormonal
xxxxxxx 
xx 
yyyy-mm-dd 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Listing 2.6 
Prior and Concomitant Medications 
Safety Population 
 
 
Subject 
ID 
Drug Name/ 
  Prefered Term/ 
    ATC Class [1] 
Start/Stop 
Date(Ongoing) 
(Study Day[2]) 
Dose 
Unit  
Route 
Frequency 
Reason for 
Use 
(Specify) 
 
Prior/ 
Concomitant/ 
Post-dose 
xxxxxx 
Xxxxxx/ 
  Xxxxxxxxxxxxx/ 
    xxxxxxxxxxxxxxxxxx 
yyyy-mm-dd(-8)/
Ongoing 
xxx 
xx 
xxx 
xx 
xxxxxx 
 
 
Yes/No/No 
xxxxxx 
Xxxxxx/ 
  Xxxxxxxxxxxxx/ 
    xxxxxxxxxxxxxxxxxx 
yyyy-mm-dd(5)/ 
yyyy-mm-dd(6) 
xxx 
xx 
xxx 
xx 
Rescue 
Therapy 
(Febrile 
Neutropenia) 
 
 
Yes/Yes/No 
  
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
  
 
  
 
 
 
 
 
 
 
Prior medications are any medications taken prior to the date of first dose of study drug; Concomitant medications are those ongoing at 
baseline and taken during the study treatment period up to Day 56; Post-dose medications are these taken after the Day 56 visit (or 28 
days after the last dose of study drug if no Day 56 visit). 
[1] The World Health Organization (WHO) drug dictionary (Version &whodrug) was used to code concomitant medications. 
[2] A negative number for study day denotes the number of days prior to the start of the first dose of study drug. Otherwise, study day 
is Date of interest – date of first dose of study drug + 1.  
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Listing 2.7 
BMT/GVHD Medications 
Safety Population 
 
 
Subject 
ID 
Category/ 
  Drug Name [1] 
Route 
Start/Ongoing 
Or Stop Date 
 
Study Day[2]  
Prior/ 
Concomitant/ 
Post-dose 
xxxxxx 
Xxxxxx/ 
  Xxxxxxxxxxxxx 
xxx 
yyyy-mm-dd/ 
Ongoing 
 
 
Day 5 
 
 
Yes/No/No 
xxxxxx 
Xxxxxx/ 
  Xxxxxxxxxxxxx 
xxx 
yyyy-mm-dd/ 
yyyy-mm-dd 
 
 
Day 11 
 
 
Yes/Yes/No 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
  
  
 
 
Prior BMT/GVHD medications are any medications taken prior to the date of first dose of study drug; Concomitant BMT/GVHD medications 
are those ongoing at baseline and taken during the study treatment period. 
[1] The drug categories and drug names specified on the CRF were used to code BMT/GVHD medications. 
[2] A negative number for study day denotes the number of days prior to the start of the first dose of study drug. Otherwise, study day 
is Date of interest – date of first dose of study drug + 1.  
 
 
 
 
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Listing 2.8 
Systemic Corticosteroid Administration 
Safety Population 
 
 
Subject 
ID 
Corticosteroid Name (Other, Specify) 
[1] 
Start/Stop 
Date(Ongoing) 
(Study Day[2]) 
Dose 
Unit  
Route 
Frequency 
 
Prior/ 
Concomitant 
xxxxxx 
Xxxxxxxxxxxxx 
(xxxxxxxxxxxxxxxxxx) 
yyyy-mm-dd(-8)/ 
Ongoing 
xxx 
xx 
xxx 
xx 
 
 
Yes/No 
xxxxxx 
Xxxxxxxxxxxxx 
 
yyyy-mm-dd(5)/ 
yyyy-mm-dd(6) 
xxx 
xx 
xxx 
xx 
 
 
Yes/Yes 
  
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
 
 
  
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
  
  
 
 
 
 
 
 
Prior Systemic corticosteroid administration are any medications taken prior to the date of first dose of study drug; Concomitant 
Systemic corticosteroid administration are those ongoing at baseline and taken during the study treatment period. 
[1] The corticosteroid names specified on the CRF were used to report systemic corticosteroid medications.  
[2] A negative number for study day denotes the number of days prior to the start of the first dose of study drug. Otherwise, study day 
is Date of interest – date of first dose of study drug + 1.  
 
 
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Listing 2.9 
Glossary of Medication Classes, Preferred Terms, and Verbatim Terms for Medications 
Safety Population 
 
ATC Class 
Preferred Term 
Verbatim Term 
AMIDES 
BUPIVACAINE 
MARCAINE 
 
LIDOCAINE 
INJECTION LIDOCAINE 
 
 
LIDOCAINE 
WHO-DDE xxxxx version was used to code medications. 
 
 
 
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3. SAFETY ANALYSIS 
 
3.1. EXTENT OF EXPOSURE TO STUDY DRUG 
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Table 3.1.1 
Exposure to Study Drug 
Safety Population 
 
 
Total 
(N=XX) 
Number of Treatments [1] 
 
  Mean 
xx.x  
  SD 
xx.x 
  Median 
xx  
  Min, Max 
xx, xx 
  n 
xxx 
 
 
Treatment Duration (days)[2] 
 
  Mean 
xx.x  
  SD 
xx.x 
  Median 
xx  
  Min, Max 
xx, xx 
  n 
xxx 
 
 
Total F-652 Received (mg)[3] 
 
  Mean 
xx.x  
  SD 
xx.x 
  Median 
xx  
  Min, Max 
xx, xx 
  n 
xxx 
 
 
Number of Subjects with Doses Interrupted or Discontinued Prematurely 
 
  Any Dose 
xx 
  Dose 1 
xx 
  Dose 2 
xx 
  Dose 3 
xx 
  Dose 4 
xx 
 
 
N = number of subjects in the Safety population. n = number of subjects contributing to summary statistics.  
% = Percentages are based on n. 
[1] Number of Treatments = Number of infusions started, regardless of the completion status.  
[2] Treatment Duration (days) = Date of last dose of F-652– Date of first dose of F-652 + 1. 
[3] Total F-652 Received (mg) = The total dosage of F-652 received. The starting dose was 45 μg/kg.  Subsequent doses may have been 
reduced, as determined by the Investigator, to 30 μg/kg or 10 μg/kg. The drug administered was prepared as a 100 mL IV bag. Dose 
received (mg) was calculated as (Weight in kg * Dose Level in mg/kg) * (Actual Volume Administrated in mL/100 mL). 
 
Source: Listing 3.1.1 
 
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Listing 3.1.1 
Study Drug Administration  
Safety Population 
 
Subject ID 
 
Dose 
Treatment 
Infusion 
Date and Start 
and Stop Times 
(24 hr clock) 
/Day [1] 
Dose Level 
Actual Volume 
Infused (mL) 
Was Study Drug 
Administration 
Interrupted or 
Discontinued 
Prematurely? 
If Yes, Please 
Indicate 
Reason(s) 
If 
Infusion 
Related 
Reaction 
or Other 
Toxicity, 
Worst 
CTCAE 
Grade  
If Other 
Reason, 
Specify 
 
xxxx 
Dose 
1 
yyyy-mm-dd 
hh:mm/hh:mm/xx 
45 μg/kg 
xxx.x 
No 
 
 
 
 
 
Dose 
2 
yyyy-mm-dd 
hh:mm/hh:mm/xx 
45 μg/kg 
xxx.x 
No 
 
 
 
 
 
Dose 
3 
yyyy-mm-dd 
hh:mm/hh:mm/xx 
45 μg/kg 
xxx.x 
No 
 
 
 
 
 
Dose 
4 
yyyy-mm-dd 
hh:mm/hh:mm/xx 
45 μg/kg 
xxx.x 
Yes 
Infusion 
Related 
Reaction 
2 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxxx 
Dose 
1 
yyyy-mm-dd 
hh:mm/hh:mm/xx 
45 μg/kg 
xxx.x 
Yes 
Other 
Toxicity, 
Other Reason 
3 
xxxxxxxxxxx 
 
 
Dose 
2 
 
 
 
 
 
 
 
 
 
Dose 
3 
 
 
 
 
 
 
 
 
 
Dose 
4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CTCAE = National Cancer Institute Common Terminology Criteria for Adverse Events.  
[1] Treatment Day = Dosing date - first dose date + 1. 
 
 
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3.2. CONCOMITANT MEDICATIONS 
 
Table 3.2.1 
Concomitant Medications 
Safety Population 
 
 
Total 
ATC Class/ 
(N=XX) 
  Preferred Term 
n 
(%) 
Any Concomitant Medications  
xx 
(xx.x) 
 
 
 
ATC Class 1 
xx 
(xx.x) 
  Preferred Term1 
xx 
(xx.x) 
  Preferred Term2 
xx 
(xx.x) 
     …… 
 
 
 
 
 
ATC Class 2 
xx 
(xx.x) 
  Preferred Term1 
xx 
(xx.x) 
  Preferred Term2 
xx 
(xx.x) 
     …… 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
The World Health Organization (WHO) drug dictionary (Version &whodrug) was used to code concomitant medications. 
Concomitant medication is defined as any medication taken during the study between the date of the first dose of study drug and the 
last study date of the subject, up to the Day 56  visit. 
N = number of subjects in the Safety population.  
n = Number of subjects within a specific ATC class or medication. Percentages are calculated as 100 x (n/N). 
Multiple uses of a specific medication for a subject were counted once in the frequency for the medication. Likewise, multiple uses 
within a specific medication class for a subject were counted once in the frequency for the medication class. 
 
Source: Listing 2.6  
 
Programmer note: Classes sorted alphabetically. Medications sorted within classes in decreasing order of frequency in the total 
group.  
 
 
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Table 3.2.2 
Concomitant BMT/GVHD Medications 
Safety Population 
 
 
Total 
Category/ 
(N=XX) 
  Drug Name 
n 
(%) 
Any BMT/GVHD Medications  
xx 
(xx.x) 
 
 
 
  Antibacterials 
xx 
(xx.x) 
    Ciprofloxacin (Cipro) 
xx 
(xx.x) 
    Levofloxacin (Levaquin) 
xx 
(xx.x) 
     …… 
 
 
 
 
 
  Antifungals 
xx 
(xx.x) 
    Voriconazole (Vfend) 
xx 
(xx.x) 
    Posaconazole (Noxafil) 
xx 
(xx.x) 
     …… 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
The drug categories and drug names specified on the CRF were used to code BMT/GVHD medications. 
Concomitant BMT/GVHD medication is defined as any BMT/GVHD medication taken during the study between the date of the first dose of 
study drug and the last study date of the subject, up to the Day 56 visit. 
N = number of subjects in the Safety population.  
n = Number of subjects within a specific category or drug name. Percentages are calculated as 100 x (n/N). 
Multiple uses of a specific medication for a subject were counted once in the frequency for the medication. Likewise, multiple uses 
within a specific medication category for a subject were counted once in the frequency for the medication category. 
 
Source: Listing 2.7 
 
Programmer note: Categories sorted alphabetically. Medications sorted within classes in decreasing order of frequency in the total 
group.  
 
 
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Table 3.2.3 
Concomitant Systemic Corticosteroid Administration 
Safety Population 
 
 
Total 
Corticosteroid 
(N=XX) 
  Name 
n 
(%) 
Any Corticosteroid Administration  
xx 
(xx.x) 
 
 
 
  Prednisone 
xx 
(xx.x) 
  Methylprednisolone 
xx 
(xx.x) 
  Other 
xx 
(xx.x) 
 
 
 
   
 
 
The corticosteroid names specified on the CRF were used to report systemic corticosteroid medications. 
Concomitant systemic corticosteroid administration is defined as any medication taken during the study between the date of the first 
dose of study drug and the last study date of the subject, up to the Day 56 visit. 
N = number of subjects in the Safety population.  
n = Number of subjects within a corticosteroid name. Percentages are calculated as 100 x (n/N). 
Multiple uses of a specific medication for a subject were counted once in the frequency for the medication.  
 
Source: Listing 2.8 
 
Programmer note: Medications sorted in decreasing order of frequency in the total group.  
 
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3.3. ADVERSE EVENT  
 
 
 
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Table 3.3.1 
Overall Summary of Treatment Emergent Adverse Events 
Safety Population 
 
 
Total 
 
(N = xx)
 
n(%) 
 
 
Total Subjects with at Least 1 TEAE 
xx (xx.x) 
Total Number of TEAEs 
xx 
 
 
Total Subjects with at Least 1 TESAE 
xx (xx.x) 
Total Number of TESAEs 
xx 
 
 
Total Number of Deaths 
xxx 
 
 
Subjects with at least 1 TEAE 
 
Leading to Study Drug Interruption 
xx (xx.x) 
Leading to Study Drug Discontinuation 
xx (xx.x) 
   
 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N). 
TEAE = any adverse event that begins on or after treatment or is a worsening of a pre-existing medical condition. 
TESAE = Treatment Emergent Serious adverse event. 
 
Source: Listing 3.3.1. 
 
 
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Table 3.3.2 
Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
Safety Population  
 
 
Total 
 
(N=XX) 
System Organ Class 
  Preferred Term 
n (%) 
# of TEAE 
 
 
 
Any TEAE 
xx (xx.x) 
xx 
 
 
 
System Organ Class 1 
xx (xx.x) 
xx 
  Preferred Term 1 
xx (xx.x) 
xx 
… 
 
 
 
 
 
System Organ Class 2 
xx (xx.x) 
xx 
… 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
MedDRA version &meddra was used to code adverse events. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N). 
TEAE = any adverse event that begins on or after treatment or is a worsening of a pre-existing medical condition. 
 
Source: Listing 3.3.1. 
 
Programmer note: SOCs sorted alphabetically and preferred term (PT) sorted in decreasing frequency of occurrence.  
 
 
 
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Table 3.3.3 
Treatment Emergent Serious Adverse Events by System Organ Class and Preferred Term 
Safety Population  
 
 
Total 
 
(N = XX)
System Organ Class 
    Preferred Term 
N (%) 
# of SAE 
 
 
 
Any SAE 
xx (xx.x) 
xx 
 
 
 
System Organ Class 1 
xx (xx.x) 
xx 
Preferred Term 1 
xx (xx.x) 
xx 
… 
 
 
 
 
 
System Organ Class 2 
xx (xx.x) 
xx 
… 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
MedDRA version &meddra was used to code adverse events. 
SAE = serious adverse event. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N). 
 
Source: Listing 3.3.1. 
 
 
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Table 3.3.4 
Treatment Related Treatment Emergent Adverse Events by System Organ Class and Preferred Term 
Safety Population  
 
 
Total  
N = XX 
 
(N=XX) 
System Organ Class 
    Preferred Term 
n (%) 
# of TEAE 
 
 
 
Any Treatment Related TEAE 
xx (xx.x) 
xx 
 
 
 
System Organ Class 1 
xx (xx.x) 
xx 
Preferred Term 1 
xx (xx.x) 
xx 
… 
 
 
 
 
 
System Organ Class 2 
xx (xx.x) 
xx 
… 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
MedDRA version &meddra was used to code adverse events. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N). 
Related = possible, probable or definite. 
TEAE = any adverse event that begins on or after treatment or is a worsening of a pre-existing medical condition. 
 
Source: Listing 3.3.1. 
 
 
 
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Table 3.3.5 
Treatment Emergent Adverse Events Leading to Study Drug Discontinuation by System Organ Class and Preferred Term 
Safety Population  
 
 
Total 
 
 
 
(N=XX) 
System Organ Class 
    Preferred Term 
N (%) 
# of TEAE 
 
 
 
Any TEAE Leading to Study Drug Discontinuation 
xx (xx.x) 
xx 
 
 
 
System Organ Class 1 
xx (xx.x) 
xx 
  Preferred Term 1 
xx (xx.x) 
xx 
… 
 
 
 
 
 
System Organ Class 2 
xx (xx.x) 
xx 
… 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
MedDRA version &meddra was used to code adverse events.  
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N). 
TEAE = any adverse event that begins on or after treatment or is a worsening of a pre-existing medical condition. 
 
Source: Listing 3.3.1. 
 
 
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Table 3.3.6 
Treatment Emergent Adverse Events by Maximum NCI-CTCAE Grade 
Safety Population 
 
System Organ Class 
Preferred Term 
  NCI-CTCAE Grade 
Total 
 
 
(N=XX) 
 
n (%) 
 
 
Any TEAE 
xx (xx.x) 
 
 
System Organ Class  1 
xx (xx.x) 
Grade 1 
xx (xx.x) 
Grade 2 
xx (xx.x) 
Grade 3 
xx (xx.x) 
Grade 4 
xx (xx.x) 
Grade 5 
xx (xx.x) 
 
 
  Preferred Term 1 
xx (xx.x) 
Grade 1 
xx (xx.x) 
Grade 2 
xx (xx.x) 
Grade 3 
xx (xx.x) 
Grade 4 
xx (xx.x) 
Grade 5 
xx (xx.x) 
 
 
  Preferred Term 2 
xx (xx.x) 
Grade 1 
xx (xx.x) 
Grade 2 
xx (xx.x) 
Grade 3 
xx (xx.x) 
Grade 4 
xx (xx.x) 
Grade 5 
xx (xx.x) 
… 
 
System Organ Class  2 
 
... 
 
MedDRA version &meddra was used to code adverse events.  
NCI-CTCAE version 4.0 was used to grade the severity of adverse events. 
If a subject had more than one occurrence of the same event category, only the most severe occurrence was counted. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N). 
Grade 1 = Mild; Grade 2 = Moderate; Grade 3 = severe; Grade 4 = Life-threatening/Disabling; Grade 5 = Death. 
TEAE = any adverse event that begins on or after treatment or is a worsening of a pre-existing medical condition. CTCAE = National 
Cancer Institute Common Terminology Criteria for Adverse Events. 
 
Source: Listing 3.3.1. 
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Table 3.3.7 
Treatment Emergent Adverse Events by Relationship to Study Drug 
Safety Population 
 
System Organ Class 
Preferred Term 
       Relationship to Study Drug 
Total 
 
 
(N=XX) 
 
n (%) 
 
 
Any TEAE 
xx (xx.x) 
 
 
System Organ Class  1 
xx (xx.x) 
UNR 
xx (xx.x) 
UNL 
xx (xx.x) 
POS 
xx (xx.x) 
PROB 
xx (xx.x) 
DEF 
xx (xx.x) 
  Preferred Term 1 
 
UNR 
xx (xx.x) 
UNL 
xx (xx.x) 
POS 
xx (xx.x) 
PROB 
xx (xx.x) 
DEF 
xx (xx.x) 
  Preferred Term 2 
 
UNR 
xx (xx.x) 
UNL 
xx (xx.x) 
POS 
xx (xx.x) 
PROB 
xx (xx.x) 
DEF 
xx (xx.x) 
… 
 
System Organ Class  2 
xx (xx.x) 
... 
 
MedDRA version &meddra was used to code adverse events. 
If a subject had more than one occurrence of the same event category, only the most treatment-related occurrence was counted. 
TEAE = any adverse event that begins on or after treatment or is a worsening of a pre-existing medical condition. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N). 
UNR = Unrelated; UNL = Unlikely; POS = Possible; PROB = Probable; DEF = Definite.  
Source: Listing 3.3.1. 
 
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Table 3.3.8 
Common Treatment Emergent Adverse Events > 5% Incidence Rate by System Organ Class and Preferred Term 
Safety Population 
 
System Organ Class 
Preferred Term 
 
Total 
 
 
(N=XX) 
 
n (%) 
 
 
 
 
System Organ Class  1 
xx (xx.x) 
  Preferred Term 1 
xx (xx.x) 
  Preferred Term 2 
xx (xx.x) 
… 
 
System Organ Class  2 
 
... 
 
MedDRA was version &meddra was used to code adverse events.  
TEAE = any adverse event that begins on or after treatment or is a worsening of a pre-existing medical condition. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N). 
 
Source: Listing 3.3.1. 
 
 
 
 
 
 
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Table 3.3.9 
Post-Treatment Serious Adverse Events by System Organ Class and Preferred Term 
Safety Population  
 
 
Total 
 
(N = XX)
System Organ Class 
    Preferred Term 
N (%) 
# of SAE 
 
 
 
Any SAE 
xx (xx.x) 
xx 
 
 
 
System Organ Class 1 
xx (xx.x) 
xx 
Preferred Term 1 
xx (xx.x) 
xx 
… 
 
 
 
 
 
System Organ Class 2 
xx (xx.x) 
xx 
… 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
MedDRA version &meddra was used to code adverse events. 
SAE = serious adverse event. 
n = Number of subjects in Preferred Term category. Percentages are calculated as 100 x (n/N). 
Post-treatment SAE’s are SAEs that start after Day 56 
 
Source: Listing 3.3.1. 
 
 
 
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Listing 3.3.1 
Adverse Events  
Safety Population 
 
Subject 
ID 
Age/ 
Sex/ 
Race 
Date of 
First/Last 
Dose  
AE Onset/ 
Stop 
Date/Ongoin
g 
AE Onset/ 
Stop Day 
System Organ 
Class/ 
Preferred Term/ 
(Verbatim Term) 
CTCAE Grade / 
Relationship 
to IMP 
SAE?/ 
TEAE? 
Trt. 
Given
Outcome
Action Taken 
with Study Drug 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
xx/x/x 
yyyy-mm-dd/ 
yyyy-mm-dd  
yyyy-mm-dd 
/ ongoing 
xx/xx 
xxxxxxxxxxxxx/ 
xxxxxxxxxxxxxxx/ 
(xxxxxxxxxxxx) 
Severe/ 
Not related 
Yes/Ye
s 
xxxx 
xxxxx 
Dose Not 
Changed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MedDRA version &meddra was used to code adverse events.  
A negative number for study day denotes the number of days prior to the start of the first dose. Otherwise, study day is  
Date of interest – date of first dose + 1.  
M = Male, F = Female. 
 
 
 
Programmer note: Sort by Site ID, Subject ID, AE Onset Date and AE Resolution Date.  If hospitalized, add hospital admission and 
discharge day, i.e. 3 (Day xx-Day xx). 
 
 
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Listing 3.3.2 
Serious Adverse Events  
Safety Population 
Subject 
ID 
Age/ 
Sex/ 
Race  
System Organ 
Class/ 
Preferred Term/ 
(VerbatimTerm) 
Onset Date 
(Study day)/ 
Resolution 
Date(Study 
Day)/ ongoing  
CTCAE 
Grade[1] / 
Relationship 
to Study 
Drug 
Outcome 
Treatment 
for AE?  
Action Taken 
with Study 
Drug 
Seriousness criteria 
xxxxxxx 
xx/x/x 
XXXXXXXXXXXX/ 
 XXXXXXXXX/  
 
 (XXXXXXXXXX) 
YYYY-MM-DD 
(xx) 
YYYY-MM-DD 
(xx) 
Severe/ 
Probably 
related 
Recovered
/Resolved 
Yes  
Drug 
Interrupted 
Stopped:  
YYYY-MM-DD 
hh:mm  
AE abated  
Restarted: 
YYYY-MM-DD 
hh:mm 
AE 
reoccurred 
Hospitalization/prol
ongation.  
Admission on YYYY-
MM-DD 
Discharged on YYYY-
MM-DD 
 
 
 
 
 
 
 
 
 
Additional Case Details: xxxxxxxxxxxxxxx 
Relevant Diagnostic Tests: xxxxxxxxxxxxxxxxxxx 
 
 
 
 
 
 
 
 
 
xxxxxxx 
xx/x/x 
XXXXXXXXXXXX/ 
 XXXXXXXXX/  
 
 (XXXXXXXXXX) 
YYYY-MM-DD 
(xx) 
ongoing 
Severe/ 
Unlikely 
related 
Not 
recovered
/not 
resolved 
Yes 
None 
Death on 
YYYY-MM-DD  
Autopsy performed 
 
 
 
 
 
 
 
 
 
xxxxxxx 
xx/x/x 
XXXXXXXXXXXX/ 
 XXXXXXXXX/  
 
 (XXXXXXXXXX) 
YYYY-MM-DD 
(xx) 
ongoing 
Severe/ 
Unlikely 
related 
Not 
recovered
/not 
resolved 
Yes 
Drug 
Withdrawn 
Last dose 
date 
YYYY-MM-DD 
Life-threatening 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
A negative number for study day denotes the number of days prior to the start of the first dose. Otherwise, study day is  
Date of interest – date of first dose + 1.  
MedDRA version &meddra was used to code adverse events.  
[1] NCI-CTCAE version 4.0 was used to grade the severity of adverse events. 
M = Male, F = Female. 
 
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Programmer note: Sort by Site ID, Subject ID, AE Onset Date and AE Resolution Date.  If hospitalized, add hospital admission and 
discharge day, i.e. 3 (Day xx-xx).  
 
 
 
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Listing 3.3.3 
Deaths  
Safety Population 
Subject 
ID 
Age/ 
Sex/ 
Race  
Efficacy 
Evaluable 
Population? Date of 
Death
Study Day of 
Death
Transplant-
Related 
Mortality 
(TRM)?
Autopsy 
Performed?
Date of First/Last Dose
xxxxxx 
 
Yes 
YYYY-MM-
DD
xx 
Yes 
Yes 
YYYY-MM-DD/YYYY-MM-DD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M = Male, F = Female. 
 
 
Programmer note: Sort by Site ID, Subject ID, Death date 
 
 
 
 
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Listing 3.3.4 
Adverse Events for Subjects Who Discontinued the Study Due to AE  
Safety Population  
 
Subject 
ID 
System Organ Class/ 
   Preferred Term / 
      (Verbatim Term)  
Day of 
Onset/ 
Outcome 
(Resolution 
Day or 
Ongoing) / 
Grade [1] 
Relationship 
to Study 
Drug/ 
Action Taken 
with Study 
Drug 
Serious AE (Yes/No)/ 
Reason 
Treatment 
Given 
Transplant-
Related 
Mortality /Other 
AE? 
 
 
 
 
 
 
xxxxxx xxxxx/ 
   xxxxx / 
      xxxxxxx 
5/ Unknown/ 
15/III 
Unrelated/ 
Dose Not 
Changed 
Yes/ 
Hospitalization/Prolongation 
of existing hospitalization 
(Day xx-Day xx) 
Yes/No 
Other AE 
 
 
 
 
 
 
 
 A negative number for study day denotes the number of days prior to the start of the first dose. Otherwise, study day is  
Date of interest – date of first dose + 1.  
MedDRA version &meddra was used to code adverse events. All AEs are listed for a subject who discontinued due to an adverse event. 
[1] NCI-CTCAE version 4.0 was used to grade the severity of adverse events.  
 
 
Programmer note: Sort by Site ID, Subject ID, AE Onset Date and AE Resolution Date.  If hospitalized, add hospital admission and 
discharge day, i.e. 3 (Day xx-Day xx).  
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Listing 3.3.5 
Adverse Events of Special Interest: Toxicity  
Safety Population 
 
Subject 
ID 
Study Drug 
Administration Date 
(Study Day) [1] 
Was Study Drug 
Administration 
Delayed or Dose 
Reduced Due to 
Toxicity? 
Type(s) of 
Toxicity 
If Hematology 
Toxicity, Blood 
Counts (ANC) 
If Skin 
Toxicity, 
Infusion 
Related 
Reaction, or 
Other 
Toxicity, 
Worst CTCAE 
Grade  
If Other 
Toxicity, Specify 
 
 
 
xxxxxx yyyy-mm-dd (5) 
Yes 
Hematology 
Toxicity, 
Infusion Related 
Reaction 
 
>= 500/mm^3 
3 
 
xxxxxx yyyy-mm-dd (10) 
Yes 
Skin Toxicity, 
Other Toxicity 
 
2, 4 
xxxxxxxx 
 
[1] Study day = Date of study drug administration – date of first dose + 1. 
[2] Study day = Date of onset of AE – date of first dose + 1. 
 
Programmer note: Sort by Site ID, Subject ID, AE Onset Date and AE Resolution Date.  If hospitalized, add hospital admission and 
discharge day, i.e. 3 (Day xx-Day xx). 
 
 
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Listing 3.3.6 
Glossary of System Organ Class, Preferred Term and Verbatim Term for Adverse Event 
Safety Population 
 
System Organ Class 
Preferred Term 
Verbatim Term 
CARDIAC DISORDERS 
ANGINA PECTORIS 
ANGINA PECTORIS 
 
CARDIAC MURMUR NOS 
HEART MURMUR 
 
 
CARDIAC MURMUR 
 
 
 
 
 
 
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3.4. CLINICAL LABORATORY MEASUREMENTS 
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Table 3.4.1  
Shifts from Baseline to Post-baseline Laboratory Abnormality for Hematology Parameters  
Safety Population 
 
Laboratory Parameter: Hemoglobin (Unit) 
 
Baseline Grade 
Post-Baseline Highest Grade 
Low 
Normal 
High 
Missing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Low   (N=xxx) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx 
Normal   (N=xxx) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx 
High   (N=xxx) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx 
Any Grade (N=xxx) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x)
xx
 
 
 
 
 
Low   (N=xxx) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx 
Normal   (N=xxx) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx 
High   (N=xxx) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx 
Any Grade (N=xxx) 
xx (xx.x) 
xx (xx.x) 
xx (xx.x) 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
….Repeat Above for each laboratory test required within Hematology.   
 
 
 
Baseline was the subject’s last assessment prior to the initiation of study drug (Dose 1).  
N = number of subjects who received the treatment and had data in the Baseline category with non-missing data Post-Baseline. n = number 
of subjects in baseline and post-baseline category.  % = 100 x n/N. 
 
Source: Listing 3.4.1. 
 
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Post-hoc Table 3.4.1a  
Shifts from Baseline to Post-baseline Laboratory Abnormality for Platelet Count  
Safety Population 
 
 
 
Programming Note: Follow the shell of 3.4.1. 
 
Table 3.4.2 
Shifts from Baseline to Post-baseline Laboratory Abnormality for Chemistry Parameters  
Safety Population  
 
Programmer note: Change Source footnote to Listing 3.4.2. 
 
 
 
 
 
 
 
Post-hoc Table 3.4.3  
Hematology Parameters of Special Interest: Platelet by Weight Subgroup 
Safety Population 
 
Hematology Parameter (unit) 
  Visit 
    Statistics 
  Subjects with Weight <= xx.x kg 
 
 
Subjects with Weight > xx.x kg  
Total 
 
 
(N=XX) 
(N=XX) 
(N=XX) 
Platelet (10^9/L) 
 
 
 
 Baseline 
 
 
 
 
Actual Value: 
 
 
 
  Mean 
xx.x  
xx.x  
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
  Median 
xx 
xx  
xx  
  Min, Max 
xx, xx 
xx; xx 
xx, xx 
n 
xxx 
xxx 
xxx 
 Day 7  
 
 
 
 
Actual Value: 
 
 
 
  Mean 
xx.x  
xx.x  
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
  Median 
xx 
xx  
xx  
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  Min, Max 
xx, xx 
xx; xx 
xx, xx 
  n 
xxx 
xxx 
xxx 
  
Change from Baseline: 
 
 
 
  Mean 
xx.x  
xx.x  
xx.x  
  SD 
xx.x 
xx.x 
xx.x 
  Median 
xx 
xx  
xx  
  Min, Max 
xx, xx 
xx; xx 
xx, xx 
  n 
xxx 
xxx 
xxx 
… Day 14 … 
 
 
 
… 
 
 
 
…  
 
 
 
… 
 
 
 
… Day 21 … 
 
 
 
… 
 
 
 
… Day 28 … 
 
 
 
 Day 56 
 
 
 
 
 
 
 
Repeat above for all other 
Hematology lab results 
 
 
 
 
 
Post-hoc Figure 3.4.4   
Hematology Parameters of Special Interest: Platelet Count by Visit for Subjects with AE Platelet Count Decreased 
Safety Population 
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Listing 3.4.1 
Laboratory Parameters – Hematology by Visit 
Safety Population  
 
Hematology Parameter: XXXXXXXXXXXX <unit>  
Subject 
ID 
Laboratory 
Name 
Lab 
ID 
# 
Visit 
Date of 
Collection 
 
Original 
Result 
Original 
Unit 
 
 
Standard 
Result 
Change from 
Baseline [1] 
Reference 
Range 
(Low – 
High) 
 
Outside 
Normal 
Range 
(Y/N) 
  
 
 
 
 
 
 
 
 
 
 
xxxxxx 
 
 
Screening 
yyyy-mm-dd 
xx.x 
xxxx 
xxxx 
 
0 - 5 
 
 
 
 
 
Day 7 
yyyy-mm-dd 
xx.x 
xxxx 
xxxx 
 
0 - 5 
 
 
 
 
 
Day 14 
 
 
 
 
 
 
 
 
 
 
 
Day 21 
 
 
 
 
 
 
 
 
 
 
 
Day 28 
 
 
 
 
 
 
 
 
 
 
 
Day 56 
 
 
 
 
 
 
 
 
 
 
 
Unscheduled  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Baseline was the subject’s last assessment prior to the initiation of study drug (Dose 1).  
 
 
Programmer note:  
1. Order records by Parameter, subject number, and date of sample. 
2. Repeat pages for all hematology parameters. 
 
 
 
 
 
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Listing 3.4.2 
Laboratory Parameters – Chemistry by Visit 
Safety Population 
Programmer note: Similar to Listing 3.4.1. 
 
 
Listing 3.4.3 
Hematology Parameters of Special Interest: Platelet for these subjects with AE Platelet count decreased 
Safety Population 
 
Subject 
ID 
Age/ 
Sex/ 
Race 
Date of 
First/Last 
Dose  
AE Onset/ 
Stop 
Date/Ongoin
g 
CTCAE 
Grade / 
Relations
hip to 
IMP 
SAE?/ TEAE?
Trt. Given 
Outcom
e 
Action 
Taken with 
Study Drug
Visit 
Date of 
Collectio
n 
 
 
Platelet 
(10^9/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
xxxxx 
xx/x/x 
yyyy-mm-dd/ 
yyyy-mm-dd  
yyyy-mm-dd 
/ ongoing 
Severe/ 
Not 
related 
Yes/Yes 
xxxx 
xxxxx 
Dose Not 
Changed 
Screeni
ng 
yyyy-mm-
dd 
xxxx 
 
 
 
 
 
 
 
 
 
Day 7 
yyyy-mm-
dd 
xxxx 
 
 
 
 
 
 
 
 
 
… 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Post-hoc Listing 3.4.4  
Hematology Parameters of Special Interest: Platelet Count by Visit for Subjects with AE Platelet Count Decreased 
Safety Population 
Programmer note: Similar to Listing 3.4.3. 
 
 
 
Figure 3.4.3 
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Platelet for these subjects with AE Platelet count decreased – Subject xxxx 
Safety Population 
 
 
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VITAL SIGNS 
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Table 0.1 
Descriptive Statistics for Vital Signs by Visit and Timepoint 
Safety Population 
 
Vital Sign Parameter (unit) 
  Visit 
    Statistics 
Total 
 
 
(N=XX) 
Temperature (oC) 
 
 Screening 
 
 
Actual Value: 
 
  Mean 
xx.x  
  SD 
xx.x 
  Median 
xx  
  Min, Max 
xx, xx 
  n 
xxx 
 
 
 Day 0, 15 Minutes After Start of Infusion 
 
 
Actual Value: 
 
  Mean 
xx.x 
  SD 
xx.x 
  Median 
xx 
  Min, Max 
xx, xx 
  n 
xxx 
 
 
  
Change from Baseline: 
 
  Mean 
xx.x  
  SD 
xx.x 
  Median 
xx  
  Min, Max 
xx, xx 
  n 
xxx 
 
 
 Day 0, Completion of Infusion 
 
… 
 
 Day 0, 1 Hour After End of Infusion 
 
… 
 
 Repeat for Days 7, 14, and 21 for the 3 timepoints above, and for Days 28, 56, 180, 365, 
and Unscheduled, with no time point. 
 
Repeat above for 
 
Heart Rate (beats/min) 
 
Systolic Blood pressure (mmHg) 
 
Diastolic Blood pressure (mmHg) 
 
Respiratory Rate (breaths/min) 
 
 
 
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 Repeat for Screening, Days 0, 7, 14, 21, 28, 56, 180, 365, and Unscheduled, with no time 
point for 
 
 
 
Weight (kg) 
 
 
 
 Repeat for Screening only, with no time point for 
 
 
 
Height (cm) 
 
 
 
Baseline was the subject’s last assessment prior to the initiation of study drug.  
N = number of subjects in the Safety Population. 
n = number of subjects contributing to summary statistics. 
SD = standard deviation.  
 
Source: Listing 3.5.1. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Listing 0.1 
Vital Signs  
Safety Population 
 
Subject 
ID 
Date of 
Assessment 
(Study 
Day)[1] 
Visit 
Time Point  
Temperature 
(oC) 
Heart Rate 
(beats/min) 
Systolic 
 Blood 
Pressure 
(mmHg)  
Diastolic 
Blood 
Pressure 
(mmHg) 
Respiratory 
Rate 
(breaths/min) 
Weight 
(kg) 
Height 
(cm) 
xxxxxx yyyy-mm-dd 
(xx) 
Screening  
xx.x 
xxx 
xxx 
xx 
xxx 
xx.x 
xx.x 
 
 
Day 0 
 
 
 
 
 
 
xx.x 
 
 
 
 
15 Minutes 
After Start 
of Infusion 
xx.x 
xxx 
xxx 
xx 
xxx 
 
 
 
 
 
Completion 
of Infusion 
xx.x 
xxx 
xxx 
xx 
xxx 
 
 
 
 
 
1 Hour After 
End of 
Infusion 
xx.x 
xxx 
xxx 
xx 
xxx 
 
 
 
 
Day 7 
 
 
 
 
 
 
xx.x 
 
 
 
 
15 Minutes 
After Start 
of Infusion 
xx.x 
xxx 
xxx 
xx 
xxx 
 
 
 
 
 
Completion 
of Infusion 
xx.x 
xxx 
xxx 
xx 
xxx 
 
 
 
 
 
1 Hour After 
End of 
Infusion 
xx.x 
xxx 
xxx 
xx 
xxx 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 [1] Assessment Day = date of assessment - first dose date of study drug + 1. 
 
Programmer note: Include same visits and timepoints listed in table above. 
 
 
 
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3.5. ECG PARAMETERS 
 
 
 
 
 
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Listing 3.5.1 
ECG Results by Visit 
Safety Population 
 
 
Subject 
ID 
Age(yrs)/Sex/Race  
Visit 
Date of ECG 
 Performed 
 
 
 
Parameters 
(Units) 
Results 
Any Clinically 
Significant 
Abnormalities? 
(Yes/No) 
xxxxxx 
60/F/Caucasian 
Screening 
yyyy-mm-dd 
 
 
No  
 
 
 
 
 
 
 
 
 
Day 28 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unscheduled 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M = Male, F = Female. 
 
Programmer note: Include Heart Rate, PR Interval, RR Interval, QRS, QT, and QTc from CRF, and calculated QTcF. 
 
 
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3.6. OTHER SAFETY ASSESSMENTS 
 
 
 
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Listing 3.6.1 
Pregnancy Test  
Safety Population 
 
Subject 
ID 
Age(yrs)/Race 
 
 
 
Pregnancy Test 
 
Visit 
Performed? 
(Yes/No) 
Type 
Date 
 
Result 
  
 
 
 
 
 
xxxxxx  
Screening 
Yes 
Urine 
yyyy-mm-dd 
Positive 
  
Day 28 
 
Serum 
 
 
  
Unscheduled 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  
 
 
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Listing 3.6.2 
Physical Examination 
Safety Population 
 
Subject ID 
 
Physical Examination  
Visit 
Performed? 
(Yes/No) 
If Yes, 
Date 
Any Clinically Significant Abnormalities 
(Yes/No) 
 
 
 
 
 
xxxxxx 
Screening 
Yes 
yyyy-mm-dd 
Yes 
 
Day 0 
 
 
 
 
Day 28 
 
 
 
 
Day 56 
 
 
 
 
Day 180 
 
 
 
 
Day 365 
 
 
 
 
Unscheduled 
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
  
 
 
 
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Listing 3.6.3 
Follow-up Telephone Call 
Safety Population 
Subject ID 
Age(Yrs)/Sex/Race  
Date of Call 
Was subject contacted by telephone for follow-up? 
xxxxxx 
 
yyyy-mm-dd 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
xxx-xxx 
 
yyyy-mm-dd 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
M = Male, F = Female. 
 
 
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4. EFFICACY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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4.1. PRIMARY EFFICACY ANALYSIS 
 
 
Table 4.1.1 
Lower GI aGVHD Treatment Response Rate at Day 28 
Efficacy Evaluable Population 
 
 
Response 
Total 
(N=XX)   
n (%) 
90% Exact 
Confidence 
Interval 
 
 
 
Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
  Complete Response 
xx ( xx.x) 
(xx.x, xx.x) 
  Very Good Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
  Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
No Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
  No Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Progression 
xx ( xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
Missing aGVHD treatment response was imputed as non-response for this analysis. 
N = Number of subjects in the Efficacy Evaluable Population. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N).  
 
Source: Listing 4.2.1 
 
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Post-hoc Table 4.1.1a 
Lower GI aGVHD Treatment Response Rate at Day 28 by Risk Group 
Efficacy Evaluable Population 
 
 
High Risk Group 
(N=xx) 
Low Risk Group 
(N=xx) 
Overall 
(N=xx) 
 
Response 
Total 
(N=XX)   
n (%) 
90% Exact 
Confidence 
Interval 
Total 
(N=XX)   
n (%) 
90% Exact 
Confidence 
Interval 
Total 
(N=XX)   
n (%) 
90% Exact 
Confidence 
Interval 
 
 
 
 
 
 
 
Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
  Complete Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
  Very Good Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
  Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
No Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
  No Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
    Progression 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing aGVHD treatment response was imputed as non-response for this analysis. 
N = Number of subjects in the Efficacy Evaluable Population. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N).  
 
Source: Listing 4.2.1 
 
Post-hoc Table 4.1.1b 
Lower GI aGVHD Treatment Response Rate at Day 28 by Risk Group and Weight Subgroup 
Efficacy Evaluable Population 
 
 
High Risk Group 
(N=xx) 
Standard Risk Group 
(N=xx) 
 
Weight <= xxx kg 
Weight > xxx kg 
Weight <= xxx kg 
Weight > xxx kg 
 
Response 
Total 
(N=XX)   
n (%) 
90% Exact 
Confidence 
Interval 
Total 
(N=XX)   
n (%) 
90% Exact 
Confidence 
Interval 
Total 
(N=XX)   
n (%) 
90% Exact 
Confidence 
Interval 
Total 
(N=XX)   
n (%) 
90% Exact 
Confidence 
Interval 
 
 
 
 
 
 
 
 
 
Treatment 
Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
  Complete 
Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
  Very Good 
Partial 
Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
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  Partial 
Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
No Treatment 
Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
  No Response 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
    Progression 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
xx ( xx.x) 
(xx.x, xx.x) 
xx ( xx.x) 
(xx.x, 
xx.x) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Missing aGVHD treatment response was imputed as non-response for this analysis. 
N = Number of subjects in the Efficacy Evaluable Population. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N).  
 
Source: Listing 4.2.1 
 
 
Post-hoc Figure 4.1 – Subject xxxxx 
Lower GI aGVHD Treatment Response over Time 
 
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Table 4.2.1 
Lower GI aGVHD Treatment Response Rate at Days 14 and 56 
Efficacy Evaluable Population 
 
 
Response 
Total 
(N=XX)   
n (%) 
90% Exact Confidence 
Interval 
 
 
 
Day 14 
 
 
  N1 
xx 
 
  Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Complete Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Very Good Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
  No Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
    No Response 
xx ( xx.x) 
(xx.x, xx.x) 
      Progression 
xx ( xx.x) 
(xx.x, xx.x) 
 
 
 
Day 56 
 
 
  N1 
xx 
 
  Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Complete Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Very Good Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
  No Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
    No Response 
xx ( xx.x) 
(xx.x, xx.x) 
      Progression 
xx ( xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the Efficacy Evaluable Population. 
n = Number of subjects within a specific category. N1= Number of subjects with Lower GI aGVHD Treatment Response at the visit. 
Percentages are calculated as 100 x (n/N1).  
Source: Listing 4.2.1 
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Pos-hoc Table 4.2.1a 
Lower GI aGVHD Treatment Response Rate at Days 14 and 56 by Risk Group 
Efficacy Evaluable Population 
 
Pos-hoc Table 4.2.1b 
Lower GI aGVHD Treatment Response Rate at Days 14 and 56 by Risk Group and Weight Subgroup 
Efficacy Evaluable Population 
 
 
 
 
Table 4.2.2 
Overall aGVHD Treatment Response Rate at Days 14, 28, and 56 
Efficacy Evaluable Population 
 
 
Response 
Total 
(N=XX)   
n (%) 
90% Exact Confidence 
Interval 
 
 
 
Day 14 
 
 
  N1 
xx 
 
  Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Complete Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Very Good Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Mixed Response 
xx ( xx.x) 
(xx.x, xx.x) 
  No Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
    No Response 
xx ( xx.x) 
(xx.x, xx.x) 
      Progression 
xx ( xx.x) 
(xx.x, xx.x) 
 
 
 
Day 28 
 
 
  N1 
xx 
 
  Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Complete Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Very Good Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Mixed Response 
xx ( xx.x) 
(xx.x, xx.x) 
  No Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
    No Response 
xx ( xx.x) 
(xx.x, xx.x) 
      Progression 
xx ( xx.x) 
(xx.x, xx.x) 
 
 
 
Day 56 
 
 
  N1 
xx 
 
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  Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Complete Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Very Good Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Partial Response 
xx ( xx.x) 
(xx.x, xx.x) 
    Mixed Response 
xx ( xx.x) 
(xx.x, xx.x) 
  No Treatment Response 
xx ( xx.x) 
(xx.x, xx.x) 
    No Response 
xx ( xx.x) 
(xx.x, xx.x) 
      Progression 
xx ( xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
N = Number of subjects in the Efficacy Evaluable Population. 
n = Number of subjects within a specific category. N1= Number of subjects with Overall aGVHD Treatment Response at the visit. 
Percentages are calculated as 100 x (n/N1).  
Source: Listing 4.2.1 
 
 
Post-hoc Table 4.2.2a 
Overall aGVHD Treatment Response Rate at Days 14, 28, and 56 by Risk Group 
Efficacy Evaluable Population 
 
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Post-hoc Table 4.2.2b 
Overall aGVHD Treatment Response Rate at Days 14, 28, and 56 by Risk Group and Weight Subgroup 
Efficacy Evaluable Population 
 
Table 4.2.3 
Discontinuation of Immunosuppressive Medication at Day 180 and 1 Year Post Initial Dosing of F-652 
Efficacy Evaluable Population 
 
 
Discontinuation of Immunosuppressive Medication 
Total 
(N=XX)   
n (%) 
90% Exact Confidence 
Interval 
 
 
 
Day 180 
 
 
  N1 
xx 
 
  Yes 
xx ( xx.x) 
(xx.x, xx.x) 
  No 
xx ( xx.x) 
(xx.x, xx.x) 
 
 
 
1 Year (Day 365) 
 
 
  N1 
xx 
 
  Yes 
xx ( xx.x) 
(xx.x, xx.x) 
  No 
xx ( xx.x) 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
 
N = number of subjects in the Efficacy Evaluable Population. N1 = number of subjects completed the visit. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N1).  
Immunosuppresive medications were identified as those collected on the BMT/GVHD Medications CRF and categorized as Immunosuppressants.  
Subjects who discontinued at Day 180 and at 1 year were defined as those who stopped all immunosuppressant medications that were being 
taken at or after the first dose of F-652. 
Source: Listing 4.2.2 
 
 
 
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Table 4.2.4 
Immune Recovery 
Efficacy Evaluable Population 
 
B and T Lymphocyte Parameter (unit) 
  Visit 
    Statistics 
Total 
 
 
(N=XX) 
ALC (Cell/mcL)   
 
 Day 0 
 
 
Actual Value: 
 
  Mean 
xx.x  
  SD 
xx.x 
  Median 
xx  
  Min, Max 
xx, xx 
n 
xxx 
 Day 28 
 
 
Actual Value: 
 
  Mean 
xx.x  
  SD 
xx.x 
  Median 
xx  
  Min, Max 
xx, xx 
  n 
xxx 
  
Change from Baseline: 
 
  Mean 
xx.x  
  SD 
xx.x 
  Median 
xx  
  Min, Max 
xx, xx 
  n 
xxx 
 
 
 
 
Repeat above for all other immune reconstitution panel parameters as listed in SAP section 
6.3.3. 
 
ALC = Absolute Lymphocyte Count. PHA = Phytohemagglutinin-P.  
N = number of subjects in the Efficacy Evaluable Population. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N).  
Change from baseline values includes only those subjects with both Day 0 and Day 28 values. 
 
Source: Listing 4.2.3.  
 
 
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Figure 4.2.2 
Median Absolute Lymphocyte Count (ALC) Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.3 
Mean CD45+ Lymphocytes Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.4 
Median CD45+ Lymphocytes Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.5 
Mean CD3+ T cells Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.6 
Median CD3+ T cells Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.7 
Mean CD3+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.8 
Median CD3+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.9 
Mean CD3+4+8- T Subset Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.10 
Median CD3+4+8- T Subset Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.11 
Mean CD3+4+8- Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.12 
Median CD3+4+8- Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.13 
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Mean CD4+45RA+ T Subset Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.14 
Median CD4+45RA+ T Subset Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.15 
Mean CD4+45RA+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.16 
Median CD4+45RA+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.17 
Mean CD3+4-8+ T Subset Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.18 
Median  CD3+4-8+ T Subset Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.19 
Mean CD3+4-8+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.20 
Median CD3+4-8+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.21 
Mean CD3+4+8+ T Subset Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.22 
Median CD3+4+8+ T Subset Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.23 
Mean CD3+4+8+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.24 
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Median CD3+4+8+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.25 
Mean CD3+4-8- T Subset Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.26 
Median CD3+4-8- T Subset Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.27 
Mean CD3+4-8- Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.28 
Median CD3+4-8- Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.29 
Mean CD3-19+ B cells Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.30 
Median CD3-19+ B cells Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.31 
Mean CD3-19+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.32 
Median CD3-19+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.33 
Mean CD3-56+16+ NK cells Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.34 
Median CD3-56+16+ NK cells Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.35 
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Mean CD3-56+16+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.36 
Median CD3-56+16+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.37 
Mean CD3+56+16+ NKT cells Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.38 
Median CD3+56+16+ NKT cells Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.39 
Mean CD3+56+16+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.40 
Median CD3+56+16+ Absolute Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.41 
Mean CD3+4+8-/CD3+4-8+ Ratio Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.42 
Median CD3+4+8-/CD3+4-8+ Ratio Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.43 
Mean PHA (Phytohemagglutinin-P)Over Time 
Efficacy Evaluable Population 
 
Figure 4.2.44 
Median PHA (Phytohemagglutinin-P)Over Time 
Efficacy Evaluable Population 
 
 
 
 
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Table 4.2.6 
Overall Survival 
Efficacy Evaluable Population 
 
 
Response 
 
Statistic 
Total 
 
 
 
(N=XX) 
Time to Death (Days) 
Subjects with the Event 
xx (xx.x%) 
 
Censored 
xx (xx.x%) 
 
Median Time to Response 
xxx.x 
 
90% CI for Median 
(xxx.x, xxx.x) 
 
25th – 75th Percentile 
xxx, xxx 
 
Min – Max 
xxx, xxx 
 
 
 
 
Survival rate (90% CI) 
 
 
Day 28 
xx (xx.x%, xx.x%) 
 
Day 56 
xx (xx.x%, xx.x%) 
 
Day 180 
xx (xx.x%, xx.x%) 
 
Day 365 
xx (xx.x%, xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N = number of subjects in the Efficacy Evaluable Population. 
n = Number of subjects within a specific category. Percentages are calculated as 100 x (n/N).  
Time to death is the number of days from the date of the first infusion of F-652 to the date of death (Date of death – Date of first 
infusion +1) for subjects who die. Subjects who did not die were censored with survival time based on the subject’s study completion or 
discontinuation date (Date of completion/discontinuation – Date of first infusion +1). 
Summary statistics are Kaplan-Meier estimates. 
 
 
Source: Listing 4.2.4. 
 
 
 
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Figure 4.2.45 
Kaplan-Meier Plot for Overall Survival 
Efficacy Evaluable Population 
 
 
Programmer note:  
1. AXES: Display Days on the X axis, from 0 to 365 (label “Study Day”). Display Overall Survival Rate on the Y axis (label “Overall Survival Rate”) 
2. LEGEND: No Legend 
3. Graph should have one line. 
3. Number of Patients at Risk- Change to Number of Subjects.  Only include one row of numbers. 
3. Source: Listing 4.2.4 
 
 
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Post-hoc Table 4.23.1 
Maintenance of Lower GI aGVHD Response at Day 56 in High Risk Group 
Efficacy Evaluable Population 
 
 
Response at Day 28 
Treatment 
Response 
n (%) 
CR 
n (%) 
VGPR 
n (%) 
PR 
n (%) 
NR 
n (%) 
Progression
n (%) 
Missing 
n 
 
 
 
 
 
 
 
 
Treatment Response (N1 = XX) 
xx ( xx.x) 
xx ( 
xx.x) 
xx ( xx.x) 
xx ( 
xx.x) 
xx ( xx.x) xx ( xx.x)
xx 
 Complete Response (N1 = XX) 
xx ( xx.x) 
xx ( 
xx.x)
xx ( xx.x) 
xx ( 
xx.x)
xx ( xx.x) xx ( xx.x)
xx 
 Very Good Partial Response (N1 = 
XX) 
xx ( xx.x) 
xx ( 
xx.x)
xx ( xx.x) 
xx ( 
xx.x)
xx ( xx.x) xx ( xx.x)
xx 
 Partial Response (N1 = XX) 
xx ( xx.x) 
xx ( 
xx.x)
xx ( xx.x) 
xx ( 
xx.x)
xx ( xx.x) xx ( xx.x)
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CR = Complete Response; VGPR = Very Good Partial Response; PR = Partial Response; NR = No Response.  
N1 = number of subject with the response at Day 28 who were not missing a response at Day 56.  
n = Number of subjects who maintained response at day 56. 
Percentages are calculated as 100 x (n/N1) 
 
 
 
 
 
 
 
 
 
 
Post-hoc Table 4.23.2 
Maintenance of Lower GI aGVHD Response at Day 56 in Standard Risk Group 
Efficacy Evaluable Population 
 
 
Response at Day 28 
Treatment 
Response
CR 
n (%) 
VGPR 
n (%) 
PR 
n (%) 
NR 
n (%) 
Progression
n (%) 
Missing 
n 
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n (%) 
 
 
 
 
 
 
 
 
Treatment Response (N1 = XX) 
xx ( 
xx.x) 
xx ( xx.x) xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) xx ( xx.x) 
xx 
 Complete Response (N1 = XX) 
xx ( 
xx.x)
xx ( xx.x) xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) xx ( xx.x) 
xx 
 Very Good Partial Response (N1 = XX)
xx ( 
xx.x)
xx ( xx.x) xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) xx ( xx.x) 
xx 
 Partial Response (N1 = XX) 
xx ( 
xx.x)
xx ( xx.x) xx ( xx.x) 
xx ( xx.x) 
xx ( xx.x) xx ( xx.x) 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CR = Complete Response; VGPR = Very Good Partial Response; PR = Partial Response;  
N1 = number of subject with the response at Day 28 who were not missing a response at Day 56. 
n = Number of subjects who maintained response at day 56. 
Percentages are calculated as 100 x (n/N1) 
 
 
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Listing 4.2.1 
aGVHD Treatment Response by Visit 
Efficacy Evaluable Population 
 
 
Subject ID 
Age(yrs)/Sex/Race  
Visit 
Date of Assessment 
 
 
 
Was GVHD Treatment 
Response Assessed? 
(Yes/No) 
Lower GI aGVHD 
Treatment Response 
Overall aGVHD 
Treatment 
Response 
xxxxxx 
60/F/Caucasian 
Day 14 
yyyy-mm-dd 
Yes 
CR 
PR 
 
 
 
 
 
 
 
 
 
Day 28 
 
 
 
 
 
 
 
 
 
 
 
 
 
Day 56 
 
 
 
 
 
 
 
 
 
 
 
 
 
Unscheduled 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CR = Complete Response. VGPR = Very Good Partial Response. PR = Partial Response. MR = Mixed Response. NR = No Response. M = Male, F = 
Female. 
 
 
 
 
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Listing 4.2.2 
Discontinuation of Immunosuppressive Medication 
Efficacy Evaluable Population 
 
 
Subject 
ID 
Age(yrs)/Sex/Race  
Drug Name 
Start Date/ Stop Date/ 
Study Day [1] 
Discontinuation at Day 
180? (Yes/No) 
Discontinuation at Day 
365? (Yes/No) 
xxxxxx 
60/F/Caucasian 
 
yyyy-mm-dd/ 
yyyy-mm-dd/ 
5 
No 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M = Male, F = Female. 
[1] Study Day = Date of interest – date of first dose of study drug + 1. 
 
 
 
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Listing 4.2.3 
Immune Recovery by Visit 
Efficacy Population  
 
B and T Lymphocyte Parameter: XXXXXXXXXXXX <unit>  
Subject 
ID 
Laboratory 
Name 
Lab ID 
# 
Visit 
Date of 
Collection 
 
Result 
Unit 
Change from Baseline 
[1] 
  
 
 
 
 
 
 
xxxxxx 
 
 
Day 0 
yyyy-mm-dd 
xx.x 
xxxx 
 
 
 
 
Day 28 
yyyy-mm-dd 
xx.x 
xxxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Baseline was the subject’s Day 0 value.  
 
Programmer note:  
1. Order records by Parameter, subject number, and date of sample. 
2. Repeat pages for all B and T Lymphocyte parameters. 
 
 
 
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Listing 4.2.4 
Overall Survival 
Efficacy Evaluable Population 
 
 
Subject ID 
Age(yrs)/Sex/Race  
Date of First Dose 
of F-652 
 
 
 
Did Subject Die? 
(Yes/No) 
If Subject Died, Date 
of Death (Study Day) 
[1] 
If Subject Did Not Die, Date 
of Study 
Completion/Discontinuation 
(Study Day) [2] 
xxxxxx 
60/F/Caucasian 
yyyy-mm-dd 
Yes 
yyyy-mm-dd (xx) 
yyyy-mm-dd (xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Study Day is the number of days from the date of the first infusion of F-652 to the date of death (Date of death – Date of first 
infusion +1) for subjects who die.  
[2] Study Day is the number of days from the date of the first infustion of F-652 to the date of study completion or discontinuation 
(Date of completion/discontinuation – Date of first infusion +1) for subjects who do not die. 
M = Male, F = Female. 
 
 
 
Programmer note: One record per subject for all subjects. 
 
 
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Report generated by program: /sasdir/xxxx.sas                                                         
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Post-hoc Listing 4.2.5 
Lower GI aGVHD Response in High Risk Group 
Efficacy Evaluable Population 
 
 
Subject 
ID 
Age(yrs)/Sex/Race 
Days since 
Diagnosis 
Weight 
(kg) 
Number of Doses 
Received 
Analysis Visit 
Response 
Category 
xxxxxx 
60/F/Caucasian 
xx 
xx 
4 
Day 14 
Complete 
Response 
 
 
 
 
 
       Day 28 
       Day 56 
 Partial 
Response 
     Etc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
M = Male, F = Female. 
 
 
 
 
 
Additional Analysis(Just run the SAS procedure and saved the outputs as lst): 
1. Run a SAS model with response variable = WK28 response category (continuous -1 to 3 with 0=No Response), independent 
variables Days since Diagnosis, 
Weight (kg), Number of Doses Received – see if anything is significant; 
2. Run a MMRM model with response variable = response (continuous -1 to 3 with 0=No Response), independent variables 
Visit (Day 14, 28, 56), Days since Diagnosis, 
Weight (kg), Number of Doses Received – see if anything is 
significant; 
 
 
 
 
Post-hoc Listing 4.2.6 
Lower GI aGVHD Response in Subjects with a Treatment Response that Subsequently Lost the Response  
Efficacy Evaluable Population 
 
 
Subject ID 
Age(yrs)/Sex/Race  
Visit 
Date of 
Assessment 
Lower GI aGVHD Treatment 
Response 
Overall aGVHD Treatment 
Response 
xxxxxx 
60/F/Caucasian 
Day 14 
yyyy-mm-dd 
CR 
PR 
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Day 28 
 
 
 
 
 
 
 
 
 
 
 
Day 56 
 
 
 
 
 
 
 
 
 
 
 
Unscheduled 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CR = Complete Response; VGPR = Very Good Partial Response; PR = Partial Response; MR = Mixed Response; NR = No Response. 
M = Male, F = Female. 
 
Programming notes: 
Similar to Listing 4.2.1 
 
 
 
 
 
 
TBD 
 
 
 
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Report generated by program: /sasdir/xxxx.sas                                                         
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Report generated by program: /sasdir/xxxx.sas                                                  
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Report generated by program: /sasdir/xxxx.sas                                                  
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Report generated by program: /sasdir/xxxx.sas                                                  
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Report generated by program: /sasdir/xxxx.sas                                                  
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Report generated by program: /sasdir/xxxx.sas                                                  
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Report generated by program: /sasdir/xxxx.sas                                                  
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Report generated by program: /sasdir/xxxx.sas                                                  
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Report generated by program: /sasdir/xxxx.sas                                                  
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Report generated by program: /sasdir/xxxx.sas                                                  
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
CONFIDENTIAL 
Page 1 of 33 
STATISTICAL ANALYSIS PLAN 
Trial Sponsor: 
Generon (Shanghai) Corporation Ltd. 
Protocol Number: 
GC-652-02 
IND Number: 
 
Investigational Drug: F-652
Indication: 
Gastrointestinal Graft versus Host Disease 
Dosage Form/Strength F-652, 45 μg/kg IV 
Protocol Title: A Phase IIa Study of Recombinant Human Interleukin-22 IgG2-Fc (F-652) in 
Combination with Systemic Corticosteroids for the Treatment of Newly Diagnosed Grade II-IV 
Lower Gastrointestinal Acute Graft-versus-Host Disease (aGVHD) in Hematopoietic Stem Cell 
Transplantation Recipients 
Last Revision Date: 
07 October 2019 
Version: 
1.0  
Final Sign-off Date: 
Archive Date: 
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Protocol No: GC-652-02
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
CONFIDENTIAL 
Page 3 of 33 
Change Log for Changes Made after the Initial Approval 
Revision 
Date** 
Section(s)M
odified 
Brief Description of Revision(s) or 
Reason(s) for Revision 
Modifications Reviewed and 
Approved by* 
Sponsor, Everest 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*   Provide person’s initial and last name. 
** Update the Last Revision Dates on the cover page and the document header. 
 
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
CONFIDENTIAL 
Page 4 of 33 
TABLE OF CONTENTS 
APPROVAL SIGNATURES ........................................................................................................................ 2 
GLOSSARY OF ABBREVIATIONS .......................................................................................................... 6 
1. 
INTRODUCTION ................................................................................................................................ 8 
2. 
STUDY OBJECTIVES AND ENDPOINTS ........................................................................................ 8 
2.1 
Study Objective .......................................................................................................................... 8 
2.2 
Safety Endpoints ......................................................................................................................... 8 
2.3 
Primary Efficacy Endpoint ......................................................................................................... 8 
2.4 
Secondary Efficacy Endpoints .................................................................................................... 8 
2.5 
 ................................................................................................................ 9 
2.6 
 ........................................................................................................ 9 
3. 
STUDY DESIGN .................................................................................................................................. 9 
3.1 
Study Design ............................................................................................................................... 9 
3.2 
Schedule of Procedures and Events .......................................................................................... 13 
3.3 
Randomization .......................................................................................................................... 15 
3.4 
Hypothesis Testing ................................................................................................................... 15 
3.5 
Interim Analysis ....................................................................................................................... 15 
3.5.1 
Hold and Discontinuation Rules for the Clinical Trial ............................................... 15 
3.6 
Sample Size .............................................................................................................................. 16 
4. 
DATA AND ANALYTICAL QUALITY ASSURANCE .................................................................. 16 
5. 
ANALYSIS POPULATIONS ............................................................................................................. 16 
5.1 
Safety Population ...................................................................................................................... 16 
5.2 
Efficacy Evaluable Population ................................................................................................. 16 
5.3 
 ..................................................................................................... 16 
6. 
SPECIFICATION OF ENDPOINTS AND VARIABLES ................................................................. 16 
6.1 
Demographic and Baseline Characteristics .............................................................................. 17 
6.1.1 
Demographics and Baseline Characteristics .............................................................. 17 
6.1.2 
Medical and Surgery History, Prior Chemotherapy ................................................... 17 
6.2 
Safety ........................................................................................................................................ 18 
6.2.1 
Safety Baseline and Study Day .................................................................................. 18 
6.2.2 
Extent of Exposure to Study Medication.................................................................... 18 
6.2.3 
Prior and Concomitant Medication ............................................................................ 18 
6.2.4 
Adverse Events ........................................................................................................... 19 
6.2.5 
Laboratory Data .......................................................................................................... 21 
6.2.6 
Vital Signs .................................................................................................................. 22 
6.2.7 
Electrocardiogram ...................................................................................................... 22 
6.2.8 
Other Safety Assessments .......................................................................................... 22 
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Statistical Analysis Plan 
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6.3 
Efficacy ..................................................................................................................................... 23 
6.3.1 
Study Day ................................................................................................................... 23 
6.3.2 
Primary Efficacy Variables ........................................................................................ 23 
6.3.3 
Secondary Efficacy Variables .................................................................................... 23 
6.3.4 
................................................................................................. 24 
6.4 
 ....................................................................................................... 25 
7. 
STATISTICAL ANALYSIS ............................................................................................................... 26 
7.1 
General Data Handling Rules and Definitions ......................................................................... 26 
7.1.1 
Missing Data and Imputation ..................................................................................... 26 
7.1.2 
Analysis Visit and Visit Window Definitions ............................................................ 26 
7.2 
Subject Disposition ................................................................................................................... 27 
7.3 
Demographic and Baseline Characteristics .............................................................................. 27 
7.4 
Safety Analyses ........................................................................................................................ 27 
7.4.1 
Extent of Exposure to Study Medication.................................................................... 27 
7.4.2 
Concomitant Medications........................................................................................... 27 
7.4.3 
Adverse Events ........................................................................................................... 28 
7.4.3.1 
Incidence of Adverse Events ..................................................................... 28 
7.4.4 
Laboratory Data .......................................................................................................... 29 
7.4.5 
Vital Signs .................................................................................................................. 29 
7.4.6 
Electrocardiogram ...................................................................................................... 29 
7.4.7 
Other Safety Assessments .......................................................................................... 29 
7.5 
Efficacy Analyses ..................................................................................................................... 29 
7.5.1 
Primary Efficacy ........................................................................................................ 29 
7.5.1.1 
Sensitivity Analyses ................................................................................... 29 
7.5.2 
Secondary Efficacy..................................................................................................... 29 
7.6 
................................................................................................................ 30 
7.7 
 ...................................................................................................... 30 
8. 
CHANGES FROM METHODS PLANNED IN THE PROTOCOL .................................................. 31 
9. 
STATISTICAL SOFTWARE ............................................................................................................. 31 
10. REFERENCES .................................................................................................................................... 31 
APPENDIX 1 
 DATA HANDLING RULES .................................................................................... 32 
APPENDIX 2 
 SAS CODE FOR STATISTICAL ANALYSES ....................................................... 32 
APPENDIX 3 
 MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) ..................................... 33 
 
 
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
CONFIDENTIAL 
Page 6 of 33 
GLOSSARY OF ABBREVIATIONS 
Abbreviation 
Term 
aGVHD 
Acute Graft-versus-Host Disease 
AE 
Adverse event 
ANC 
Absolute neutrophil count 
AUC 
Area under the curve 
BLOQ 
Below the limit of quantitation 
BMI 
Body mass index 
BMT 
Bone marrow transplant 
BPM 
Beats per minute 
BSA 
Body surface area 
Cmax  
Concentration Maximum  
CBC 
Complete Blood Count 
CI 
Confidence interval 
CL 
Clearance 
CMV 
Cytomegalovirus 
CR 
Complete response 
eCRF 
Electronic Case Report Form 
CTCAE 
National Cancer Institute Common Terminology Criteria for 
Adverse Events 
ECG 
Electrocardiogram 
GI 
Gastrointestinal 
HSCT 
Hematopoietic Stem Cell Transplantation 
IBMTR 
International Bone Marrow Transplant Registry 
IV 
Intravenous 
IWRS 
Interactive Web-based Response System 
λz 
Elimination half-life 
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
CONFIDENTIAL 
Page 7 of 33 
Abbreviation 
Term 
MedDRA 
Medical Dictionary for Regulatory Activities 
MR 
Mixed response 
NCA 
Non-compartmental analysis 
NCI 
National Cancer Institute 
NR 
No response 
OTC 
Over-the-counter 
PE 
Physical examination 
PK  
Pharmacokinetics  
PR 
Partial response 
PT 
Preferred term 
QA 
Quality assurance 
QC 
Quality control 
QTcF 
Fridericia corrected QT interval 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SI units 
International System of Units 
SOC 
System organ class 
SOP 
Standard operating procedure 
TEAE 
Treatment Emergent Adverse Event 
TRM 
Transplant-related mortality 
Vd 
Volume of distribution 
VGPR 
Very good partial response 
VS 
Vital signs 
WHO-DD 
World Health Organization Drug Dictionary 
 
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
CONFIDENTIAL 
Page 8 of 33 
1. INTRODUCTION 
This Statistical Analysis Plan (SAP) outlines the statistical methods for the display, summary and analysis 
of data collected within the scope of Generon (Shanghai) Corporation Ltd. protocol GC-652-02, Protocol 
Amendment 4.0 dated May 30, 2017. The purpose of this plan is to provide general guidelines from 
which the analysis will proceed. Nevertheless, deviations from these guidelines must be substantiated by a 
sound statistical rationale. 
The SAP should be read in conjunction with the study protocol and the Case Report Forms (CRFs). This 
version of the SAP has been developed using the final version of the protocol mentioned above and the 
study CRFs, Version 4.  
This is a Phase IIa open label single arm study to investigate the safety, efficacy, and pharmacokinetics 
(PK) of F-652 (recombinant human IL-22), administered as an intravenous (IV) infusion once a week for 
a total of 4 doses at 45 μg/kg, in combination with systemic corticosteroids for the treatment of newly 
diagnosed grade II-IV lower gastrointestinal (GI) acute graft-versus-host disease (aGVHD) in 
Hematopoietic Stem Cell Transplantation (HSCT) recipients. 
2. STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objective 
The objective of the study is to assess the safety, efficacy and PK of F 652 in combination with systemic 
corticosteroids for the treatment of newly diagnosed grade II-IV lower GI aGVHD in HSCT recipients. 
GVHD cytokines and biomarkers will be explored. 
2.2 
Safety Endpoints 
The safety endpoints of this study are the following:  
 
Adverse event (AE) reporting 
 
Vital sign (VS) measurements 
 
Laboratory measurements 
 
Physical Examination (PE) 
2.3 
Primary Efficacy Endpoint 
 
To assess the lower GI aGVHD treatment response rate at Day 28.  
2.4 
Secondary Efficacy Endpoints 
 
Lower GI aGVHD treatment response at Days 14 and 56 categorized by complete response (CR), 
very good partial response (VGPR), partial response (PR), no response (NR)/stable, and progression. 
 
Overall aGVHD treatment response at Days 14, 28, and 56 categorized by CR, VGPR, PR, mixed 
response (MR), NR, and progression. 
 
Discontinuation of immunosuppressive medication at Day 180 and 1 year post initial dosing of F-652. 
 
Characteristics of immune reconstitution after F-652 treatment. 
 
Overall survival at 1 year after first infusion of F-652. 
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
CONFIDENTIAL 
Page 10 of 33 
efficacy. If 7 or more subjects of the first 16 subjects have a treatment response, an additional 11 subjects 
will be required to complete enrollment into the study for a total sample size of 27 subjects (Figure 1). 
All subjects will be followed for efficacy through Day 56, safety through Day 180, and subject survival 
status will be collected at Day 365 (1 year from the date of initial dosing of F-652). 
Prior to each dosing of F-652, subjects are required to meet the following criteria: absolute neutrophil 
count (ANC) ≥500/mm3, serum creatinine ≤3.0 mg/dl, and all non-hematologic toxicity (except alopecia) 
attributed to the study drug as probable or greater to resolved to ≤ Grade 1 or returned to the subject’s 
baseline condition. Failure to meet these criteria will result in treatment delay, dose reduction, or 
withdrawal from the study, as outlined in Protocol Section 3.3.2 (Hold and Stop Rules). A review of 
excess subject mortality at Day 56 will occur for every 6 subjects accrued into the study. 
During the course of the study, systemic corticosteroids (prednisone or methylprednisolone equivalent) 
will be administered concurrently with F-652. Tapering of corticosteroids is permitted as outlined in 
Protocol Section 5.2 (Treatment Administrations); however, tapering should result in no less than 0.25 
mg/kg/day of prednisone (or IV equivalent) by Day 28, after which tapering may be according to local 
institutional guidelines. 
All subjects should be treated to the institutional allogeneic bone marrow transplant (BMT) standard of 
care guidelines for prophylaxis against infection. This includes, Pneumocystis carinii, Herpes simplex, 
Herpes Zoster, and fungal infections. Subjects will be closely monitored for cytomegalovirus (CMV) 
reactivation according to the each local center standard practice. 
The study drug will be administered on an inpatient or outpatient basis, depending on the subject’s 
clinical condition. The route of administration of F-652 is IV and will be administered once a week on 
Days 0, 7, 14, and 21. Following infusion of F-652, vital signs will be obtained and nursing assessment 
will be performed according to the BMT institutional standard of care. PK sampling will occur as per the 
schedule listed in the Protocol in Appendix 3 and serum samples to test the immunogenicity of F-652 will 
be taken. Subjects will be evaluated for grade 3-4 toxicities, graded by the National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE). A complete description of the study 
procedures for each clinical visit is presented in the Protocol in Appendix 1. 
GVHD biomarkers will be assessed at baseline and post-treatment. Baseline assessment of GVHD 
markers in the peripheral blood and GI tissue will be performed at the time of GVHD diagnosis, pending 
specimen availability. Due to the extensive processing of the peripheral blood for the assessment of 
GVHD cytokine markers, cytokine samples are optional for subjects participating in this study.  The 
biomarker panel will include ST2 and REG3α whereas the cytokine panel will include IL-21, IL-22, and 
IL-23 levels. A stool sample will be collected for intestinal microbiota analysis and GVHD biology, 
including histology and epithelial gene expression, will also be analyzed in biopsy samples from the GI 
tract as the specimen allows. Post-treatment evaluation of GVHD biomarkers/cytokines in the peripheral 
blood, stool sample for intestinal microbiota, and GI tract biopsies will be performed approximately 28 
days after study drug initiation or at least 3 days after receiving last dose of study drug (subject and 
sample availability permitting). Sampling may be withheld in subjects who are critically ill. 
A study visit schematic is provided in Figure 2 and a complete schedule of study procedures and events 
are presented in Section 1.1 (Schedule of Procedures and Events). 
 
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Protocol No: GC-652-02
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
CONFIDENTIAL 
Page 13 of 33 
3.2 
Schedule of Procedures and Events 
Table 1 Schedule of Assessments 
Assessments 
Screening Day 0 
Day 7 
Day 14 
Day 21 
Day 28* 
Day 56 
Day 180 Day 365 
Window for visit (days) 
(5) days 
  
(±) 2 
(±) 2 
(±) 2  
(±) 4 
(±) 14 
(±) 30 
(±) 30 
Signing of Informed Consent 
X 
 
 
 
 
 
 
 
 
Relevant Medical History 
X 
 
 
 
 
 
X 
X 
X 
Body Temperature, Weight, Vital Signs (BP, heart rate, respiratory 
rate) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical examination 
X 
X 
 
 
 
X 
X 
X 
X 
CBC1 
X 
  
X 
X 
X 
X 
X 
 
 
Blood chemistry1 
X 
  
X 
X 
X 
X 
X 
 
 
Urinalysis  
X 
 
 
 
 
X 
 
 
 
Immune recovery (per institutional standard)2 
 
X 
 
 
 
X 
 
 
 
Serum for F-652 antibody testing (pre dosing of F-652)  
 
X 
X 
X 
X 
X 
X 
 
 
ECG 
X 
 
 
 
 
X 
 
 
 
Stool C. Difficile testing (if not done within 7 days) 
X 
 
 
 
 
 
 
 
 
Stool microbiota test 
X 
 
 
 
 
X 
 
 
 
Pregnancy test3 
X 
 
 
 
 
 
 
 
 
Current therapy and concomitant medications4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
GI Biopsy5 
X 
 
 
    
 
X 
 
 
 
 (see additional schedule) 
 
X 
X 
X 
X 
X 
X 
 
 
Administration of F-6527 (within 5 days of consent)  
 
X 
X 
X 
X 
 
 
 
 
Collection of AEs and toxicity assessment8 
X 
X 
X 
X 
X 
X 
X 
 
 
aGVHD blood research samples ( cytokine samples optional) 
 
X 
 
 
 
X 
 
 
 
Skin biopsy, subject permitting or if skin rash develops during 
treatment 
X 
 
 
X 
 
X 
 
 
 
GVHD treatment response 
 
 
 
X 
 
X 
X 
 
 
aGVHD evaluation  
X 
 
X 
X 
X 
X 
X 
X 
X 
Abbreviations: AE = adverse event; aGVHD = acute graft-versus-host disease; BP = blood pressure; CBC = complete blood count; ECG = electrocardiogram; F-652 = 
recombinant human interleukin-22-IgG2-Fc; GI = gastrointestinal; GVHD = graft-versus-host disease; PK = pharmacokinetics.* End of treatment visit 
1 Blood samples are taken predose at Screening and Days 7, 14, 21, 28, and 56, and at 72 hours post-dose for CRP determination only at Screening and Days 7, 14, and 21. 
2 Immune recovery assessed on Day 0 as baseline and Days 28, post initial dose of F-652. Testing can be withheld if the subject has very low circulating white blood cells. 
3 For females with reproductive potential, serum test. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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3.3 
Randomization 
There is no randomization as this is a single arm study. An Interactive Web-based Response System 
(IWRS) with a 24-hour live support help desk will be used to assign subject numbers and to assign study 
drug. Authorized study site personnel will access the web-based system using a user ID and password. 
Prior training and a user’s manual will be provided to all the study participating sites. 
3.4 
Hypothesis Testing 
In this exploratory Phase IIa study, all statistical tests will be two-sided with no adjustment for 
multiplicity.  All statistical tests and confidence intervals (CI) will use a Type I error rate of 10%. No 
adjustment will be made for multiple testing. 
3.5 
Interim Analysis 
No interim analysis is planned for this study.   
3.5.1 
Hold and Discontinuation Rules for the Clinical Trial 
Subjects will be closely monitored for clinical deterioration (i.e., disease progression) by the study 
Investigators, the study Medical Monitor, and the Sponsor’s medical expert. In addition to standard 
toxicities such as alterations in blood chemistries or hematology, this monitoring will also include disease 
progression and treatment efficacy. 
Clinical Trial Termination: 
The study includes stopping criteria in the event that excessive Day 56 TRM is observed. The historical 
rate of TRM deaths is approximately 15-20%.3 A TRM of 40% at Day 56 would be considered 
unexpected and an unacceptable number of excess deaths. TRM is defined as death at any time from the 
commencement of pre-transplant conditioning due to any cause other than disease relapse with the 
exception of automobile or other accidents. 
In this study, there will be an ongoing review for excessive TRM. The study will be stopped for interim 
evaluation if the number of deaths is 3 or more in the first 5 subjects treated, 4 or more in the first 9 
subjects treated, etc. as per Table 3. This evaluation will occur for the subject’s Day 56 visit (post their 
initial F-652 dosing). Subjects removed from the study due to negative biopsy for aGVHD will not be 
accountable for the mortality rate rule analysis. 
Table 3 Stopping criteria for excessive mortality based on a Pocock boundary 
Failure Type 
Mortality Rate Rule for 
Study Termination 
Death rate in the 
population 
Probability boundary 
is crossed  
Transplant-Related 
Mortality (day +56)   
3 deaths in the first 5 
subjects treated 
0.15 
0.10 
4 deaths in the first 9 
subjects treated 
5 deaths in the first 13 
subjects treated 
0.40 
0.93 
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6.1 
Demographic and Baseline Characteristics 
6.1.1 
Demographics and Baseline Characteristics 
Demographic parameters collected include:  
 
Age 
 
Sex 
 
Race 
 
Ethnicity 
 
Reproductive status 
Baseline characteristics include: 
 
Weight (kg) 
 
Height (cm) 
 
Body mass index (BMI) in kg/m2 
 
Body surface area (BSA) in m2 
 
Days since clinical lower GI aGVHD diagnosis 
 
Screening aGVHD stage for each target organ (Skin, Lower GI Tract, Upper GI Tract, and Liver) 
using the modified keystone criteria 
 
IBMTR Severity Grade 
 
Type of HSCT (Blood, Bone Marrow, Cord, or Haploidentical) 
 
CMG IgG serostatus (Positive, Negative, or Equivocal) 
 
CMG IgM serostatus (Positive, Negative, or Equivocal) 
 
Physical examination clinically significant abnormalities (Yes or No) 
 
Age, BMI, BSA, and days since clinical lower GI aGVHD diagnosis will be computed as: 
Table 4 Data Handling Rules for Demographic Data 
Description 
Data Handling Rule 
Age (years) 
Age = integer((date of screening-date of birth)/365.25)   
BMI 
BMI = Weight (kg) / [Height (cm)/100]2 
BSA 
BSA =( [Height (cm) x Weight (kg) ]/ 3600 )1/2 
Days since clinical lower 
GI aGVHD diagnosis 
Days since clinical lower GI aGVHD diagnosis = Date of screening – 
Date of Clinical Lower GI aGVHD diagnosis 
 
6.1.2 
Medical and Surgery History, Prior Chemotherapy 
Medical and surgical history and prior chemotherapy will be collected. 
General medical and surgical history will include a description of the diagnosis or procedures, start and 
end date, and if the condition is still ongoing. 
Prior chemotherapy agent name, number of cycles, and date of last dose will be recorded on the eCRF.   
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6.2 
Safety 
 
AE reporting 
 
VS measurements 
 
Laboratory measurements (hematology, serum chemistry, and urinalysis) 
 
Electrocardiogram (ECG) measurements 
 
PE 
Standard safety parameters include hematology, blood chemistry and urinalysis parameters, vital signs, 
physical examination, and toxicity management. The National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI-CTCAE) v 4.03 will be used to grade potential AEs. 
6.2.1 
Safety Baseline and Study Day  
The baseline of safety measures are the last measure before first dose of F-652. 
Study day will be computed from Day 0 as:   
Study day = (Date of interest) – (Date of Day 0) + 1 
6.2.2 
Extent of Exposure to Study Medication 
Extent of exposure to study drug (F-652) will be assessed using the following variables: 
Table 5 Data Handling Rules for Extent of Exposure to Study Medication Data 
Description 
Definition/ Data Handling Rule 
Number of Treatments 
Number of infusions started, regardless of the completion status. 
Treatment duration 
Treatment duration (days) = Date of last dose of F-652– Date of first 
dose of F-652 + 1 
Total F-652 Received 
(mg) 
The total dosage of F-652 received. The starting dose is 45 μg/kg.  
Subsequent doses may be reduced, as determined by the Investigator, to 
30 μg/kg or 10 μg/kg.   
The drug administered is at a concentration of 5 mg/mL.  Dose infused 
(mg) can be calculated as (Volume infused (mL) * 5 mg/mL). 
Number of Subjects with 
Doses Interrupted or 
Discontinued Prematurely 
(Overall and for each 
dose) 
Number of subjects administered study drug but who had the infusion 
interrupted or discontinued prematurely. 
 
6.2.3 
Prior and Concomitant Medication 
Prior and concomitant medications, including BMT/GVHD and systemic corticosteroid medications, will 
be recorded at screening and during the study. Prior medication is defined as any medication taken before 
the first dose of F-652. Concomitant medication is defined as any medication taken during the study 
between the date of the first dose of F-652 and the last study date of the subject, up to the Day 56 visit.  
Any medications started after the last study date of the subject will not be considered concomitant 
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medications. After Day 56, only concomitant medications related to a SAE will be documented on the 
eCRFs and will be considered as post-dose medications. 
Any medication which cannot be identified as prior or concomitant will be considered as being in both of 
the categories that are possible from the available information. 
All relevant information, including reason for use, dose, unit, frequency and route, will be recorded for 
any medication administered or received prior and during the study. 
Summaries of all concomitant medications taken during the course of the study will be presented in 
tabular form using Anatomical Therapeutic Chemical 4 classification codes and preferred drug name via 
the World Health Organization Drug Dictionary (WHO-DD) with latest version to be specified in the 
Clinical Study Report. For the summary tables, if a subject has taken a concomitant medication more than 
once, the subject will be counted only once for the medication. 
For medications with incomplete dates, imputation will be used to convert to a complete date. Imputed 
dates will be used to determine the study day. 
Partial medication start dates will be imputed as follows:  
1. Only the year is reported: If the subject started receiving study treatment in the year reported, 
then the date of the first dose of study treatment will be used as the starting date of the 
medication. Otherwise, January 1 will be used as the start of the medication. 
2. The month and year is reported: If the subject started receiving study treatment during the month 
and year reported, then the date of first dose of study treatment will be used as the starting date of 
the medication. Otherwise, the first day of the month will be used as the start of the medication. 
Partial medication end dates will be imputed for non-ongoing medications as follows:  
1. Only the year is reported: If the subject stopped receiving study treatment in the year reported, 
then the date of the last dose of study treatment will be used as the end date of the medication. 
Otherwise, December 31 will be used as the end of the medication.  
2. The month and year is reported: If the subject stopped receiving study treatment during the month 
and year reported, then the date of last dose of study treatment will be used as the end date of the 
medication. Otherwise, the last day of the month will be used as the end of the medication. 
The above rules are subject to logical sense, for example, imputed start date should be on or prior to 
imputed end date. 
6.2.4 
Adverse Events 
Adverse events (AEs) will be collected and coded using the latest version of the Medical Dictionary for 
Regulatory Activities (MedDRA). Analysis of adverse events will be carried out on the Safety 
Population. 
All AEs from the time of randomization, regardless of suspected causal relationship to the investigational 
product, will be documented on the AE page(s) of the eCRF up to and including Study Day 56.  After 
Day 56,  SAEs deemed possibly, probably, or definitely related to the investigational product are required 
to be recorded through to the end of the study (Day 365). 
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A treatment-emergent adverse event (TEAE) is any adverse event that begins on or after first dose of F-
652, or is a worsening of a pre-existing medical condition, up to Day 56. SAEs that start after Day 56 will 
be considered post-treatment.  Incidence of TEAE will be presented overall for all subjects.  
The severity of each AE will be classified using the NCI-CTCAE toxicity scale as follows: 
 
Grade 1 = Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
 
Grade 2 = Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental Activities of Daily Living (ADL) 
 
Grade 3 = Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self-care ADL 
 
Grade 4 = Life-threatening consequences; urgent intervention indicated.  
 
Grade 5 = Death related to AE. 
The relationship of each AE will be assessed by the investigator and assigned to  1 of the following 
categories: 
 
Unrelated 
 
Unlikely 
 
Possible 
 
Probable 
 
Definite 
An AE will be considered “related” to study drug if the relationship is “possible”, “probable” or 
“definite”. 
Serious adverse events (SAE) are defined as any adverse events occurring at any dose that suggests a 
significant hazard, contraindication, side effect, or precaution. SAEs will be collected from the time of 
study entry until 30 days after completion of the trial or 30 days after premature withdrawal of a subject 
from the trial. 
If the death of a subject is reported at any point during the study, the date of death, autopsy performed 
(yes/no), and any clarifying information should be collected. The event causing death will be reported as a 
SAE. 
Adverse Events Counting Rules: 
1. In the analyses, a subject having the same event (AE preferred term) more than once during the study 
will be counted only once for that event type.  
2. A subject with more than one different adverse event in a particular system organ class (SOC) will be 
counted only once in the total of subjects experiencing adverse events in that particular SOC. 
3. If an event changes in intensity or in seriousness during the study, it will be counted only once with 
the worst grade and seriousness respectively. 
4. If the causal relationship to the study drug is assessed differently, it will be counted only once by 
considering the “Worst” documented degree of relationship. 
Missing values will be treated as missing except for relationship, grade and seriousness of an AE, at 
which occurrence a “worst case” approach will be taken. Thus, if relationship is missing the AE will be 
regarded as related to the study drug, if the grade is missing the grade of the AE will be regarded as 
severe (Grade 3), if seriousness is missing the AE will be regarded as an SAE. 
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Events with Irregular Start Dates: All treatment-emergent adverse events will be included in the 
tabulations regardless the completeness of the onset dates. Partial dates may be imputed when 
appropriate, as discussed below. 
If a partial date is reported for the start of an adverse event, a complete date will be estimated by the 
following algorithm: 
1. Only the year is reported: If the subject started receiving study medication in the prior year, then 
January 1 will be used as the starting date of the event. If the subject started receiving study 
medication in the year reported, then the date of the first dose of study medication will be used as the 
start of the event.  
2. The month and year are reported: If the subject started receiving study medication prior to the month 
and year reported, then the first day of the month will be used as the starting date of the event. If the 
subject started receiving medication during the month and year reported, then the date of the first dose 
of study medication will be used as the start of the event.  
If a partial date is reported for the end of an adverse event and the adverse event is not continuing, a 
complete date will be estimated by the following algorithm:  
1. Only the year is reported: If the subject started receiving study medication in the prior year, then the 
date of final study contact with the subject will be used as the end of the adverse event. If the subject 
started receiving study medication in the year reported, the earlier of December 31 or the date of final 
study contact with the subject will be used as the end of the adverse event.  
2. The month and year are reported: The earlier of the last day of the month or the date of final contact 
with the subject will be used as the end of the adverse event.  
Before the database lock, uncoded events will be assigned the string “UNCODED” as the body system, 
and the verbatim term will be used as the preferred term, so they can be included in the summary tables. 
In the final dataset, all the adverse events should have been coded.  
6.2.5 
Laboratory Data 
This study will be conducted in up to 4 clinical centers in North America.  Blood samples for hematology, 
serum chemistry, and serum hCG, as well as stool samples for C. difficile will be collected and analyzed 
by a local laboratory.  Blood samples collected for PK will be analyzed by a central laboratory.   
Conversion to the International System of Units 
All laboratory data will be stored in the database with the units in which they are originally reported. 
Laboratory data in summary tables and subject data listings will be presented in the International System 
of Units (SI units). Laboratory data not reported in SI units will be converted to SI units before further 
processing or data analysis. 
Hematology and blood chemistry data will be graded according to NCI-CTCAE severity grade.  
Baseline laboratory parameters (blood chemistry, hematology, and urinalysis) are defined as the subject’s 
last assessment prior to the first dose of F-652.    
Change in laboratory parameters post baseline can be computed as: 
Change from baseline = Current Value – Baseline Value 
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Missing laboratory values will not be imputed for the safety analysis. In case of repeated measurements at 
a given visit, the latest value will be used for analysis.   
6.2.6 
Vital Signs 
Vital signs are collected at Screening, Days 0, 7, 14, 21, 28, 56, 180, and 365, and include the following 
parameters: 
 
Height (cm) (Screening only) 
 
Weight (kg) 
 
Temperature (oC) 
 
Heart rate (beats per minute [BPM]) 
 
Diastolic and systolic blood pressure (mmHg) 
 
Respiratory rate (beats/minute) 
Weight at Days 0, 7, 14, and 21 will be measured once.  Temperature, heart rate, blood pressure, and 
respiratory rate at Days 0, 7, 14, and 21 will be measured 15 minutes after the start of infusion, at the 
completion of infusion, and 1 hour after the end of infusion.  All parameters will be collected one time 
each at Screening and on Days 28, 56, 180, and 365.     
Baseline and change from baseline are defined similarly as in Section 6.2.5.  
6.2.7 
Electrocardiogram 
Standard 12-lead ECG will be measured at screening and Day 28. The following parameters are included:  
 
PR Interval 
 
QRS Duration 
 
QT Interval 
 
RR Interval 
 
Heart Rate 
 
QTc Fridericia Interval (QTcF) 
QTcF will be calculated as:  𝑄𝑇√𝑅𝑅
3
⁄
.   
Another version of QTc was also collected from the CRF and will only be listed.  
6.2.8 
Other Safety Assessments 
Other safety assessments include: 
 
Serum pregnancy test 
 
Urine pregnancy test  
 
Physical examination 
Any clinically significant abnormalities from physical examination will be reported as medical history if 
observed at Screening, or as an AE if observed after enrollment. 
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6.3 
Efficacy 
The Efficacy Evaluable Population will be used for the efficacy analyses.  
Missing aGVHD treatment response will be imputed as non-response for this analysis. Handling of 
missing values is covered in section 7.1.1. 
6.3.1 
Study Day 
The date of the first dose of F-652 represents Study Day 1. 
Study day will be computed from day 1 as:   
Study day = (date of interest) – (date of Study Day 1) + 1 
6.3.2 
Primary Efficacy Variables 
 
The lower GI aGVHD treatment response rate 28 days following the initiation of therapy will be 
assessed by examining the proportion of subjects with a CR, VGPR, PR or have NR/stable or 
progression of lower GI aGVHD symptomatology.  Treatment Response will be defined as CR, 
VGPR, or PR.  No Treatment Response will be defined as NR/stable or progression. 
6.3.3 
Secondary Efficacy Variables 
 
The lower GI aGVHD treatment response rate at Days 14 and 56 will be assessed by examining the 
proportion of subjects with a CR, VGPR, PR or have NR/stable or progression of lower GI aGVHD 
symptomatology.  Treatment Response will be defined as CR, VGPR, or PR.  No Treatment 
Response will be defined as NR/stable or progression. 
 
The overall aGVHD treatment response rate at Days 14, 28, and 56 will be assessed by examining the 
proportion of subjects with a CR, VGPR, PR, MR, or have NR/stable or progression of overall 
aGVHD symptomatology.  Treatment Response will be defined as CR, VGPR, PR, or MR.  No 
Treatment Response will be defined as NR/stable or progression. 
 
Discontinuation of immunosuppressive medication at Day 180 and 1 year post initial dosing of F-652 
will be assessed by estimating the proportion of subjects who have stopped immunosuppressive 
medication at Day 180 and 1 year.  Immunosuppresive medications will be identified as those 
collected on the BMT/GVHD Medications CRF and categorized as Immunosuppressants.  Subjects 
who discontinue at Day 180 and at 1 year will be defined as those who have stopped all 
immunosuppressant medications that were being taken at or after the first dose of F-652.   
 
Characteristics of immune reconstitution after F-652 treatment will be evaluated through the B and T 
lymphocytes recovery and will be measured on Study Days 0 and 28 post-initial dose of F-652.  
Graphical and summary measures will be used to describe the CD3+CD4+, CD3+CD8+, and CD19+ 
populations.  The entire immune reconstitution panel consists of the following: 
 
ALC (absolute lymphocyte count) (Cell/mcL) 
 
CD45+ Lymphocytes (%) 
 
CD3+ T cells (%) 
 
CD3+ Absolute (Cell/mcL) 
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7.2 
Subject Disposition 
Disposition tables will be presented for all subjects.  
The number and percentage of subjects who did not meet the screening criteria, were enrolled into the 
study, and completed each of the four doses will be tabulated. The number and percentage of subjects 
included and excluded from the defined analysis populations and reasons for study discontinuation will 
also be summarized.  Other disposition information, reasons for screen failure and study discontinuation 
details will be provided in individual subject data listings.  
7.3 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics data will be summarized and tabulated. 
Continuous baseline parameters (such as age) will be summarized descriptively. For categorical 
demographic parameters (such as gender, race, ethnicity) frequencies of subjects will be provided. 
All medical history, acute graft-versus-host disease (aGVHD) diagnosis, prior chemotherapy, physical 
examination (abnormalities only), prior/concomitant medications, BMT/GVHD medications, and 
systemic corticosteroid administration data collected on the eCRF will be presented in listings. 
7.4 
Safety Analyses 
All safety analysis will be performed on the Safety Population. Safety will be assessed based on AE 
reporting, physical examination, vital sign measurement, and clinical laboratory test results.  Summaries 
of safety parameters will be presented for all treated subjects.  
Wherever applicable for a safety parameter, the last assessment made before the first dose of F-652 will 
be used as the baseline for all analyses of that safety parameter.  
In case of repeated measurements at a given timepoint, the latest value will be used for analysis. 
Measurements at unscheduled visits will only be listed, unless it is actually a repeat of the scheduled 
measurement.  
7.4.1 
Extent of Exposure to Study Medication 
Descriptive statistics will be presented for the number of treatments, treatment duration (days), total F-
652 received (mg), and number of incompleted doses.  Study drug dose, date and time, and volume will 
be provided in listings. 
7.4.2 
Concomitant Medications 
The number and percent of subjects with concomitant medications will be tabulated by ATC class and 
preferred term.  Other details, including medication verbatim and coding, will be provided in listings.  
The number and percent of subjects with BMT/GVHD medications will be tabulated by category and 
Day 56 
43 to 61  
57 
Day 180 
151 to 211 
181 
Day 365 
336 to 396 
366 
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drug name, as defined in the CRF.  Other details will be provided in listings.  The number and percent of 
subjects with systemic corticosteroid medications will be tabulated by corticosteroid name (Prednisone, 
Methylprednisolone, and Other).  Other details, including other specified corticosteroid names, will be 
provided in listings.   
7.4.3 
Adverse Events 
Analysis of adverse events will be carried out on the Safety Population. All adverse events will be 
included in the analyses, summaries, and individual subject data listings.  
A TEAE overview summary table will be provided for all treated subjects including the number and 
percentage of subjects reporting at least one TEAE and the number of TEAEs reported for the following 
categories: 
 
Any TEAEs 
 
Serious TEAEs  
 
Deaths  
 
TEAE leading to study drug interruption 
 
TEAE leading to discontinuation of study drug 
7.4.3.1 
Incidence of Adverse Events 
TEAEs will be summarized by SOC and preferred term (PT). The summary tables will display the total 
number and percentage of subjects reporting a specific TEAE, and the number of TEAE reported. TEAEs 
will be presented by SOC sorted alphabetically and PT sorted in decreasing frequency of occurrence. 
Summary tables will be prepared for: 
 
Summary of TEAEs 
 
All TEAEs 
 
Serious TEAEs 
 
Treatment-related TEAEs 
 
TEAE leading to study drug discontinuation 
 
TEAEs by maximum severity 
 
TEAEs by relationship to study drug 
 
Common TEAEs with > 5% incidence rate 
 
Post-treatment SAE's 
Supporting data listings will be provided, including: 
 
All adverse events (including any AEs reported in the study)  
 
Serious adverse events  
 
Deaths 
 
Adverse events for subjects who discontinued the study due to AE 
 
Glossaries of Preferred terms to verbatim by System Organ Class (SOC) 
Infusion related reactions details will also be listed.   
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7.4.4 
Laboratory Data 
For analysis purposes, the study visit/timepoint will be recalculated from the date of the first dose 
collected from Study Drug Administration eCRF page. 
Shift tables from screening visit to the worst post-baseline value will be presented for clinical laboratory 
measurements (serum chemistry and hematology) for all treated subjects.  
All data will be all displayed in subject data listings for all safety subjects. 
7.4.5 
Vital Signs 
Descriptive statistics will be prepared for vital sign measurements, by visit and time (after dose), for 
actual values and changes from baseline.  All data will be all displayed in subject data listings for all 
safety subjects. 
7.4.6 
Electrocardiogram 
All ECG parameters will be listed. 
7.4.7 
Other Safety Assessments 
Physical examination and pregnancy test results will be presented in listings for all Safety subjects.   
7.5 
Efficacy Analyses 
All testing will be two-sided, with “statistical significance” defined as a corresponding p-value < 0.10. 
The analyses of the secondary endpoints will be performed with no adjustment for multiplicity.  
7.5.1 
Primary Efficacy 
The primary endpoint of lower GI aGHVD treatment response rate 28 days following the initiation of 
therapy will be reported as the proportion of subjects who provide a response as defined as Treatment 
Response (CR, VGPR, or PR), and No Treatment Response (NR and progression). 
7.5.1.1 Sensitivity Analyses 
No sensitivity analyses are planned at this time to evaluate the robustness of the primary efficacy results. 
7.5.2 
Secondary Efficacy 
Secondary efficacy endpoints will be analyzed as follows: 
 
Response to therapy will be explored by examining the proportion of subjects with a Treatment 
Response (CR, VGPR, or PR), and No Treatment Response (NR/stable or progression) lower GI 
aGVHD symptomatology at 14 and 56 days post treatment initiation. 
 
Overall aGVHD response to therapy will be explored by examining the proportion of subjects with a 
Treatment Response (CR, VGPR, PR, or MR), and No Treatment Response (NR/stable or 
progression) of aGVHD at Days 14, 28, and 56 post-treatment initiation. 
 
The proportion of subjects who have stopped immunosuppressive medication at Day 180 and 1 year 
post initial dosing of F-652 will be estimated. 
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Protocol No: GC-652-02
Clinical Study Report 
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
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8. CHANGES FROM METHODS PLANNED IN THE PROTOCOL  
No changes are planned from the protocol. 
9. STATISTICAL SOFTWARE 
All analyses will be done using SAS version 9.4. 
10. REFERENCES 
1. Przepiorka D, Weisdorf D, Martin P, et al. 1994 Consensus Conference on Acute GVHD 
Grading. Bone Marrow Transplant. 1995;15(6):825-828. 
2. Rowlings PA, Przepiorka D, Klein JP, et al. IBMTR Severity Index for grading acute graft-
versus-host disease: retrospective comparison with Glucksberg grade. British Journal of 
Haematology. 1997;97(4):855-864. 
3. Levine JE, Logan B, Wu J, et al. Graft-versus-host disease treatment: predictors of survival. Biol 
Blood Marrow Transplant. 2010;16(12):1693-1699. 
4. Ivanova A, Qaqish BF and Schell MJ. (2005). Continuous Toxicity Monitoring in Phase II Trials 
in Oncology. Biometrics 61, 540-545. 
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Protocol No: GC-652-02
Clinical Study Report 
CSR Final, 12 Feb 2021
 
 
 
 
 
Confidential
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
CONFIDENTIAL 
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APPENDIX 1 DATA HANDLING RULES 
Category 
Description 
Data Handling Rules 
Demographics 
Age (years) 
Age = integer((date of screening-date of 
birth)/365.25)   
Demographic 
BMI 
BMI = Weight(kg) / [Height(cm)/100]2 
Demographic 
BSA 
BSA = ( [Height(cm) x Weight(kg)]/ 3600 )1/2 
Demographic 
Days since clinical lower GI 
aGVHD diagnosis 
Days since clinical lower GI aGVHD diagnosis = 
Date of screening – Date of Clinical Lower GI 
aGVHD diagnosis 
Medical History 
Any Medical history 
flags are none, but data are present, change the flag 
to “Yes” 
Efficacy 
Stop day of 
immunosuppresive 
medication 
= Stop date of immunosuppresive medication – Date 
of first dose of F-652 + 1 
Efficacy 
Overall survival time 
= Date of completion/discontinuation – Date of first 
infusion + 1 
Extent of Exposure to 
Study Medication 
Actual volume infused 
Collected on the CRF in mL, rounded to 1 decimal 
place. 
Safety Lab 
Assessment day 
Assessment day = (Date of assessment) – (Date of 
first dose) + 1. 
Safety Lab 
Change from baseline 
Change from baseline = Current Value – Value at 
last assessment prior to dose 1 treatment. 
APPENDIX 2 SAS CODE FOR STATISTICAL ANALYSES 
The SAS code for the efficacy endpoint analyses are given below.   
Proportion of Subjects 
with Response- Primary 
Efficacy Endpoint 
proc freq; 
   tables aval/binomial(exact) alpha=0.1; 
run; 
 
Note:  Use for Primary Efficacy endpoint, lower GI aGHVD response at day 28. 
Proportion of Subjects 
with Response- 
Secondary Efficacy 
Endpoints 
proc freq; 
   tables aval/binomial(exact) alpha=0.1; 
   by avisitn; 
run; 
 
Note:  Use for Secondary Efficacy endpoints, lower GI aGHVD 
response at days 14 and 56, overall aGVHD response at days 14, 28, 
and 56, and proportion of subjects who have stopped 
immunosuppressive medication at days 180 and 365. 
Kaplan Meier Survival 
Estimate- Secondary 
proc lifetest; 
   time survdays*censor(1); 
run; 
Generon (Shanghai) Corporation, F-652 
Protocol No: GC-652-02
Clinical Study Report 
CSR Final, 12 Feb 2021
 
 
 
 
 
Confidential
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Statistical Analysis Plan 
Protocol Number: GC-652-02 
 
 
CONFIDENTIAL 
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Efficacy Endpoint 
Overall Survival 
   
APPENDIX 3 MOCKUP TABLES, LISTINGS, AND GRAPHS (TLGS) 
Mockup tables, listings, and graphs are presented in a separate document prior to the final signoff of this 
SAP. 
 
Generon (Shanghai) Corporation, F-652 
Protocol No: GC-652-02
Clinical Study Report 
CSR Final, 12 Feb 2021
 
 
 
 
 
Confidential
Page 179 of 179