Conditions: Chronic Graft-Versus-Host Disease Immune System Diseases
Keywords: cGvHD Arsenic Trioxide Hematology
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 21
Healthy volunteers: no

Brief summary:
This study aims to evaluate the early chronic GvHD events (first line therapy), if the addition of arsenic trioxide to standard therapy with corticosteroids, with or without cyclosporine, will be effective in controlling chronic GvHD and to reduce the duration of corticosteroid therapy

Detailed description:
Graft-versus-host disease (GvHD) is the most common long-term complication in patients who underwent allogeneic transplantation.

First-line therapy for chronic GVHD is based on immunosuppressive agents (corticosteroids with or without cyclosporine) achieving satisfactory response in around 30% of patients.

This is a prospective, national, multicenter, non-randomized Phase II study that will include a total number of 24 patients in which, trioxide d'arsenic will be administrated at 0,15mg/kg/day.

Clinical response will be evaluated based on the Working Group Report 2015, published by the National Institute of Health Consensus.

Follow-up visits will be weekly for four weeks (ATO cycle), every two weeks from second to third month of ATO treatment, every month from the fourth to sixth month of ATO treatment and every 3 months, at 9 months and 12 months (final visit).

Arms:
arm 1: Single arm : Arsenic trioxide

Interventions: intervention 1: Arsenic Trioxide Injectable Solution
Intervention descriptions: intervention 1: Each patient will receive eleven perfusions of arsenic trioxide (0,15 mg/kg/Day - IV administration) over a 4 weeks period (one cycle).

Patients in partial response after the 1st cycle of ATO will be eligible to receive a second cycle of ATO as consolidation therapy. A delay of 8 weeks (from the first infusion of ATO) will be observed between the two cycles of ATO therapy.

The study duration will be 2 years (12 months recruitment + 12 months follow-up).

Protocol document:
Prot_000.pdf: 
Protocol GMED16-001 – Version 7.0 
 
 
 
 
 
 
 
 
 
 
Official Title: Phase II study of first line treatment of Chronic Graft versus Host 
Disease with Arsenic Trioxide 
 
 
 
NCT Number: 02966301 
 
 
 
Document Dates: Protocol GMED16-001 – Version 7.0 2018/12/18 
 
 
 
 


Protocol GMED16-001 – Version 7.0 
 
 
 
Phase II study of first line treatment of  
Chronic Graft versus Host Disease with Arsenic Trioxide 
 
GvHD-ATO Study 
Protocol Number: GMED16-001 
 
 
CLINICAL STUDY PROTOCOL 
Development phase 
II 
Methodology 
Prospective, national, multicenter,  
 
 
non-randomized study 
Pathology 
Chronic Graft versus Host Disease 
Investigational product 
Arsenic Trioxyde 
Eudract N° 
2016-002358-18 
Version N° 
7.0 
Date 
18th of December 2018 
Sponsor 
MEDSENIC  
 
204, avenue de Colmar 
                                                  67100 Strasbourg 
Coordinator 
Pr Mohamad MOHTY 
 
Service d’Hématologie Clinique 
 
Hôpital Saint Antoine AP-HP 
 
75012 - Paris Cedex 12 
 
 
 
The information contained in this document is the property of MEDSENIC. The 
disclosure of the information to others without written prior approval from MEDSENIC 
is forbidden. 


Protocol GMED16-001 – Version 7.0 
 
Page 1 
ADMINISTRATIVE STRUCTURE 
Sponsor 
MEDSENIC 
204, avenue de Colmar 
F-67100 - Strasbourg 
 
CEO - Scientific Director 
Pr François Rieger 
Mail: fr@medsenic.org 
Executive Director 
Véronique Pomi 
Clinical Project Leader: 
Dominique Gaïda, PhD 
Coordinating Investigator 
Pr Mohamad MOHTY 
Service d’Hématologie Clinique 
Hôpital Saint Antoine AP-HP 
F-75012 - Paris 
 
 
Contract Research Organization 
PopsiCube - Fovea 
6 rue Jean-Pierre Timbaud 
Le Campus - Bât A1 Sud 
F-78180 Montigny le Bretonneux 
 
 


Protocol GMED16-001 – Version 7.0 
 
Page 2 
 
PARTICIPATION APPROVAL 
I, Dr  _____________________, investigator, confirm that I have read and understood the 
protocol . 
I have fully discussed the objectives and procedures of the study with the sponsor 
representatives. 
I will conduct the study in all respects in accordance with the study protocol and its 
amendments, and the ethical and regulatory principles. 
 
 
 
Date: __________________ 
 
Signature: 
 
 
 
 


Protocol GMED16-001 – Version 7.0 
 
Page 3 
SYNOPSIS 
Sponsor : 
MEDSENIC  
204, avenue de Colmar 
F-67100 – Strasbourg 
Title 
Phase II study of first line treatment of Chronic Graft versus 
Host Disease with Arsenic Trioxide (GvHD-ATO Study) 
Eudract Number 
2016-002358-18 
Coordinating 
investigator 
Pr Mohamad MOHTY 
Centre Hospitalier Saint Antoine (AP-HP) 
Service d'Hématologie Clinique 
Phase of development 
Phase II 
Objectives 
Main Objective 
• To improve the response rate (complete and partial 
remission) at 6 months after diagnosis of chronic graft 
versus host disease (GvHD) and treatment with arsenic 
trioxide (ATO) in combination with prednisone with or 
without ciclosporine as a first line treatment 
Secondary Objectives 
• To evaluate failure-free survival (FFS), defined as death, 
recurrent or progressive malignancy, or initiation of a new 
systemic treatment for chronic GvHD 
• To decrease non-relapse mortality (NRM) of infectious and 
non-infectious origin 
• To improve overall survival (OS) and progression-free 
survival (PFS) 
• To spare patients from long-term use of corticosteroids (and 
their long-term side effects) 
• To improve quality of life self-reported by patient using the 
Lee Symptom Scale (LSS) and Functional Assessment of 
Chronic 
Illness 
Therapy 
with 
Bone 
Marrow 
Transplantation subscale (FACT-BMT) 
• To evaluate tolerability and safety of ATO in combination 
with prednisone, with or without ciclosporine, in patients 
with chronic GvHD after allo-SCT 
Study design 
Prospective, national, multicenter, non-randomized  


Protocol GMED16-001 – Version 7.0 
 
Page 4 
Number of patients 
planned 
24  patients planned to be included in the study 
Study centres 
11 sites planned to participate to the study 
Studied population 
Inclusion criteria 
- Adult patients (≥18 years) who have received a first 
allogeneic stem cell transplantation for a hematological 
disease (any source of hematopoietic stem cells is 
authorized; any category of conditioning regimen prior to 
allo-SCT is authorized; any type of stem cell donors is 
authorized) 
- Confirmed diagnosis of a first episode of chronic GvHD 
requiring systemic immunosuppressive therapy (any prior 
GvHD prophylaxis previously used is accepted). Chronic 
GvHD diagnosis is defined according to the NIH Working 
Group Consensus. Chronic GvHD diagnosis will be based 
on the evaluation of the severity of the different clinical 
manifestations including: 
a/ Performance status evaluation 
b/ Cutaneous evaluation measured by the percentage of 
extension or the presence of sclerotic features. If relevant, 
confirmation with a biopsy should be performed whenever 
possible 
c/ Oral symptoms 
d/ Ocular symptoms 
e/ Gastro-intestinal symptoms 
f/ Evaluation of liver involvement (total bilirubin, 
transaminases and alkaline phosphatases) 
g/ Pulmonary function evaluation 
h/ Evaluation of the musculoskeletal manifestations, 
especially the amplitude of the relevant articulations 
i/ Genital tract symptoms 
- Signed informed consent 
- Absence of contra-indications to the use of ATO 
- Subjects affiliated with an appropriate social security 
system 
- Men must use a medically acceptable method of 
contraception throughout the treatment period and for at 
least 4 months and 10 days following the last treatment 
administration 
 
 


Protocol GMED16-001 – Version 7.0 
 
Page 5 
Studied population 
Inclusion criteria (con’t) 
- Women who are of childbearing potential must have a negative 
serum pregnancy test and agree to use a medically acceptable 
method of contraception throughout the study and for 3 months 
following the end of the study 
- 
Patient not participating or not having participated in a clinical 
study in the 30 days prior to his/her inclusion in the study 
 
Exclusion criteria 
- 
Patient developing acute GvHD (whether early or “late onset” 
form) 
- 
Patients developing overlap GvHD as defined by the 2015 
NIH Working Group Consensus (presence of one or more 
acute GvHD manifestations in a patient with a diagnosis of 
chronic GvHD) 
- 
A “mild” form of chronic GvHD not requiring systemic 
immunosuppressive therapy 
- 
A “moderate” form of chronic GvHD limited to one organ site 
not requiring systemic immunosuppressive therapy 
- 
Patient receiving mycophenolate mofetil 
- 
Second allogeneic stem cell transplant 
- 
Severe cardiac diseases (congestive heart failure (NYHA class 
III), recent myocardial infarction (in the past 6 months before 
the inclusion), histories of unexplained syncope, …) 
- 
Significant 
arrhythmias, 
electrocardiogram 
(EKG) 
abnormalities: 
- 
Congenital QT syndromes 
- 
History or presence of significant ventricular or atrial 
tachyarrhythmia 
- 
Clinically significant resting bradycardia (< 50 beats per 
minutes) 
- 
QTc > 450 msec for men and > 470 msec for women on 
screening EKG (using the QTcF formula) 
- 
Right bundle branch block plus left anterior hemiblock, 
bifascicular block 
- 
Central or peripheral neuropathy 
 
 
 


Protocol GMED16-001 – Version 7.0 
 
Page 6 
 
 
Exclusion criteria (con’t) 
- 
Neutrophils < 0.5 × 109/L 
- 
Platelets < 50 × 109/L 
- 
Potassium ≤ 4 mEq/l* 
- 
Magnesium ≤ 1.8 mg/dl* 
- 
Calcium ≤ 2.15 mmol/l* 
- 
Hepatic impairment due to a suspected or proven liver 
damage, other than direct hepatic cGvHD involvement  
- 
PT < 50% 
- 
Renal impairment (creatinine ≥ 100 µmol/l) 
- 
Uncontrolled systemic infection which in the opinion of the 
investigator is associated with an increased risk of the 
patients’ death within 1 month after the start of therapy 
- 
Severe neurological or psychiatric disorders 
- 
Denied informed consent 
- 
Pregnancy 
- 
Women breastfeeding at selection and throughout the 
treatment period 
 
* If abnormal at selection, to be corrected and re-validated 
following electrolytes infusion, before inclusion and each drug 
perfusion. 
 
 
 
 
 


Protocol GMED16-001 – Version 7.0 
 
Page 7 
Investigational 
product 
Arsenic trioxide 10 mg, concentrate for solution for infusion 1 
mg/mL (aqueous sterile, clear, colorless). 
Arsenic trioxide is administrated either via the marketed 
product named TRISENOX® or the investigational medicinal 
product named ARSCIMED®.  
Patients under TRISENOX® treatment will not switch to 
ARSCIMED® treatment nor vice versa: 
- Patients already recruited and receiving TRISENOX® will 
continue receiving only TRISENOX®  
- All patients recruited after this amendment has been 
approved will receive ARSCIMED® only and not TRISENOX®.  
Treatment scheme 
As soon as the diagnosis of chronic GvHD requiring systemic 
immunosuppressive therapy is confirmed, patients will receive 
in addition to corticosteroids (prednisone) 1 mg/kg/day, with 
or without ciclosporine A, a daily infusion of ATO 0.15 
mg/kg/day on days 1 to 5 (first week), 3 times per week during 
the second week (for example, days 8, 10 and 12), 2 times per 
week during the third week (for example, days 15 and 17) and 
one time during the fourth week (for example, day 24) (the 
latter four weeks represent one cycle). 
ATO should be administered within 10 days of starting 
prednisone at 1mg/kg/day for cGvHD treatment. Follow-up 
dates for response assessment and laboratory tests relate to the 
date of ATO infusion. 
Patients who are in partial response after the 1st cycle of ATO 
will be eligible to receive a second cycle of ATO infusions 
during 4 weeks (similar schedule to first cycle starting around 
day 60). In another word, a delay of 8 weeks to a maximum of 
11 weeks (from the first infusion of ATO) will be observed 
between the two cycles of ATO therapy. 
Response definition is as follows: 
- Complete remission (CR) is defined as complete 
disappearance of any sign of chronic GvHD 
- Partial remission (PR) is defined as improvement of 1 or 
more point on a 4 to 7-point scale or an improvement of 2 or 
more points on a 10 to 12-points scale in at least 1 organ or site 
without progression in any other organ or site. For patients 
with Bronchiolitis Obliterans Syndrome (BOS), an absolute 
improvement in % FEV1 of 10% predicted or more (eg, 50% 
to 60%) is considered a PR as long as the initial % FEV1 is < 
70%. Normalization (≥80%) is considered a CR. 
- Failure is defined as death, recurrent or progressive 
malignancy or the initiation of new systemic treatment for 
chronic GvHD. Increased dosing of existing treatment will not 
be considered as failure. Early failure is defined as failure 
within 2 weeks after the end of the first ATO cycle. 


Protocol GMED16-001 – Version 7.0 
 
Page 8 
Investigational 
product (con’t) 
Indications for secondary systemic treatment of chronic GvHD 
Secondary systemic immunosuppressive treatment or other 
systemic treatment for control of chronic GvHD will be given 
at the discretion of the investigator in consultation with the 
GvHD team. In general, secondary systemic treatment is not 
indicated as long as there is continuing improvement in at least 
one manifestation of chronic GvHD and no progression of any 
other manifestations.  
Study endpoints 
Primary endpoint 
- Evaluation of response rate (complete and partial 
remission) of chronic GvHD at 6 months after diagnosis of 
chronic GvHD and treatment with arsenic trioxide (ATO) 
in combination with prednisone, with or without 
cyclosporine, as first line treatment 
Secondary endpoints 
- Percentage of patients with documented failure free 
survival (FFS), defined as death, recurrent or progressive 
malignancy, or the initiation of a new systemic treatment 
for chronic GvHD 
- Corticosteroids dosage and percentage of reduction in 
corticosteroids dosage at 6 and 12 months after diagnosis of 
chronic GvHD and treatment with ATO as first line 
treatment 
- Cumulative incidence of transplant-related mortality 
(TRM) of infectious and non-infectious origin at 6 and 
12 months after diagnosis of chronic GvHD and treatment 
with ATO as first line treatment 
- OS and PFS at 6 and 12 months after diagnosis of chronic 
GvHD and treatment ATO as first line treatment 
- Descriptive analysis of quality of life parameters at 
inclusion, at 6 and 14 weeks, and at 6, 9 and 12 months after 
diagnosis of chronic GvHD and treatment with ATO as first 
line treatment 
- Tolerability and safety of ATO in combination with 
prednisone, with or without cyclosporine, in patients with 
chronic GvHD after allo-SCT 


Protocol GMED16-001 – Version 7.0 
 
Page 9 
Statistical methods 
Sample size calculation 
Based on results from the literature, the hypothesis for the 
primary endpoint is an improvement in response rate 
(complete and partial remission) at 6 months after the 
diagnosis of chronic GvHD and start of corticosteroids, ATO, 
with or without cyclosporine, from 60% to 85%. Using a one 
step A Hern procedure (and anticipating a dropout rate around 
10%), 24 (21+3) patients are needed (A'Hern RP, 2001). 
If the number of successful cases is 17 or more among the 21 
patients, the hypothesis that the CR rate at 6 months is less 
than 60% is rejected with a target error rate of 0.05 (alpha 
probability). The beta probability in this case is 0.2. 
Statistical analyses 
Every patient included in the study and who has received at 
least one infusion of ATO will be taken into account at time of 
data analysis. A descriptive analysis will be conducted on the 
following parameters: 
- 
Patients and transplant characteristics 
- 
Primary and secondary endpoints 
Patients who do not receive any injection of ATO will not be 
analyzed and will be replaced to obtain 24 patients provided in 
the statistical analysis 
Qualitative data will be described in frequency and percentage 
and will be represented using histograms or diagrams of 
distribution. Quantitative data will be described using the 
calculations of average, standard deviation, median, and 
extreme values. 
The toxicities rate will be calculated and will be given with 
their 95% confidence intervals.  
The probabilities of survival will be estimated by the Kaplan-
Meier method and by calculating the cumulative incidences 
for relapse/progression, and non-relapse mortality incidence.  
 
 


Protocol GMED16-001 – Version 7.0 
 
Page 10 
Study Duration 
The total duration of the study is expected to be 46 months 
(duration of recruitment: 34 months and study duration for a 
considered patient: 12 months). 
Study Calendar 
First patient first visit: September 2016 
Last patient last visit: June 2020 
Database lock: September 2020 
Clinical study Report: November 2020 
 


Protocol GMED16-001 – Version 7.0 
 
Page 11 
LIST OF ABBREVIATIONS 
 
AAN 
Antinuclear Antibody 
AE 
Adverse Event 
Ag 
Antigen 
ALAT/SGPT 
Alanine Amino-Transferase 
Allo-SCT 
Allogeneic Stem-Cell Transplantation 
ANCA 
Antineutrophil Cytoplasmic Antibody 
ANSM 
French National Health Authority 
APC 
Antigen Presenting Cells 
APL 
Acute Promyelocytic Leukemia 
ASAT/SGOT 
Aspartate Amino-Transferase 
ASR 
Annual Safety Report 
ATC 
Anatomic-Therapeutic-Chemical 
Classification 
ATO 
Arsenic Trioxide 
ATRA 
All-trans Retinoic Acid (tretinoin) 
BAFF 
B-cell Activation Factor 
BCR 
B-cell receptor 
BOS 
BSA 
Bronchiolitis obliterans syndrome 
Extent of Skin Involvement 
CBC 
Complete Blood Count 
cGvHD 
Chronic Graft Versus Host Disease 
CIBMTR 
Center for International Blood and 
Marrow Transplant Research 
CMV 
Cytomegalovirus 
CPP 
Protection of Persons Committee 
CR 
CsA 
Complete Remission 
Cyclosporine A 
CTC 
Common Toxicity Criteria 
DIBD 
Development International Birth Date 
DLI 
Donor Lymphocytes Infusion 
DNA 
 
EBMT 
European Society for Blood and 
Marrow Transplantation 
EBV 
Epstein Barr Virus 
ECIL 
European Conference on Infections in 
Leukemia 
e-CRF 
Electronic Case Report Form 
EKG 
Electrocardiogram 
FACT-BMT 
Functional Assessment of Chronic 
Illness Therapy with Bone Marrow 
Transplantation subscale 
FEV 
Forced Expiratory Volume 
FFS 
Failure-free Survival 
FORT 
Free Oxygen Radicals Test 
GCP 
Good Clinical Practice 
GGT 
Gamma Glutamyl-Transferase 


Protocol GMED16-001 – Version 7.0 
 
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GHVD 
Graft Versus Host Disease 
GI 
Gastro-intestinal 
GMP 
Good Manufacturing Practice 
Hep 
Hepatitis 
HLA 
Human Leucocyte Antigen 
HR 
Heart Rate 
HY 
Y-chromosome–encoded 
IB 
Investigator’s Brochure 
ICH 
International Conference on 
Harmonization 
IFN-γ 
Interferon Gamma 
IL  
Interleukine 
IVIG 
Intravenous Immunoglobulin 
LSS 
Lee Symptom Scale 
MedDRA 
 
Medical Dictionary for Regulatory  
Activities 
NIH 
National Institutes of Health 
NRM 
Non-relapse Mortality 
OS 
Overall Survival 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
Progressive Disease 
PDC 
Plasmacytoid Dendritic Cells 
PDGFR 
Platelet-derived growth factor receptor 
PFS 
Progression-free Survival 
PFT 
Pulmonary Function Tests 
PML-RARa 
Promyelocytic Leukemia-retinoic Acid 
Receptor-a 
PR 
Partial Remission 
P-ROM 
PT 
Photographic-range and Motion                
Prothrombin time 
RIC 
Reduced Intensity Conditioning 
ROS 
Reactive Oxygen Species 
SAE 
Serious Adverse Event 
SAR 
Serious Adverse Reactions 
SOP 
Standard Operating Procedure 
SPC 
Summary of Product Characteristics 
TCR 
T-cell receptor 
TNBS 
Trinitrobenzenesulfonic 
Th 
T-helper cell 
TNF- α 
Tumor Necrosis Factor 
TRM 
Transplant-related Mortality 
WHO 
World Health Organization 
 
 
 


Protocol GMED16-001 – Version 7.0 
 
Page 13 
TABLE OF CONTENTS 
 
ADMINISTRATIVE STRUCTURE................................................................................ 1 
SIGNATURE PAGE ............................................................................................................ 2 
SIGNATURE PAGE ............................................................................................................ 3 
PARTICIPATION APPROVAL ...................................................................................... 2 
SYNOPSIS ............................................................................................................................. 3 
LIST OF ABBREVIATIONS .......................................................................................... 11 
TABLE OF CONTENTS .................................................................................................. 13 
1. Study rationale and background ................................................................................ 16 
1.1 
Risk factors and treatment of chronic GvHD......................................................... 16 
1.2 
Pathophysiology of chronic GvHD ............................................................................ 19 
1.3 
Arsenic trioxide .............................................................................................................. 21 
1.4 
Arsenic trioxide for chronic GvHD ........................................................................... 23 
2. Study Objectives ............................................................................................................. 26 
2.1 
Primary Objective ......................................................................................................... 26 
2.2 
Secondary Objectives .................................................................................................... 26 
3. 
Study design ................................................................................................................ 27 
4. 
Patients selection ........................................................................................................ 28 
4.1 
Inclusion criteria ............................................................................................................ 28 
4.2 
Exclusion criteria ........................................................................................................... 29 
4.3 
Withdrawal/premature discontinuation criteria ........................................... 31 
5. 
Study treatment .......................................................................................................... 32 
5.1. 
Description of study treatment ................................................................................... 32 
5.2. 
Labelling and packaging of study treatment .......................................................... 34 
5.3. 
Handling and accountability of study treatment ................................................... 35 
5.4. 
Conditions for storage of study treatment............................................................... 36 
6. 
Concomitant treatments ........................................................................................... 38 
6.1. 
Ciclosporine A ................................................................................................................ 38 
6.2. 
Prednisone ....................................................................................................................... 39 
6.3. 
Preventive treatments for infections ......................................................................... 41 
6.4. 
Prohibited concomitant treatments ........................................................................... 42 
7. 
Study procedures: inclusion procedure, treatment schema and calendar of 
evaluations ............................................................................................................................ 43 
7.1 
Patients selection ............................................................................................................ 45 
7.1.1 
Diagnosis of chronic GvHD ................................................................................................ 45 
7.1.2 
Definition of mild, moderate and severe chronic GvHD........................................... 46 
7.1.3 
Indication for systemic therapy .......................................................................................... 47 
7.2 
Pre-treatment evaluations (1 week before ATO treatment) ............................... 48 
7.3 
Inclusion and treatment plan ...................................................................................... 49 
7.3.1 
Inclusion ..................................................................................................................................... 49 
7.3.2 
Treatment plan ......................................................................................................................... 50 
8. 
Examinations and evaluations ................................................................................ 55 


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8.1. 
Calendar of evaluations ................................................................................................ 55 
8.2. 
Evaluations during treatment with ATO................................................................. 55 
8.3. 
Surveillance post-treatment with ATO .................................................................... 56 
8.4. 
Pharmacokinetic measurement .................................................................................. 58 
9. 
Evaluation criteria ..................................................................................................... 60 
9.1. 
Study endpoints .............................................................................................................. 60 
9.1.1. Primary endpoint ........................................................................................................... 60 
9.1.2. Secondary endpoints ..................................................................................................... 60 
9.2. 
Assessment of chronic GvHD ..................................................................................... 61 
9.3. 
Response criteria ............................................................................................................ 64 
9.4. 
Infections .......................................................................................................................... 67 
9.5. 
Cause of death ................................................................................................................ 67 
10. 
Statistical considerations ..................................................................................... 68 
10.1. 
General considerations ................................................................................................. 68 
10.2. 
Analyses data set ............................................................................................................ 68 
10.3. 
Statistical analyses ......................................................................................................... 68 
10.4. 
Definition of Endpoints ................................................................................................ 69 
10.4.1. 
Efficacy success ................................................................................................................. 69 
10.4.2. 
Efficacy failure ................................................................................................................... 69 
10.4.3. 
Secondary systemic therapy ........................................................................................... 70 
10.4.4. 
Recurrent malignancy ...................................................................................................... 71 
10.5. 
Missing data handling................................................................................................... 72 
10.6. 
Early stopping rules ...................................................................................................... 72 
10.7. 
Calculation of the number of patients ...................................................................... 72 
11. 
Safety Management............................................................................................... 73 
11.1. 
Adverse Events ............................................................................................................... 73 
11.2. 
Reporting Period ............................................................................................................ 73 
11.3. 
Definitions ........................................................................................................................ 74 
11.3.1. 
Definition of an AE........................................................................................................... 74 
11.3.2. 
Abnormal Test Findings .................................................................................................. 75 
11.3.3. 
Definition of a Serious Adverse Event ....................................................................... 75 
11.3.4. 
Hospitalization .................................................................................................................... 76 
11.4. 
Severity Assessment ...................................................................................................... 77 
11.5. 
Causality Assessment .................................................................................................... 78 
11.6. 
Exposure In Utero ......................................................................................................... 79 
11.7. 
Reporting ......................................................................................................................... 81 
11.7.1. 
Reporting Requirements .................................................................................................. 81 
11.7.2. 
Serious Adverse Event Reporting Requirements.................................................... 81 
11.7.3. 
Non-Serious AE Reporting Requirements ................................................................ 82 
11.8. 
Frequent AEs .................................................................................................................. 82 
11.9. 
Safety Committee ........................................................................................................... 85 
11.10. 
Annual Safety Report .............................................................................................. 85 
12. 
Quality Control ...................................................................................................... 86 
12.1. 
Good Clinical Practice .................................................................................................. 86 
12.2. 
Auditing ............................................................................................................................ 86 
12.3. 
Monitoring ....................................................................................................................... 86 
12.4. 
Data management .......................................................................................................... 87 
12.4.1. 
Data entry ............................................................................................................................. 87 
12.4.2. 
Consistency checks ........................................................................................................... 88 
12.4.3. 
Data Coding ......................................................................................................................... 88 


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13. 
Ethical and Regulatory Considerations ........................................................... 89 
13.1. 
Regulatory Authorities Approval (CPP and ANSM) ........................................... 89 
13.2. 
Informed consent ........................................................................................................... 90 
13.3. 
Investigators responsibilities ....................................................................................... 90 
13.4. 
Sponsor responsibilities ................................................................................................ 92 
13.5. 
Biocollections .................................................................................................................. 92 
13.6. 
Insurance............................................................................... Erreur ! Signet non défini. 
13.7. 
Archiving.......................................................................................................................... 93 
13.8. 
Final report and publications rules ........................................................................... 93 
14. 
References ............................................................................................................... 94 
15. 
Appendices .............................................................................................................. 98 
 
Appendix 1: Signs and symptoms of cGvHD ............................................................ 102 
Appendix 2: Organ scoring of cGvHD ...................................................................... 103 
Appendix 3: Genital tract cGvHD assessment and scoring Form ............................. 106 
Appendix 4: Performance Status (WHO) .................................................................. 107 
Appendix 5: Karnofsky Performance Scale Index..................................................... 108 
Appendix 6: Rule of 9s for body surface area ........................................................... 109 
Appendix 7: Drugs reported to prolong QT interval and/or induce torsade de pointes
.................................................................................................................................... 110 
Appendix 8: cGvHD activity assessment Clinician Form A (Lee SJ et al. Biol Blood 
Marrow Transplant, 2015) ......................................................................................... 112 
Appendix 9: cHVHD assessment patient self-report Form B .................................... 118 
Appendix 10 : Lee Symptom Scale ........................................................................... 121 
Appendix 11: FACT-BMT ........................................................................................ 122 
Appendix 12: ATO – Summary of Product Characteristics (version 14-Nov-2016) 125 
Appendix 13: Reporting Form of Serious Adverse Event ......................................... 158 
Appendix 14: Sample of Informed Consent Form ..................................................... 164 
Appendix 15: List of Investigation centers ................................................................ 174 
 
 
 
 
 
 
 


Protocol GMED16-001 – Version 7.0 
 
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1. Study rationale and background 
Chronic Graft-versus-Host Disease (GvHD) is one of the most common and clinically 
significant complication affecting long-term survivors of allogeneic stem cell 
transplantation (allo-SCT). It is estimated that 30% to 70% of patients surviving more 
than 100 days will develop chronic GvHD (Lee and Flowers, 2008). Chronic GvHD is 
the cause of death in up to one third of all long-term survivors after transplantation for 
leukemia (Atkinson et al., 1990). Furthermore, chronic GvHD is consistently associated 
with decreased quality of life (Lee, 2005), impaired functional status, ongoing need for 
immunosuppressive medications and infectious complications. The chronic GvHD 
condition is clinically challenging and corticosteroids remain the only effective therapy. 
 
1.1 
Risk factors and treatment of chronic GvHD 
Despite a global improvement in the outcome of patients undergoing allo-SCT, chronic 
GvHD continues to account for significant morbidity and mortality after allo-SCT. 
Although improvements have been made in the prevention of acute GvHD, these 
advances have not resulted in a concomitant decrease in the incidence of chronic GvHD 
(Lee, et al 2002). On the contrary, the CIBMTR recently reported an increase incidence 
of chronic GvHD in the recent years (Arai et al., 2015). Similarly, we have reported, in 
a single-center retrospective study, that the 5 years cumulative incidence of chronic 
GvHD has significantly increase between the 90’ and the 2000s (Malard et al., 2014). 
This sustained incidence of chronic GvHD is likely related to changes in clinical allo-
SCT practice (Malard et al., 2014). Allo-SCT is used in increasingly older patients, in 
whom the risk for chronic GvHD is greater. The use of unrelated donors and related but 
non HLA identical donors is expanding. Acute and chronic GvHD are larger problems, 
both in incidence and in severity, in recipients of alternative-donor allo-SCT. 


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The use of donor lymphocyte infusion (DLI) to treat relapsed disease or to achieve full 
donor chimerism after non-myeloablative transplantation has also resulted in the 
development of chronic GvHD in a substantial number of such patients. Patients 
receiving allogeneic peripheral blood stem cell transplants have a similar incidence of 
acute GvHD but a higher incidence of chronic GvHD than comparable patients 
receiving marrow grafts (Savani et al., 2016). Finally, used reduced intensity 
conditioning regimen, have been developed in order to reduce transplant-related 
toxicities, compared to classic myeloablative conditioning (Sengsayadeth et al., 2015). 
While, RIC regimens have succeeded to reduced non-relapse mortality, the incidence 
of chronic GvHD is not lower after RIC compared to myeloablative conditioning (Socie 
and Ritz, 2014). For these reasons, the number of patients with chronic GvHD continues 
to grow, and prevention or treatment of chronic GvHD must be considered one of the 
major obstacles still facing the field of blood and marrow transplantation. 
 
Despite improvement in supportive care, most of chronic GvHD patients continue to 
have poor clinical function and altered quality of life. None of the present therapies for 
chronic GvHD (cGvHD) are successful in the majority of patients. Standard first line 
systemic treatment for cGvHD is orally administered corticosteroids (prednisolone 1 
mg/Kg) and ciclosporine (Wolff et al., 2010). Over the past 10 years, alternative 
methods for the treatment of established chronic GvHD have been studied. Without 
treatment, less than 20% of patients with extensive chronic GvHD survive with 
Karnofsky 
performance 
scores 
>70%. 
On 
the 
other 
hand, 
long-term 
immunosuppressive treatment is generally required to control the disease (Lee and 
Flowers, 2008). Stewart et al. reported that the median duration of immunosuppressive 
treatment (corticosteroids + ciclosporine) was 23 months (Stewart et al., 2004). 
Interestingly, treatment was prolonged in patients who received peripheral blood stem 
cell transplant, in male patients with female donors and in those with HLA mismatched 
donors (Stewart et al., 2004). 


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Furthermore, in a randomized trial of immunosuppressive therapy for chronic GvHD, 
Koc et al. (Koc, et al 2002) reported the median duration of therapy with corticosteroids 
and ciclosporine was 1.6 years (range 0.3-8.2 years). The study further illustrated the 
difficulty in coming off all immunosuppression in chronic GvHD therapy. Despite dual 
immunosuppressive therapy, only 54% of patients were successfully weaned from 
immunosuppressive medications at 5 years and mortality directly attributable to chronic 
GvHD was 17% in the combination immunosuppressive arm. Finally, in this trial, 
addition of ciclosporine to corticosteroids was associated with a reduction in 
corticosteroid related morbidity, the incidence of avascular necrosis was 13% in the 
corticosteroids + ciclosporine arm compared to 22% in patients receiving 
corticosteroids alone (Koc, et al 2002). 
 
Thus, treatment of this major complication remains a challenging issue that requires 
new and innovative approaches (Pavletic, et al 2006a). Attempts to identify novel 
agents or strategies to improve initial therapy for chronic GvHD have not improved on 
the combination of corticosteroids and a calcineurin inhibitor (Arora et al., 2001; Martin 
et al., 2009; Wolff et al., 2010). In addition, strategies to reduce the incidence of chronic 
GvHD have not reproducibly had beneficial effects. Failure to improve chronic GvHD 
prophylaxis and therapy can be partly attributed to an incomplete understanding of the 
pathophysiology of chronic GvHD. 
 
Therefore, whether it is in the standard myeloablative allo-SCT setting or in the RIC 
allo-SCT setting, it is clear that advances in the therapy of chronic GvHD (a total of 
1700 allo-transplants are performed every year in France with RIC allo-SCT 
representing >50% of all cases) are urgently required. Therapy with corticosteroids is 
often unrewarding and the toxicities from prolonged corticosteroid administration are 
great. With this steroid toxicity in mind, we believe that clinically meaningful endpoints 
for phase II testing of promising chronic GvHD drugs, may be whether their addition 
to high-dose corticosteroids would enable a higher response rate and successful 
corticosteroid taper. 
 
 


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1.2 
Pathophysiology of chronic GvHD 
Chronic GvHD emerges from alloreactive processes between donor-derived immune 
cells and host cell populations. While its pathophysiology is still poorly understood in 
contrast to that of acute GvHD, it is now evident that the clinical manifestations of 
cGvHD are the result of a highly complex immune pathology involving donor B cells 
and T cells as well as other cells. 
Regarding B cells, it has been recognized since the early description of the disease that 
patients with cGvHD frequently have circulating antibodies that are reactive with 
recipient cells (Shimabukuro-Vornhagen et al., 2009). Two classes of recipient-reactive 
antibodies have been associated with cGvHD. The first class includes antibodies 
directed against antigens in the recipient that are not present in the donor. Antibodies 
directed against Y-chromosome–encoded (HY) proteins that develop in male patients 
who receive stem cell grafts from female donors exemplify this class of allo-antibodies. 
HY antibodies have been detected in more than 80% of patients with chronic GvHD 
but only in male recipients who had female donors (Miklos et al., 2005; Miklos et al., 
2004; Zorn et al., 2004). HY antibodies very seldom develop in male recipients who 
have male donors. Anti-HY antibodies can be detected as soon as 3 months post-
transplantation and seem to predict the subsequent development of chronic GvHD 
(Nakasone et al., 2015). Most studies of allo-antibodies have focused on HY antigens 
because male recipients who have female donors are relatively common compared with 
mismatches for autosomal epitopes. Nevertheless, antibodies specific for alloantigens 
derived from autosomal disparities have also been identified. 
 
Antibodies directed against nonpolymorphic autoantigens represent a second class of 
antibodies frequently present in patients with chronic GvHD. For example, antibodies 
specific for platelet-derived growth factor receptor (PDGFR) have been described in 
patients with systemic sclerosis and chronic GvHD (Baroni et al., 2006; Svegliati et al., 
2007). 


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These antibodies recognize native PDGFR, induce tyrosine phosphorylation and 
accumulation of reactive oxygen species (ROS), and stimulate type 1 collagen gene 
expression through the Ha-Ras-ERK1/2-ROS signaling pathway. The biologic activity 
of these autoantibodies thus suggests a role in the development of fibrosis. In addition 
to antibody production, accumulating evidence suggests that B cells contribute to the 
immune response by antibody-independent mechanisms such as antigen presentation, 
by production of cytokines and chemokines, and by acting as regulatory cells 
(Shimabukuro-Vornhagen et al., 2009). Low B-cell counts and increased risk of 
infections have long been recognized in patients with chronic GvHD. As in 
autoimmune diseases, distortion of normal B-cell homeostasis exists in chronic GvHD 
(Corre et al., 2010; Kuzmina et al., 2011; Sarantopoulos et al., 2007; Sarantopoulos et 
al., 2009). Patients with chronic GvHD have increased B-cell activation factor 
(BAFF)/B-cell ratios, delayed reconstitution of naive B cells, and increased numbers of 
pre-germinal center B cells. High levels of BAFF in the presence of low numbers of 
naive B cells have been proposed to foster the survival of activated alloreactive and 
autoreactive B cells, resulting in immune pathology (Sarantopoulos et al., 2007).  
Donor T cells also clearly play an important role in the immune pathology of chronic 
GvHD. In humans, in vivo T-cell depletion is the only prophylactic measure that 
effectively decreases the incidence of cGvHD. Although early experimental studies 
have supported the paradigm of acute GvHD being a T-helper cell 1 (Th1) process and 
chronic GvHD being a T-helper cell 2 (Th2) process (Coghill et al., 2011), this old 
concept has been revisited, and recent data in humans suggest that Th1 (TC1)-Th17 
responses are present in skin GvHD. The immune response occurring in chronic 
lichenoid GvHD showed a mixed Th1/Th17 signature with upregulated Th1/Th17 
cytokine/chemokine transcripts and elevated numbers of interferon gamma– and 
interleukin 17 (IL-17) –producing CD8+ T cells (Bruggen et al., 2014). Patients with 
active chronic GvHD also have a lower frequency of CD4+ regulatory T cells (Tregs) 
when compared with patients without chronic GvHD (Bruggen et al., 2014; Matsuoka 
et al., 2010; Zorn et al., 2005). 


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The role of antigen presenting cells (APC) in chronic GvHD have also been recently 
emphasized by the observation that costimulation of donor T cells through CD80 or 
CD86 on either host or donor APC is necessary to induce chronic GvHD (Anderson et 
al., 2005). In particular, plasmacytoid dendritic cells (PDC) are involved in the 
pathophysiology of chronic GvHD, because the adoptive transfer of mature PDC 
exacerbate chronic GvHD, and they can stimulate donor T cells to trigger chronic 
GvHD in the absence of other APC (Koyama et al., 2009). 
 
Thus, data in humans support a role of both T and B cells in a highly complex network 
leading to chronic GvHD. How these T- and B-cell networks interact has not been 
resolved.  
 
1.3 
Arsenic trioxide 
Arsenic derivatives have been identified as compounds with therapeutic potential for 
over 2000 years in Greek and Chinese medicine. In the 1990s, researchers from China 
demonstrated complete clinical remissions in approximately 66% of patients with acute 
promyelocytic leukemia (APL) who received arsenic and a survival rate of 60% at 7 
years (Zhang et al., 2000). At the same time, it was demonstrated that arsenic trioxide 
(As2O3 [ATO]) induced apoptosis in APL cells, interpreted as being through 
modulation of the promyelocytic leukemia-retinoic acid receptor-a (PML-RARa) 
fusion protein (Chen et al., 1996). The combination of ATO and oral all-trans retinoic 
acid (tretinoin [ATRA]) currently constitutes the standard of care for most patients with 
newly diagnosed and/or relapsed APL (de The et al., 1990). The use of ATO has also 
been explored in many other hematologic malignancies (Falchi et al., 2015) and in solid 
tumors (Subbarayan and Ardalan, 2014). 


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ATO has been initially investigated in 52 APL patients, previously treated with an 
anthracycline and a retinoid regimen, in two open-label, single-arm, non-comparative 
studies (Soignet et al., 2001; Soignet et al., 1998). One was a single investigator clinical 
study (n=12) and the other was a multicenter, 9-institution study (n=40). Patients in the 
first study received a median dose of 0.16 mg/kg/day of ATO (range 0.06 to 0.20 
mg/kg/day) and patients in the multicenter study received a fixed dose of 0.15 
mg/kg/day; ATO was administered intravenously over 1 to 2 hours until the bone 
marrow was free of leukaemic cells, up to a maximum of 60 days. Patients with 
complete remission received consolidation therapy with ATO for 25 additional doses 
over a 5 weeks period. Consolidation therapy began 6 weeks (range, 3-8) after induction 
in the single institution study and 4 weeks (range, 3-6) in the multicenter study. 
Complete remission rate were 92% and 85% in the single center and the multicenter 
study respectively. These results led to the approval of ATO for induction of remission 
and consolidation in adult patients with relapsed/refractory APL by the European 
Medicines Agency. ATO must be administered intravenously at a fixed dose of 0.15 
mg/kg/day, given daily until the bone marrow remission is achieved (up to 50 days). 
Consolidation treatment must begin 3 to 4 weeks after completion of induction therapy. 
ATO is to be administered intravenously at a dose of 0.15 mg/kg/day for 25 doses given 
5 days per week, followed by 2 days interruption, repeated for 5 weeks. 
 
Arsenic Trioxide has been further evaluated for first line treatment of APL. A phase 3 
multicenter trial compared ATRA + ATO (n=77), versus ATRA + chemotherapy 
(n=79) (Lo-Coco et al., 2013). ATO was administered intravenously at a fixed dose of 
0.15 mg/kg/day, daily until complete remission (up to 60 days). Four courses of ATO 
consolidations were administered at 0.15 mg/kg/day, 5 days a week, 4 weeks on, 4 
weeks off. Complete remission was achieved in all 77 patients in the ATRA–arsenic 
trioxide group who could be evaluated (100%) and in 75 of 79 patients in the ATRA–
chemo- therapy group (95%) (P=0.12). 


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The ATRA + chemotherapy combination results in more frequent prolongation of 
cytopenias, mucositis, and infections, whereas the ATRA + ATO combination results 
in more frequent prolongation of the QTc interval and liver-function abnormalities. 
 
As concerning its toxicity profile, ATO is usually well tolerated and its use is associated 
with a series of manageable adverse events including hyperleucocytosis, the APL 
differentiation syndrome, prolongation of the QT interval, peripheral neuropathy, mild 
myelosuppression, hyperglycemia and hypokalemia (Sanz et al., 2005). Of these, QT 
prolongation and, particularly, the so-called APL differentiation syndrome are the most 
serious ones as they can evolve into severe and potentially fatal ventricular arrhythmias 
(torsade de points) or respiratory failure, respectively. The APL differentiation 
syndrome is specific to APL as indicated by his name. Severe QT prolongation leading 
to fatal torsade de points has been reported in patients treated with locally formulated 
arsenic but never with arsenic trioxide used in clinical trials during post-marketing 
surveillance (Sanz et al., 2005; Unnikrishnan et al., 2001; Westervelt et al., 2001). 
However, stringent monitoring of serum electrolyte levels (K+ and Mg++) is 
recommended during therapy with ATO to minimize the risk of severe arrhythmias, 
particularly in patients receiving concomitant drugs that induce hypokalemia or 
hypomagnesemia.  
 
1.4 
Arsenic trioxide for chronic GvHD 
The role of ATO has also been explored in murine models of autoimmune and 
autoinflammatory diseases. MRL/lpr mice develop a human lupus-like syndrome and, 
as in autoimmune lymphoproliferative syndrome, massive lymphoproliferation due to 
Fas-mediated apoptosis. In this model, mice developed cutaneous lesions, 
hypergammaglobulinemia and high levels of autoantibodies, including anti-DNA 
antibodies. Administration of ATO is able to achieve quasi-total regression of antibody- 
and cell-mediated manifestations in MRL/lpr mice (Bobe et al., 2006). 


Protocol GMED16-001 – Version 7.0 
 
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ATO eliminated, through activation of caspases, activated autoreactive T lymphocytes 
responsible for lymphoproliferation and skin, lung and kidney lesions, leading to 
significant prolonged survival rates. ATO also markedly reduced anti-DNA 
autoantibodies, rheumatoid factor, Interleukine IL-18, interferon gamma (IFN-γ), nitric 
oxide metabolite, Tumor necrosis factor alpha (TNF-α), Fas ligand, and IL-10 levels. 
Furthermore, ATO restored cellular reduced glutathione levels, thereby limiting the 
toxic effect of nitric oxide overproduced in MPR/lpr mice. Overall, ATO protected 
young mice from developing the syndrome and induced almost total disease 
disappearance in older affected mice. 
 
Similarly, ATO has been evaluated in a TNBS-induced colitis model of inflammatory 
bowel disease (Singer et al., 2011). In this model, ATO used either in a preventive or 
curative mode markedly reduced the induced colitis, leading to prolonged mice 
survival. In addition, ATO was able to inhibit NF-κB expression and DNA-binding in 
colon extracts, leading to decreased cytokine gene expression (i.e. TNFα, IL-1β, IL-12, 
IL-17, IL-18 and IL-23). Furthermore, ATO reduced nitric oxide synthase and highly 
enhanced procaspase-3 and activated caspase-3, leading to neutrophil elimination. 
 
ATO has also proven to be effective in a murine model of systemic sclerosis, another 
autoimmune disease (Kavian et al., 2012b). In this model, ATO inhibited the production 
of autoantibodies and was associated with a clinical benefit, as shown by the reduced 
skin and lung fibrosis. These beneficial effects were mediated through reactive oxygen 
species (ROS) generation that selectively killed activated pathogenic fibroblast 
containing low levels of glutathione. 
 
Chronic GvHD presents clinical features that mimic autoimmune diseases such as 
systemic sclerosis, lupus erythematosus or Sjögren syndrome, and autoimmune-like 
manifestations are a defining characteristic of cGvHD. The effectiveness of ATO in 
murine models of autoimmune disease has prompted evaluation of ATO in murine 
model of chronic GvHD (Kavian et al., 2012a). 


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Sclerodermatous chronic GvHD was induced in BALB/c mice by body irradiation, 
followed by B10.D2 bone marrow and spleen cell transplantation. Mice were 
simultaneously treated with daily intra-peritoneal injections of ATO. While 
transplanted mice displayed severe clinical symptoms (diarrhea, alopecia, vasculitis, 
and fibrosis of the skin and visceral organs), the symptoms were dramatically abrogated 
in mice treated with ATO. Treatment with ATO was associated with a decrease 
percentage of CD4+ T cells and PDC. Furthermore, IL-4, a Th2 related cytokine and 
IL-17, a Th17 related cytokine and autoantibodies were significantly reduced in mice 
treated with ATO. These beneficial effects were mediated through the depletion of 
glutathione and the overproduction of H2O2 that killed activated CD4+ T cells and 
PDC. 
 
From the above studies, it appears that ATO is administered routinely and safely to 
patients with hematologic malignancies. The effectiveness of ATO in human APL 
patients and in the mice models of autoimmune diseases have in common targeting of 
the cells involved in these different diseases by inducing their apoptosis. In a murine 
model of chronic GvHD, ATO effect was mediated through the depletion of glutathione 
and the overproduction of H2O2 that killed activated CD4+ T cells, in particular Th17 
cells, and PDC, two key cells in chronic GvHD pathophysiology initiation. 
Furthermore, autoantibody production was also inhibited by ATO in this model, 
suggesting that ATO also trigger B cells mediated chronic GvHD. 
 
This leads to the hypothesis that ATO delivered early at diagnosis of chronic GvHD 
will be an effective treatment. To test this hypothesis, we propose this study of ATO in 
combination with ciclosporine-A and corticosteroids as first line therapy for newly 
diagnosed chronic GvHD after allo-SCT. We hypothesize the addition of ATO to 
prednisone and ciclosporine-A for the initial treatment of chronic GvHD will increase 
the overall response rate, and enable a more rapid and effective corticosteroids taper.  
 
 


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2. Study Objectives 
2.1 
Primary Objective 
The primary objective is to improve the response rate (complete and partial remission) 
at 6 months after diagnosis of chronic GvHD and treatment with arsenic trioxide (ATO) 
in combination with prednisone with or without ciclosporine as first line treatment. 
 
2.2 
Secondary Objectives 
The secondary objectives are: 
- To evaluate failure-free survival (FFS), defined as death, recurrent or progressive 
malignancy, or initiation of a new systemic treatment for chronic GvHD 
- To decrease non-relapse mortality (NRM) of infectious and non-infectious origin 
- To improve overall survival (OS) and progression-free survival (PFS) 
- To spare patients from long-term use of corticosteroids (and their long-term side 
effects) 
- To improve quality of life self-reported by patient using the Lee Symptom Scale (LSS) 
and Functional Assessment of Chronic Illness Therapy with Bone Marrow 
Transplantation subscale (FACT-BMT) 
- To evaluate tolerability and safety of ATO in combination with prednisone, with or 
without ciclosporine, in patients with chronic GvHD after allo-SCT 
 
 


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3. 
Study design 
This is a prospective, national, multicenter, non-randomized Phase II study that will 
include a total number of 24 patients. 
The duration of participation planned is as follows: 
- Duration of recruitment: 34 months 
- Study duration for a considered patient: 12 months 
- Total duration of the study: 46 months 
 
Several visits are scheduled in the study as follows: 
- 
At the time of diagnosis for the screening visit 
- 
Follow-up visits to be performed every week during ATO treatment 
- 
Follow-up visits to be performed every 2 weeks from second to third 
month of ATO treatment 
- 
Follow-up visits to be performed every month from the fourth to sixth 
month of ATO treatment 
- 
Follow-up visits to be performed every 3 months: at 9 months and 
12 months (final visit) 
Arsenic trioxide is administrated either via the marketed product named TRISENOX® or 
the investigational medicinal product named ARSCIMED® (Cf. section 5 for more detail).  
 
  
 


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4. 
Patients selection 
4.1 
Inclusion criteria 
Patient will be eligible for inclusion in this study if the patient met all the following 
criteria: 
- 
Adult patients (≥18 years) who have received a first allogeneic stem cell 
transplantation for a hematological disease (any source of hematopoietic stem 
cells is authorized; any category of conditioning regimen prior to allo-SCT is 
authorized; any type of stem cell donors is authorized) 
- 
Confirmed diagnosis of first episode of chronic GvHD requiring systemic 
immunosuppressive therapy (any prior GvHD prophylaxis previously used is 
accepted). Chronic GvHD diagnosis is defined according to the National 
Institutes of Health (NIH) Working Group Consensus. Chronic GvHD 
diagnosis will be based on the evaluation of the severity of the different clinical 
manifestations including: 
 a/ Performance status evaluation 
 b/ Cutaneous evaluation measured by the percentage of extension or the 
presence of sclerotic features. If relevant, confirmation with a biopsy should 
be performed whenever possible 
c/ Oral symptoms 
d/ Ocular symptoms 
e/ Gastro-intestinal symptoms 
f/ Evaluation of liver involvement (total bilirubin, transaminases and alkaline 
phosphatases) 
g/ Pulmonary function evaluation 
h/ Evaluation of the musculoskeletal manifestations, especially the amplitude 
of the relevant articulations 
i/ Genital tract symptoms 
- 
Signed informed consent (see Appendix 14) 
- 
Absence of contra-indications to the use of ATO 


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- 
Subjects affiliated with an appropriate social security system 
- 
Men must use a medically acceptable method of contraception throughout the 
treatment period and for at least 4 months and 10 days following the last 
treatment administration 
- 
Women who are of childbearing potential must have a negative serum 
pregnancy test and agree to use a medically acceptable method of contraception 
throughout the study and for 3 months following the end of the study 
- 
Patient not participating or not having participated in a clinical study in the 30 
days prior to his/her inclusion in the study 
 
4.2 
Exclusion criteria 
Patients fulfilling ONE or MORE of the following criteria will not be included in the 
study: 
- 
Patient developing acute GvHD (whether early or “late onset” form) 
- 
Patients developing overlap GvHD as defined by the 2015 NIH Working Group 
Consensus (presence of one or more acute GvHD manifestation in a patient with 
a diagnosis of chronic GvHD) 
- 
A “mild” form of chronic GvHD not requiring systemic immunosuppressive 
therapy 
- 
A “moderate” form of chronic GvHD limited to one organ site not requiring 
systemic immunosuppressive therapy 
- 
Patient receiving mycophenolate mofetil 
- 
Second allogeneic stem cell transplant 
- 
Severe cardiac diseases (congestive heart failure (NYHA class III), recent 
myocardial infarction (in the past 6 months before the inclusion), histories of 
unexplained syncope, …) 
 
 


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- 
Significant arrhythmias, EKG abnormalities: 
 
- Congenital QT syndromes 
 
- History or presence of significant ventricular or atrial tachyarrhythmia 
 
- Clinically significant resting bradycardia (<50 beats per minutes) 
 
- QTc > 450 msec for men and > 470 msec for women on screening 
EKG (using the QTcF formula, in Section 11.8) 
 
- Right bundle branch block plus left anterior hemiblock, bifascicular 
block 
- 
Central or peripheral neuropathy 
- 
Neutrophils < 0.5 × 109/L 
- 
Platelets < 50 × 109/L 
- 
Potassium ≤ 4 mEq/l* 
- 
Magnesium ≤ 1.8 mg/dl* 
- 
Calcium ≤ 2.15 mmol/l* 
- 
Hepatic impairment due to a suspected or proven liver damage, other than 
direct hepatic cGvHD involvement  
- 
PT < 50% 
- 
Renal impairment (creatinine ≥ 100 µmol/l) 
- 
Uncontrolled systemic infection which in the opinion of the investigator is 
associated with an increased risk of the patients death within 1 month after the 
start of therapy 
- 
Severe neurological or psychiatric disorders 
- 
Denied informed consent 
- 
Pregnancy 
- 
Women breastfeeding at selection and throughout the treatment period 
* If abnormal at selection, to be corrected and re-validated following electrolytes 
infusion, before inclusion and each drug perfusion. 
 
 


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4.3 
Withdrawal/premature discontinuation criteria 
A premature discontinuation is defined when a patient selected in a study ceases his/her 
participation before the end of study. 
The criteria for premature discontinuation of the study are: 
- 
Withdrawal of informed consent 
- 
Lost to follow-up 
- 
Occurrence of AE/SAE 
- 
Inclusion criteria not met requiring premature discontinuation 
- 
Protocol deviation 
- 
Other reason 
Patients who do not receive any injection of ATO will not be analyzed and will be 
replaced to obtain the total 24 patients required in the statistical analysis. 
 
 


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5. 
Study treatment 
5.1.Description of study treatment 
Arsenic trioxide (ATO) is administrated either via a marketed product, i.e. TRISENOX®, 
or an Investigational Medicinal Product, i.e. ARSCIMED®.  
TRISENOX® was administered to patients from the start of the clinical trial. ARSCIMED® 
will be administered to patients included in the clinical trial after approval from the 
ANSM for its use in this clinical trial. Patients under TRISENOX® treatment will not 
switch to ARSCIMED® treatment nor vice versa. 
- All patients already included in the trial and who received TRISENOX® will continue 
with TRISENOX® until completion of their participation in the clinical trial.  
- All patients recruited after this amendment has been approved will receive 
ARSCIMED® only and not TRISENOX®.  
TRISENOX® and ARSCIMED® have the same active substance, excipients, dosage form 
and route of administration (Summary of Product Characteristics (Trisenox)) and 
Investigator brochure (ARSCIMED®) for details) and are considered equivalent. The 
decision in switching to ARSCIMED® during the clinical trial is based on the fact that the 
availability of ARSCIMED®, treatment being developed by MEDSENIC in the 
population included in this trial, will avoid repeated and further impact on recruitment 
in the study related to any further supply disruptions of TRISENOX®, as it occurred in 
2014 and again in 2017.  
Both formulations (TRISENOX® and ARSCIMED®) are adjusted to pH 8 with dilute 
hydrochloric acid. Whereas TRISENOX® is manufactured by TEVA and supplied as a 
glass ampoule; ARSCIMED® is manufactured by IRPF1-Toulouse and supplied as a glass 
vial. Further information on ARSCIMED® is available in the Investigational Medical 
Product Dossier of this product.  
 
 
 
1 Institut de Recherche Pierre Fabre 


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The investigational medication has the following characteristics: 
- 
ATC code: L01XX27 
- 
Pharmacotherapeutic group: other antineoplastic agents 
- 
Form/Presentation: concentrate for solution for intravenous infusion / 1 mg/1 
mL / 10 mL  
- 
Excipients: sodium hydroxide,  hydrochloric acid as pH adjuster and water for 
injections  
- 
Administration:  
   
 - 0,15 mg/kg/infusion on days 1 to 5 (first week), 3 times per week 
during the second week (for example, days 8, 10 and 12), 2 times per 
week during the third week (for example, days 15 and 17) and one time 
during the fourth week (for example, day 24), in addition to ciclosporine 
A (if relevant) and corticosteroids. The latter four weeks represent one 
cycle of 11 administrations. 
- Must be administered intravenously over 1-2 hours. The infusion 
duration may be extended up to 4 hours if vasomotor reactions are 
observed. A central venous catheter is not required. Patients must be 
hospitalized at the beginning of treatment due to ensure adequate 
monitoring. 
- Aseptic technique must be strictly observed throughout handling of 
ATO since no preservative is present. 


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- Must be diluted with 100 to 250 mL of glucose 50 mg/mL (5%) 
solution for injection or sodium chloride 9 mg/mL (0.9%) solution for 
injection immediately after withdrawal from the ampoule for single use 
only. Unused portions of each ampoule must be discarded properly. 
Unused portions for later administration must not be saved. 
- Must not be mixed with or concomitantly administered in the same 
intravenous line with other medicinal products.  
- The diluted solution must be clear and colorless. All parenteral 
solutions must be inspected visually for particulate matter and 
discoloration prior to administration. The preparation must not be used 
if foreign particulate matter is present.  
- Should be administered within 10 days of starting prednisone at 
1mg/kg/day for cGvHD treatment. Treatment with persistent prednisone 
(or equivalent) at doses lower than 1 mg/kg/day at the time of enrollment 
is allowed (i.e patient was treated for acute GvHD with prednisone and 
developed evolving chronic GvHD). 
- A delay of 8 weeks to a maximum of 11 weeks (from the first infusion 
of ATO) will be observed between the two cycles of ATO therapy.  
 
5.2.Labelling and packaging of study treatment 
 
Packaging and labeling will be in accordance with Good Manufacturing Practice 
(GMP) for clinical trials.  
• ATO (TRISENOX®) is a commercial product with a marketing authorization for 
a type of acute myeloid leukaemia called acute promyelocytic leukaemia (APL). 
At each inclusion of a patient in the study, ATO (TRISENOX®) will be bought by 
the central pharmacy of the hospital. One box contains 10 ampoules containing 
10 mL of a sterile, clear, colorless solution (1 mg arsenic trioxide/1 mL). At 
reception of product by the central pharmacy of the hospital, the boxes will be 
identified by labels which will include the information required in the Annex 
13 of the Volume 4 of "The rules governing medicinal products in the European 
Union" (current EU GMP practices). 


Protocol GMED16-001 – Version 7.0 
 
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• ATO (ARSCIMED®) will be sent by the manufacturer on behalf of the Sponsor 
to the central pharmacy of the hospital at each inclusion of a patient in the 
study. One box contains 11 vials containing 10 mL of a sterile, clear, colorless 
solution (1 mg arsenic trioxide/1 mL). No identification of boxes by labels is 
performed at reception of the product because labeling is already ensured by 
the manufacturer in accordance with the Annex 13 of the Volume 4 of "The 
rules governing medicinal products in the European Union" (current EU GMP 
practices). 
• The traceability of the therapeutic units will be ensured by the standard 
procedures of the pharmacy and the management of product will be monitored 
regularly. 
• Depending on the patient weight and the number of cycles, the number of vials 
required will be 11, 22 or 44. 
• TRISENOX® and ARSCIMED® must not be used beyond expiration date printed 
on the label.  
 
5.3.Handling and accountability of study treatment 
At each inclusion of a patient in the study, ATO (TRISENOX®) will be bought by the 
central pharmacy of the hospital concerned with a medical prescription written by the 
principal investigator. Once introduced in the study and at each inclusion of a patient 
in the study, ATO (ARSCIMED®) will be provided to the central pharmacy of the hospital 
by the IRPF (Institut de Recherche Pierre Fabre, manufacturer mandated by the 
sponsor). 
The investigator and the study site are responsible for investigational product 
accountability. To this end, it is assumed that all clinical study supplies will be delivered 
to and by the responsibility of a suitably qualified and authorized person such as a 
hospital pharmacist, who will document drug disposition and accountability for the 
duration of the study. 
 


Protocol GMED16-001 – Version 7.0 
 
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Investigators and pharmacists should note that the clinical study supplies may only be 
used for the clinical study for which they are indicated. They must not be employed for 
any other study or for any other clinical use.  
Except for ATO, the investigational drug, all other drugs used in this study will be taken 
from the normal stocks of each participating centre. 
Inventory records must be readily available and must include at least the following 
information: quantities, dates, batch number, expiration date, study code number, and 
patient identification numbers. 
In the context of this study, the preparation of ATO, the packaging, the labelling and 
batch release will be undertaken by the pharmacy of each participating centre.  
ATO (ARSCIMED®) will be provided to the clinical site as already packaged, labeled 
and released. 
All unused and/or partially used study drugs will be kept by the central pharmacy of 
the hospital concerned upon completion or termination of the study at the latest. At the 
study end, the unused vials will be collected by a provider designated by the Sponsor.  
 
5.4.Conditions for storage of study treatment 
TRISENOX® and ARSCIMED® will be stored in a secure location at 25°C (77°F); 
excursions will be permitted to 15-30°C (59-86°F), but TRISENOX® must not be frozen 
and ARSCIMED® must not be refrigerated or frozen.  
After dilution of TRISENOX® in intravenous solutions, ATO is chemically and 
physically stable for 24 hours at 15-30°C and 48 hours at refrigerated (2-8°C) 
temperatures. From a microbiological point of view, the product must be used 
immediately. If not used immediately, in-use storage times and conditions prior to use 
are the responsibility of the user and would normally not be longer than 24 hours at 2-
8°C, unless dilution has taken place in controlled and validated aseptic conditions. 
After dilution of ARSCIMED® in intravenous solutions, ATO is chemically and 
physically stable for 4 hours at 15-25°C. The product must not be stored at refrigerated 
(2-8°C) temperatures after dilution since its stability under these conditions has not 
been studied yet. From a microbiological point of view, the product must be used 


Protocol GMED16-001 – Version 7.0 
 
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immediately. 


Protocol GMED16-001 – Version 7.0 
 
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6. 
Concomitant treatments 
6.1.Ciclosporine A  
➢ Ciclosporine A will be delivered using local standard criteria, (if relevant). 
However:  
- 
Ciclosporine level should lie within the therapeutic range (i.e. 200-400 ng/mL): 
to harmonize CsA target levels 
- 
Ciclosporine-induced renal insufficiency should lead to dose adjustment and 
even temporary withdrawal of the drug 
 
➢ Suggested guidelines for initial dose of Ciclosporine A: 
Oral administration of ciclosporine should continue for patients who are being 
treated with ciclosporine at the time of enrolment, or if it is relevant, the 
administration should commence initially at 6mg/kg daily. 
 
➢ Monitoring of ciclosporine level: 
- 
Concentrations of ciclosporine in the plasma may be monitored at the discretion 
of the investigator. Dose adjustments may be made to maintain ciclosporine 
concentrations at 200-400 ng/ml. Monitoring may be especially helpful in 
patients with renal impairment and in patients being treated with medications 
that may affect the concentration of ciclosporine. 
- 
Medications that could increase the concentration of ciclosporine include 
diltiazem, nicardipine, verapamil, metoclopramide, ketoconazole, fluconazole, 
itraconazole, erythromycin and methylprednisolone.  
- 
Medications that could decrease the concentration of ciclosporine include 
rifampycin, phenytoin, phenobarbital and carbamazepine. 
 
 


Protocol GMED16-001 – Version 7.0 
 
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➢ Deviations from guidelines for administration of ciclosporine 
Deviations from the above guidelines may be made at the discretion of the 
investigator in consultation with the transplant centre. Toxicity associated with 
the administration of ciclosporine may require dose adjustments, which should 
be managed according to individual transplant centre practice. 
 
6.2.Prednisone 
➢ The initial dose of prednisone is 1.0 mg/kg/day, this dose should be maintained 
for 2 weeks, after which a tapering schedule should commence up until 
response assessment at 6 weeks, after which treatment is as follows: 
• CR: continue tapering of Prednisone dose (see Table below)  
• No CR: maintain Prednisone dose at 1 mg/kg/day on alternate days or 0.5 
mg/kg/day every day 
Usual prevention of steroid-induced gastro-intestinal (GI) side effect should be 
given (omeprazole or other drugs, according to local practice). 
➢ The investigator will determine the regimen for administration of prednisone 
after enrolment in the study. The following taper schedule is given as a general 
guideline:  


Protocol GMED16-001 – Version 7.0 
 
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Table 1 : Prednisone Taper Schedule  
Week 
Dose (mg/kg actual body weight/day) 
0 
1.0 qod 
2 
0.75 qod 
4 
0.65 qod 
6 
0.50  qod (if CR, continued tapering of 
corticosteroids dose) 
 0.50  qod (if No CR, maintain this dose until 
resolution of all reversible clinical 
manifestations or adjust the required dose) 
8 
0.40 qod 
10 
0.30 qod 
12 
0.20 qod 
14 
0.15 qod 
20 
0.0 
 
• 
 The investigator should examine the patient before each reduction in the dose 
of prednisone. If there is exacerbation or recurrence of chronic GvHD at any 
step of the taper, the dose of prednisone should be increased by 2 levels with 
daily administration for 2-4 weeks, followed by resumption of alternate day 
administration. Prednisone may be discontinued after 2 weeks of treatment at a 
dose of 0.15 mg/kg every other day. Qod prednisone dosing is not required, and 
the use of qod dosing is at the discretion of the investigator. It is suggested, but 
not required, that patients taper off steroids before tapering of other 
immunosuppressive medications.  
• 
Toxicity associated with the administration of prednisone should be managed 
according to individual transplant center practice.  
 
 


Protocol GMED16-001 – Version 7.0 
 
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6.3.Preventive treatments for infections 
- Antibiotic prophylaxis for prevention of Pneumocystis pneumonia and infections with 
encapsulated organisms must be given to all patients until 6 months after 
discontinuation of all systemic immunosuppressive treatment. Suggested antibiotic 
regimens are: Trimethoprim/Sulfamethoxazole DS 1 tab PO qMWF, or if sulfa allergic, 
Atovaquone 1500 mg PO qMWF or Pentamidine 300 mg inhaled q4 weeks. Additional 
prophylactic antibiotics are at the discretion of the physician.  
- Prophylactic antiviral and antifungal medications must also be given until the steroid 
dose is stable < 0.15 mg/kg/day. All patients who are at risk of CMV infection should 
be monitored for occult CMV infection, and appropriate treatment should be instituted 
per institutional practice. Populations at risk of CMV infection include all CMV-
seropositive patients, all CMV-seronegative patients with CMV-seropositive donors, 
and all patients receiving blood product transfusions from CMV-seropositive donors.  
- Antifungal prophylaxis: No specific antifungal prophylaxis is recommended. In case 
it is the routine policy of a centre to give an antifungal prophylaxis in patients with 
chronic GvHD (i.e., fluconazole, oral amphotericin B, itraconazole, posaconazole or 
other drugs for which there are published data of controlled trials showing the 
antifungal prophylaxis of this drug in allo-SCT patients), it is required that this policy 
is being documented in the CRF and the same policy be applied to all the patients 
included in the centre.  
- In all cases, physicians can refer to the recommendations made by the European 
Conference on Infections in Leukemia (ECIL). The full version is available on the 
website of the EBMT:  
https://www.ebmt.org/Contents/Resources/Library/ECIL/Pages/ECIL.aspx 
- All treatments given for prevention of infectious complications must be reported in 
the electronic CRF of the study. 
 
 


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6.4.Prohibited concomitant treatments 
- 
Patient receiving mycophenolate mofetil 
- 
Any other investigational study drugs than ATO 
 
 
 


Protocol GMED16-001 – Version 7.0 
 
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7. Study procedures: inclusion procedure, treatment schema and calendar of 
evaluations 
Patients will undergo the procedures and examinations which must be performed as 
shown in the following flow chart: 
 
 
Table 2. Study Summary  
 
 
Selection 
(V1) 
(10 days 
before 
ATO 
treatment) 
During 
ATO 
treatment 
(1st and 2nd 
cycles) 
 
 
Every 2 
weeks 
(from M2 
to M3) 
 
 
+/- 5 days 
Every 
month 
(M4, M5, 
M6) 
 
 
+/- 5 days 
At 6 and 
14 weeks 
and every 
3 months 
(M6, M9, 
M12) 
+/- 5 days 
Study 
drop-
out 
 
 
+/- 5 
days 
Information and patient 
consent  
* 
  
 
  
  
  
Inclusion/exclusion criteria 
check 
* 
  
 
  
  
  
Socio-demographics 
* 
 
 
 
 
 
Concomitant diseases 
* 
 
 
 
 
 
Recipient, Donor and 
Transplant characteristics10 
* 
 
 
 
 
 
Diagnosis & Scoring of 
chronic GvHD  
* 
 
 
 
 
 
Chronic GvHD activity 
assessment form A  
* 
 
 
 
* 
* 
Chronic GvHD activity 
assessment form B  
* 
 
 
 
* 
* 
Lee Symptom scale 
* 
 
 
 
* 
* 
FACT-BMT 
* 
 
 
 
* 
* 
Physical examination 
* 
*1 
* 
* 
* 
* 
EKG – QTc1 measurement 
* 
*1 
* 
 
 
 
Hematology3  
* 
*9 
* 
* 
* 
* 
Biochemistry4 
* 
*2/9 
* 
* 
* 
* 
Coagulation test5 
* 
*9 
* 
* 
* 
* 
Infectious disease 
surveillance 
* 
*2 
 
* 
* 
* 
Serum immunoglobulin 
level 
* 
 
 
* 
* 
* 
 
 
 


Protocol GMED16-001 – Version 7.0 
 
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Table 2. Study Summary (continued) 
 
 
 
Selection 
(V1) 
(10 days 
before 
ATO 
treatment) 
During 
ATO 
treatment 
(1st and 2nd 
cycles) 
Every 2 
weeks 
(from M2 
to M3) 
 
 
 
+/- 5 days 
Every 
month 
(M4, M5, 
M6) 
 
 
 
+/- 5 days 
At 6 and 
14 weeks 
and every 
3 months 
(M6, M9, 
M12) 
 
+/- 5 days 
Study 
drop-
out 
 
 
 
+/- 5 
days 
Autoantibodies (AAN, 
ANCA) 
* 
*2 
 
* 
* 
* 
Serum pregnancy test 
* 
  
 
 
 
  
Immunological evaluation 
(Saint Antoine) 
* 
*  
 
 
* 
* 
Pharmacokinetic 
evaluation 
 
*6  
 
 
 
 
Pulmonary function test 
(FEV1) 
* 
  
 
 
* 
* 
Chest x-ray 
* 
  
 
 
 
  
Cutaneous biopsy (if 
relevant) 
* 
 
 
 
 
 
ATO treatment (date, 
dose, reason of change) 
 
* 
 
 
 
 
Response to treatment 
 
 
 
 
* 
 
Associated treatment(s)8 
*7 
* 
* 
* 
* 
* 
Adverse event(s) 
  
* 
* 
* 
* 
* 
1 During ATO treatment, must be performed daily before each ATO administration. 
2 Must be performed weekly. 
3 CBC included leucocytes, neutrophils, lymphocytes, monocytes, and eosinophils counts, hemoglobin 
and platelets. 
4 Biochemistry included measurement of glycaemia9, creatinine1, uric acid, calcium1, potassium1, 
magnesium1, total protein, albumin, total bilirubin, alkaline phosphatases, SGOT9, SGPT9, and LDH. 
5 Prothrombin time [PT], activated partial thromboplastin time [APTT]. 
6 Pharmacokinetic evaluation: the samples must be performed before each administration at D2, D3, D4, 
D5, D8, D12, D17 and D24 of cycle 1 and cycle 2 (if applicable).  
7   History of GvHD prophylaxis : documentation of any associated treatments and topical therapy since 
graft for acute GvHD or progressive form of cGvHD treated by corticotherapy < 1 mg/kg/day, whenever 
possible given collected clinical history 
8 Documentation of any associated treatments and topical therapy for chronic GvHD (including 
glucocorticoid creams, topical tacrolimus, oral beclomethasone or budesonide, topical azathioprine and 
ophthalmic glucocorticoids…) 
9 Must be performed twice a week. 
10 Documentation on the diagnosis of hemopathy requiring transplant and DLI modality.   
 


Protocol GMED16-001 – Version 7.0 
 
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7.1 
Patients selection  
Only patients meeting the National Institutes of Health (NIH) criteria for chronic GvHD 
requiring systemic therapy are eligible for inclusion in this study (Jagasia et al., 2015) 
(see Appendix 1 for full details).  
Allogeneic stem cell recipients who develop a first episode of chronic GvHD will be 
screened for eligibility. If they fulfill inclusion and exclusion criteria and give their 
informed consent (see Appendix 14), they will be included in the study. 
 
7.1.1 Diagnosis of chronic GvHD 
Minimum one diagnostic manifestation of chronic GvHD OR presence of at least 1 
distinctive manifestation plus a pertinent biopsy, laboratory, or other tests (eg, 
pulmonary function tests [PFT], Schirmer’s test), evaluation by a specialist 
(ophthalmologist, gynecologist), or radiographic imaging showing chronic GvHD in 
the same or another organ, unless stated otherwise (see Appendix 1 and Appendix 2). 
Differential diagnosis of chronic GvHD must be excluded e.g. toxicity, infection. 
Diagnostic and distinctive manifestations of chronic GvHD can be found in the skin 
and appendages, mouth, eyes, genitalia, esophagus, lungs, and connective tissues. 
Biopsy or other testing is often valuable to confirm the presence of chronic GvHD, but 
is not always feasible and is not mandatory if the patient has at least one of the 
diagnostic findings of chronic GvHD. Thus, organ biopsies are per physician discretion. 
 
 


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7.1.2 Definition of mild, moderate and severe chronic GvHD 
Eight organs or sites (skin, mouth, eyes, gastrointestinal tract, liver, lungs, joint and 
fascia, and genital tract) are considered for calculating global score. Elements included 
in the proposed global scoring include both the number of organs or sites involved and 
the severity score within each affected organ. Performance status scoring is not 
incorporated into the global scoring system. Organ scoring is performed according to 
the NIH Working Group consensus (Jagasia et al., 2015) (see Appendix 2).  
For skin, the composite score is split into 2 scores to document the extent of skin 
involvement (BSA) and the specific skin features, separately (see Appendix 6).The 
higher of the 2 scores is to be used for computation of global severity. 
Eyes, are better assessed by a specialist, however, it is not mandatory. 
For lung, pulmonary function tests to assess the first forced expiratory volume (FEV1) 
are mandatory in this protocol. The composite score is split in 2 score, a symptom score 
and a FEV1 score based. In case of discrepancy between both score, the FEV1 score is 
used for the final lung scoring. 
For genital tract, scoring is based on severity of the signs instead of symptoms, both in 
man and woman, according to the figure provided in Appendix 3. Genital tract scoring 
must be performed by a specialist or a trained practitioner in chronic GvHD grading. 
Female or male genital GvHD is not scored if a practitioner is unable to examine the 
patient. 
For joint and fascia, the photographic-range and motion (P-ROM) score is an 
exploratory measure and is not included in the calculation of global severity. 
Abnormality present but explained entirely by non-chronic GvHD documented cause 
must be specified and the organ will be excluded from calculation of the global severity. 


Protocol GMED16-001 – Version 7.0 
 
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Computation of the chronic GvHD global severity, as mild, moderate or severe is 
indicated in the table below: 
Table 3. NIH global severity of chronic GvHD 
Mild  
1 or 2 Organs involved with no more than score 1 plus Lung 
score 0  
Moderate  
3 or More organs involved with no more than score 1  
OR  
At least 1 organ (not lung) with a score of 2  
OR  
Lung score 1  
Severe 
At least 1 organ with a score of 3  
OR  
Lung score of 2 or 3  
Key points: 
- 
In skin: higher of the 2 scores to be used for calculating global severity.  
- 
In lung: FEV1 is used instead of clinical score for calculating global severity.  
- 
If the entire abnormality in an organ is noted to be unequivocally explained by 
a non-GvHD documented cause, that organ is not included for calculation of the 
global severity. If the abnormality in an organ is attributed to multifactorial 
causes (GvHD plus other causes) the scored organ will be used for calculation 
of the global severity regardless of the contributing causes (no downgrading of 
organ severity score).  
 
7.1.3 Indication for systemic therapy 
Symptomatic mild chronic GvHD may often be managed with local therapies alone (eg, 
topical corticosteroids for the skin involvement).  
In contrast, in patients with moderate or severe chronic GvHD (eg chronic GvHD that 
involves 3 or more organs or with a score of 2 or greater in any single organ), systemic 
immunosuppressive therapy should be considered.  
However, in some organ sites (mouth, eyes, genital tract), aggressive local therapy 
alone may be reasonable, as response to systemic therapy may be suboptimal or may 
not warrant the risk of treatment.  
 
 


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7.2 
Pre-treatment evaluations (1 week before ATO treatment) 
In addition to chronic GvHD assessment detailed above, the following evaluations must 
be performed within one week prior to the first ATO cycle: 
- 
Patients’ sociodemographics including data on age, gender, and contraception 
- 
Recipient, donor and transplant characteristics  
- 
DLI modality (if relevant) 
- 
Evaluation of GvHD using the chronic GvHD Activity Assessment-Clinician 
Form A (see below and Appendix 8) 
- 
Patient self-reported outcome using the chronic GvHD activity assessment-
patient self-report (Form B) (see Appendix 9)  
- 
History of GvHD prophylaxis : documentation of any associated treatments and 
topical therapy since graft for acute GvHD or progressive form of cGvHD 
treated by corticotherapy < 1 mg/kg/day, whenever possible given collected 
clinical history 
- 
Concomitant diseases 
- 
Physical examination, including vital signs, weight and size (see Appendix 4 to 
Appendix 5) 
- 
Documentation of daily steroid dose 
- 
Documentation of any associated treatments and topical therapy for chronic 
GvHD 
(including 
glucocorticoid 
creams, 
topical 
tacrolimus, 
oral 
beclomethasone or budesonide, topical azathioprine and ophthalmic 
glucocorticoids…) 
- 
Hematology: complete blood count (CBC) with differential counts (leucocytes, 
neutrophils, lymphocytes, monocytes, eosinophils counts, hemoglobin, 
platelets) 
- 
Serum Chemistries: creatinine, uric acid, total bilirubin, alkaline phosphatases, 


Protocol GMED16-001 – Version 7.0 
 
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LDH, total protein, albumin, SGOT (Aspartate amino-transferase, ASAT), 
SGPT (Alanine amino-transferase, ALAT), calcium, glycaemia 
- 
Infectious disease surveillance: cytomegalovirus (CMV), Epstein Barr virus 
(EBV) and other infectious diseases (Hepatitis [hep] B surface Antigen (Ag), 
Hep B surface antibody if relevant) 
- 
Immunology: quantitative immunoglobulin measurement; lymphocyte subset 
analysis of B cells, T cells, and auto-antibodies 
- 
Tumor evaluation 
- 
Quality of life questionnaire (LSS and FACT-BMT) (see Appendix 10 to 
Appendix 11) 
- 
The patient must undergo an electrocardiogram (EKT) before ATO treatment 
with QTc measurement 
- 
In addition, serum levels of electrolytes (potassium, magnesium) will be 
measured 
- 
If appropriate, a serum pregnancy test will be performed at the study start before 
any administration of the study drug 
- 
Other tests including pulmonary function (FEV1) and imagery (chest-X ray) 
tests will be carried out 
- 
A cutaneous biopsy if relevant and a coagulation test with measurement of PT 
and APTT will be performed 
 
7.3 
Inclusion and treatment plan  
7.3.1 Inclusion 
If a patient fulfills the inclusion criteria of the protocol and has signed the informed 
consent, he will be eligible for inclusion in the study. For inclusion purposes, a specific 
“Registration form” will be used, and the patient will be given a unique identification 
number, according to standard procedures. 
The consent form must be documented by obtaining the dated signature both of the 
patient and of the person involved in the study, conducting the consent discussion on 
the consent form (see Appendix 14). The patient should have an oral and written 
language able to perfectly understand the language of the informed consent form. The 


Protocol GMED16-001 – Version 7.0 
 
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investigator site should write in the patient file who submitted the informed consent 
and the date of the submission and signatures.  
The consent form should be signed before any procedure related to the protocol. 
A copy of the inform consent and consent form should be given to the patient before 
participation, the original should be kept by the investigator site.  
The initial informed consent and any amendment should be reviewed and approved by 
the Protection of Persons Committee (CPP) before submission and signature. 
The patient and his/her legally representative should be informed in a timely manner if 
new information becomes available that may be relevant to the patient’s willingness to 
continue participation in the study. This should be documented in the patient file. 
Registration of patients included in the study will be performed in the PROMISE 
database of the European society for Blood and Marrow Transplantation (EBMT) and 
in the specific electronic CRF of the study.  
When connecting to the electronic CRF patient and inputting criteria for 
inclusion/exclusion, a number will be automatically assigned to the patient. This 
number will serve as reference for any exchange with the Sponsor. 
 
7.3.2 Treatment plan 
7.3.2.1 Arsenic trioxide therapy 
As soon as the diagnosis of chronic GvHD requiring systemic immunosuppressive 
therapy is confirmed, patients will receive in addition to ciclosporine A (if relevant) 
and corticosteroids 1 mg/kg/day, ATO 0,15 mg/kg/day over a 4 weeks period (one 
cycle). 
The treatment plan is indicative, but it is important to respect the number of 11 
perfusions per cycle. In the case of a temporary discontinuation of ATO therapy for 
medical or other reasons, the canceled infusions will be scheduled as soon as possible. 
- 
Week 1: day 1 to 5 
- 
Week 2: 3 times per week (example: day 8, 10 and 12) 
- 
Week 3: 2 times per week (example: day 15 and 17) 
- 
Week 4: 1 time per week (example: day 24) 


Protocol GMED16-001 – Version 7.0 
 
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ATO should be administered within 10 days of starting prednisone 1mg/kg/day. 
Follow-up dates for response assessment and laboratory tests relate to the date of ATO 
infusion.  
Patients in partial response after the 1st cycle of ATO will be eligible to receive a second 
cycle of ATO as consolidation therapy. A delay of 8 weeks to a maximum of 11 weeks 
(from the first infusion of ATO) will be observed between the two cycles of ATO 
therapy. 
 
Response definition is as follows: 
- 
Complete remission (CR) is defined as complete disappearance of any sign of 
chronic GvHD 
- 
Partial remission (PR) is defined as improvement of 1 or more point on a 4 to 
7-point scale or an improvement of 2 or more points on a 10 to 12-points scale 
in at least 1 organ or site without progression in any other organ or site. For 
patients with BOS, an absolute improvement in %FEV1 of 10% predicted or 
more (eg, 50% to 60%) is considered a PR as long as the initial % FEV1 is < 
70%. Normalization (≥80%) is considered a CR.  
- 
Progressive disease (PD) is defined as at least one organ system has worsened 
by at least one stage without improvement of any other organ systems from 
baseline: 
- 
For skin, eye, esophagus, and upper and lower gastro-intestinal (GI) tract, a 
worsening of 1 point or more on the 0 to 3 scale is considered progression, except 
a change from 0 to 1, which is considered trivial progression since it often reflects 
mild, nonspecific, intermittent, self-limited symptoms and signs that do not warrant 
a change of therapy. 
- 
For joint/fascia, a worsening of 1 point or more on the 0 to 3 scale is considered 
progression, even if from 0 to 1, because a change to score 1 was considered 
meaningful progression that would prompt a change in therapy. For joints assessed 
by the photographic range of motion, a worsening of 1 or more points for the 7- 
point scales and 1 or more points for the 4-point scale is considered progression.  
- 
For mouth, a worsening of 2 or more points on the 1-point scale indicates 


Protocol GMED16-001 – Version 7.0 
 
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progression.  
- 
Worsening of liver GvHD is defined by an increase of 2 or more times the upper 
limit of normal for the assay for alanine transaminase, alkaline phosphatase, or total 
bilirubin.  
- 
For patients with lung involvement, absolute worsening of FEV1 by 10% pre-dicted 
or more (eg, 50% to 40%) is considered progression, as long as the final %FEV1 is 
< 65% (because initial %FEV1 must be < 75% to establish the diagnosis of lung 
involvement). If PFTs are not available, then worsening of the clinical lung score 
based on symptoms by 1 or more points should be scored as progression, except 
from score 0 to 1, which is considered trivial progression because of its lack of 
specificity for lung chronic GvHD.  
- 
Mixed response is defined as CR or PR in at least one organ accompanied by 
progression in another organ 
- 
Unchanged: outcome that do not meet criteria for CR, PR, PF or mixed 
response are considered unchanged 
Response determination for chronic GvHD is indicated in the table below: 
Table 4. Response determination for chronic GvHD 
:
 
- 
Resistance is defined as lack of a CR/PR 2 weeks after the last ATO infusion, 


Protocol GMED16-001 – Version 7.0 
 
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requirement for alternative therapy or death from GvHD before the last ATO 
infusion 
- 
Treatment failure is defined as death, recurrent or progressive malignancy or 
the initiation of new systemic treatment for chronic GvHD. Increased dosing of 
existing treatment will not be considered as failure. 
 
Indications for secondary systemic treatment of chronic GvHD: 
Secondary systemic immunosuppressive treatment or other systemic treatment for 
control of chronic GvHD will be given at the discretion of the investigator in 
consultation with the GvHD team. In general, secondary systemic treatment is not 
indicated as long as there is continuing improvement in at least one manifestation of 
chronic GvHD and no progression of any other manifestations. 
 
Figure 1. Study plan of investigational product and secondary systemic treatment 
 
 
 
 
 
 
Months 


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Dose delay, modification and reinitiation 
Treatment with ATO must be interrupted, adjusted, or discontinued before the 
scheduled end of therapy at any time that a toxicity grade 3 or greater, on the National 
Cancer Institute Common Toxicity Criteria, is observed and judged to be possibly 
related to ATO treatment. Patients who experience such reactions that are considered 
ATO related must resume treatment only after resolution of the toxic event or after 
recovery to baseline status of the abnormality that prompted the interruption. In such 
cases, treatment must resume at 50% of the previous daily dose. If the toxic event does 
not recur within 3 days of restarting treatment at the reduced dose, the daily dose can 
be escalated back to 100% of the original dose. Patients who experience a recurrence 
of toxicity must be removed from treatment. 
 
ECG and Electrolyte Monitoring Recommendations 
During therapy with ATO, potassium concentrations must be kept above 4 mEq/l and 
magnesium concentrations must be kept above 1.8 mg/dl. In case of increase of QTc > 
500 msec (Summary of Product Characteristics (Trisenox)), syncope, rapid or irregular 
heartbeat development, the treatment is immediately interrupted and the patient must 
be hospitalized, the EKG monitored continuously, serum electrolytes assessed and a 
cardiological advice requested. 
ATO therapy must be discontinued until the QTc interval regresses to below 460 msec, 
electrolyte abnormalities are corrected, the syncope and irregular heartbeat cease. In 
accordance with the Safety Committee, the treatment could be reinitiated after the 
validation of the posology. 
 


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8. Examinations and evaluations 
8.1. Calendar of evaluations  
The total length of follow up period for this protocol will be for 12 months following 
the first infusion of ATO, with a first follow up at 6 and 14 weeks, then at 6, 9 and 12 
months post-inclusion.  
In case of postponement of several administrations of Arsenic trioxide or second cycle 
of treatment, the visit of follow up must also be postponed to respect the 2 weeks delay 
after the end of the cycle (for 6 and 14 weeks only). 
 
8.2.Evaluations during treatment with ATO  
The following evaluations must be performed: 
• Before each administration of ATO during the first and the second cycle (if 
applicable): 
- Physical examination, including vital signs 
- EKG with measurement of the QTc interval according to the formula in 
Section 11.8  
- Serum chemistries: calcium, potassium, magnesium, creatinine 
- Collection of whole blood (5 mL) for pharmacokinetic assessment (see Section 
8.4) 
• At time of treatment initiation each week (for example, days 1, 8, 15 and 24): 
- Physical examination, including vital signs, weight 
- GvHD assessment 
- Monitoring and recording of treatment associated, particular attention must be 
paid to drugs reported to prolong QT interval and/or induce torsade de pointes 
(see Appendix 7) 
- EKG with measurement of the QTc interval according to the formula in 
Section 11.8 
- Serum chemistries: potassium, magnesium, creatinine, uric acid, total 
bilirubin, alkaline phosphatases, LDH, total protein, albumin, SGOT (ASAT) 
and SGPT (ALAT) (twice a week), calcium, glycaemia (twice a week) 
- Hematology: complete blood count (CBC) with differential counts (twice a 


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week) 
- Coagulation test with measurement of PT and APTT (twice a week) 
- Infectious disease surveillance: CMV, EBV as per centre practice (and Hep B 
surface Ag, Hep B surface antibody if relevant) 
- Monitoring the kinetics of certain autoantibodies [antinuclear antibody 
(AAN), anti-neutrophil cytoplasmic antibody (ANCA)] 
- Collection of whole blood (5 mL) for pharmacokinetic assessment (see Section 
8.4) 
- Collect of whole blood (35 mL) for immunological evaluations ((see Section 
8.3) 
 
8.3.Surveillance post-treatment with ATO 
➢ Participation in this study should not substantially modify the clinical and 
biological surveillance of this type of patients with chronic GvHD. The 
monitoring and evaluation timetable are outlined in the appendices. 
➢ Clinical monitoring performed weekly during the first month of ATO therapy, 
then twice a month up to three months, and then on a monthly basis during six 
months, and then on a trimester basis at 9, 12 months (whenever possible no 
more than +/- 5 days before or after calculated visit date allowed): 
Note : if a second cycle needed, the corresponding follow-up visit Week 8 
becomes optional because it is very close to the first visit of the second cycle 
(Week 9)  
o Physical examination 
o GvHD assessment 
o Documentation of daily steroid dose 
o Monitoring and recording of all adverse events (AEs) and therapeutic 
measures taken (medications and other significant interventions) during all 
the study 
o Documentation of any associated treatments and topical therapy for chronic 
GvHD (including glucocorticoid creams, topical tacrolimus, oral 
beclomethasone or budesonide, topical azathioprine and ophthalmic 
glucocorticoids…) 
o Documentation of disease progression or relapse 


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o Documentation of any introduction of new systemic therapy 
o Evaluation of GvHD using the chronic GvHD Activity Assessment-
Clinician Form A (see below and Appendix 8) at 6 and 14 weeks, and at 6, 
9 and 12 months 
o Biological monitoring performed weekly or twice weekly (according to the 
parameters) during the first month of ATO therapy, then twice a month up 
to three months, and then on a monthly basis during 6 months, and a 
trimester basis at 9 and 12 months 
o Hematology: complete blood count (CBC) with differential counts 
o Coagulation test with measurement of PT and APTT 
o Serum Chemistries: potassium, magnesium, creatinine, uric acid, total 
bilirubin, alkaline phosphatase, LDH, total protein, albumin, SGOT 
(ASAT), SGPT (ALAT), calcium 
o Infectious disease surveillance: CMV, EBV as per centre practice (and Hep 
B surface Ag, Hep B surface antibody if relevant) 
o Serum immunoglobulin levels will be measured at baseline entry on the 
study and monthly per centre practice. Repletion of intravenous 
immunoglobulin (IVIG) is advised for patients with recurrent infections or 
IgG levels <400 mg/dL 
o Monitoring the kinetics of certain autoantibodies [antinuclear antibody 
(AAN), anti-neutrophil cytoplasmic antibody (ANCA)] 
➢ Immunological evaluations: 
o Given the apoptotic effects of ATO on the immune system, and as a 
secondary endpoint, this protocol will include some immunological 
evaluations at inclusion, at one, 3, 6 and 14 weeks (at 9, 10 and 12 weeks in 
case of second treatment cycle) and at 6 months and later at 9 and 12 months 
(as described in the protocol flow-chart), aiming to assess the immune 
effects of the drug. 
o Therefore, peripheral blood samples (30 mL on heparin tubes) and serum (5 
mL) at each time point will be drawn to assess allogeneic and protective 
antibody responses prior to and after ATO therapy : at one week (W1D1), 
at second and fourth week (W2D8 and W4D24), at evaluation visits 6 et 14 
weeks (at 9, 10 and 12 weeks in case of second treatment cycle) and at 6 
months and later at 9 and 12 months (as described in the protocol flow-


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chart).,:  
▪ To evaluate the effect of ATO on the oxidative stress pathway: 
Evaluation of the circulating level of ROS using the free oxygen 
radicals test (FORT) 
▪ To decipher the relation between dendritic cells, in particular 
plasmacytoid dendritic cells, helper T cells (Th1, Th2, Th17) and 
follicular helper T cells and B cells in the context of chronic GvHD 
under treatment by ATO: 
Peripheral blood mononuclear cells (PBMC) phenotype and 
immunophenotype  
RNA sequencing of sorted CD4+ lymphocytes and dendritic cells to 
evaluate the effect of ATO on cell signaling 
Circulating level of Th1, Th2 and Th17 related cytokines 
▪ Evaluate the effect of ATO on T cells and B cells diversity (if 
relevant) 
T-cell receptor (TCR) and B-cell receptor (BCR) sequencing 
Immunological evaluations are centralized at Saint-Antoine Hospital (Paris, 
France). The whole blood samples of patients (except for patients included at 
Hôpital Saint-Antoine) will be shipped within 24 hours to the Hôpital Saint-
Antoine, at room temperature by a carrier. The serum of patients are frozen at -
80°C and should be globally sent at the end of each cycle or at the end of study 
by a carrier.  
➢ Quality of life parameters: 
o Quality of life questionnaire at inclusion (LSS and FACT-BMT), at 6 and 
14 weeks, and 6, 9 and 12 months (LSS and FACT-BMT) (see Appendix 
10 to Appendix 11) 
➢ Tumor response assessment: 
o These examinations will be made depending on the type of the underlying 
disease and according to each centre practice. 
 
8.4. Pharmacokinetic measurement 
A sample of 5 mL of whole blood on heparin tube will be taken before each 
administration at D2, D3, D4, D5, D8, D12, D17 and D24 of cycle 1 and cycle 2 (if 


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applicable). Plasma and red cells will harvested and frozen at –20°C or –80°C and 
should be globally carried by a professional carrier at the end of each cycle or at the 
end of study to the Lariboisière laboratory (Pr Poupon).  
 
Determination of plasma and erythrocyte arsenic 
Blood will be drawn on heparin tube. At arrival at the laboratory, the blood will be 
centrifuged and the plasma will be separated from blood cells. The arsenic dosage is 
determined in the plasma and red blood cells by spectrometry in inductively coupled 
plasma mass spectrometers (ICP-MS) on Elan DRCE (Perkin Elmer) equipped of a 
reaction cell. In this technique, the pre-diluted sample will be sent in aerosol form in 
argon plasma of which temperature is about 8,000 K. All the species present in the 
sample are then reduced to the state of atom, mostly in ionized form.  
The ions formed are then extracted from the plasma and introduced into the reaction 
cell, and then, in the mass spectrometer which separates the ions according to their mass 
to charge ratio. At the output of the mass spectrometer, a sensor counts the number of 
ions given mass (Poupon J, 2008). As the arsenic contents only a mass 75 isotope (75As) 
interfered by 40Ar35Cl, oxygen will be used as the reaction gas for forming the read 91 
AsO mass free of interference. Internal quality controls (Seronorm® serum levels 1 and 
2, Seronorm® whole blood levels 1, 2 and 3, Sero, distributed by Ingen) will be analyzed 
in each series. The detection limit will be 1 nmol L (0.001 mol/L) in the serum. 
After analysis, the samples will be stored at -40 ° C until the end of the study. 


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9. 
Evaluation criteria 
9.1. Study endpoints 
9.1.1. 
Primary endpoint  
The primary endpoint will be the evaluation of response rate (CR and PR) of chronic 
GvHD at 6 months after diagnosis of chronic GvHD and treatment with ATO in 
combination with prednisone, with or without cyclosporine, as first line treatment. 
 
9.1.2. 
Secondary endpoints 
The secondary endpoints will be as follows: 
- 
Percentage of patients with documented failure free survival (FFS), defined as 
death, recurrent or progressive malignancy, or the initiation of a new systemic 
treatment for chronic GvHD 
- 
Corticosteroids dosage and percentage of reduction in corticosteroids dosage at 
6 and 12 months after diagnosis of chronic GvHD and treatment with ATO as 
first line treatment 
- 
Cumulative incidence of transplant-related mortality (TRM) of infectious and 
non-infectious origin at 6 and 12 months after diagnosis of chronic GvHD and 
treatment with ATO as first line treatment 
- 
OS and PFS at 6 and 12 months after diagnosis of chronic GvHD and treatment 
ATO as first line treatment  
- 
Descriptive analysis of quality of life parameters at inclusion, at 6 and 14 weeks, 
and at 6, 9 and 12 months after diagnosis of chronic GvHD and treatment with 
ATO as first line treatment 
- 
Tolerability and safety of ATO in combination with prednisone, with or without 
cyclosporine, in patients with chronic GvHD after allo-SCT 
 
 


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9.2. Assessment of chronic GvHD 
The clinical stage of chronic GvHD will be assessed in each patient at 6 weeks post-
inclusion, then again at 14 weeks and 6 months, then a check-up will be performed at 
9, and 12 months post-inclusion. The revised grading system proposed by the NIH (see 
Appendix 1) will be used (Jagasia et al., 2015). Thus the global scoring of chronic 
GvHD according to the NIH proposal will be performed (Lee et al., 2015). As far as is 
possible, a single senior physician, (or fellow with advanced and specific training), at 
each centre will review the organ status of all patients enrolled in this study. Therefore, 
for documenting chronic GvHD assessment, the investigator will complete the Chronic 
GvHD Activity Assessment-Clinician Form A (see Appendix 2). In addition, patients 
will complete the Chronic GvHD Activity Assessment-Patient self-reported Form B, 
the “Lee Chronic GvHD Symptom Scale” and the FACT-BMT. The Lee symptom scale 
was developed as a 30-item symptom scale with 7 subscales to capture the chronic 
GvHD-specific symptom burden. The symptom scale showed to correlate with patients 
self-assessed mild, moderate, and severe chronic GvHD manifestations in cross-
sectional analysis. Longitudinal assessments showed that changes in overall health 
status correlated best with changes in quality of life as measured by the FACT-BMT. 
In contrast, changes in chronic GvHD severity were best detected by changes in the Lee 
symptom scale. 
➢ The NIH consensus scoring system for individual organs is used in this study; 
Organ sites considered include skin, mouth, eyes, GI tract, liver, lungs, joints and 
fascia, and female genital tract.  
- 
For skin, the composite score is split into 2 scores to document the extent of 
skin involvement (BSA) and the specific skin features, separately (see 
Appendix 6). The higher of the 2 scores is to be used for computation of global 
severity. 
- 
For eyes, scoring from 0 to 3 is based on symptoms, need for eye drops, and use 
of therapeutic procedure or devices. 


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- 
For lung, scoring from 0 to 3 is based on symptoms. In addition, pulmonary 
function tests to assess FEV1 are mandatory in this protocol. For patients with 
bronchiolitis obliterans, an absolute improvement in FEV1 of 10% predicted or 
more is considered a PR as long as the initial FEV1 is < 70%. Normalization (≥ 
80%) is considered CR. 
- 
For joint and fascia, scoring from 0 to 3 is based on symptoms. The P-ROM 
score is an exploratory measure that could be very useful in that exploration. 
- 
For mouth, scoring from 0 to 12 is based on symptoms. 
- 
For gastrointestinal tract, scoring from 0 to 3 is performed for the upper and 
lower gastrointestinal tract and esophagus. In addition patient weight must be 
recorded. 
- 
For liver, total serum bilirubin, alkaline phosphatase and alanine 
aminotransferase must be recorded. 
- 
Genital tract requires a specialist exam and measure of genital response are 
considered exploratory. Therefore, genital tract is not included in evaluation of 
chronic GvHD response. 
Abnormality present but explained entirely by non-chronic GvHD documented 
cause must be specified and the organ will not be considered as involved for 
evaluation of chronic GvHD response. 


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In addition, physician should provide a subjective assessment of current overall chronic 
GvHD severity on a 4-points scale (no chronic GvHD, mild, moderate or severe) 
without knowledge of the calculated NIH global severity score. They should also 
provide an assessment of current overall chronic GvHD severity on a 11-point 
numerical scale (0 indicates no GvHD manifestation; 10 indicates most severe chronic 
GvHD symptoms possible). Clinicians should also provide their evaluations of chronic 
GvHD changes since the last assessment scored on a 7-point scale (very much better, 
moderately better, a little better, about the same, a little worse, moderately worse, very 
much worse). These semi-quantitative assessments may detect qualitative 
improvements that are clinically meaningful but not well captured using other 
measures. 
➢ Patient reported outcome 
Patient reported outcome included chronic GvHD-specific core measure with the 
chronic GvHD activity assessment-patient self-report (Lee Symptom Scale: LSS - 
Form B) and chronic GvHD non-specific ancillary measure with the FACT-BMT. 
Patients reported outcome are exploratory and will not be used for decision making 
response evaluation. 
- Organ sites considered in the chronic GvHD activity assessment-patient self-report 
included skin and joint, mouth, genital tract and eyes. In addition, similarly to clinician 
assessed chronic GvHD, at each assessment, patients should score their perceptions of 
overall chronic GvHD severity, overall severity of symptoms, and change in symptom 
severity compared with the last assessment, using the same response options used by 
clinicians.  


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- 
For skin, patients should report their most severe itching during the past week, 
rated according to a 0 to 10 scale, as itching is the most frequent cutaneous 
symptom of chronic GvHD. These are considered recommended measures. A 
semi-quantitative exploratory measure, “Your skin and/or joint tightening at its 
worst,” on a 0 to 10 scale has been added to capture severity of skin sclerosis. 
Informal cognitive testing suggested that including both “skin” and “joint” 
tightening in the question was not confusing for patients. 
- 
For mouth, patients should report their mouth sensitivity (irritation resulting 
from normally tolerated spices, foods, liquids, or flavors), rated according to a 
0 to 10 scale for peak severity during the past week. 
- 
For genital tract, both female and male genital symptoms may be captured by 
the exploratory item rating “worst genital discomfort” on a scale from 0 to 10. 
- 
For eyes, patients should report a “chief eye complaint” rated according to a 0 
to 10 scale for peak severity during the past week. The complaint can change 
from visit to visit, but only 1 “chief eye complaint” is graded. 
 
9.3. Response criteria 
➢ Numbering of weeks/timing of events 
Week 1 is the week corresponding to the first infusion of ATO. Weeks are counted 
from this week onwards, unless stated to the contrary. Investigators should take care 
not to confuse weeks post-ATO with weeks post-transplantation.  


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➢ Response to the study regimens: 
- 
Assessment of response (CR vs. PR): The main issue in chronic GvHD is the lack 
of consensus criteria for the assessment of the response. In 2015 an NIH sponsored 
meeting was held with a panel of experts on chronic GvHD. Their proposal for 
grading of chronic GvHD will be used in this protocol (see Appendix 1). 
- 
The following definitions will be used: 
- 
Complete remission (CR) is defined as complete disappearance of any sign of 
chronic GvHD 
- 
Partial remission (PR) is defined as improvement of 1 or more point on a 4 to 7-
point scale or an improvement of 2 or more points on a 10 to 12-points scale in at 
least 1 organ or site without progression in any other organ or site. For patients 
with BOS, an absolute improvement in %FEV1 of 10% predicted or more (eg, 50% 
to 60%) is considered a PR as long as the initial % FEV1 is < 70%. Normalization 
(≥ 80%) is considered a CR.  
- 
Progressive disease (PD) is defined as at least one organ system has worsened by 
at least one stage without improvement of any other organ systems from baseline 
- 
For skin, eye, esophagus, and upper and lower GI tract, a worsening of 1 point or 
more on the 0 to 3 scale is considered progression, except a change from 0 to 1, 
which is considered trivial progression since it often reflects mild, nonspecific, 
intermittent, self-limited symptoms and signs that do not warrant a change of 
therapy. 
- 
For joint/fascia, a worsening of 1 point or more on the 0 to 3 scale is considered 
progression, even if from 0 to 1, because a change to score 1 was considered 
meaningful progression that would prompt a change in therapy. For joints assessed 
by the photographic range of motion, a worsening of 1 or more points for the 7- 
point scales and 1 or more points for the 4-point scale is considered progression.  
 
 


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- For mouth, a worsening of 2 or more points on the 1-point scale indicates 
progression. 
- 
Worsening of liver GvHD is defined by an increase of 2 or more times the upper 
limit of normal for the assay for alanine transaminase, alkaline phosphatase, or 
total bilirubin.  
- 
For patients with lung involvement, absolute worsening of FEV1 by 10% pre-
dicted or more (eg, 50% to 40%) is considered progression, as long as the final 
%FEV1 is < 65% (because initial %FEV1 must be < 75% to establish the diagnosis 
of lung involvement). If PFTs are not available, then worsening of the clinical lung 
score based on symptoms by 1 or more points should be scored as progression, 
except from score 0 to 1, which is considered trivial progression because of its lack 
of specificity for lung chronic GvHD.  
- 
Mixed response is defined as CR or PR in at least one organ accompanied by 
progression in another organ 
- 
Unchanged: outcome that does not meet criteria for CR, PR, PF or mixed response 
are considered unchanged 
- 
Resistance is defined as lack of a CR/PR 2 weeks after the last ATO infusion, 
requirement for alternative therapy or death from GvHD before the last ATO 
infusion 
- 
Failure is defined as death, recurrent or progressive malignancy or the initiation of 
new systemic treatment for chronic GvHD increased dosing of existing treatment 
will not be considered as failure 
 
 


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9.4. Infections 
These will be classified, as far as is possible, by pathogenic agent, clinical syndrome, 
and localization according to the definitions of the Infectious Diseases Working Party 
of the EBMT, available on the website of the EBMT: 
https://www.ebmt.org/Contents/Research/TheWorkingParties/IDWP/Pages/Infectious
-Diseases.aspx 
Date of onset, duration, treatment and outcome will also be noted, as well as 
prophylaxis prior to infective episode. 
 
9.5. Cause of death  
When determining the cause of death, investigators should classify deaths occurring 
from infection and from multiple organ failure in the presence of chronic GvHD, as 
being caused or related to GvHD. 


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10. Statistical considerations 
10.1. 
General considerations 
A statistical analysis plan which describes the statistical analyses planned for the study 
will be written and signed before database lock. 
Data will be described using qualitative and quantitative data as follows: 
- 
Qualitative data will be described in frequency and percentage and will be 
represented using histograms or diagrams of distribution 
- 
Quantitative data will be described using the calculations of average, standard 
deviation, median, and extreme values 
 
10.2. 
Analyses data set 
Every patient included in the study and who has received at least one infusion of ATO 
will be taken into account at time of data analysis. 
Patients who do not receive any injection of ATO will not be analyzed and will be 
replaced to obtain 24 patients provided in the statistical analysis.  
 
10.3. 
Statistical analyses 
A descriptive analysis will be conducted on the following parameters: 
- 
Patients and transplant characteristics 
- 
Primary and secondary endpoints 
The toxicities rate will be calculated and will be given with their 95% confidence 
intervals. 
The probabilities of survival will be estimated by the Kaplan-Meier method and by 
calculating the cumulative incidences for relapse/progression, and non-relapse 
mortality incidence.  


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10.4. 
Definition of Endpoints 
10.4.1. 
Efficacy success 
Efficacy success is defined as the response rate (CR+PR) at 6 months after the first 
ATO infusion, with no secondary systemic therapy (defined below) at any time. Death 
or dropout with lack of follow-up information after response of chronic GvHD but 
before the final analysis is expected to occur infrequently and will not be used to negate 
categorization as efficacy success for purposes of this study, since the treatment had 
been effective in controlling chronic GvHD. It is possible that systemic 
immunosuppressive treatment will be discontinued before resolution of all reversible 
manifestations of chronic GvHD in some patients. Topical therapy may be continued 
in this situation, at the discretion of the managing physician. Discontinuation of 
immunosuppressive medications for the purpose of inducing an anti-tumor response 
after the development of recurrent or secondary malignancy will not be categorized as 
efficacy success.  
It is possible that initial treatment with ATO might improve the prospects of success 
after secondary systemic therapy. This endpoint will not be used, however, to avoid any 
confounding biases. 
 
10.4.2. 
Efficacy failure 
Efficacy failure is defined as early treatment failure is first checked at week 6 post 
ATO. Treatment failure will be defined as: 
- 
Required initiation of a new systemic treatment for chronic GvHD before 
week 6 
- 
Recurrent or progressive malignancy before week 6 
- 
Death before week 6 
Failure-free survival (FFS), is defined as death, recurrent or progressive malignancy, 
or the initiation of a new systemic treatment for chronic GvHD (defined below). 


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From the perspective of the patient, secondary therapy and death have very different 
significance with respect to efficacy, since the need for secondary therapy does not 
inevitably lead to death. From the perspective of the clinical trial, however, both events 
indicate that the study-drug did not have the desired efficacy. 
Discontinuation of treatment with study-drug because of toxicity will not be 
categorized as efficacy failure in and of itself, since it is possible that a short period of 
treatment with the study-drug could have long lasting benefit ultimately resulting in 
efficacy success. After a toxic study-drug outcome, patients will be followed for any 
subsequent initiation of secondary systemic treatment development of recurrent 
malignancy, death from causes other than recur- rent malignancy, or dropout with lack 
of follow-up information. Any of these events occurring during primary treatment for 
chronic GvHD will be categorized as efficacy failure. 
 
10.4.3. 
Secondary systemic therapy 
Secondary systemic therapy includes any intervention intended to control chronic 
GvHD through an immunosuppressive effect from oral or parenteral administration of 
any systemic medication not originally given under auspices of this protocol. Examples 
include, but are not limited to the following: azathioprine, rapamycin, infliximab, 
daclizumab, 
etanercept, 
antithymocyte 
globulin, 
thalidomide, 
chloroquine, 
clofazimine, extracorporeal photopheresis, and psoralen with UVA irradiation. 
Topical therapy, including glucocorticoid creams, topical tacrolimus, oral 
beclomethasone or budesonide, topical azathioprine and ophthalmic glucocorticoids, is 
not considered as secondary systemic therapy. 


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An increase in the dose of prednisone and any resumption of treatment with prednisone 
or study-drug after previous discontinuation for any reason is not considered as 
secondary systemic therapy. Any increase in the dose of ciclosporine or resumption of 
treatment with ciclosporine after previous discontinuation for any reason is not 
considered as secondary systemic treatment, if the drug in question was included in the 
immunosuppressive regimen when treatment for chronic GvHD was started. 
A change in treatment from ciclosporine to tacrolimus because of drug toxicity is not 
considered as secondary treatment. This information must be reported in the electronic 
CRF of the study. 
 
10.4.4. 
Recurrent malignancy 
For purposes of this study, recurrent malignancy after allo-SCT is defined as clinical or 
histopathologic evidence demonstrating the presence of any malignancy considered as 
the indication for transplant. Recurrent malignancy after allo-SCT will also be defined 
as any post-transplant intervention not routinely used to prevent the development of 
overt recurrence, prompted by laboratory evidence of persisting malignant cells but 
without clinical or histopathologic evidence of recurrence. Recurrent malignancy after 
a non- myeloablative or reduced intensity conditioning regimen will be defined as any 
ad hoc post- transplant intervention intended to induce a donor immune-mediated anti-
neoplastic effect, prompted by clinical or laboratory evidence indicating the need to 
eliminate persistent or progressive malignancy. Examples of such interventions include 
accelerated withdrawal of systemic immunosuppressive medications and donor 
lymphocyte infusion. 


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10.5. 
Missing data handling 
Every effort will be made to keep the number of missing values for all parameters to a 
minimum. Missing data on overall survival is assumed to be 0 as patient care after 
transplantation is very close. 
 
10.6. 
Early stopping rules  
Experience acquired with the use of ATO in various clinical situations does not suggest 
a significant risk of study drug-related severe toxicities. Therefore, for the purpose of 
this study, no criterion for early stopping will be defined in advance. 
 
10.7. 
Calculation of the number of patients  
Based on results from the literature, the hypothesis for the primary endpoint is an 
improvement in response rate (CR and PR) at 6 months after the diagnosis of chronic 
GvHD and start of ATO from 60% to 85%. Using a one-step A’Hern procedure (A'Hern 
RP, 2001) (and anticipating a dropout rate around 10%), 24 (21+3) patients are needed. 
If the number of successful cases is 17 or more among the 21 patients, the hypothesis 
that the CR rate at 6 months is less than 60% is rejected with a target error rate of 0.05 
(alpha probability). The beta probability in this case is 0.2.  
 
 


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11. 
Safety Management 
11.1. 
Adverse Events 
The following definitions and explanations are given to enable investigators and study 
nurses to correctly record, report and review adverse eventss (AEs) in order to comply 
with the safety requirements according to Good Clinical Practice (GCP) standards and 
the local and European requirements.  
For all AEs, the investigator must pursue and obtain information adequate both to 
determine the outcome of the AE and to assess whether it meets the criteria for 
classification as a serious AE (SAE) (see Section 11.3.3) requiring immediate 
notification to Sponsor. For all AEs, sufficient information should be obtained by the 
investigator to determine the causality of the AE. The investigator is required to assess 
causality. For AEs with a causal relationship to the investigational medicinal product, 
follow-up by the investigator is required until the event or its sequelae resolve or 
stabilize at a level acceptable to the investigator, and Sponsor concurs with that 
assessment. 
 
11.2. 
Reporting Period 
SAEs require immediate notification to Sponsor beginning from the time that the 
subject provides informed consent, which is obtained prior to the subject’s participation 
in the clinical trial, i.e., prior to undergoing any trial-related procedure and/or receiving 
investigational medicinal product, through 30 days after the administration of the last 
dose.  
Any SAE occurring any time after the reporting period must be promptly reported if a 
causal relationship to investigational medicinal product is suspected.  
AEs (serious and non-serious) should be recorded on the electronic CRF from the time 
the subject has taken at least one dose of trial treatment through last subject visit. 
 
 


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11.3. 
Definitions 
11.3.1. 
Definition of an AE 
An AE is any untoward medical occurrence in a clinical investigation subject 
administered an investigational medicinal product; the event do not need necessarily 
have a causal relationship with the treatment or usage. 
Examples of AEs include but are not limited to:   
• Abnormal test findings; 
• Clinically significant symptoms and signs; 
• Changes in physical examination findings. 
 
Additionally, they may include the signs or symptoms resulting from: 
• Drug overdose; 
• Drug abuse; 
• Drug misuse; 
• Medication error; 
• Drug interactions; 
• Exposure in utero. 
Worsening of signs and symptoms of the cGVHD should not be reported as AEs in the 
appropriate section of the electronic CRF. PD is defined as at least one organ system 
has worsened by at least one stage without improvement of any other organ systems 
from baseline. 
 
 


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11.3.2. 
Abnormal Test Findings  
The criteria for determining whether an abnormal objective test finding should be 
reported as an AE are as follows:  
• Test result is associated with accompanying symptoms, and/or 
• Test result requires additional diagnostic testing or medical/surgical 
intervention, and/or 
• Test result leads to a change in trial dosing (outside of protocol-stipulated dose 
adjustments) or discontinuation from the trial, significant additional 
concomitant drug treatment, or other therapy, and/or 
• Test result is considered to be an AE by the investigator or sponsor. 
Merely repeating an abnormal test, in the absence of any of the above conditions, does 
not constitute an AE. Any abnormal test result that is determined to be an error does 
not require reporting as an AE. 
 
11.3.3. 
Definition of a Serious Adverse Event 
A SAE or serious adverse drug reaction is any untoward medical occurrence at any 
dose that: 
• Results in death; 
• Is life-threatening (immediate risk of death); 
• Requires inpatient hospitalization or prolongation of existing hospitalization for 
medical reasons (e.g. prolongation of hospitalization for social reasons is 
excluded); 
• Results in persistent or significant disability/incapacity; 
• Results in congenital anomaly/birth defect. 
 
 


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Progression of the cGVHD (including signs and symptoms of progression) should not 
be reported as a SAE unless the outcome is fatal during the trial or within the safety 
reporting period. Hospitalization due to signs and symptoms of disease progression 
should not be reported as SAE.  
Medical and scientific judgment should be exercised in determining whether an event 
is an important medical event. An important medical event may not be immediately 
life-threatening and/or result in death or hospitalization. However, if it is determined 
that the event may jeopardize the subject and/or may require intervention to prevent 
one of the other outcomes listed in the definition above, the important medical event 
should be reported as serious. 
 
11.3.4. 
Hospitalization  
AEs reported from clinical trials associated with hospitalization or prolongation of 
hospitalization are considered serious. Any initial admission (even if less than 24 hours) 
to a healthcare facility meets these criteria. Admission also includes transfer within the 
hospital to an acute/intensive care unit. 
Hospitalization does not include the following: 
• Rehabilitation facilities; 
• Hospice facilities; 
• Respite care (e.g., caregiver relief); 
• Skilled nursing facilities; 
• Nursing homes; 
• Routine emergency room admissions; 
• Same day surgeries (as outpatient/same day/ambulatory procedures). 
 
 


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Hospitalization or prolongation of hospitalization in the absence of a precipitating, 
clinical AE is not in itself a SAE.  Examples include:  
• Admission for treatment of a preexisting condition not associated with the 
development of a new AE or with a worsening of the preexisting condition (eg, 
for work-up of persistent pre-treatment lab abnormality); 
• Social admission (e.g., subject has no place to sleep); 
• Administrative admission (eg, for yearly physical exam); 
• Protocol-specified admission during a clinical trial (e.g., for a procedure 
required by the trial protocol); 
• Pre-planned treatments or surgical procedures should be noted in the baseline 
documentation for the entire protocol and/or for the individual subject. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, 
should not be reported as AEs.  However, the medical condition for which the procedure 
was performed should be reported if it meets the definition of an AE.  For example, an 
acute appendicitis that begins during the AE reporting period should be reported as the 
AE, and the resulting appendectomy should be recorded as treatment of the AE. 
 
11.4. 
Severity Assessment 
Treatment related toxicities and other AE and SAE are classified according to the NCI 
common toxicity criteria (CTC), specification for stem cell transplantation, as 
outlined in the appendix of this protocol. The updated CTC can be downloaded from 
the worldwide web using the following URL: 
http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-
14_QuickReference_5x7.pdf 
 
 


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Please note the distinction between the severity and the seriousness of an AE.  A severe 
event is not necessarily a serious event. For example, a headache may be severe 
(interferes significantly with subject's usual function) but would not be classified as 
serious unless it met one of the criteria for SAEs, listed above. 
 
11.5. 
Causality Assessment 
The investigator’s assessment of causality must be provided for all AEs (serious and 
non-serious). An investigator’s causality assessment is the determination of whether 
there exists a reasonable possibility that the investigational medicinal product caused 
or contributed to an AE. 
Not Related: Where a temporal (timely) relationship of the onset of the event, relative 
to the administration of the investigational medicinal product is not reasonable (e.g. as 
crash as passenger), or where another cause can explain the occurrence of the event by 
itself. [Considered as having not a reasonable possibility to be related to the 
investigational medicinal product] 
Unlikely: Where a temporal (timely) relationship of the onset of the event, relative to 
the administration of the investigational medicinal product is unlikely and or because 
another cause may be suspected. [Considered as having not a reasonable possibility to 
be related to the investigational medicinal product] 
Possibly Related: Where a temporal (timely) relationship of the onset of the event, 
relative to the administration of the investigational medicinal product is reasonable, but 
the event could have been due to an equally likely cause. [Considered as having a 
reasonable possibility to be related to the investigational medicinal product] 
Probably Related: Where a temporal (timely) relationship of the onset of the event, 
relative to the administration of the investigational medicinal product is reasonable and 
the event is more likely to be explained by the investigational medicinal product than 
by another cause. [Considered as having a reasonable possibility to be related to the 
investigational medicinal product] 
 
 


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Definitely Related: Where a temporal (timely) relationship of the onset of the event, 
relative to the administration of the investigational medicinal product is reasonable and 
there is no other cause to explain the event or a re-challenge is positive. [Considered as 
having a reasonable possibility to be related to the investigational medicinal product] 
If the investigator’s final determination of causality is unknown and the investigator 
does not know whether or not investigational medicinal product caused the event, then 
the event will be handled as “related to investigational medicinal product” for reporting 
purposes. If the investigator's causality assessment is "unknown but not related to 
investigational medicinal product", this should be clearly documented on trial records.   
In addition, if the investigator determines a SAE 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, if applicable. 
 
11.6. 
Exposure In Utero  
For investigational medicinal products within clinical trials and for marketed products, 
an exposure in-utero (EIU) occurs if: 
1) a female becomes, or is found to be, pregnant either while receiving or having 
been directly exposed to (e.g., environmental exposure) the investigational 
medicinal product, or the female becomes, or is found to be, pregnant after 
discontinuing and/or being directly exposed to the investigational medicinal 
product (maternal exposure); 
2) a male has been exposed, either due to treatment or environmental, to the 
investigational medicinal product prior to or around the time of conception 
and/or is exposed during the partner pregnancy (paternal exposure). 
 
 


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If any trial subject or trial subject’s partner becomes or is found to be pregnant during 
the trial subject’s treatment with the investigational medicinal product, the investigator 
must submit this information to Sponsor on an Exposure in Utero Form. In addition, 
the investigator must submit information regarding environmental exposure to a 
Sponsor product in a pregnant woman using the Exposure in Utero 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. 
Follow-up is conducted to obtain pregnancy outcome information on all Exposure in 
Utero reports with an unknown outcome.  The investigator will follow the pregnancy 
until completion or until pregnancy termination (ie, induced abortion) and then notify 
Sponsor of the outcome. The investigator will provide this information as a follow up 
to the initial Exposure in Utero Form.   
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. 
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 
medicinal product should be reported. 
 
 


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11.7. 
Reporting 
11.7.1. 
Reporting Requirements 
Each AE is to be assessed to determine if it meets the criteria for SAE. If a SAE occurs, 
expedited reporting will follow local and European regulations, as appropriate. 
All AEs will be reported on the AE page(s) of the eCRF.  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. 
 
11.7.2. 
Serious Adverse Event Reporting Requirements 
If a SAE occurs, Sponsor is 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 to 
Sponsor must be made immediately, irrespective of the extent of available AE 
information. This timeframe also applies to additional new information (follow-up) on 
previously forwarded SAE reports as well as to the initial and follow-up reporting of 
Exposure in Utero cases.   
For all serious AEs, the investigator is obligated to pursue and provide information to 
Sponsor in accordance with the timeframes for reporting specified above. In addition, 
an investigator may be requested by Sponsor to obtain specific additional follow-up 
information in an expedited fashion. This information may be more detailed than that 
captured on the AE case report form.  In general, 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 Sponsor.  
 
 


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It is the investigators responsibility to maintain an accurate and up to date record of all 
AEs/occurrences in patients participating in the clinical trial. This record, including 
details of nature, onset, duration, severity, outcome and any relationship to 
investigational medicinal product, should be noted in the patient s medical notes. It is 
the investigators responsibility to review all events occurring at their site and as such 
the investigator must ensure that the patients are not compromised. Any appropriate 
action must be taken to protect the patients whilst ensuring validity of the results. It is 
the investigator responsibility to report correctly and on time to the sponsor SAE and 
to answer to queries at time.  
All SAE Form must be sent to the sponsor by fax or e-mail to: 
AnticipSanté 
40, rue de Fontenelle – 78160 ~ Marly le roi 
E-mail: sae-medsenic@anticipsante.com 
 
11.7.3. 
Non-Serious AE Reporting Requirements 
Non-serious AEs are to be reported on the AE eCRFs, which are to be submitted to 
Sponsor. 
 
11.8. 
Frequent AEs 
The most frequently reported AEs of ATO are specified in the SPC (See Appendix 12) 
and provided below: 
The most frequent events related to ATO are those: 
- 
Related to cardiovascular system (tachycardia, QT prolongation…) 
Prolongation of the QT interval in the EKG has been observed during treatment with 
ATO. This can lead to ventricular tachycardia (torsade de pointes) with a fatal outcome. 
In this context, possible interaction with other drugs that prolong the QT interval must 
also be taken into account (see Appendix 7 for drugs reported to prolong QT interval 
and/or induce torsade de pointes). 
 
 


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For this reason, close monitoring of the EKG and of the electrolytes is necessary during 
treatment with ATO. In particular, the Mg++ and K+ levels should always be kept in 
the high-normal range, taking in consideration possible concomitant treatments that 
deplete electrolyte levels (e.g. amphotericin B, furosemide etc.). In the EKG, the QT 
interval is represented by the QRS complex, the ST segment and the T wave. Its 
measurement starts from the deepest point of Q wave to the end of T wave. This interval 
greatly depends on the heart rate and several formulas have been proposed to adjust the 
QT interval for heart rate in order to obtain the corrected QT interval (QTc); however, 
no one of these proposed formulas is satisfactory (Indik JH, 2006; Luo S, 2004; Sagie 
A, 1992). Despite that, data from medical literature indicate that one of the most simple 
method for adjusting the QT interval for heart rate is the Framingham formula  (Indik 
JH, 2006; Luo S, 2004; Sagie A, 1992):  
QTc=QT+0.154*(1000-RR) 
Using this formula, the upper normal limits of QTc interval calculated from the EKC 
of 10,303 subjects collected from 4 US hospitals (Luo S, 2004) are reported in the table 
below:  
 
Table 5. Upper Limits (98%,in msec) of Normal QTc for Framingham formula 
(Luo S, 2004) 
Heart Rate (HR) 
MALE (5,420) 
FEMALE (4,883) 
 BOTH (10,303) 
All HR 
454 
461 
457 
HR < 60 
455 
463 
459 
HR 60 to 99 
454 
462 
458 
HR > 99 
436 
434 
436 
 
 
 


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For increased accuracy, the QT interval should be measured on serial EKGs and several 
successive beats and averaged for each EKG. The averaged QT value obtained should 
be used in the above formula in which all measurement must be expressed in msec (i.e.: 
0,500 sec=500 msec). Applying this formula, a QTc interval > 500 msec must be 
considered prolonged (Summary of Product Characteristics (Trisenox)). 
- 
Related to hepatotoxicity:  increase in serum bilirubin and/or SGOT and/or 
SGPT and/or alkaline phosphatase, 
- 
Related to Hematological toxicity. This drug may induce severe and prolonged 
myelosuppression with subsequent anemia, neutropenia, thrombocytopenia. 
Less frequently hyperleucocytosis or leucopenia have been reported.  
- 
Related to general tolerance (fever, chills, fatigue, bleeding, edema…) 
- 
Related to immunosuppression such as infectious complications (candidosis, 
herpes-zoster, pneumonia, bacteremia, septicemia, septic choc…),  
- 
Related to digestive toxicity (nausea, vomiting, diarrhea...), 
- 
Related 
to 
metabolism 
disorders 
(hyperglycemia, 
hypokalemia, 
hypomagnesaemia…), 
- 
Renal insufficiency, 
- 
Related to nervous system (paraesthesia, dizziness, headache…), 
- 
Related to eye disorder (vision blurred), 
- 
Related to cutaneous tissues (prurit, rash ), 
- 
Related to musculoskeletal, connective tissue and bone disorders (myalgia, 
arthralgia, bone pain…). 
- 
Related to pulmonary disorders (dyspnea,,,) 
All AE not previously described in the Summary of Product Characteristics of 
TRISENOX® or in the Investigator Brochure of ARSCIMED® should be considered as 
unexpected AE.  
 
 


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11.9. 
Safety Committee  
An independent safety committee (including experts in the field) will be established by 
the sponsor to assess at regular intervals the progress of the trial, the safety data, and 
the critical efficacy endpoints, and to recommend to the sponsor whether to continue, 
modify, or stop the trial.  
During the study, meetings of the Independent Data Monitoring Committee will be 
organized periodically. 
 
11.10. 
Annual Safety Report  
A safety report will be produced annually. The “Development International Birth Date” 
(DIBD) is used to determine the start of the annual period for the Annual Safety report 
(ASR). This date is the sponsor’s first authorization to conduct a clinical trial in any 
country worldwide. The start of the annual period for the ASR is the month and date of 
the DIBD. The start of the annual period for the ASR is the month and date of the 
DIBD.  The data lock point of the ASR can be designated as the last day of the month 
prior to the month of the DIBD. 
This report will be prepared by the sponsor according to the current ICH guideline E2F 
on development safety update report. Additionally, the two following listings will be 
provided: Interval line listings of the Serious Adverse Reactions (SARs) that were 
reported to the sponsor during the period covered by the ASR; and Cumulative 
summary tabulations of serious adverse events that have been reported to the sponsor 
since the DIBD.  
This report will be submitted to the competent authorities and to the ethics committees 
by the sponsor within 60 days from the above anniversary date.  
In addition, an independent data safety committee will be constituted to assist the 
sponsor (please see Section 11.9). 


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12. 
Quality Control 
12.1. 
Good Clinical Practice  
The study will be performed according to the Guidelines for Good Clinical Practice 
(ICH Harmonized Tripartite Guideline for Good Clinical Practice, (17.01.1997)). 
The investigator will be thoroughly familiar with the appropriate use of the study drug 
as described in the protocol and SPC. Essential clinical documents will be maintained 
to demonstrate the validity of the study and the integrity of the data collected. A trial 
master file should be established at the beginning of the study, maintained for the 
duration of the study and retained according to the appropriate regulations. 
 
12.2. 
Auditing  
To guarantee a high quality of treatment for the patients within the present study, the 
sponsor will insure that the participating centres fulfill the following criteria: 
- 
fulfilling of legal requirements 
- 
experience of the principle investigator of the entire study and the respective 
centre with respect to study conduct 
- 
International Conference on Harmonization (ICH)/GCP knowledge and 
certifications  
 
12.3. 
Monitoring  
Regular monitoring is an essential part of the study conduct. It will be performed by 
the Sponsor of the study. After the initiation visit, the frequency of monitoring visits 
will depend on the course of the study, and recruitment. It is the monitor’s responsibility 
to make the local investigators and all the staff who is involved into the study or the 
care of the patients familiar with the protocol.  


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During the course of the study, the monitor will control the progress of the study, the 
commitment to the protocol, the documentation and careful usage of the study 
medication, and the maintenance of GCP guidelines and legal obligations. Problems as 
well as changes in reported data will be worked out in collaboration with the local 
investigator, who is obliged to cooperate with the monitor and to allow access to the 
patients’ charts. Source data verification is performed by the monitor. This protocol is 
classified as a “D” risk level estimated for the patients (Phase II= very high risk 
predictable).  
Inclusion criteria will be verified in 100% of patients. The monitor will have to respect 
that the data she/he comes into contact with are highly confidential. A monitoring report 
will be provided for each visit. 
 
12.4. 
Data management 
The coding and data control for the exploitation of results of the study will be conducted 
by the Contract research Organization (CRO) in charge of the study, FOVEA (Rueil-
Malmaison, France), according to its standard operating procedures, ICH guidelines, 
and under the supervision of the Sponsor. 
 
12.4.1. 
Data entry 
All study data will be recorded and stored in a computerized database within the CRO, 
under the supervision of the Data Manager and under appropriate procedures. The data 
are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
 
 


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12.4.2. 
Consistency checks 
Procedures for control of electronic data (Data Computer Management) will be defined 
to ensure the validity of information gathered as part of this study. They will cover all 
of the data and will aim to highlight abnormalities as missing data or inconsistent data. 
These controls will be fully described in a manual of Data Management and will be 
implemented in the e-CRF. The computerized handling of the data by the Sponsor may 
generate additional requests (discrepancy resolution forms) to which the Investigator is 
obliged to respond by confirming or modifying the data questioned. The requests with 
their responses will be managed through the e-CRF. 
 
12.4.3. 
Data Coding 
The AEs will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA), while previous treatments will be coded using the World Health 
Organization (WHO) dictionary according to anatomic-therapeutic-chemical 
classification (ATC). 
 
 


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13. 
Ethical and Regulatory Considerations 
The study will be conducted according to the European Union directive (ICH 
Harmonized Tripartite Guideline for Good Clinical Practice, (17.01.1997)). The study 
has to be conducted in compliance with the protocol, GCP and all applicable regulatory 
requirements:  
- 
Helsinki declaration from1964, revised in Washington in 2002, 
- 
GCP of the International Harmonization Conference (ICH E6, 17/07/96),  
- 
European Directive (2001/20/CE) on the conduct of clinical trials, 
- 
French law n° 2004-801 dated 6 August 2004, 
- 
French bioethics law n° 2004-800 dated 6 August 2004. 
Accordingly, investigating physicians have to provide direct access to study documents 
to monitoring, audits, institutional internal control, external authorities, and the 
members of the ethical committee. Written informed consent by the patient is 
mandatory. 
The coordinating investigator and all investigators will be given an up-to-date 
investigator’s brochure containing full details of the status of the pre-clinical and 
clinical knowledge of the study medication. As soon as new information is obtained, 
an updated version will be sup- plied or an amendment added to the existing 
investigator s brochure. 
 
13.1. 
Regulatory Authorities Approval (CPP and ANSM)  
No patient may be included in the study before the respective requirements of the 
national health authorities are fulfilled. The study will begin only after the positive vote 
of the responsible Ethics Committee (CPP) and after the approval by the appropriate 
national health authority (ANSM).  


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The protocol has to be followed strictly, protocol violations have to be documented and 
the reason has to be given (e.g. emergency measures). Any changes in the protocol can 
only be performed by the principle investigator or the protocol writing committee. Any 
subsequent changes will be reported or submitted for approval to the ethical committee 
and to local and national authorities. 
 
13.2. 
Informed consent  
Written informed consent is obtained by each patient before inclusion into the study 
(see Appendix 14). Using patient information sheets, as well as personal oral 
explanation by a local investigator at the patient’s transplant centre, the patient will be 
informed of the aims and the investigational nature of the study, the exact procedures 
that will be done during treatment and evaluation, the possible risks and side effects, 
and of alternative treatment options. They will be informed as to the strict 
confidentiality of their patient data, but that authorized individuals other than their 
treating physician may review their medical records for study purposes. Further, the 
patient will be informed that their anonymized data will be scientifically analyzed and 
published. It will be emphasized that the participation is voluntary and that consent can 
be withdrawn by the patient at any time without explanation of the reason. The patient 
is allowed to refuse further participation in the protocol, whenever he/she wants. The 
patient's further treatment will not be influenced by this decision. 
 
13.3. 
Investigators responsibilities  
In collaboration and according to the Standard Operating Procedure (SOP) of the 
sponsor, a detailed list of delegation of responsibilities has been established. It is held 
by the sponsor, who is finally responsible for the correct performance of delegated 
responsibilities by the respective persons or institutions. A copy of this list will be 
delivered to the participating institutions.  


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The investigator of each institution undertakes to conduct the study according to the 
protocol which was approved by the ethics (CCP) and health authorities (ANSM). The 
investigator must not make any changes to the protocol without the permission of the 
sponsor and without the CCP has given a favorable opinion on the proposed 
amendments.  
It is the responsibility of the investigator responsible for the study in the participating 
centre: 
- 
To provide his curriculum vitae as well as co-investigators 
- 
To identify team members, who will participate in the study and define their 
responsibilities 
- 
To start recruiting patients after authorization of the sponsor 
- 
To try to include the required number of patients within the period of 
recruitment 
It is the responsibility of each investigator: 
- 
To obtain the informed consent dated and signed personally by the patient 
before any selection process specific to the study 
- 
To fill in an electronic case report form (e-CRF) for each patient included in the 
study and allow direct access to source documents to validate e-CRF data 
- 
To correct, sign and date the correction(s) of the e-CRF for each patient enrolled 
- 
To notify the sponsor of any SAE(s) within the time required 
- 
To accept regular monitoring visits and possibly those of auditors mandated by 
the sponsor or inspectors from authorities 
All documentation on the study (protocol, consents, notebooks observation, file 
investigator, etc.) and original documents (laboratory results, x-rays, minutes of 
consultations, review reports...) must be kept in a safe place and considered confidential 
material. 


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The Investigator will maintain the confidentiality of the identity of subjects enrolled in 
the study and the information contained in the study records. 
 
13.4. 
Sponsor responsibilities  
It is the responsibility of the sponsor to: 
- 
Subscribe insurance to cover its liability for the harmful consequences of 
research 
- 
Provide the investigators with all information necessary to conduct the research 
- 
Apply for authorization from a relevant CPP 
- 
Apply for authorization from ANSM 
- 
Inform the Directors and Pharmacists of health facilities 
- 
Inform ANSM of any serious incidents that may be due to research 
 
13.5. 
Biocollections  
Biological samples collected for the immunological assessment will be stored in a 
biocollection. The patient informed consent will be collected and the samples will be 
stored in one of the biocollections of Assistance Publique-Hôpitaux de Paris: the 
Hematology biobank approved by INCa and located at the Saint-Antoine Hospital 
(Declaration N° DC-2009-963 and authorization N° AC-2013-1992). 
The Sponsor shall finance the study and endorses a policy of insurance covering the 
financial consequences of its civil liability in accordance with regulations in order to 
guarantee against possible damage resulting from the research. 
Non-compliance with the Research Legal Conditions is a cause for guarantee exclusion. 


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13.6. 
Archiving 
The data archiving will be under the responsibility of the investigator and, as required 
by law.  
Data will be kept for a minimum of 15 years after the end of the study. 
 
13.7. 
Final report and publications rules 
At the end of the study evaluation, the principle investigator presents a final report, 
containing the clinical report, single tables, and the final conclusions. Publication of the 
results is realized independently from the outcome of the study. The study or parts of 
the study should be published by the writing committee only which consists of the 
persons in charge of the study as mentioned on the front page. According to the EBMT 
rules, co-authors will be offered to the local PI of participating centres, the order 
depending on the number of patients included by the respective centres, or depending 
on their contribution to the protocol or the realization of the study. Other investigators 
will be mentioned in the addendum. All publications and/or communications related to 
this study should at least mention the PI of the study and the sponsor.  


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14. 
References 
 
A'Hern RP. 2001. Sample size tables for exact single-stage phase II designs. Stat Med. 
2001, 20(6):859-66. 
Anderson BE, McNiff, JM, Jain, D, Blazar BR, Shlomchik WD, and Shlomchik 
MJ. 2005. Distinct roles for donor- and host-derived antigen-presenting cells and 
costimulatory molecules in murine chronic graft-versus-host disease: requirements 
depend on target organ. Blood. 2005, 105:2227-34. 
Arai S, Arora M, Wang T, Spellman SR, He W, Couriel DR, et al. 2015. Increasing 
incidence of chronic graft-versus-host disease in allogeneic transplantation: a report 
from the Center for International Blood and Marrow Transplant Research. Biol Blood 
Marrow Transplant. 2015, 21:266-74. 
Arora M, Wagner JE, Davies SM, Blazar BR, Defor T, Enright H, et al. 2001. 
Randomized clinical trial of thalidomide, cyclosporine, and prednisone versus 
cyclosporine and prednisone as initial therapy for chronic graft-versus-host disease. . 
Biol Blood Marrow Transplant. 2001, 7:265-73. 
Atkinson K, Horowitz MM, Gale RP, Van Bekkum DW, Gluckman E, Good RA, 
et al. 1990. Risk factors for chronic graft-versus-host disease after HLA-identical 
sibling bone marrow transplantation. Blood. 1990, 75:2459-64. 
Baroni SS, Santillo M, Bevilacqua F, Luchetti M, Spadoni T, Mancini M, et al. 
2006. Stimulatory autoantibodies to the PDGF receptor in systemic sclerosis . N Engl 
J Med . 2006, 354:2667-76. 
Bobe P, Bonardelle D, Benihoud K, Opolon P, Chelbi-Alix MK. 2006. Arsenic 
trioxide: A promising novel therapeutic agent for lymphoproliferative and autoimmune 
syndromes in MRL/lpr mice. Blood . 2006, 108:3967-75. 
Bruggen MC, Klein I, Greinix H, Bauer W, Kuzmina Z, Rabitsch W, et al. 2014. 
Diverse T-cell responses characterize the different manifestations of cutaneous graft-
versus-host disease. Blood. 2014, 123:290-99. 
Chen GQ, Zhu J, Shi XG, Ni JH, Zhong HJ, Si GY, et al. 1996. In vitro studies on 
cellular and molecular mechanisms of arsenic trioxide (As2O3) in the treatment of 
acute promyelocytic leukemia: As2O3 induces NB4 cell apoptosis with downregulation 
of Bcl-2 expression and modulation of PML-RAR alpha/PML proteins. Blood. 1996, 
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Coghill JM, Sarantopoulos S, Moran TP, Murphy WJ, Blazar BR , Serody JS. 
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and something new. Blood . 2011, 117:3268-76. 
Corre E, Carmagnat M, Busson M, de Latour RP, Robin M, Ribaud P, et al. 2010. 
Long-term immune deficiency after allogeneic stem cell transplantation: B-cell 
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De The H, Chomienne C, Lanotte M, Degos L, Dejean A. 1990. The t(15;17) 
translocation of acute promyelocytic leukaemia fuses the retinoic acid receptor alpha 
gene to a novel transcribed locus. Nature . 1990, 347:558-61. 
Falchi L, Verstovsek S, Ravandi-Kashani F, Kantarjian HM. 2016. The evolution 
of arsenic in the treatment of acute promyelocytic leukemia and other myeloid 
neoplasms: Moving toward an effective oral, outpatient therapy. The evolution of 
arsenic in the treatment of acute promyelocytic leukemia and other myeloid neopl. 
Cancer. 2016, 122(8):1160-68. 
Indik JH, Pearson EC, Fried K, Woosley RL. 2006. Bazett and Fridericia QT 
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2015. (2015). National Institutes of Health Consensus Development Project on Criteria 
for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2014 Diagnosis and 
Staging Working Group report. Biol Blood Marrow Transplant. 2015, 21:389-401. 
Kavian N, Marut W, Servettaz A, Laude H, Nicco C, Chereau C, et al. 2012a. 
Arsenic trioxide prevents murine sclerodermatous graft-versus-host disease. J 
Immunol. 2012a, 188:5142-9. 
Kavian N, Marut W, Servettaz A, Nicco C, Chereau C, Lemarecha H, et al. 2012b. 
Reactive oxygen species-mediated killing of activated fibroblasts by arsenic trioxide 
ameliorates fibrosis in a murine model of systemic sclerosis. Arthritis Rheum . 2012b, 
64:3430-4. 
Koyama M, Hashimoto D, Aoyama K, Matsuoka K, Karube K, Niiro H, et al. 2009. 
Plasmacytoid dendritic cells prime alloreactive T cells to mediate graft-versus-host 
disease as antigen-presenting cells. Blood. 2009, 113:2088-95. 
Kuzmina Z, Greinix HT, Weigl R, Kormoczi U, Rottal A, Frantal S et al. 2011. 
Significant differences in B-cell subpopulations characterize patients with chronic 
graft-versus-host disease-associated dysgammaglobulinemia. Blood . 2011, 117:2265-
74. 
Lee SJ. 2005. New approaches for preventing and treating chronic graft-versus-host 
disease. Blood . 2005, 105:4200-6. 
Lee SJ, Flowers ME. 2008. Recognizing and managing chronic graft-versus-host 
disease. Hematology Am Soc Hematol Educ Program. 2008, 2008:134-41. 
Lee SJ, Wolff, D, Kitko C, Koreth J, Inamoto Y, Jagasia M, Pidala J, Olivieri A, 
et al. 2015. Measuring therapeutic response in chronic graft-versus-host disease. 
National Institutes of Health consensus development project on criteria for clinical 
trials in chronic graft-versus-host disease: IV. The 2014 response Criteria Working 
Group Report. Biol Blood Marrow transplant. 2015, 21:984-99. 
Lo-Coco F, Avvisati G, Vignetti M, Thiede C, Orlando SM, Iacobelli S, et al. 2013. 
Retinoic acid and arsenic trioxide for acute promyelocytic leukemia. N Engl J Med. 
2013, 369:111-21. 
Luo S, Michler K, Johnston P, Macfarlane PW. 2004. A comparison of commonly 
used QT correction formulae: the effect of heart rate on the QTc of normal ECGs. J 
Electrocardiol . 2004, 37 Suppl:81-90. 
Malard F, Chevallier P, Guillaume T, Delaunay J, Rialland F, Harousseau JL, et 
al. 2014. Continuous reduced nonrelapse mortality after allogeneic hematopoietic stem 
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Transplant. 2014, 20:1217-23. 
Martin PJ, Storer BE, Rowley SD, Flowers ME, Lee SJ, Carpenter PA, Wingard 
JR, et al. 2009. Evaluation of mycophenolate mofetil for initial treatment of chronic 
graft-versus-host disease. Blood. 2009, 113:5074-82. 
Matsuoka K, Kim HT, McDonough S, Bascug G, Warshauer B, Koreth J, et al. 
2010. Altered regulatory T cell homeostasis in patients with CD4+ lymphopenia 
following allogeneic hematopoietic stem cell transplantation. J Clin Invest . 2010, 
1479-93. 
Miklos DB, Kim HT, Miller KH, Guo L, Zorn E, Lee SJ, et al. 2005. Antibody 
responses to H-Y minor histocompatibility antigens correlate with chronic graft-versus-
host disease and disease remission. Blood. 2005, 105;2973-8. 
Nakasone H, Tian L, Sahaf B, Kawase T, Schoenrock K., Perloff S et al. 2015. 
Allogeneic HY antibodies detected 3 months after female-to-male HCT predict chronic 
GVHD and nonrelapse mortality in humans. Blood. 2015, 125:3193-3201. 


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Poupon J. 2008. Analyse des molécules inorganiques et des éléments minéraux par 
spectrométrie de Analyse des molécules inorganiques et des éléments minéraux par 
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biologie moléculaire. s.l. : Hainque B, Baudin B, Lefebvre P (Eds), Flammarion 
Médecine-Sciences, 2008. 153-7. 
Sagie A, Larson MG, Goldberg RG, Bengtson JR, Levy D. 1992. An improved 
method for adjusting the QT interval for heart rate (the Framingham Heart Study). Am 
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Sanz MA, Fenaux P, Lo Coco F. 2005. Arsenic trioxide in the treatment of acute 
promyelocytic leukemia. A review of current evidence. Haematologica. 2005, 90:1231-
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Sarantopoulos S, Stevenson KE, Kim HT, Bhuiya NS, Cutler CS, Soiffer RJ, et al. 
2007. High levels of B-cell activating factor in patients with active chronic graft-versus-
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Savani BN, Labopin M, Blaise D, Niederwieser D, Ciceri F, Ganser A, et al. 2016. 
Peripheral blood stem cell graft compared to bone marrow after reduced intensity 
conditioning regimens for acute leukemia: a report from the ALWP of the EBMT. . 
Haematologica. 2016, 101:256-62. 
Schowalter M., Ho VT, et al. 2009. Altered B-cell homeostasis and excess BAFF in 
human chronic graft-versus-host disease. Blood. 2009, 113:3865-74. 
Sengsayadeth S, Savani BN, Blaise D, Malard F, Nagler A, Mohty M. 2015. 
Reduced intensity conditioning allogeneic hematopoietic cell transplantation for adult 
acute myeloid leukemia in complete remission - a review from the Acute Leukemia 
Working Party of the EBMT. Haematologica. 2015, 100:859-69. 
Shimabukuro-Vornhagen A, Hallek MJ, Storb RF, Von Bergwelt-Baildon MS. 
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Singer M, Trugnan G, Chelbi-Alix MK. 2011. Arsenic trioxide reduces 2,4,6-
trinitrobenzene sulfonic acid-induced murine colitis via nuclear factor-kappaB down-
regulation and caspase-3 activation. Innate Immun . 2011, 17:365-74. 
Socie G, and Ritz J. 2014. Current issues in chronic graft-versus-host disease. Blood. 
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2001. United States multicenter study of arsenic trioxide in relapsed acute 
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Soignet SL, Maslak P, Wang ZG, Jhanwar S, Callej E, Dardashti LJ, et al. 1998. 
Complete remission after treatment of acute promyelocytic leukemia with arsenic 
trioxide. N Engl J Med. 1998, 339:1341-8. 
Stewart BL, Storer B, Storek J, Deeg HJ, Storb R, Hansen JA, et al. 2004. Duration 
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Subbarayan PR, Ardalan B. 2014. In the war against solid tumors arsenic trioxide 
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Svegliati S, Olivieri A, Campelli N, Luchetti M, Poloni A, Trappolini S, et al. 2007. 
Stimulatory autoantibodies to PDGF receptor in patients with extensive chronic graft-
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Unnikrishnan D, Dutcher JP, Varshneya N, Lucariello R, Api M, Garl S, et al. 
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Blood. 2001, 97:1514-6. 


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Westervelt P, Brown RA, Adkins DR, Khoury H, Curtin P, Hurd D, et al. 2001. 
Sudden death among patients with acute promyelocytic leukemia treated with arsenic 
trioxide. Blood. 2001, 98:266-71. 
Wolff D, Gerbitz A, Ayuk F, Kiani A, Hildebrandt GC, Vogelsang GB, et al. 2010. 
Consensus conference on clinical practice in chronic graft-versus-host disease 
(GVHD): first-line and topical treatment of chronic GVHD. Biol Blood Marrow 
Transplant . 2010, 16:1611-28. 
Zhang P, Wang S, Hu L, Qiu F, Yang H, Xiao Y, et al. 2000. [Seven years' summary 
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analysis of 242 cases]. . Zhonghua Xue Ye Xue Za Zhi. 2000, 21:67-70. 
Zorn E, Kim HT, Lee SJ, Floyd BH, Litsa D, Arumugarajah S, et al. 2005. Reduced 
frequency of FOXP3+ CD4+CD25+ regulatory T cells in patients with chronic graft-
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Zorn E, Miklo DB, Floy BH, Mattes-Ritz A, Guo L, Soiffe RJ, et al. 2004. Minor 
histocompatibility antigen DBY elicits a coordinated B and T cell response after 
allogeneic stem cell transplantation. J Exp Med . 2004, 199:1133-42. 
 
 
 


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15. 
Appendices 
 


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Appendix 1: Signs and symptoms of cGvHD 
(NIH consensus criteria, Jagasia et al. Bone Marrow Transplant, 2015) 
 
 


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Appendix 2: Organ scoring of cGvHD 
(NIH consensus criteria, Jagasia et al. Bone Marrow Transplant, 2015) 
 
 


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Appendix 3: Genital tract cGvHD assessment and scoring Form 
 (NIH consensus criteria, Jagasia et al. Bone Marrow Transplant, 2015) 
 
 
Name:____________________________________ Date of birth: ________________Assessment date: ____________ 
 
 
      SCORE 0 
        SCORE 1 
        SCORE 2 
SCORE 3 
GENITAL TRACT 
 
Check: 
 
 
 Male    
 Female 
  No signs  
 Mild signs and 
females may have 
symptoms* WITH 
discomfort on exam  
 Moderate signs   
and may have  
symptoms* with 
discomfort on exam 
 Severe signs with  
or without 
symptoms *  
 
Currently sexually active: 
 
 Yes    
 No  
 
Check all signs that apply: 
 
  Lichen planus-like features  
   
  Lichen sclerosis-like features  
 
  Vaginal scarring (female) 
 
  Clitoral/labial agglutination (female) 
 
  Labial resorption (female) 
 
 
 
 
 
  Erosions 
 
  Fissures 
 
  Ulcers 
 
  Phimosis (male) 
 
  Urethral meatus scarring/ stenosis (male) 
 
  Abnormality present but NOT  thought to represent GVHD (specify cause):________________________________ 
  Abnormality thought to represent GVHD PLUS other causes(specify cause):_______________________________  
*Genital symptoms are not specific to cGVHD and can represent premature gonadal failure or genital tract infection.   
 
If a gynecologist is unavailable, external examination may be performed to determine “discomfort on exam” as follows: 
a) Spread the labia majora to inspect the vulva for the above signs.  Touch the vestibular gland openings (Skene’s and 
Bartholin’s), labia minora and majora gently with a qtip.  Vulvar pain elicited by the gentle touch of a qtip is 
classified as discomfort on examination. Palpate the vaginal walls with a single digit to detect bands, shortening, 
narrowing or other signs of vaginal scarring. 
b) If the woman is sexually active, determine whether qtip palpation or gentle palpation of scarred ridges elicits pain 
similar to that which the woman experiences during intercourse. 
 
Female genitalia: Severity of signs: 
1) Mild (any of the following); erythema on vulvar mucosal surfaces, vulvar lichen-planus or vulvar lichen-sclerosis.  
2) Moderate (any of the following); erosive inflammatory changes of the vulvar mucosa, fissures in vulvar folds    
3) Severe (any of the following); labial fusion, clitoral hood agglutination, fibrinous vaginal adhesions, circumferential 
fibrous vaginal banding, vaginal shortening, synechia, dense sclerotic changes, and complete vaginal stenosis.   
 
Male genitalia: Diagnostic features include lichen planus-like or lichen sclerosis-like features and phymosis or urethral 
scarring or stenosis. Severity of signs:  
1) Mild: lichen planus-like feature;  
2) Moderate: lichen sclerosus-like feature or moderate erythema;   
3) Severe: phimosis or urethral/meatal scarring. 
 
 
Biopsy obtained: 
 Yes     
 No     Site  biopsied:______________GVHD confirmed by histology: 
 Yes      
 No 
 
Change from previous evaluation:  
 No prior or current GVHD   
 Improved      
 Stable        
 Worse   
 N/A (baseline) 
 
 
Completed by (print name):_______________________________________Date form completed: _____________ 


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Appendix 4: Performance Status (WHO) 
 
0 - Asymptomatic 
 
1 - Symptomatic, fully ambulatory 
 
2 - Symptomatic, in bed < 50 % of day 
 
3 - Symptomatic, in bed > 50 % of day but not bedridden 
 
4 - Bedridden 


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Appendix 5: Karnofsky Performance Scale Index 
 
Able to carry on normal activity and to work; no special care needed. 
100 - Normal no complaints; no evidence of disease. 
90 - Able to carry on normal activity; minor signs or symptoms of disease. 
80 - Normal activity with effort; some signs or symptoms of disease. 
 
Unable to work; able to live at home and care for most personal needs; varying amount 
of assistance needed. 
70 - Cares for self; unable to carry on normal activity or to do active work. 
60 - Requires occasional assistance, but is able to care for most of his personal needs. 
50 - Requires considerable assistance and frequent medical care. 
 
Unable to care for self; requires equivalent of institutional or hospital care; disease may 
be progressing rapidly. 
40 - Disabled; requires special care and assistance. 
30 - Severely disabled; hospital admission is indicated although death not imminent. 
20 - Very sick; hospital admission necessary; active supportive treatment necessary. 
10 - Moribund; fatal processes progressing rapidly. 
0 - Dead 
 
 


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Appendix 6: Rule of 9s for body surface area 
 
 


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Appendix 7: Drugs reported to prolong QT interval and/or induce torsade de 
pointes 
(Gowda RM et al. Torsade de pointes: the clinical considerations, Int J Cardiol, 
2004) 
 
 
Category 
Drugs 
Antiarrhythmics  
 
Disopyramide, procainamide, n-acetyl-procainamide, 
quinidine, beperdil, mexiletine, propafenone, flecainide, 
amiodarone, bretylium, sotalol, ibutilide, dofetilide, 
azimilide, aprindine, ajmaline, almokalant, mibefradil, 
clofilium, sematilide  
 
Antimicrobials  
 
Erythromycin, clarithromycin, azithromycin, ampicillin, 
levofloxacin, moxifloxacin, sparfloxacin, gatifloxacin, 
grepafloxacin, trimethoprim-sulfamethoxazole, 
troleandomycin, Pentamidine, quinine, foscarnet, 
fluconazole, itraconazole, ketoconazole, chloroquine, 
halofantrine, mefloquine, amantadine, spiramycin  
 
Antihistamines  
 
Astemizole, diphenhydramine, terfenadine, ebastine, 
hydroxyzine  
 
Antidepressants  
 
Doxepin, fluoxetine, desipramine, imipramine, 
clomipramine, paroxetine, sertraline, venlafaxine, 
citalopram, ketanserin  
 
Antipsychotics  
 
Chlorpromazine, prochlorperazine, trifluoperazine, 
fluphenazine, felbamate, haloperidol, droperidol, 
mesoridazine, pimozide, quetiapine, risperidone, 
thioridazine, ziprasidone, lithium, chloral hydrate, 
pericycline,  
 
Anticonvulsants  
 
Felbamate, fosphenytoin  
 
Anesthetics  
 
Sevoflurane  
 
Antianginal/vasodilators  
 
Bepridil, lipoflazine, prenylamine, intracoronary 
papaverine  
 
Antihypertensives  
 
Isradipine, nicardipine, moexipril/ hydrochlorthiazide  
 
Anticancer agents  
 
Arsenic trioxide, tamoxifen  
 
Antilipemic  
 
Probucol  
 
Antimigraine agents  
 
Sumatriptan, zolmitriptan, naratriptan  
 


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Diuretics  
 
Indapamide thiazide, furosemide  
 
Endocrine  
 
octreotide, vasopressin  
 
Gastrointestinal 
stimulants  
Cisapride, metoclopramide, domperidone, erythromycin  
 
Others  
 
Arsenic trioxide, tizanidine, tacrolimus, salmeterol, 
levomethadyl, pinacidil, cromakalin, aconitine, veratridine, 
batrachotoxin, anthopleurin A, ketanserin, vincamine, 
terodiline, budipine, cesium chloride, tiapride, 
levomethadyl acetate, cocaine, organophosphorus 
compounds  


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Appendix 8: cGvHD activity assessment Clinician Form A (Lee SJ et al. Biol Blood Marrow Transplant, 2015) 
 
 
 
Current Patient Weight: ___________________  
 
 
 
Today’s Date: ________________________       MR#/Name: 
____________________    
 
 
CHRONIC GvHD ACTIVITY ASSESSMENT- CLINICIAN 
Health Care 
Provider Global 
Ratings: 
 
0=none 
1= mild 
2=moderate 
3=severe 
 
Where would you rate the severity  of this patient’s chronic GvHD 
symptoms on the following scale, where 0 is cGvHD symptoms that are 
not at all severe and 10 is the most severe cGvHD symptoms possible: 
  
             0       1         2         3         4         5         6         7         8          9         
10 
cGvHD symptoms 
                                                                                           
Most severe cGvHD 
not at all severe                                                   
symptoms possible 
Over the <<time>>  would you say that this 
patient’s  cGvHD is 
+3= Very much better  
+2= Moderately better 
+1= A little better 
  0= About the same 
-1=A little worse 
-2=Moderately worse  
-3=Very much worse 
 
Mouth 
Erythema 
None 
0 
Mild erythema or 
moderate erythema 
(<25%) 
1 
Moderate (≥25%) 
or Severe erythema 
(<25%) 
2 
Severe erythema 
(≥25%)  
3 
Lichenoid 
None 
0 
Lichen-like changes 
(<25%) 
1 
Lichen-like changes 
(25-50%) 
2 
Lichen-like 
changes (>50%) 
3 
Ulcers 
None 
0 
 
 
Ulcers involving 
(≤20%) 
3 
Severe ulcerations 
(>20%) 
6 
            
 
 
 
 
 
 
 
 
Total score for all mucosal changes  
 
Gastrointestinal-
Esophageal 
• Dysphagia     OR 
Odynophagia 
0= no esophageal symptoms 
1=Occasional dysphagia or odynophagia with solid food or pills during the past week 
2=Intermittent dysphagia or odynophagia with solid foods or pills, but not for liquids or soft foods, during the past week 
3=Dysphagia or odynophagia for almost all oral intake, on almost every day of the past week 
Gastrointestinal-Upper GI  
• Early satiety  OR 
• Anorexia     OR 
• Nausea & Vomiting 
0= no symptoms 
1=mild, occasional symptoms, with little reduction in oral intake during the past week 
2=moderate, intermittent symptoms, with some reduction in oral intake during the past week 
3=more severe or persistent symptoms throughout the day, with marked reduction in oral intake, on almost every day of the 
past week 
 
 
FORM A 


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Gastrointestinal-Lower GI 
• Diarrhea 
0= no loose or liquid stools during the past week 
1= occasional  loose or liquid stools, on some days during the past week 
2=intermittent loose or liquid stools throughout the day, on almost every day of the past week, without requiring 
intervention to prevent or correct volume depletion 
3=voluminous diarrhea on almost every day of the past week, requiring intervention to prevent or correct volume depletion 
Lungs (Liters and % 
predicted) 
• Bronchiolitis 
Obliterans 
FEV1 
FVC 
Single Breath DLCO (adjusted for 
hemoglobin) 
TLC 
RV 
Liver Values 
Total serum 
bilirubin 
 
                            
mg/dL 
ULN 
                            
                     
mg/dL 
ALT 
 
                          
U/L 
   ULN                    
 
                                 
U/L 
Alkaline 
Phosphatase 
 
                                  
U/L 
ULN 
                        
                              
U/L 
Baseline Values 
Total Distance Walked in 2 or 6 Mins:  
 
                                               ❑  2 min   
❑ 6 min 
Karnofsky or 
Lansky  
Platelet Count            
                                  
K/uL 
Total WBC                 
                                    
K/uL 
Eosinophils 
                            
                            
%                
 
 Abnormality present but explained entirely by non-GvHD documented cause (specify site/alternate 
cause):_______________________________ 
 Abnormality present but explained entirely by non-GvHD documented cause (specify site/alternate 
cause):_______________________________ 
 Abnormality present but explained entirely by non-GvHD documented cause (specify site/alternate 
cause):_______________________________ 


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CHRONIC GvHD ACTIVITY ASSESSMENT- CLINICIAN (FORM A) 
 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
SKIN 
 
GvHD features to be 
scored      
by BSA: 
Check all that apply: 
 Maculopapular rash / 
erythema 
 Lichen planus-like 
features  
 Sclerotic features 
 Papulosquamous 
lesions or 
    ichthyosis 
 Keratosis pilaris-like 
 
  No BSA   
involved 
 
  1-18% BSA  
 
  19-50% BSA   
  >50% BSA 
 Abnormality present but explained entirely by non-GvHD documented cause 
(specify):_______________________ 
 
 
 
 


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SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
 
SKIN FEATURES  
SCORE: 
 
 
 No 
sclerotic 
features 
 
 
 
 
 Superficial  
   sclerotic features 
“not hidebound” 
(able to pinch) 
Check all that 
apply: 
 Deep sclerotic       
features  
 “Hidebound”        
(unable to pinch)  
 Impaired mobility 
 Ulceration 
If skin features score = 3, BSA% of non-moveable sclerosis/fasciitis  ___________ 
 
How would you rate the severity of this patient’s skin and/or joint tightening on the following scale, 
where 0 is not at all severe and 10 is the most severe symptoms possible: 
  
             0       1         2         3         4         5         6         7         8          9         10 
Symptoms                                                                                                   Most severe 
not at all severe                                                                                             symptoms possible 
 


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SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
EYES 
 
 
 
 
  No 
symptoms  
     symptoms  
  Mild dry eye 
symptoms not 
affecting ADL 
(requirement 
of lubricant 
eye drops  < 3 
x per day)  
 
  Moderate dry eye 
symptoms partially 
affecting ADL 
(requiring 
lubricant eye drops 
> 3 x per day or 
punctal plugs), 
WITHOUT new 
vision impairment 
due to KCS 
  Severe dry eye 
symptoms 
significantly 
affecting ADL 
(special eyeware 
to relieve pain) 
OR unable to 
work because of 
ocular symptoms 
OR loss of 
vision due to 
KCS 
 Abnormality present but explained entirely by non-GvHD documented cause 
(specify):_______________________ 
LUNGS 
 
 
  
 
 
 
 No 
symptoms 
 
 
 
  Mild 
symptoms 
(shortness of 
breath after 
climbing one 
flight of steps) 
 
  Moderate 
symptoms 
(shortness of 
breath after 
walking on flat 
ground) 
 
  Severe 
symptoms 
(shortness of 
breath  at rest; 
requiring 02) 
 Abnormality present but explained entirely by non-GvHD documented cause 
(
if )


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Page 114 
 
 
SCORE 0 
SCORE 1 
SCORE 2 
SCORE 3 
JOINTS AND 
FASCIA 
 
 
  No 
symptoms 
  Mild tightness 
of arms or legs, 
normal or mild 
decreased range 
of motion (ROM) 
AND not 
affecting ADL 
  Tightness of arms 
or legs OR joint 
contractures, 
erythema thought due 
to fasciitis, moderate 
decrease ROM AND 
mild to moderate 
limitation of ADL 
  Contractures 
WITH significant 
decrease of ROM 
AND significant 
limitation of ADL 
(unable to tie shoes, 
button shirts, dress 
self etc.)  
 Abnormality present but explained entirely by non-GvHD documented cause 
(specify):_______________________ 
 
 


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❑ Not done 
❑ Not done 
❑ Not done 
❑ Not done 


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Appendix 9: cHVHD assessment patient self-report Form B 
(Lee SJ et al. Biol Blood Marrow Transplant, 2015) 
 
Today’s Date: ________________________ 
 
MR#/Name: ________________________ 
 
CHRONIC GvHD ACTIVITY ASSESSMENT-PATIENT SELF REPORT 
 
 
 
Symptoms 
 
 
Not                                                                                                                               As Bad As 
You 
Present                                                                                                                           Can 
Imagine 
 
Non présent                                                                                                                                Le plus sévère 
                                                                                                                               que vous puissiez imaginer 
 
  0              1             2             3              4             5            6            7             8              9            10 
Please rate how severe the following 
symptoms have been in the last seven days.  
Please fill in the circle below from 0 
(symptom has not been present) to 10 (the 
symptom was as bad as you can imagine it 
could be) for each item. 
(SVP évaluez la sévérité des symptômes suivants 
au cours des sept derniers jours. SVP cochez le 
cercle correspondant entre 0 (symptôme non 
présent) à 10 (symptôme le plus sévère que vous 
puissiez imaginer) pour chaque élément. 
Your skin itching at its WORST? 
(démangeaisons de la peau au pire moment) 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Your skin and/or joint tightening at their 
WORST? (raidissement de la peau et/ou de 
l’articulation au pire moment) 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Your mouth sensitivity at its WORST? 
(sensibilité buccale au pire moment) 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
FORM B 


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Your genital discomfort at its WORST? 
(gêne au niveau génital  au pire moment) 
(Women – vagina, vulva, or labia) 
(Men – penis) 
(Femmes - vagin, vulve, ou lèvres) 
(Hommes - pénis) 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
O 
Eyes (Yeux) 
What is your main complaint with regard to your eyes? 
(Quelle est votre principale plainte concernant vos yeux?) 
Please rate how severe this symptom is, from 0 (not at all 
severe) to 10 (most severe): 
SVP cotez la sévérité de ce symptôme, de 0 (pas du tout sévère) à 10 
(le plus sévère) 
 
0    1     2     3     4     5     6     7     8      9    10 
Patient Global Ratings: 
 
1. Overall, do you think that your chronic graft versus host disease is mild, moderate or severe? (Dans l'ensemble, pensez-vous que votre 
maladie chronique du greffon contre l'hôte est légère, modérée ou sévère ?) 
1= mild (légère) 
2=moderate (modérée) 
3=severe (sévère) 
 
2. Please circle the number indicating how severe your chronic graft versus host disease symptoms are, where 0 is cGvHD symptoms 
that are not at all severe and 10 is the most severe chronic GvHD symptoms possible. 
(SBP entourer le chiffre indiquant la gravité de vos symptômes de votre maladie chronique du greffon contre l'hôte, où 0 correspond à des symptômes de 
cGvHD qui ne sont pas du tout sévères et 10 aux symptômes de GvHD chronique les plus sévères). 
 
          0         1           2           3           4           5           6           7           8            9           10 
cGvHD symptoms                                                                                        Most severe cGvHD  
   not at all severe                                                                                           symptoms  possible 
Symptômes pas du tout sévères                                                                         Symptômes les plus sévères 


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3. Compared to a month ago, overall would you say that your cGvHD symptoms are: 
(Par rapport à il y a un mois, dans l'ensemble diriez-vous que vos symptômes de cGvHD sont) 
 
+3= Very much better (Beaucoup mieux) 
+2= Moderately better (Modérément mieux) 
+1=A little better (Un peu mieux) 
 0= About the same (A peu près identiques) 
-1=A little worse (Un peu plus mauvais) 
-2=Moderately worse (Modérément plus mauvais) 
-3=Very much worse (Beaucoup plus mauvais)  


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Appendix 10 : Lee Symptom Scale 
(Lee SJ et al. Biol Blood Marrow Transplant, 2004) 
 


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SAP_001.pdf: 
 
SAP version 3.0: GvHD-ATO Study 
December 21 2020 
Page 1 of 120 
 
 
 
 
 
 
 
 
Official Title: Phase II study of first line treatment of Chronic Graft versus Host Disease 
with Arsenic Trioxide 
 
 
 
NCT Number: 02966301 
 
 
 
Document Dates: SAP Amendment / Version 3 : 2020/12/21 
 
 
 
 
 


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STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
Phase II study of first line treatment of 
Chronic Graft versus Host Disease with Arsenic Trioxide 
Protocol 
Number: 
GMED16-001 
Eudract number: 2016-002358-18 
Compound: 
ATO ® 
Phase: 
Phase II 
Sponsor: 
MEDSENIC 
204, avenue de Colmar 
F-67100 - Strasbourg 
SAP Author: 
Marine RAGOT-BENSEGHIR 
SAP Version: 
Version 3.0 
SAP Date: 
21/12/2020 
 
Notice of Confidential and Proprietary Information: 
The information contained in this document is the property of MEDSENIC. The disclosure 
of the information to others without written prior approval from MEDSENIC is forbidden. 
 
 
 
 


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STATISTICAL ANALYSIS PLAN  
DOCUMENT HISTORY 
 
 
 
Version 
Date 
Author 
Final v1 
13/06/2018 
Myriam Labopin 
Final v2 
08/08/2019 
Maëva Dupuis-Deniaud 
Final v3 
21/12/2020 
Marine Ragot-Benseghir 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. SIGNATURE PAGE AND APPROVALS 
 
Written by  
Marine RAGOT-BENSEGHIR 
Statistical project leader 
SOLADIS 
 
 Date 
Approved by 
Maëva DUPUIS-DENIAUD 
Biostatistician consultant 
MDSTAT 
 
 Date 
Sponsor’s representative 
Pr François RIEGER 
CEO – Scientific Director 
MEDSENIC 
 
 Date 
Sponsor’s representative 
Dominique GAIDA 
Clinical Project Manager 
MEDSENIC 
 
 Date 
 
 


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2. SYNOPSIS 
Sponsor: 
MEDSENIC 
204, avenue de Colmar 
F-67100 - Strasbourg 
Title 
Phase II study of first line treatment of Chronic Graft versus Host 
Disease with Arsenic Trioxide (GvHD-ATO Study) 
Eudract Number 
2016-002358-18 
Coordinating 
investigator 
Pr Mohamad MOHTY 
Centre Hospitalier Saint Antoine (AP-HP) 
Service d’Hématologie Clinique 
Phase of 
development 
Phase II 
Objectives 
Main Objective 
• 
To improve the response rate (complete and partial 
remission) at 6 months after diagnosis of chronic graft versus 
host disease (GvHD) and treatment with arsenic trioxide 
(ATO) in combination with prednisone with or without 
cyclosporine as a first line treatment 
Secondary Objectives 
• 
To evaluate failure-free survival (FFS), defined as death, 
recurrent or progressive malignancy, or initiation of a new 
systemic treatment for chronic GvHD 
• 
To decrease non-relapse mortality (NRM) of infectious and 
non-infectious origin 
• 
To improve overall survival (OS) and progression-free 
survival (PFS) 
• 
To spare patients from long-term use of corticosteroids (and 
their long-term side effects) 


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• 
To improve quality of life self-reported by patient using the 
Lee Symptom Scale (LSS) and Functional Assessment of 
Chronic Illness Therapy with Bone Marrow Transplantation 
subscale (FACT-BMT) 
• 
To evaluate tolerability and safety of ATO in combination with 
prednisone, with or without cyclosporine, in patients with 
chronic GvHD after allo-SCT 
Study design 
Prospective, national, multicentre, non-randomized 
Number of 
patients 
planned 
24 patients planned to be included in the study 
Study centres 
11 sites planned to participate to the study 
Studied 
population 
Inclusion criteria 
- Adult patients (≥18 years) who have received a first allogeneic stem 
cell transplantation for a hematological disease (any source of 
hematopoietic stem cells is authorized; any category of conditioning 
regimen prior to allo-SCT is authorized; any type of stem cell donors 
is authorized)  
- Confirmed diagnosis of first episode of chronic GvHD requiring 
systemic immunosuppressive therapy (any prior GvHD prophylaxis 
previously used is accepted). Chronic GvHD diagnosis is defined 
according to the National Institutes of Health (NIH) Working Group 
Consensus.  
a/ Performance status evaluation 
b/ Cutaneous evaluation measured by the percentage of extension 
or the presence of sclerotic features. If relevant, confirmation with a 
biopsy should be performed whenever possible 
c/ Oral symptoms 
d/ Ocular symptoms 
e/ Gastro-intestinal symptoms 
f/ Evaluation of liver involvement manifestations (total bilirubin, 
transaminases and alkalines phosphatases) 
g/ Pulmonary function evaluation 


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h/ Evaluation of the musculoskeletal manifestations, especially the 
amplitude of relevant articulations 
i/ Genital tract symptoms 
-  Signed informed consent  
-  Absence of contra-indications to the use of ATO  
- Subjects affiliated with an appropriate social security system  
- Men must use a medically acceptable method of contraception 
throughout the treatment period and for at least 4 months and 10 
days following the last treatment administration  
- Women who are of childbearing potential must have a negative 
serum pregnancy test and agree to use a medically acceptable 
method of contraception throughout the study and for 3 months 
following the end of the study  
- Patient not participating or not having participated in a clinical study 
in the 30 days prior to his/her inclusion in the study 
Exclusion criteria 
- Patient developing acute GvHD (whether early or “late onset” form)  
- Patients developing overlap GvHD as defined by the 2015 NIH 
Working Group Consensus (presence of one or more acute GvHD 
manifestation in a patient with a diagnosis of chronic GvHD) 
- A “mild” form of chronic GvHD not requiring systemic 
immunosuppressive therapy 
-  A “moderate” form of chronic GvHD limited to one organ site not 
requiring systemic immunosuppressive therapy 
- Patient receiving mycophenolate mofetil 
- Second allogeneic stem cell transplant 
- Severe cardiac diseases (congestive heart failure (NYHA class III), 
recent myocardial infarction (in the past 6 months before the 
inclusion), histories of unexplained syncope, …)  
- Significant arrhythmias, EKG abnormalities 
- Congenital QT syndromes  
- History or presence of significant ventricular or atrial 
tachyarrhythmia  


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- Clinically significant resting bradycardia (<50 beats per 
minutes)  
- QTc > 450 msec for men and > 470 msec for women on 
screening EKG  
- Right bundle branch block plus left anterior hemiblock, 
bifascicular block  
 
- Central or peripheral neuropathy  
- Neutrophils < 0.5 × 109/L 
- Platelets < 50 × 109/L 
- Potassium ≤ 4 mEq/l* 
- Magnesium ≤ 1.8 mg/dl* 
- Calcium ≤ 2.15 mmol/l* 
- Hepatic impairment due to a suspected or proven liver damage, 
other than direct hepatic cGvHD involvement 
- PT < 50% 
- Renal impairment (creatinine ≥ 100 μmol/l) 
- Uncontrolled systemic infection which in the opinion of the 
investigator is associated with an increased risk of the patients death 
within 1 month after the start of therapy 
- Severe neurological or psychiatric disorders 
- Denied informed consent 
- Pregnancy 
- Women breastfeeding at selection and throughout the treatment 
period 
* If abnormal at selection, to be corrected and re-validated following 
electrolytes infusion, before inclusion and each drug perfusion. 
Investigational 
product 
Arsenic trioxide 10 mg, concentrate for solution for infusion 1 mg/mL 
(aqueous sterile, clear, colorless). 


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Arsenic trioxide is administrated either via the marketed product 
named TRISENOX® or the investigational medicinal product named 
ARSCIMED®. 
Patients under TRISENOX® treatment will not switch to ARSCIMED® 
treatment nor vice versa: 
- 
Patients already recruited and receiving TRISENOX® will 
continue receiving only TRISENOX®. 
- 
All patients recruited after this amendment has been 
approved will receive ARSCIMED®  only and not 
TRISENOX®. 
Treatment scheme 
As soon as the diagnosis of chronic GvHD requiring systemic 
immunosuppressive therapy is confirmed, patients will receive in 
addition to corticosteroids (prednisone) 1/mg/kg/day, with or without 
cyclosporine A, a daily infusion of ATO 0.15 mg/kg/day on days 1 to 
5 (first week), 3 times per week during the second week (for example, 
days 8, 10 and 12), 2 times per week during the third week (for 
example, days 15 and 17) and one time during the fourth week (for 
example, day 24) (the latter four weeks represent one cycle). 
ATO should be administered within 10 days of starting prednisone at 
1mg/kg/day for cGvHD treatment. Follow-up dates for response 
assessment and laboratory tests relate to the date of ATO infusion. 
Patients who are in partial response after the 1st cycle of ATO will be 
eligible to receive a second cycle of ATO infusions during 4 weeks 
(similar schedule to first cycle starting around day 60). In another 
word, a delay of 8 weeks to a maximum of 11 weeks (from the first 
infusion of ATO) will be observed between the two cycles of ATO 
therapy. 
Response definition is as follows: 
- 
Complete 
remission 
(CR) 
is 
defined 
as 
complete 
disappearance of any sign of chronic GvHD 
- 
Partial remission (PR) is defined as improvement of 1 or more 
point on a 4 to 7-point scale or improvement of 2 or more 
points on a 10 to 12-points scale in at least 1 organ or site 
without progression in any other organ or site. For patients 
with Bronchiolitis Obliterans Syndrome (BOS), an absolute 


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improvement in % FEV1 of 10% predicted or more (eg, 50% 
to 60%) is considered a PR as long as the initial % FEV1 is < 
70%. Normalization (≥ 80%) is considered a CR. 
- 
Failure is defined as death, recurrent or progressive 
malignancy or the irritation of new systemic treatment for 
chronic GvHD. Increased dosing of existing treatment will not 
be considered as failure. Early failure is defined as failure 
within 2 weeks after the end of the first ATO cycle. 
Indications for secondary systemic treatment of chronic GvHD 
Secondary systemic immunosuppressive treatment or other 
systemic treatment for control of chronic GvHD will be given at the 
discretion of the investigator in consultation with the GvHD team. In 
general, secondary systemic treatment is not indicated as long as 
there is continuing improvement in at least one manifestation of 
chronic GvHD and no progression of any other manifestations. 
Study endpoints 
Primary endpoint 
- 
Evaluation of response rate (complete and partial remission) 
of chronic GvHD at 6 months after diagnosis of chronic GvHD 
and treatment with arsenic trioxide (ATO) in combination with 
prednisone, with or without cyclosporine, as first line 
treatment. 
Secondary endpoints 
- 
Percentage of patients with documented failure free survival 
(FFS), 
defined 
as 
death, 
recurrent 
or 
progressive 
malignancy, or the initiation of a new systemic treatment for 
chronic GvHD 
- 
Corticosteroids dosage and percentage of reduction in 
corticosteroids dosage at 6 and 12 months after diagnosis of 
chronic GvHD and treatment with ATO as first line treatment 
- 
Cumulative dosage and percentage of reduction in 
corticosteroids dosage at 6 and 12 months after diagnosis of 
chronic GvHD and treatment with ATO as first line treatment 
- 
OS and PFS at 6 and 12 months after diagnosis of chronic 
GvHD and treatment ATO as first line treatment 


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- 
Descriptive analysis of quality of life parameters at inclusion, 
at 6 and 14 weeks, and at 6, 9 and 12 months after diagnosis 
of chronic GvHD and treatment with ATO as first line 
treatment. 
- 
Tolerability and safety of ATO in combination with 
prednisone, with or without cyclosporine, in patients with 
chronic GvHD after allo-SCT. 
Statistical 
methods 
Sample size calculation 
Based on results from the literature, the hypothesis for the primary 
endpoint is an improvement in response rate (complete an partial 
remission) at 6 months after the diagnosis of chronic GvHD and start 
of corticosteroids, ATO, with or without cyclosporine, from 60% to 
85%. Using a one step A Hern procedure (and anticipating a dropout 
rate around 10%), 24 (21+3) patients are needed (A’Hern RP, 2001). 
If the number of successful cases is 17 or more among the 21 
patients, the hypothesis that the CR rate at 6 months is less than 
60% is rejected with a target error rate of 0.05 (alpha probability). 
The beta probability in this case is 0.2. 
Statistical analyses 
Every patient included in the study and who has received at least one 
infusion of ATO will be taken into account at time of data analysis. A 
descriptive analysis will be conducted on the following parameters: 
- 
Patients and transplant characteristics 
- 
Primary and secondary endpoints 
Patients who do not receive any injection of ATO will not be analysed 
and will be replaced to obtain 24 patients provided in the statistical 
analysis. 
Qualitative data will be described in frequency and percentage and 
will be represented using histograms or diagrams of distribution. 
Quantitative data will be described using the calculations of average, 
standard deviation, median, and extreme values. 
The toxicities rate will be calculated and will be given with their 95% 
confidence intervals. 


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The probabilities of survival will be estimated by the Kaplan-Meier 
method and by calculating the cumulative incidences for 
relapse/progression, and non-relapse mortality incidence. 
Study duration 
The total duration of the study is expected to be 46 months (duration 
of recruitment: 34 months and study duration for a considered 
patient: 12 months) 
Study calendar 
First patient first visit: September 2016 
Last patient last visit: June 2020 
Database lock: December 2020 
Clinical study Report: March 2020 
 


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3. TABLE OF CONTENTS 
1. 
SIGNATURE PAGE AND APPROVALS .......................................................... 4 
2. 
SYNOPSIS .......................................................................................................... 5 
3. 
TABLE OF CONTENTS ................................................................................... 13 
4. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .......................... 16 
5. 
ETHICS ............................................................................................................. 17 
5.1 
REGULATORY AUTHORITIES APPROVAL (CPP AND ANSM) ......................................17 
5.2 
INFORMED CONSENT ........................................................................................................18 
5.3 
INVESTIGATORS RESPONSABILITIES ............................................................................18 
5.4 
SPONSOR RESPONSABILITIES .......................................................................................20 
5.5 
BIOCOLLECTIONS .............................................................................................................20 
5.6 
ARCHIVING ..........................................................................................................................20 
6. 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE .............. 21 
7. 
INTRODUCTION .............................................................................................. 22 
8. 
STUDY OBJECTIVES AND ENDPOINTS ...................................................... 24 
8.1 
OBJECTIVES .......................................................................................................................24 
8.1.1 
Primary objective ..............................................................................................................24 
8.1.2 
Secondary objectives .......................................................................................................24 
8.2 
ENDPOINTS .........................................................................................................................24 
8.2.1 
Primary endpoint ..............................................................................................................24 
8.2.2 
Secondary endpoints .......................................................................................................25 


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9. 
INVESTIGATIONAL PLAN .............................................................................. 27 
9.1 
OVERALL STUDY DESIGN AND PLAN.............................................................................27 
9.2 
SELECTION OF STUDY POPULATION .............................................................................28 
9.2.1 
Inclusion criteria ...............................................................................................................28 
9.2.2 
Exclusion criteria ..............................................................................................................28 
9.3 
TREATMENTS .....................................................................................................................30 
9.3.1 
Treatments administered .................................................................................................30 
9.3.2 
Identity of Investigational Product(s) ................................................................................32 
9.3.3 
Administration ...................................................................................................................32 
9.3.4 
Method of Assigning Patients to Treatments Groups ......................................................33 
9.3.5 
Blinding .............................................................................................................................33 
9.3.6 
Prior and Concomitant Therapy .......................................................................................34 
9.4 
EFFICACY AND SAFETY VARIABLES..............................................................................38 
9.4.1 
Efficacy and Safety Measurements Assessed and Schedule of Assessments ...............38 
9.5 
DATA QUALITY ASSURANCE ...........................................................................................40 
9.5.1 
GOOD CLINICAL PRACTICE .............................................................................................40 
9.5.2 
AUDITING ........................................................................................................................40 
9.5.3 
MONITORING ..................................................................................................................40 
9.5.4 
DATA MANAGEMENT .....................................................................................................41 
12.4 
STATISTICAL ANALYSIS METHODES PLANNED IN THE PROTOCOL AND 
DETERMINATION OF SAMPLE SIZE .............................................................................................43 
12.4.3 
Statistical and Analytical Plans ....................................................................................43 
12.5 
CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS....................45 
10. PATIENTS ........................................................................................................ 46 
10.1 
DISPOSITION OF PATIENTS..............................................................................................46 
10.2 
PROTOCOL DEVIATIONS ..................................................................................................47 
11. EFFICACY EVALUATION ............................................................................... 48 
11.1 
ANALYSES POPULATIONS ...............................................................................................48 
11.2 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.....................................49 
11.2.1 
Demographic characteristics .......................................................................................49 
11.2.2 
Baseline characteristics ...............................................................................................50 
11.2.3 
Signs and symptoms of cGvHD at baseline ................................................................55 


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11.3 
ATO AND ASSOCIATED TREATMENTS ...........................................................................61 
11.3.1 
Arsenic trioxide therapy ...............................................................................................61 
11.3.2 
Associated treatment ...................................................................................................66 
11.4 
EFFICACY ANALYSIS ........................................................................................................69 
11.4.1 
Primary Endpoint analysis ...........................................................................................69 
11.4.2 
Secondary Endpoint analyses .....................................................................................71 
 SAFETY EVALUATION ................................................................................... 95 
12.1 
ADVERSE EVENTS .............................................................................................................95 
12.2 
LABORATORY PARAMETERS ..........................................................................................97 
12.3 
PHYSICAL EXAMINATION .................................................................................................99 
 DISCUSSION AND OVERALL CONCLUSIONS.......................................... 101 
 TABLES, FIGURES AND GRAPHS ............................................................. 102 
14.1 
TABLES ............................................................................................................................ 102 
14.2 
FIGURES AND GRAPHS ................................................................................................. 105 
 REFERENCE LIST ......................................................................................... 109 
 LISTINGS........................................................................................................ 110 
 APPENDICES................................................................................................. 111 
17.1 
RESPONSE CALCULATION ALGORITHM .................................................................... 111 
17.2 
FACT-BMT ........................................................................................................................ 116 
17.2.1 
FACT-BMT items ...................................................................................................... 116 
17.2.2 
Details of FACT-BMT calculation.............................................................................. 118 
17.3 
LEE SYMPTOM SCALE ................................................................................................... 119 
 


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4. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
 
 
 
 
 
Adverse Event 
ALAT/SGPT   
 
 
 
Alanine Amino-Transferase 
Allo-SCT  
 
 
 
 
Allogeneic Stem-Cell Transplantation 
APL  
 
 
 
 
 
Acute Promyelocytic Leukemia 
ASAT/SGOT   
 
 
 
Aspartate Amino-Transferase 
ATO  
 
 
 
 
 
Arsenic Trioxide 
ATRA   
 
 
 
 
All-trans Retinoic Acid (tretinoin) 
CBC   
 
 
 
 
Complete Blood Count 
cGvHD  
 
 
 
 
Chronic Graft Versus Host Disease 
CMV   
 
 
 
 
Cytomegalovirus 
CR  
 
 
 
 
 
Complete Remission 
DLI  
 
 
 
 
 
Donor Lymphocytes Infusion 
EBV  
 
 
 
 
 
Epstein Barr Virus 
e-CRF   
 
 
 
 
Electronic Case Report Form 
EKG   
 
 
 
 
Electrocardiogram 
FACT-BMT  
Functional Assessment of Chronic Illness 
Therapy with Bone Marrow Transplantation 
subscale 
FAS 
Full Analysis Set 
FEV  
 
 
 
 
 
Forced Expiratory Volume 
FFS  
 
 
 
 
 
Failure-free Survival 
GHVD   
 
 
 
 
Graft Versus Host Disease 
Hep  
 
 
 
 
 
Hepatitis 
HLA  
 
 
 
 
 
Human Leucocyte Antigen 
HY  
 
 
 
 
 
Y-chromosome–encoded 
ICH  
 
 
 
 
 
International Conference on Harmonization 
IQR  
 
 
 
 
 
inter-quartile range 
IVIG  
 
 
 
 
 
Intravenous Immunoglobulin 
HSCT   
 
 
 
 
Hematopoietic Stem Cell Transplantation 
LSS  
 
 
 
 
 
Lee Symptom Scale 
MedDRA 
 
 
 
 
Medical Dictionary for Regulatory Activities 
NIH  
 
 
 
 
 
National Institutes of Health 
NRM   
 
 
 
 
Non-relapse Mortality 
OS  
 
 
 
 
 
Overall Survival 
PDC   
 
 
 
 
Plasmacytoid Dendritic Cells 
PFS  
 
 
 
 
 
Progression-free Survival 
PI 
 
 
 
 
 
Principal Investigator 
PP 
 
 
 
 
 
Per Protocol 
PR  
 
 
 
 
 
Partial Remission 
RIC  
 
 
 
 
 
Reduced Intensity Conditioning 
ROS   
 
 
 
 
Reactive Oxygen Species 
SAE  
 
 
 
 
 
Serious Adverse Event 
TRM   
 
 
 
 
Transplant-related Mortality 
WHO  
 
 
 
World Health Organization 


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5. ETHICS 
The study will be conducted according to the European Union directive (ICH Harmonized 
Tripartite Guideline for Good Clinical Practice, (17.01.1997)). The study has to be 
conducted in compliance with the protocol, GCP and all applicable regulatory requirements: 
- 
Helsinki declaration from 1964, revised in Washington in 2002, 
- 
GCP of the International Harmonization Conference (ICH E6, 17/07/96), 
-    European Directive (2001/20/CE) on the conduct of clinical trials, 
- 
French law no 2004-801 dated 6 August 2004, 
 
 French bioethics law no 2004-800 dated 6 August 2004. 
Accordingly, investigating physicians have to provide direct access to study documents to 
monitoring, audits, institutional internal control, external authorities, and the members of 
the ethical committee. Written informed consent by the patient is mandatory. 
The coordinating investigator and all investigators will be given an up-to-date investigator's 
brochure containing full details of the status of the pre-clinical and clinical knowledge of the 
study medication. As soon as new information is obtained, an updated version will be sup- 
plied or an amendment added to the existing investigator s brochure. 
5.1 
REGULATORY AUTHORITIES APPROVAL (CPP AND ANSM) 
No patient may be included in the study before the respective requirements of the national 
health authorities are fulfilled. The study will begin only after the positive vote of the 
responsible Ethics Committee (CPP) and after the approval by the appropriate national 
health authority (ANSM). 
The protocol has to be followed strictly, protocol violations have to be documented and the 
reason has to be given (e.g. emergency measures). Any changes in the protocol can only 
be performed by the principle investigator or the protocol writing committee. Any 


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subsequent changes will be reported or submitted for approval to the ethical committee and 
to local and national authorities. 
5.2 
INFORMED CONSENT 
Written informed consent is obtained by each patient before inclusion into the study. Using 
patient information sheets, as well as personal oral explanation by a local investigator at 
the patient's transplant centre, the patient will be informed of the aims and the 
investigational nature of the study, the exact procedures that will be done during treatment 
and evaluation, the possible risks and side effects, and of alternative treatment options. 
They will be informed as to the strict confidentiality of their patient data, but that authorized 
individuals other than their treating physician may review their medical records for study 
purposes. Further, the patient will be informed that their anonymized data will be 
scientifically analyzed and published. It will be emphasized that the participation is voluntary 
and that consent can be withdrawn by the patient at any time without explanation of the 
reason. The patient is allowed to refuse further participation in the protocol, whenever 
he/she wants. The patient's further treatment will not be influenced by this decision. 
5.3 
INVESTIGATORS RESPONSABILITIES 
In collaboration and according to the Standard Operating Procedure (SOP) of the sponsor, 
a detailed list of delegation of responsibilities has been established. It is held by the 
sponsor, who is finally responsible for the correct performance of delegated responsibilities 
by the respective persons or institutions. A copy of this list will be delivered to the 
participating institutions. 
The investigator of each institution undertakes to conduct the study according to the 
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investigator must not make any changes to the protocol without the permission of the 
sponsor and without the CCP has given a favorable opinion on the proposed amendments. 
It is the responsibility of the investigator responsible for the study in the participating centre: 
- 
To provide his curriculum vitae as well as co-investigators 
- 
To identify team members, who will participate in the study and define their 
responsibilities 
- 
To start recruiting patients after authorization of the sponsor 
- 
To try to include the required number of patients within the period of recruitment 
It is the responsibility of each investigator: 
- 
To obtain the informed consent dated and signed personally by the patient before 
any selection process specific to the study 
- 
To fill in an electronic case report form (e-CRF) for each patient included in the study 
and allow direct access to source documents to validate e-CRF data  To correct, 
sign and date the correction(s) of the e-CRF for each patient enrolled 
- 
To notify the sponsor of any SAE(s) within the time required 
- 
To accept regular monitoring visits and possibly those of auditors mandated by the 
sponsor or inspectors from authorities 
All documentation on the study (protocol, consents, notebooks observation, file 
investigator, etc.) and original documents (laboratory results, x-rays, minutes of 
consultations, review reports...) must be kept in a safe place and considered confidential 
material. 
The Investigator will maintain the confidentiality of the identity of subjects enrolled in the 
study and the information contained in the study records. 


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5.4 
SPONSOR RESPONSABILITIES 
It is the responsibility of the sponsor to: 
- 
Subscribe insurance to cover its liability for the harmful consequences of research 
- 
Provide the investigators with all information necessary to conduct the research 
- 
Apply for authorization from a relevant CPP 
- 
Apply for authorization from ANSM 
- 
Inform the Directors and Pharmacists of health facilities 
- 
Inform ANSM of any serious incidents that may be due to research 
 
5.5 
BIOCOLLECTIONS 
Biological samples collected for the immunological assessment will be stored in a 
biocollection. The patient informed consent will be collected and the samples will be stored 
in one of the biocollections of Assistance Publique-Hôpitaux de Paris: the Hematology 
biobank approved by INCa and located at the Saint-Antoine Hospital (Declaration N O DC-
2009-963 and authorization N O AC-2013-1992). 
The Sponsor shall finance the study and endorses a policy of insurance covering the 
financial consequences of its civil liability in accordance with regulations in order to 
guarantee against possible damage resulting from the research. 
Non-compliance with the Research Legal Conditions is a cause for guarantee exclusion. 
5.6 
 ARCHIVING 
The data archiving will be under the responsibility of the investigator and, as required by 
law. 
Data will be kept for a minimum of 15 years after the end of the study. 
 


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6. INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
Sponsor 
MEDSENIC 
204, avenue de Colmar  
F-67100 Strasbourg 
Tel: + 33 (0) 1 79 25 14 42 
CEO- Scientific Director 
Pr François Rieger 
Mail:  
Executive Director 
Véronique Pomi 
Mail:  
Clinical Project Leader 
Dominique Gaïda, PhD 
Mail:  
Coordinating Investigator 
Pr Mohamad MOHTY 
Service d’Hématologie Clinique 
Hôpital Saint Antoine AP-HP 
F-75012 – Paris 
Tel:  
Contract Reasearch Organization 
PopsiCube – Fovea 
6 rue Jean-Pierre Timbaud 
Le Campus – Bât A1 Sud 
F-78180 Montigny le Bretonneux 
Tel:  
Fax:  
 


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7. INTRODUCTION 
Chronic Graft-versus-Host Disease (GvHD) is one of the most common and clinically 
significant complication affecting long-term survivors of allogeneic stem cell transplantation 
(allo-SCT). Chronic GvHD (cGvHD) is the cause of death in up to one third of all long-term 
survivors after transplantation for leukemia and is consistently associated with decreased 
quality of life, impaired functional status, ongoing need for immunosuppressive medications 
and infectious complications. Standard first line systemic treatment for cGvHD is orally 
administered corticosteroids (prednisolone 1 mg/Kg/d) and cyclosporine, with a median 
duration reported between 18 and 23 months. Therapy with corticosteroids is often 
unrewarding and the toxicities from prolonged corticosteroid administration are great. 
Chronic GvHD emerges from alloreactive processes between donor-derived immune cells 
and host cell populations. While its pathophysiology is still poorly understood, data in 
humans support a role of both T and B cells in a highly complex network. How these T- and 
B-cell networks interact has not been resolved. 
Arsenic derivatives have been identified as compounds with therapeutic potential for over 
2000 years in Greek and Chinese medicine. The combination of ATO and oral all-trans 
retinoic acid tretinoin [ATRA]) currently constitutes the standard of care for most patients 
with newly diagnosed and/or relapsed acute promyelocytic leukemia (APL). The use of ATO 
has also been explored in many other hematologic malignancies and in solid tumors. Its 
role has also been explored in murine models of autoimmune and autoinflammatory 
diseases. Chronic GvHD presents clinical features that mimic autoimmune diseases such 
as systemic sclerosis, lupus erythematosus or Sjögren syndrome, and autoimmune-like 
manifestations are a defining characteristic of cGvHD. In a murine model of chronic GvHD, 
ATO effect was mediated through the depletion of glutathione and the overproduction of 
H2O2 that killed activated CD4+ T cells, in particular Th17 cells, and PDC, two key cells in 
chronic GvHD pathophysiology initiation. Furthermore, autoantibody production was also 
inhibited by ATO in this model, suggesting that ATO also triggers B cells death in a 
phenomenon which cooperates for controlling chronic GvHD.  


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This leads to the hypothesis that ATO delivered during the course of the disease or even 
early at diagnosis of chronic GvHD- and possibly in prevention of cGvHD before its 
detection- will be an effective treatment. To test this hypothesis, we proposed this study of 
ATO in combination with corticosteroids as first line therapy for newly diagnosed chronic 
GvHD after allo-SCT. We hypothesized that the addition of ATO to prednisone for the initial 
treatment of chronic GvHD will increase the overall response rate and enable a more rapid 
and effective corticosteroids taper. We authorized the use of cyclosporine A, as a somewhat 
widely adopted measure, due to its use for its supposed possible beneficial action on acute 
GvHD in the early weeks after allografting and sometimes continuously maintained in spite 
of recognized inefficacy to influence the course of the autoimmune processes going on 
under the designation of cGvHD. 


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8. STUDY OBJECTIVES AND ENDPOINTS 
8.1 
OBJECTIVES 
8.1.1 Primary objective 
The primary objective is to improve the response rate (complete and partial remission) at 6 
months after diagnosis of chronic GvHD and treatment with arsenic trioxide (ATO) in 
combination with prednisone with or without Ciclosporin as first line treatment.  
The aim of this study is to assess whether ATO allows improving response rate at 6 months 
after the diagnosis of chronic GVHD from 60% (historical rate) to 85%.  
 
8.1.2 Secondary objectives 
The secondary objectives are:  
- To evaluate failure-free survival (FFS), defined as death, recurrent or progressive 
malignancy, or initiation of a new systemic treatment for chronic GvHD  
- To decrease non-relapse mortality (NRM) of infectious and non-infectious origin  
- To improve overall survival (OS) and progression-free survival (PFS)  
- To spare patients from long-term use of corticosteroids (and their long-term side effects)  
- To improve quality of life self-reported by patient using the Lee Symptom Scale (LSS) and 
Functional Assessment of Chronic Illness Therapy with Bone Marrow Transplantation 
subscale (FACT-BMT)  
- To evaluate tolerability and safety of ATO in combination with prednisone, with or without 
Ciclosporin, in patients with chronic GvHD after allo-SCT. 
 
8.2 
ENDPOINTS 
8.2.1 Primary endpoint 
The primary endpoint is the evaluation of response rate (CR and PR) at 6 months after the 
first ATO infusion, with no secondary systemic therapy at any time before M6.  
NIH grade of chronic GVHD will be used for the exact definition of this endpoint. 
 


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• 
Complete remission (CR) is defined as complete disappearance of any sign of 
chronic GvHD  
 
• 
Partial remission (PR) is defined as improvement of 1 or more point on a 4 to 7-
points scale or an improvement of 2 or more points on a 10 to 12-points scale in at 
least 1 organ or site without progression in any other organ or site.  
 
• 
More details for response determination are given in the following table:  
 
 
8.2.2 Secondary endpoints 
• 
OS is defined as the time from first infusion of ATO to death, regardless of the cause 
• 
FFS is defined as related death, progression, or initiation of a new systemic 
treatment for chronic GvHD 
• 
PFS is defined as survival with no evidence of relapse or progression of the 
original disease 


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• 
Corticosteroids dosage and percentage of reduction in corticosteroids dosage at 6 
and 12 months after diagnosis of chronic GvHD and treatment with ATO as first 
line treatment 
• 
Quality of life parameters using FACT-BMT and Lee Symptom Scale scores at 6 
and 14 weeks, 6, 9 and 12 months after first infusion of ATO  
• 
Tolerability and safety of ATO  


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9. INVESTIGATIONAL PLAN 
9.1 
OVERALL STUDY DESIGN AND PLAN 
The study GMED16-001 is a prospective, national, multicenter, non-randomized phase II 
study that will include a total number of 24 patients. 
The duration of participation panned is as follows: 
- 
Duration of recruitment: 34 months 
- 
Study duration for a considered patient: 12 months 
- 
Total duration of the study: 46 months 
 
Several visits are scheduled in the study as follows: 
- 
At the time of diagnosis for the screening visit 
- 
Follow-up visits to be performed every week during ATO treatment 
- 
Follow-up visits to be performed every 2 weeks from second to third month of ATO 
treatment 
- 
Follow-up visits to be performed every month from the fourth to sixth month of ATO 
treatment 
- 
Follow-up visits to be performed every 3 months: at 9 months and 12 months (final 
visit) 
 


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Arsenic trioxide is administrated either via the marketed product named TRISENOX® or the 
investigational medicinal product named ARSCIMED®. 
 
9.2 
SELECTION OF STUDY POPULATION 
9.2.1 Inclusion criteria 
Patients will be eligible for inclusion in this study if the patient met all the following criteria:  
 
• 
Adult patients (≥18 years) who have received a first allogeneic stem cell 
transplantation for a hematological disease (any source of hematopoietic stem cells 
is authorized; any category of conditioning regimen prior to allo-SCT is authorized; 
any type of stem cell donors is authorized)  
• 
Confirmed diagnosis of first episode of chronic GvHD requiring systemic 
immunosuppressive therapy (any prior GvHD prophylaxis previously used is 
accepted). Chronic GvHD diagnosis is defined according to the National Institutes 
of Health (NIH) Working Group Consensus.  
• 
Signed informed consent  
• 
Absence of contra-indications to the use of ATO  
• 
Subjects affiliated with an appropriate social security system  
• 
Men must use a medically acceptable method of contraception throughout the 
treatment period and for at least 4 months and 10 days following the last treatment 
administration  
• 
Women who are of childbearing potential must have a negative serum pregnancy 
test and agree to use a medically acceptable method of contraception throughout 
the study and for 3 months following the end of the study  
• 
Patient not participating or not having participated in a clinical study in the 30 days 
prior to his/her inclusion in the study  
 
9.2.2 Exclusion criteria 
Patients fulfilling ONE or MORE of the following criteria will not be included in the study:  
 
• 
Patient developing acute GvHD (whether early or “late onset” form)  


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• 
 Patients developing overlap GvHD as defined by the 2015 NIH Working Group 
Consensus (presence of one or more acute GvHD manifestation in a patient with a 
diagnosis of chronic GvHD) 
• 
A “mild” form of chronic GvHD not requiring systemic immunosuppressive therapy 
• 
A “moderate” form of chronic GvHD limited to one organ site not requiring systemic 
immunosuppressive therapy 
• 
Patient receiving mycophenolate mofetil 
• 
Second allogeneic stem cell transplant 
• 
Severe cardiac diseases (congestive heart failure (NYHA class III), recent 
myocardial infarction (in the past 6 months before the inclusion), histories of 
unexplained syncope, …)  
• 
Significant arrhythmias, EKG abnormalities 
- Congenital QT syndromes  
- History or presence of significant ventricular or atrial tachyarrhythmia  
- Clinically significant resting bradycardia (<50 beats per minutes)  
- QTc > 450 msec for men and > 470 msec for women on screening EKG  
- Right bundle branch block plus left anterior hemiblock, bifascicular block  
 
• 
Central or peripheral neuropathy  
• 
Neutrophils < 0.5 × 109/L 
• 
Platelets < 50 × 109/L 
• 
Potassium ≤ 4 mEq/l 
• 
Magnesium ≤ 1.8 mg/dl 
• 
Calcium ≤ 2.15 mmol/l 
• 
Hepatic impairment due to a suspected or proven liver damage, other than direct 
hepatic cGvHD involvement 
• 
PT < 50% 
• 
Renal impairment (creatinine ≥ 100 μmol/l) 
• 
Uncontrolled systemic infection which in the opinion of the investigator is associated 
with an increased risk of the patients death within 1 month after the start of therapy 
• 
Severe neurological or psychiatric disorders 


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• 
Denied informed consent 
• 
Pregnancy 
• 
Women breastfeeding at selection and throughout the treatment period 
 
9.3 
TREATMENTS 
9.3.1 Treatments administered 
Arsenic trioxide (ATO) is administrated either via a marketed product, i.e. TRISENOX®, or 
an Investigational Medicinal Product, i.e. ARSCIMED®.  
TRISENOX® was administered to patients from the start of the clinical trial. ARSCIMED® 
will be administered to patients included in the clinical trial after approval from the ANSM 
for its use in this clinical trial. Patients under TRISENOX® treatment will not switch to 
ARSCIMED® treatment nor vice versa. 
- All patients already included in the trial and who received TRISENOX®  will continue 
with TRISENOX® until completion of their participation in the clinical trial.  
- All patients recruited after this amendment has been approved will receive 
ARSCIMED® only and not TRISENOX®  
TRISENOX® and ARSCIMED® have the same active substance, excipients, dosage form 
and route of administration (Summary of Product Characteristics (Trisenox)) and 
Investigator brochure (ARSCIMED®) for details) and are considered equivalent. The 
decision in switching to ARSCIMED® during the clinical trial is based on the fact that the 
availability of ARSCIMED®, treatment being developed by MEDSENIC in the population 
included in this trial, will avoid repeated and further impact on recruitment in the study 
related to any further supply disruptions of TRISENOX®, as it occurred in 2014 and again 
in 2017. 


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Both formulations (TRISENOX® and ARSCIMED® are adjusted to pH 8 with dilute 
hydrochloric acid. Whereas TRISENOX® is manufactured by TEVA and supplied as a 
glass ampoule; ARSCIMED® is manufactured by IRPF1 -Toulouse and supplied as a 
glass vial. Further information on ARSCIMED® is available in the Investigational Medical 
Product Dossier of this product. 
 
 


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9.3.2 Identity of Investigational Product(s) 
The investigational medication has the following characteristics: 
- 
ATC code: LOIXX27 
- 
Pharmacotherapeutic group: other antineoplastic agents 
- 
Form/Presentation: concentrate for solution for intravenous infusion / 1 mg/1 
mL / 10 mL 
- 
Excipients: sodium hydroxide, hydrochloric acid as pH adjuster and water for 
injections 
9.3.3 Administration 
- 
0, 15 mg/kg/infusion on days I to 5 (first week), 3 times per week during the 
second week (for example, days 8, 10 and 12), 2 times per week during the 
third week (for example, days 15 and 17) and one time during the fourth 
week (for example, day 24), in addition to Ciclosporin A (if relevant) and 
corticosteroids. The latter four weeks represent one cycle of 11 
administrations. 
 
- 
Must be administered intravenously over 1-2 hours. The infusion duration 
may be extended up to 4 hours if vasomotor reactions are observed. A 
central venous catheter is not required. Patients must be hospitalized at the 
beginning of treatment due to ensure adequate monitoring. 
 
- 
Aseptic technique must be strictly observed throughout handling of ATO 
since no preservative is present. 
 
- 
Must be diluted with 100 to 250 mL of glucose 50 mg/mL (5%) solution for 
injection or sodium chloride 9 mg/mL (0.9%) solution for injection 
immediately after withdrawal from the ampoule for single use only. Unused 


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portions of each ampoule must be discarded properly. Unused portions for 
later administration must not be saved. 
 
- 
Must not be mixed with or concomitantly administered in the same 
intravenous line with other medicinal products. 
 
- 
The diluted solution must be clear and colorless. All parenteral solutions 
must be inspected visually for particulate matter and discoloration prior to 
administration. The preparation must not be used if foreign particulate matter 
is present. 
 
- 
Should be administered within 10 days of starting prednisone at I mg/kg/day 
for cGvHD treatment. Treatment with persistent prednisone (or equivalent) 
at doses lower than 1 mg/kg/day at the time of enrollment is allowed (i.e 
patient was treated for acute GvHD with prednisone and developed evolving 
chronic GvHD). 
 
- 
A delay of 8 weeks to a maximum of 1 1 weeks (from the first infusion of 
ATO) will be observed between the two cycles of ATO therapy. 
9.3.4 Method of Assigning Patients to Treatments 
Groups 
Not Applicable 
9.3.5 Blinding 
Not Applicable 
 
 


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9.3.6 Prior and Concomitant Therapy 
9.3.6.1 
Ciclosporin A 
➢ Ciclosporin A will be delivered using local standard criteria, (if relevant). 
However: 
- 
Ciclosporin level should lie within the therapeutic range (i.e. 200-400 
ng/mL): to harmonize CSA target levels 
- 
Ciclosporin-induced renal insufficiency should lead to dose adjustment and 
even temporary withdrawal of the drug 
➢ Suggested guidelines for initial dose of Ciclosporin A: 
Oral administration of Ciclosporin should continue for patients who are being treated 
with Ciclosporin at the time of enrolment, or if it is relevant. the administration should 
commence initially at 6mg/kg daily. 
➢ Monitoring of Ciclosporin level: 
- 
Concentrations ofCiclosporin in the plasma may be monitored at the 
discretion of the investigator. Dose adjustments may be made to maintain 
Ciclosporin concentrations at 200-400 ng/ml. Monitoring may be 
especially helpful in patients with renal impairment and in patients being 
treated with medications that may affect the concentration of Ciclosporin. 
- 
Medications that could increase the concentration of Ciclosporin include 
diltiazem, 
nicardipine, 
verapamil, 
metoclopramide, 
ketoconazole, 
fluconazole, itraconazole, erythromycin and methylprednisolone. 
- 
Medications that could decrease the concentration of Ciclosporin include 
rifampycin, phenytoin, phenobarbital and carbamazepine. 
 
➢ Deviations from guidelines for administration of Ciclosporin 
Deviations from the above guidelines may be made at the discretion of the 
investigator in consultation with the transplant centre. Toxicity associated with the 


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administration of Ciclosporin may require dose adjustments, which should be 
managed according to individual transplant centre practice. 
9.3.6.2 
Prednisone 
➢ The initial dose of prednisone is 1.0 mg/kg/day, this dose should be maintained for 
2 weeks, after which a tapering schedule should commence up until response 
assessment at 6 weeks, after which treatment is as follows: 
• 
CR: continue tapering of Prednisone dose (see Table below) 
• 
No CR: maintain Prednisone dose at 1 mg/kg/day on alternate days or 0.5 
mg/kg/day every day 
Usual prevention of steroid-induced gastro-intestinal (GI) side effect should be 
given (omeprazole or other drugs, according to local practice). 
➢ The investigator will determine the regimen for administration of prednisone after 
enrolment in the study. The following taper schedule is given as a general 
guideline: 
Prednisone Taper Schedule 
Week 
Dose (mg/kg actual body weight/day) 
0 
1.0 qod 
2 
0.75 qod 
4 
0.65 qod 
6 
0.50 qod (if CR, continued tapering of 
corticosteroids dose) 
0.50 qod (if No CR, maintain this dose until 
resolution of all reversible clinical 
manifestations or adjust the required dose) 


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8 
0.40 qod 
10 
0.30 qod 
12 
0.20 qod 
14 
0.15 qod 
20 
0.0 
 
• 
The investigator should examine the patient before each reduction in the dose of 
prednisone. If there is exacerbation or recurrence of chronic GvHD at any step of 
the taper, the dose of prednisone should be increased by 2 levels with daily 
administration for 2-4 weeks, followed by resumption of alternate day 
administration. Prednisone may be discontinued after 2 weeks of treatment at a 
dose of 0.15 mg/kg every other day. Qod prednisone dosing is not required, and 
the use of qod dosing is at the discretion of the investigator. It is suggested, but 
not required, that patients taper off steroids before tapering of other 
immunosuppressive medications. 
• 
Toxicity associated with the administration of prednisone should be managed 
according to individual transplant center practice. 
 
9.3.6.3 
Preventive treatments for 
infections 
- 
Antibiotic prophylaxis for prevention of Pneumocystis pneumonia and 
infections with encapsulated organisms must be given to all patients until 6 
months after discontinuation of all systemic immunosuppressive treatment. 
Suggested antibiotic regimens are: Trimethoprim/Sulfamethoxazole DS I tab 
PO qMWF, or if sulfa allergic, Atovaquone 1500 mg PO qMWF or 
Pentamidine 300 mg inhaled q4 weeks. Additional prophylactic antibiotics 
are at the discretion of the physician. 
 


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- 
Prophylactic antiviral and antifungal medications must also be given until the 
steroid dose is stable < 0.15 mg/kg/day. All patients who are at risk of CMV 
infection should be monitored for occult CMV infection, and appropriate 
treatment should be instituted per institutional practice. Populations at risk 
of CMV infection include all CMVseropositive patients, all CMV-seronegative 
patients with CMV-seropositive donors, and all patients receiving blood 
product transfusions from CMV-seropositive donors.  
 
- 
Antifungal prophylaxis: No specific antifungal prophylaxis is recommended. 
In case it is the routine policy of a centre to give an antifungal prophylaxis in 
patients with chronic GvHD (i.e., fluconazole, oral amphotericin B, 
itraconazole, posaconazole or other drugs for which there are published data 
of controlled trials showing the antifungal prophylaxis of this drug in allo-SCT 
patients), it is required that this policy is being documented in the CRF and 
the same policy be applied to all the patients included in the centre. 
 
- 
In all cases, physicians can refer to the recommendations made by the 
European Conference on Infections in Leukemia (ECIL). The full version is 
available on the website of the EBMT: 
https:/www.ebmt.org/Contents/Resources/Library/ECIL/Pages/ECIL.aspx 
 
- 
All treatments given for prevention of infectious complications must be 
reported in the electronic CRF of the study. 
 
9.3.6.4 
Prohibited concomitant 
treatments 
- 
Patient receiving mycophenolate mofetil 
- 
Any other investigational study drugs than ATO 
 
 


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9.4 
EFFICACY AND SAFETY VARIABLES 
9.4.1 Efficacy and Safety Measurements Assessed and 
Schedule of Assessments 
Patients will undergo the procedures and examinations which must be performed as 
shown in the following flow chart: 
 
  
Selection 
(V1) 
(10 days 
before 
ATO 
treatment) 
During ATO 
treatment 
(1st and 
2nd cycles) 
Every 2 
weeks 
(from M2 
to M3) 
± 5 days 
Every 
month 
(M4, 
M5, 
M6) 
± 5 
days 
At 6 and 
14 weeks 
and every 
3 months 
(M6, M9, 
M12) 
± 5 days 
Study 
drop- 
out ± 5 
days 
Information and patient 
consent 
* 
 
 
 
 
 
Inclusion/exclusion criteria 
check 
* 
 
 
 
 
 
Socio-demographics 
* 
 
 
 
 
 
Concomitant diseases 
* 
 
 
 
 
 
Recipient, Donor and 
Transplant characteristics10 
* 
 
 
 
 
 
Diagnosis & Scoring of 
chronic GvHD 
* 
 
 
 
 
 
Chronic GvHD activity 
assessment form A 
* 
 
 
 
* 
* 
Chronic GvHD activity 
assessment form B 
* 
 
 
 
* 
* 
Lee Symptom scale 
* 
 
 
 
* 
* 
FACT-BMT 
* 
 
 
 
* 
* 
Physical examination 
* 
*1 
* 
* 
* 
* 
EKG – QTc1 measurement 
* 
*1 
* 
 
 
 
Hematology3 
* 
*9 
* 
* 
* 
* 
Biochemistry4 
* 
*2/9 
* 
* 
* 
* 
Coagulation test5 
* 
*9 
* 
* 
* 
* 
Infectious disease 
surveillance 
* 
*2 
 
* 
* 
* 
Serum immunoglobulin level 
* 
 
 
* 
* 
* 
Autoantibodies (AAN, 
ANCA) 
* 
*2 
 
* 
* 
* 
Serum pregnancy test 
* 
 
 
 
 
 


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Immunological evaluation 
(Saint-Antoine) 
* 
* 
 
 
* 
* 
Pharmacokinetic evaluation 
 
*6 
 
 
 
 
Pulmonary function test 
(FEV1) 
* 
 
 
 
* 
* 
Chest x-ray 
* 
 
 
 
 
 
Cutaneous biopsy (if 
relevant) 
* 
 
 
 
 
 
ATO treatment (date, dose, 
reason of change) 
 
* 
 
 
 
 
Response to treatment 
 
 
 
 
* 
 
Associated treatment(s)8 
*7 
* 
* 
* 
* 
* 
Adverse event(s) 
 
* 
* 
* 
* 
* 
 
1 During ATO treatment, must be performed daily before each ATO administration. 
2 Must be performed weekly. 
3 CBC included leucocytes, neutrophils, lymphocytes, monocytes, and eosinophils counts, 
hemoglobin and platelets. 
4 Biochemistry included measurement of glycaemia9, creatinine1, uric acid, calcium1, potassium1, 
magnesium1, total protein, albumin, total bilirubin, alkaline phosphatases, SGOT9, SGPT9, and 
LDH. 
5 Prothrombin time [PT], activated partial thromboplastin time [APTT]. 
6 Pharmacokinetic evaluation: the samples must be performed before each administration at D2, 
D3, D4, D5, D8, D12, D17 and D24 of cycle 1 and cycle 2 (if applicable). 
7 History of GvHD prophylaxis : documentation of any associated treatments and topical therapy 
since graft for acute GvHD or progressive form of cGvHD treated by corticotherapy < 1 mg/kg/day, 
whenever possible given collected clinical history 
8 Documentation of any associated treatments and topical therapy for chronic GvHD (including 
glucocorticoid creams, topical tacrolimus, oral beclomethasone or budesonide, topical azathioprine 
and ophthalmic glucocorticoids…) 
9 Must be performed twice a week. 
10 Documentation on the diagnosis of hemopathy requiring transplant and DLI modality. 
 
 


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9.5 
DATA QUALITY ASSURANCE 
9.5.1 GOOD CLINICAL PRACTICE 
The study will be performed according to the Guidelines for Good Clinical Practice (ICH 
Harmonized Tripartite Guideline for Good Clinical Practice, (17.01.1997)). 
The investigator will be thoroughly familiar with the appropriate use of the study drug as 
described in the protocol and SPC. Essential clinical documents will be maintained to 
demonstrate the validity of the study and the integrity of the data collected. A trial master 
file should be established at the beginning of the study, maintained for the duration of the 
study and retained according to the appropriate regulations. 
9.5.2 AUDITING 
To guarantee a high quality of treatment for the patients within the present study, the 
sponsor will insure that the participating centres fulfill the following criteria: 
- 
Fulfilling of legal requirements  experience of the principle investigator of 
the entire study and the respective centre with respect to study conduct 
- 
International Conference on Harmonization (ICH)/GCP knowledge and 
certifications 
9.5.3 MONITORING 
Regular monitoring is an essential part of the study conduct. It will be performed by the 
Sponsor of the study. After the initiation visit, the frequency of monitoring visits will depend 
on the course of the study, and recruitment. It is the monitor's responsibility to make the 
local investigators and all the staff who is involved into the study or the care of the patients 
familiar with the protocol. 


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During the course of the study, the monitor will control the progress of the study, the 
commitment to the protocol, the documentation and careful usage of the study medication, 
and the maintenance of GCP guidelines and legal obligations. Problems as well as changes 
in reported data will be worked out in collaboration with the local investigator, who is obliged 
to cooperate with the monitor and to allow access to the patients' charts. Source data 
verification is performed by the monitor. This protocol is classified as a "D" risk level 
estimated for the patients (Phase 11= very high risk predictable). 
Inclusion criteria will be verified in 100% of patients. The monitor will have to respect that 
the data she/he comes into contact with are highly confidential. A monitoring report will be 
provided for each visit. 
9.5.4 DATA MANAGEMENT 
The coding and data control for the exploitation of results of the study will be conducted by 
the Contract research Organization (CRO) in charge of the study, FOVEA (RueilMalmaison, 
France), according to its standard operating procedures, ICH guidelines, and under the 
supervision of the Sponsor. 
9.5.4.1 
 Data entry 
All study data will be recorded and stored in a computerized database within the CRO, 
under the supervision of the Data Manager and under appropriate procedures. The data 
are available within the system to the Sponsor as soon as they are entered in the e-CRF. 
9.5.4.2 
Consistency checks 
Procedures for control of electronic data (Data Computer Management) will be defined to 
ensure the validity of information gathered as part of this study. They will cover all of the 
data and will aim to highlight abnormalities as missing data or inconsistent data. 


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These controls will be fully described in a manual of Data Management and will be 
implemented in the e-CRF. The computerized handling of the data by the Sponsor may 
generate additional requests (discrepancy resolution forms) to which the Investigator is 
obliged to respond by confirming or modifying the data questioned. The requests with their 
responses will be managed through the e-CRF. 
9.5.4.3 
Data coding 
The AES will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
while previous treatments will be coded using the World Health Organization (WHO) 
dictionary according to anatomic-therapeutic-chemical classification (ATC). 
 
 
 


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12.4 STATISTICAL ANALYSIS METHODES PLANNED IN THE PROTOCOL 
AND DETERMINATION OF SAMPLE SIZE  
12.4.3 
Statistical and Analytical Plans 
12.4.3.1 General approaches 
All continuous data will be summarized using the following statistics: n (non-missing sample 
size), mean, standard deviation, median, minimum (min) and maximum (max). All 
categorical/qualitative data will be presented using the frequency and the percentage of 
patients who are in the particular category. In general, all data will be listed, sorted by site, 
subject, and by visit number within subject. All summary tables will be annotated with the 
total population size relevant to that table/treatment, including any missing observation. 
The mean and the standard deviation will be reported to one decimal place greater than the 
original data. Median, minimum and maximum will use the same number of decimal places 
as the original data. P-values ≥0.001 will be reported to 3 decimal places; p-values less 
than 0.001 will be reported as “<0.001”. 
Type 1 error rate will be set at 0.05. 
All statistical analyses will be conducted using SAS version 9.4. 
12.4.3.2 Handling of Dropouts or Missing Data 
Every effort will be made to keep the number of missing values for all parameters to a 
minimum. The number of missing values will be reported together with summary statistics 
for each variable.  
Missing data on overall survival is assumed to be null as patient care after transplantation 
is very close. Any patient prematurely withdrawn or ending the study without the event of 
interest (progression, death) will be censored at his/her last information date. 
Concerning the main endpoint (response at M6), the missing assessments will be fully 
discussed during the data review. The most plausible outcome (the clinically more relevant) 
will be used for the main analysis. Other methods of imputation (for example, worst 


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outcome: missing data=failure) could be used for sensitivity purpose, according to the final 
number of missing assessments. 
12.4.3.3 Interim Analyses 
No interim analysis is planned. 
12.4.3.4 Statistical analyses 
A descriptive analysis will be conducted on the following parameters: 
- 
Patients and transplant characteristics 
- 
Primary and secondary endpoints 
The toxicities rate will be calculated and will be given with their 95% confidence intervals. 
The probabilities of survival will be estimated by the Kaplan-Meier method and by 
calculating the cumulative incidences for relapse/progression, and non-relapse mortality 
incidence. 
12.4.3.5 Determination of sample size 
The aim of this study is to assess whether ATO allows improving response rate at 6 months 
after the diagnosis of chronic GVHD from 60% to 85%.   
For the sample size calculation in this trial, an A’Hern one stage design has been used (ref 
1). 
- Let P0 be the smallest response rate, if true, implies that the role of ATO is too low and 
therefore the present schedule does not warrant further investigation. In the present trial, 
P0 has been taken as 60%.  
- Let P1 be the highest response rate which, if true, implies that the feasibility is sufficiently 
high and therefore the current schedule warrants further investigation in clinical trials. In the 
present trial, P1 has been taken as 85%;  
- Let α be the accepted probability of recommending for further investigation a regimen with 
a true discontinuation rate at least equal to P0. In the present trial, α has been taken as 
0.05.  
- Let β be the accepted probability of rejecting for further investigation a regimen with a true 
discontinuation rate less than P1. In the present trial, β has been taken as 0.20.  


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The required number of eligible patients is 21. To compensate for a dropout of 10%, 24 
patients are planned to be included.  
 
12.5 CHANGES IN THE CONDUCT OF THE STUDY OR PLANNED ANALYSIS 
Any changes to the analyses described in the protocol or in approved versions of this plan 
will be fully documented in a specific part of the clinical study report of the study. 


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10. PATIENTS 
10.1 DISPOSITION OF PATIENTS 
All patients screened and receiving at least one infusion of ATO will be accounted for. 
Derivation 
Derived variables 
Definition 
Study completed 
Yes, if the patient is present in the study at 
M12 
No, if the patient is not present in the study 
at M12 
 
The following table will be then presented: 
 
Analysis set 
(N=XX) 
Study completed 
 
Withdrawal of informed consent 
 
Lost to follow-up 
 
Occurrence of AE/SAE requiring premature discontinuation 
 
Inclusion criteria not met requiring premature discontinuation 
 
Other reason 
n/N (XX.XX%) 
 
n/N (XX.XX%) 
 
n/N (XX.XX%) 
 
n/N (XX.XX%) 
 
n/N (XX.XX%) 
 
n/N (XX.XX%) 
 
 
 
 


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10.2 PROTOCOL DEVIATIONS 
Protocol deviations will be summarized as follows: 
Analysis set (N=XX) 
 
 
Number of patients 
Number of deviations 
No deviation 
Major deviation 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
n 
 
 


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11. EFFICACY EVALUATION 
11.1 ANALYSES POPULATIONS 
Every patient included in the study and who has received at least one infusion of ATO will 
be taken into account at time of data analysis. 
The number of patients included who did not receive any infusion of ATO will be reported 
as well as the reason for not receiving ATO.  
 
The following analyses populations will be considered: 
 
- 
The safety population consists of all patients included in the study for whom there is any 
evidence that they used at least one ATO injection. 
 
- 
The Full Analysis Set (FAS) population consists of included subjects who completed 
their first cycle of ATO and for whom the response at Week 6 after diagnosis of chronic 
GvHD has been evaluated.  
 
- 
The Per Protocol (PP) population will exclude FAS patients with any major protocol 
deviations that may impact the efficacy analysis. The exclusion of patients from the PP 
population will be determined during the final data review meeting. Reason(s) for 
exclusion will be documented for each patient. 
 
The following table will be presented: 
 
Analysis set                 
(N=XX) 
 
Safety Population 
 
Full Set Analysis Population 
 
Per Protocol Population 
n/N (XX.XX%) 
 
n/N (XX.XX%) 
 
n/N (XX.XX%) 
 
 
 


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11.2 DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
11.2.1 
Demographic characteristics 
Derivation 
Derived variable 
Definition 
Age at inclusion (in years) 
Year of inclusion – Year of birth 
 
The following table will be presented: 
Variable 
Statistics / Modality 
Safety Population 
(N = XX) 
Gender 
Male 
Female 
Missing 
 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Age at inclusion (in years) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Contraception 
Yes 
No 
Missing 
 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Weight (kg) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Height (cm) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Cardiac frequency 
(beats/min) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Systolic arterial pressure 
(mmHg) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Diastolic arterial pressure 
(mmHg) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 


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Temperature (°C) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
O2 saturation (%) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
 
11.2.2 
Baseline characteristics 
Derivation 
Derived variable 
Definition 
Time from transplant to chronic GVHD (in 
days) 
Assessment date - Date of the first 
allogeneic stem cell transplantation +1 
Daily steroid dose (Prednisone): mg/kg/d 
Considering the treatment line when the 
baseline occurs, the daily dose is 
calculated as: 
Dose*frequency/weight 
The frequency can be: once a day, twice a 
day, 1 day on 2 etc.  
Daily cyclosporine dose 
Considering the treatment line when the 
baseline occurs, the daily dose is 
calculated as: 
Dose*frequency 
The frequency can be: once a day, twice a 
day, 1 day on 2 etc. 
 
 
 


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The following table will be presented:  
Variable 
Statistics / Modality 
Safety Population 
(N = XX) 
Significant current disease 
No 
Yes 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Donor / Recipient features 
Modality 1 
Modality 2 
… 
Modality n 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
… 
n/N (XX.X%) 
n 
Conditioning regimen 
Conditioning regimen 
Modality 1 
Modality 2 
… 
Modality n 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
… 
n/N (XX.X%) 
n 
Previous infusion of DLI 
DLI 
No 
Yes 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Time from transplant to GVHD 
Time from transplant to 
chronic GVHD (in days) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Concomitant disease 
Current disease? 
No 
Yes 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Haematology 
Leucocytes 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
X.XX ± X.XX 
X.X [X.X ; X.X] 
Neutrophils 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
X.XX ± X.XX 
X.X [X.X ; X.X] 
Lymphocytes 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
X.XX ± X.XX 
X.X [X.X ; X.X] 


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Monocytes 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
X.XX ± X.XX 
X.X [X.X ; X.X] 
Eosinophils 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
X.XX ± X.XX 
X.X [X.X ; X.X] 
Hemoglobin 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.XX ± XX.XX 
XX.X [XX.X ; XX.X] 
Platelets 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XXX.X ± XXX.X 
XXX [XXX ; XXX] 
aPTT 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Serum chemistries 
Creatinine 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.XX ± XX.XX 
XX.X [XX.X ; XX.X] 
Uric acid 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XXX.X ± XXX.X 
XXX [XXX ; XXX] 
Total bilirubin 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.XX ± XX.XX 
XX.X [XX.X ; XX.X] 
Alkaline phosphatases 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XXX.X ± XXX.X 
XXX [XXX ; XXX] 
LDH 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XXX.X ± XXX.X 
XXX [XXX ; XXX] 
Total protein 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Albumin 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.XX ± XX.XX 
XX.X [XX.X ; XX.X] 
SGOT 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XXX.X ± XXX.X 
XXX [XXX ; XXX] 


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SGPT 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XXX.X ± XXX.X 
XXX [XXX ; XXX] 
Calcium 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
X.XXX ± X.XXX 
X.XX [X.XX ; X.XX] 
Glycaemia 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
X.XX ± X.XX 
X.X [X.X ; X.X] 
Infectious disease surveillance 
CMV 
Negative 
Positive 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
EBV 
Negative 
Positive 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Hepatitis B 
Negative 
Positive 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Immunology 
Gammaglobulin level 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.XX ± XX.XX 
XX.X [XX.X ; XX.X] 
Antinuclear antibody 
Negative 
Positive 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
ANCA 
Negative 
Positive 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Cardiac assessment 
EKG – Performed? 
Not realized 
Realized 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
EKG – Result 
Abnormal 
Normal 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
QTc 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XXX.X ± XXX.X 
XXX [XXX ; XXX] 
Serum levels of electrolytes 
Potassium 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
X.XX ± X.XX 
X.X [X.X ; X.X] 
Magnesium 
N (N Missing) 
XX (XX) 


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Mean ± SD 
Median [Min ; Max] 
X.XXX ± X.XXX 
X.XX [X.XX ; X.XX] 
Results of other tests 
Performance status 
0 
1 
2 
3 
4 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n/N (XX.X%) 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Karnofsky index 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Chest X ray 
Not realized 
Realized 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
If realized, chest X ray 
result 
Abnormal 
Normal 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Cutaneous biopsy 
Not realized 
Realized 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
If realized, cutaneous 
biopsy result 
Abnormal 
Normal 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
% FEV1 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Concomitant treatment 
 
 
Any concomitant  
treatments administrated? 
No 
Yes 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Daily steroid dose 
(Prednisone) 
mg/kg/d  
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Daily cyclosporine dose  
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
 
 
 


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11.2.3 
Signs and symptoms of cGvHD at baseline 
Derivation 
Derived variable 
Definition 
Liver score 
The liver score is defined as a combination 
of Total bilirubin, ALT (SGPT) and AP 
(ALK) as follows: 
 
Score 0: Normal total bilirubin and ALT < 3 
ULN and AP < 3 ULN 
 
Score 1: Normal total bilirubin with ALT ≥ 3 
to 5 ULN or AP ≥ 3 to 5 ULN 
 
Score 2: Elevated total bilirubin (> 1 ULN) 
but ≤ 3 mg/dL or ALT ≥  5 ULN or AP  ≥ 5 
ULN 
 
Score 3: Elevated total bilirubin > 3 mg/dL 
 
Missing if at least one missing serum 
chemistry 
 
Involved sites number 
Number of sites or organs with a score ≥ 1 
at baseline (V1) 
 
The following table will be presented: 
Variable 
Statistics / Modality 
Safety Population 
(N = XX) 
NIH scoring of cGVHD 
Scoring of chronic GVHD 
(NIH criteria) 
Score 0: Asymptomatic and fully 
active (ECOG 0, KPS or LPS 
100%) 
Score 1: Symptomatic, fully 
ambulatory, restricted 
only in physically strenuous activity 
(ECOG 1, KPS or LPS 
80-90 %) 
 
Score 2: Symptomatic ambulatory, 
capable of selfcare, 
n/N (XX.X%) 
 
 
n/N (XX.X%) 
 
 
 
 
 
n/N (XX.X%) 
 


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> 50 % of walking hours out of bed 
(ECOG 2, KPS or 
LPS 60-70 %) 
 
Score 3: Symptomatic, limited self-
care > 50 % of 
waking hours in bed (ECOG 3-4, 
KPS or LPS < 60 %) 
 
Missing 
 
 
 
 
n/N (XX.X%) 
 
 
 
 
n 
Skin – Abnormalities 
present but explained 
entirely by non-GvHD 
documented cause 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
Skin score 
Score 0: No BSA involved 
 
Score 1: 1-18% BSA 
 
Score 2: 19-50% BSA 
 
Score 3: > 50% BSA 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
Mouth – Abnormalities 
present but explained 
entirely by non-GvHD 
documented cause 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
Mouth score 
Score 0: No symptoms 
 
Score 1: Mild symptoms with 
disease signs but not limiting oral 
intake significantly 
 
Score 2: Moderate symptoms with 
disease signs with partial limitation 
or oral intake 
 
Score 3: Severe symptoms with 
disease signs on examination with 
major limitation or oral intake 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
 
 
n/N (XX.X%) 
 
 
 
n/N (XX.X%) 
 
 
 
n 


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Lung – Abnormalities 
present but explained 
entirely by non-GvHD 
documented cause 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
Lung score + FEV1 
Score 0: No symptoms 
 
Score 1: Mild symptoms (shortness 
of breath after climbing one flight of 
steps) 
Score 2: Moderate symptoms 
(shortness of breath after walking 
on flat ground) 
 
Score 3: Severe symptoms 
(shortness of breath at rest: 
requiring 0) 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
 
n/N (XX.X%) 
 
 
 
n/N (XX.X%) 
 
 
n 
Eyes – Abnormalities 
present but explained 
entirely by non-GvHD 
documented cause 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
Eyes score 
Score 0: No symptoms 
 
Score 1: Mild dry eye symptoms not 
affecting ADL 
 
Score 2: Moderate dry eye 
symptoms partially affecting ADL 
without new vision impairment due 
to KCS 
 
Score 3: Severe eye symptoms 
significantly affecting ADL or unable 
to work because of ocular 
symptoms of loss or vision due to 
KCS 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
 
n/N (XX.X%) 
 
 
 
n/N (XX.X%) 
 
 
 
 
n 
Gastro-intestinal – 
Abnormalities present but 
No 
 
Yes 
 
n/N (XX.X%) 
 
n/N (XX.X%) 
 


Statistical analysis plan 
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explained entirely by non-
GvHD documented cause 
Missing 
n 
Gastro-intestinal score 
 
Score 0: No symptoms 
 
Score 1: Symptoms without 
significant weight loss (< 5 %) 
 
Score 2: Symptoms associated with 
mild to moderate weight loss (5-15 
%) OR moderate diarrhea 
without significant interference with 
daily living 
 
Score 3: Symptoms associated with 
significant weight loss > 15 %, 
requires nutritional supplement for 
most calorie needs OR esophageal 
dilation OR severe 
diarrhea with significant 
interference with daily living 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
 
n/N (XX.X%) 
 
 
 
 
 
n/N (XX.X%) 
 
 
 
 
 
 
 
n 
Liver – Abnormalities 
present but explained 
entirely by non-GvHD 
documented cause 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
Liver score 
Score 0: Normal total bilirubin and 
ALT or AP < 3 ULN 
 
Score 1: Normal total bilirubin with 
ALT ≥ 3 to 5 ULN and AP ≥ 3 to 5 
ULN 
 
Score 2: Elevated total bilirubin (> 1 
ULN) but ≤ 3 mg/dL or ALT ≥  5 
ULN or AP  ≥ 5 ULN 
 
Score 3: Elevated total bilirubin > 3 
mg/dL 
 
Missing 
n/N (XX.X%) 
 
 
n/N (XX.X%) 
 
 
 
n/N (XX.X%) 
 
 
 
n/N (XX.X%) 
 
 
n 
Joint and fascia – 
Abnormalities present but 
No 
 
n/N (XX.X%) 
 


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explained entirely by non-
GvHD documented cause 
Yes 
 
Missing 
n/N (XX.X%) 
 
n 
Joints and fascia score 
Score 0: No symptoms 
 
Score 1: Mild tightness of arms or 
legs, normal or mild decreased 
range of motion (ROM) AND not 
affecting 
ADL 
 
Score 2: Tightness of rams and 
legs OR joints contractures, 
erythema thought due to fasciitis, 
moderate 
decrease ROM AND mild to 
moderate limitation of ADL 
 
Score 3: Contractures WITH 
significant decrease of ROM AND 
significant limitation of ADL (unable 
to tie shoes, button shirts, dress 
self, etc...) 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
 
 
 
n/N (XX.X%) 
 
 
 
 
 
n/N (XX.X%) 
 
 
 
 
 
 
 
n 
Involved sites number 
Involved sites number 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
X.X ± X.X 
X [X ; X] 
Current patient weight 
Current patient weight (in 
kg) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Performance score 
Performance status 
KPS 
ECOG 
LPS 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n/N (XX.X%) 
n 
If ECOG 
ECOG 1 
ECOG 2 
ECOG 3 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Chronic GVHD activity assessment - Clinician 
Overall GvHD severity 
No GVHD 
Mild 
n/N (XX.X%) 
n/N (XX.X%) 


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Moderate 
Severe 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Assessment of cGVHD 
severity (from 0 to 10) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Chronic GVHD activity assessment - Patient 
Assessment of cGVHD 
severity (from 0 to 10) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
 
 
 


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11.3 ATO AND ASSOCIATED TREATMENTS 
11.3.1 
Arsenic trioxide therapy 
Derivation 
Derived variables 
Definition 
Time from diagnosis of cGvHD to first 
infusion of ATO (in days) 
The same derivation will be applied for 
each ATO infusion 
Date of Cycle 1 onset – GvHD 
assessment date + 1  
Missing if one of the two dates is missing 
Time from starting Prednisone to first 
infusion of ATO (in days) 
Date of Cycle 1 onset – Date of 
Prednisone onset +1 
Missing if one of the two dates is missing 
Number of cycles 
1, if a date of cycle 1 onset is known 
2, if a date of cycle 2 onset is known 
Missing otherwise 
Total dose during Wi 
Calculated at Wi={W1, W2, W3, W4} of 
each cycle 
For the considered period (Wi), sum of 
each dose took 
Example: C1_D1+C1_D2+C1_D3+C1_D5 
for the first week 
Daily dose during Wi 
Calculated at Wi={W1, W2, W3, W4} of 
each cycle 
For the considered week, the daily dose 
will be calculated as follows: 
Total dose / Number of days with intake 
treatment during Wi 
Time from the first infusion of ATO to the 
first day of the second cycle (in days) 
Date of Cycle 2 onset – Date of Cycle 1 +1 
Missing if one of the two dates is missing 
Temporary discontinuation of ATO 
Yes, if at least one missing infusion during 
the cycle 1 or cycle 2 if initiated 


Statistical analysis plan 
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No, if the patient has received all the 
planned doses 
 
The following table will be presented: 
Variable 
Statistics / Modality 
Safety Population 
(N = XX) 
Time from diagnosis of 
cGvHD to first infusion of 
ATO (in days) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Time from diagnosis of 
cGvHD to second infusion 
of ATO (in days) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
… 
… 
… 
Time from diagnosis of 
cGvHD to last infusion of 
ATO (in days) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Time from starting 
Prednisone to first infusion 
of ATO (in days) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of cycles 
1 
2 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
First cycle 
Number of infusions 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of weeks 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
          Week 1 
Daily dose during W1 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of days during W1 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Total dose during W1 
N (N Missing) 
Mean ± SD 
XX (XX) 
XX.X ± XX.X 


Statistical analysis plan 
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Median [Min ; Max] 
XX [XX ; XX] 
          Week 2 
Daily dose during W2 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of days during W2 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Total dose during W2 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
          Week 3 
Daily dose during W3 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of days during W3 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Total dose during W3 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
          Week 4 
Daily dose during W4 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of days during W4 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Total dose during W4 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Temporary discontinuation 
of ATO* 
No 
Yes 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Second cycle 
Patients who entered into 
the 2nd cycle 
No 
Yes 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Time from the first infusion 
of ATO to the first day of 
the second cycle (in days) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of infusions 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 


Statistical analysis plan 
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Date 21/12/2020 
 
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          Week 1 
Daily dose during W1 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of days during W1 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Total dose during W1 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
          Week 2 
Daily dose during W2 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of days during W2 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Total dose during W2 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
          Week 3 
Daily dose during W3 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of days during W3 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Total dose during W3 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
          Week 4 
Daily dose during W4 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of days during W4 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Total dose during W4 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Temporary discontinuation 
of ATO 
No 
Yes 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
 


Statistical analysis plan 
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In case of temporary discontinuation of ATO, a listing will be provided. 
 
 


Statistical analysis plan 
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Date 21/12/2020 
 
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Page 66 of 120 
 
11.3.2 
Associated treatment 
• 
Prednisone and Ciclosporin A 
Derivation 
Derived variables 
Definition 
Time from diagnosis of cGvHD to 
Prednisone onset (in days) 
Date of Prednisone onset – GvHD 
assessment date +1 
Missing if one of the two dates is missing 
Time from diagnosis of cGvHD to 
Ciclosporin onset (in days) 
Date of Ciclosporin onset – GvHD 
assessment date +1 
Missing if one of the two dates is missing 
Treatment duration (in days) 
Calculated for Prednisone and Ciclosporin 
Last treatment line end date – First 
treatment line start date +1 
Missing if one of the two dates is missing 
Daily dose for Prednisone and Ciclosporin 
Calculated for Prednisone (mg/kg/d) and 
Ciclosporin (mg/d) separately 
First, for each treatment line, the total 
dose will be calculated as follows: 
dose*frequency*number of days 
The frequency can be: once a day, twice a 
day, 1 day on 2 etc. 
The average daily dose is then defined as 
follows: 
Sum of each dose treatment line / 
Treatment duration 
Reason of change 
As the treatment of a same patient can be 
changed several times, if a reason of 
change is met more than once, it will only 
be counted as one reason. Thus, the 
denominator will be the same as the 
analysis population (i.e. Safety Population) 


Statistical analysis plan 
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Date 21/12/2020 
 
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Secondary immunosuppressive treatment 
after first ATO infusion 
No, if no treatment intake 
Yes, if at least one treatment intake 
 
The following table will be presented: 
 
Variable 
Statistics / Modality 
Safety Population 
(N = XX) 
Prednisone 
Time from diagnosis of 
cGvHD to first Prednisone 
dose (in days) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Treatment duration (in 
days) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Daily dose (mg/kg/d) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of changes 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Reason of change 
Reason 1 
Reason 2 
… 
Reason n 
n/N (XX.X%) 
n/N (XX.X%) 
… 
n/N (XX.X%) 
Ciclosporin 
Ciclosporin intake 
No 
Yes 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
Time from diagnosis of 
cGvHD to first Ciclosporin 
dose (in days) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Treatment duration (in 
days) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Daily dose (mg/d) 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Number of changes 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 


Statistical analysis plan 
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Reason of change 
Reason 1 
Reason 2 
… 
Reason n 
n/N (XX.X%) 
n/N (XX.X%) 
… 
n/N (XX.X%) 
 
• 
Concomitant treatments 
Concomitant treatments will be presenting by descending sort of use. 
The following table will be presented: 
 
Safety Population 
(N=XX) 
 
 
Patients who received at least one concomitant treatment 
n/N (XX.X%) 
TRT 1 
n/N (XX.X%) 
TRT 2 
n/N (XX.X%) 
… 
TRT n 
… 
n/N (XX.X%) 
 
 
 
• 
Secondary immunosuppressive treatment 
 
Variable 
Statistics / Modality 
Safety Population 
(N = XX) 
Secondary 
immunosuppressive 
treatment 
No 
Yes 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
 
 
 


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11.4 EFFICACY ANALYSIS 
11.4.1 
Primary Endpoint analysis 
11.4.1.1 Response at 6 months – Main 
analysis 
• 
Complete or Partial response at 6 months (PI response) 
The proportion of response at 6 months (CR or PR) will be estimated and presented with 
its 95% exact (Clopper-Pearson) confidence interval. The null hypothesis H0: P ≤ P0 will be 
rejected in favor of the alternative hypothesis H1: P ≥ P1 if the lower bound of the 95% CI 
is lower than 60%. 
Derivation 
Derived variables 
Definition 
Complete or partial response 
Yes, if the PI judged the patient in 
complete or partial response at M6 
No otherwise 
 
The following table will be presented: 
Variable 
Modality 
FAS Population (N = XX) 
Response at M6 
Complete or partial response 
 
n/N (XX.X%) [95% CI] 
 
 
 
 


Statistical analysis plan 
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• 
Complete and Partial response at 6 months (PI response) 
Proportion of CR and PR at 6 months will also be estimated separately, and presented with 
their 95% exact (Clopper-Pearson) confidence intervals. 
The following table will be presented: 
Variable 
Modality 
FAS Population  
(N = XX) 
Response at M6 
Complete response 
Partial response 
 
n/N (XX.X%) [95% CI] 
n/N (XX.X%) [95% CI] 
 
Responses and their 95% CI will be graphically represented using a forest plot. 
 
Furthermore, previous analyses will be performed considering the following subgroups: 
• 
By sex 
• 
By center 
• 
By number of cycles of ATO (1 or 2) 
• 
By use of Ciclosporin or not 
• 
By number of organs involved in cGvHD 
• 
By GvHD severity at baseline 
11.4.1.2 Response at 6 months – 
Sensitivity analyses 
a) The analysis presented in §11.4.1.1 will be performed on PP population 
b) The analysis presented in §11.4.1.1 will be performed on the response at 6 months 
computed by Soladis. 
c) The analysis presented in §11.4.1.1 will be performed on the response at 6 months 
based on the PI response, but excluding patients 06-07, 06-08 and 06-09. 
d) The analysis presented in §11.4.1.1 will be performed on the response at 6 months 
computed by Soladis, but excluding patients 06-07, 06-08 and 06-09. 
 
 
 


Statistical analysis plan 
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11.4.2 
Secondary Endpoint analyses 
11.4.2.1 Response by organ 
The proportion of response at 6 months (Complete, partial or progressive) will be estimated 
and presented for each organ. No response is evaluated for an organ when no 
abnormalities is present at V1, except progressive disease. 
Derivation 
Derived variables 
Definition 
Complete response for each organ 
Cf Appendix 1 “Evaluation de la réponse – 
19OCT2020” 
Partial response for each organ 
Progressive disease 
Organ not involved at any moment 
 
The following table will be presented: 
Organ 
Response at M6 
FAS Population 
(N = XX) 
Organ 1 
Complete response 
Partial response 
Progressive disease 
Organ not involved at any moment 
n/N (XX.X%) 
n/N (XX.X%) 
n/N (XX.X%) 
n/N (XX.X%) 
This table will be completed for skin, mouth, lung, eyes, gastro-intestinal, liver and joint & 
fascia. 
 
 


Statistical analysis plan 
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11.4.2.2 Survival analyses 
a) Failure free survival 
A survival analysis will be conducted to describe the occurrence of failure between the 
first infusion of ATO and Vi, with Vi={M6;M12}. 
Derivation 
Derived variables 
Definition 
Failure at Vi 
Calculated at Vi={M6;M12} 
Defined as death, recurrent or progressive 
malignancy, or the initiation of a new 
systemic treatment for chronic GvHD. 
Systemic treatment are: Methotrexate, 
Rapamune, TLI, Extracorporeal 
photopheresis, Rituximab, Jakavi, Glivec, 
Prograf, Imurel or other medications 
specified into the CRF (Vi_RESP_FAIL 
and or Vi_RESP_FAIL_S) 
Time calculation from first ATO infusion to 
failure at Vi 
Calculated at Vi={M6;M12} 
If the event appears: the difference of date 
between the first ATO infusion and the first 
failure (expressed in months) is calculated. 
The event will be not censured. 
(Date of first ATO infusion – Date of first 
failure)/30.5 
If the event does not appear, the 
difference of date between the first ATO 
infusion and Vi (expressed in months) is 
calculated. The event will be censured. 
 
The following table will be presented at M6: 


Statistical analysis plan 
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Date 21/12/2020 
 
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FAS Population 
(N = XX) 
First time of failure between first ATO 
infusion and M6 (in months) 
n/M (%) of events 
n/N (XX.XX%) 
n/M (%) of censored 
n/N (XX.XX%) 
 
The Kaplan-Meier survival estimates will be plotted with the number of subjects at risk and 
95% confidence limits. 
These analyses will be also presented at M12. 
 
 


Statistical analysis plan 
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Date 21/12/2020 
 
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b) Progression free survival 
A survival analysis will be conducted to describe the occurrence of progression between 
the first infusion of ATO and Vi, with Vi={M6;M12}. 
Derivation 
Derived variables 
Definition 
Progressive disease at Vi 
Calculated at Vi={M6;M12} 
Global progressive disease as define in 
Appendix 17.1  
Time calculation from first ATO infusion to 
failure at Vi 
Calculated at Vi={M6;M12} 
If the event appears: the difference of date 
between the first ATO infusion and the first 
progression (expressed in months) is 
calculated. The event will be not censured. 
(Date of first ATO infusion – Date of first 
progression)/30.5 
If the event does not appear, the 
difference of date between the first ATO 
infusion and Vi (expressed in months) is 
calculated. The event will be censured. 
 
The following table will be presented at M6: 
 
FAS Population 
(N = XX) 
First time of progression between 
first ATO infusion and M6 (in months) 
n/M (%) of events 
n/N (XX.XX%) 
n/M (%) of censored 
n/N (XX.XX%) 
 
The Kaplan-Meier survival estimates will be plotted with the number of subjects at risk and 
95% confidence limits. 
These analyses will be also presented at M12. 
 
 


Statistical analysis plan 
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Version 3.0 
Date 21/12/2020 
 
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Page 75 of 120 
 
c) Overall survival 
A survival analysis will be conducted to describe the occurrence of death between the first 
infusion of ATO and Vi, with Vi={M6;M12}. 
Derivation 
Derived variables 
Definition 
Death at Vi 
Calculated at Vi={M6;M12} 
Yes, if the death occurs between the first 
ATO infusion and Vi 
Time calculation from first ATO infusion to 
death at Vi 
Calculated at Vi={M6;M12} 
If the event appears: the difference of date 
between the first ATO infusion and the 
date of death (expressed in months) is 
calculated. The event will be not censured. 
(Date of first ATO infusion – Date of 
death)/30.5 
If the event does not appear, the 
difference of date between the first ATO 
infusion and Vi (expressed in months) is 
calculated. The event will be censured. 
 
The following table will be presented at M6: 
 
FAS Population 
(N = XX) 
Death between first ATO infusion 
and M6 (in months) 
n/M (%) of events 
n/N (XX.XX%) 
n/M (%) of censored 
n/N (XX.XX%) 
 
The Kaplan-Meier survival estimates will be plotted with the number of subjects at risk and 
95% confidence limits. 
These analyses will be also presented at M12. 
 


Statistical analysis plan 
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Version 3.0 
Date 21/12/2020 
 
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Page 76 of 120 
 
11.4.2.3 Treatment by Corticosteroids 
Derivation 
Derived variables 
Definition 
Selection of Prednisone treatment 
line at Vi 
Calculated for Vi = {W6, W14, M6, 
M9, M12} 
For each visit of interest, the Prednisone treatment 
line selected will be the one as: 
Prednisone onset date ≤ Vi  ≤ Prednisone end date 
If the visit matches with the Prednisone onset date, 
then the previous line is selected.  
If the visit matches with the Prednisone end date, then 
the current line is selected. 
If the visit cannot match with any treatment line then a 
missing value will be considered for this visit. 
Daily dose for Prednisone at Vi 
Calculated for Vi = {W6, W14, M6, 
M9, M12} 
For each visit, the daily dose is calculated as:  
dose*frequency/weight 
The frequency can be: once a day, twice a day, 1 day 
on 2 etc. 
Then the following categories will be created: 
≤ 0.25 mg/kg/d 
0.26 – 0.50 mg/kg/d 
0.51 – 0.75 mg/kg/d 
0.71 – 1 mg/kg/d 
Change from baseline at Vi 
Calculated for Vi = {W6, W14, M6, 
M9, M12} 
Decreased, if dose category at Vi < dose category at 
baseline 
Unchanged, if dose category at Vi = dose category at 
baseline 
Increased, if dose category at Vi > dose category at 
basleine 


Statistical analysis plan 
Protocol: 2016-002358-18 
Version 3.0 
Date 21/12/2020 
 
SAP-GvHD-ATO Study PASL201637-V3.0 
Page 77 of 120 
 
If the Prednisone treatment is not started at baseline 
then the date of first ATO infusion will be considered. 
 
The following table will be then presented: 
 
Visit 
Variable 
Statistics  
FAS Population 
(N=XX) 
W6 
Daily dose for 
Prednisone 
≤ 0.25 mg/kg/d 
0.26 – 0.50 mg/kg/d 
0.51 – 0.75 mg/kg/d 
0.71 – 1 mg/kg/d 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
Change from baseline  
Decreased 
Unchanged 
Increased 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
W14 
Daily dose for 
Prednisone 
≤ 0.25 mg/kg/d 
0.26 – 0.50 mg/kg/d 
0.51 – 0.75 mg/kg/d 
0.71 – 1 mg/kg/d 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
Change from baseline  
Decreased 
Unchanged 
Increased 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
M6 
Daily dose for 
Prednisone 
≤ 0.25 mg/kg/d 
0.26 – 0.50 mg/kg/d 
0.51 – 0.75 mg/kg/d 
0.71 – 1 mg/kg/d 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
Change from baseline  
Decreased 
Unchanged 
Increased 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
M9 
Daily dose for 
Prednisone 
≤ 0.25 mg/kg/d 
0.26 – 0.50 mg/kg/d 
0.51 – 0.75 mg/kg/d 
0.71 – 1 mg/kg/d 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
Change from baseline  
Decreased 
Unchanged 
Increased 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 


Statistical analysis plan 
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Date 21/12/2020 
 
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Page 78 of 120 
 
Missing 
n 
M12 
Daily dose for 
Prednisone 
≤ 0.25 mg/kg/d 
0.26 – 0.50 mg/kg/d 
0.51 – 0.75 mg/kg/d 
0.71 – 1 mg/kg/d 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
Change from baseline  
Decreased 
Unchanged 
Increased 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
The daily dose for Prednisone over time and the change from baseline will be graphically 
represented by stacked bars. 
 
 


Statistical analysis plan 
Protocol: 2016-002358-18 
Version 3.0 
Date 21/12/2020 
 
SAP-GvHD-ATO Study PASL201637-V3.0 
Page 79 of 120 
 
11.4.2.4 Quality of life assessment 
• 
FACT-BMT 
Derivation 
Derived variables 
Definition 
Physical well-being subscore at Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
7 * (Sum of the items GP1 to GP7) / Number of items 
answered 
Missing if no item answered 
Social/family well-being subscore at 
Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
7 * (Sum of the items GS1 to GS7) / Number of items 
answered 
Missing if no item answered 
Emotional well-being subscore at Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
6 * (Sum of the items GE1 to GE6) / Number of items 
answered 
Missing if no item answered 
Functionnal well-being subscore at 
Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
7 * (Sum of the items GF1 to GF7) / Number of items 
answered 
Missing if no item answered 
BMT subscore at Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
10 * (Sum of BMT1 to BMT4 + Sum of C6 to C7 + 
Sum of BMT5 to BMT6 + BL4 + BMT8) / Number of 
items answered 
Missing if no item answered 
Global FACT-BMT score at Vi 
Calculated for Vi = {Baseine, W6, 
W14, M6, M9, M12} 
The global FACT-BMT score is defined as the sum of 
all the subscores. 
Missing if at least one subscore is missing 
Subscale score - Change from 
baseline at Vi 
Calculated for Vi = {W6, W14, M6, 
M9, M12} and for physical well-
Subscale score at Vi – Subscale score at baseline 
Missing if the subscore is missing at Vi and/or 
baseline 


Statistical analysis plan 
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Version 3.0 
Date 21/12/2020 
 
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Page 80 of 120 
 
being, family/social well-being, 
emotional well-being, functional well-
being and other concerns subscores 
Global FACT-BMT scale score - 
Change from baseline at Vi 
Calculated for Vi = {W6, W14, M6, 
M9, M12} 
Global FACT-BMT score at Vi – Global FACT-BMT 
score at baseline 
Missing if the global FACT-BMT is missing at Vi 
and/or baseline 
 
The following table will be presented: 
 
Variable 
Visit 
Statistics / Modality 
FAS Population 
(N = XX) 
First subscore 
Baseline 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
W6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
W14 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
First subscore – Change 
from baseline 
W6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 


Statistical analysis plan 
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Date 21/12/2020 
 
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Page 81 of 120 
 
W14 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
 
This table will be completed for: 
- 
Physical well-being subscore  
- 
Social/family well-being subscore 
- 
Emotional well-being subscore Eating and digestion subscore 
- 
Functionnal subscore 
- 
BMT subscore 
- 
FACT-BMT score 
 
Global score and each subscore over time will be graphically represented by boxplots. 
The change from baseline over time of the global score and each subscore will be 
graphically represented by the mean and its associated CI 95%.  
• 
Lee Symptom Scale 
Derivation 
Derived variables 
Definition 
Skin subscore at Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
If at least 2 of the following items are answered, Scores 
are linearly transformed to a 0-100 scale where 0 
means all answered items were a “0” and “100” means 
that all answered items were a “4” 
 
Items: Abnormal skin color, Rashes, Thickened skin, 
Sores on skin and Itchy skin 


Statistical analysis plan 
Protocol: 2016-002358-18 
Version 3.0 
Date 21/12/2020 
 
SAP-GvHD-ATO Study PASL201637-V3.0 
Page 82 of 120 
 
Missing otherwise 
Eyes and mouth subscore at Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
If at least 2 of the following items are answered, Scores 
are linearly transformed to a 0-100 scale where 0 
means all answered items were a “0” and “100” means 
that all answered items were a “4” 
 
Items: Dry eyes, Need to use eyedrops frequently, 
Difficulty seeing clearly, Need to avoid certain foods 
due to mouth pain, Ulcers in mouth and Receiving 
nutrition from an intravenous line and feeding tube 
Missing otherwise 
Breathing subscore at Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
If at least 2 of the following items are answered, Scores 
are linearly transformed to a 0-100 scale where 0 
means all answered items were a “0” and “100” means 
that all answered items were a “4” 
 
Items: Frequent cough, Colored sputum, Shortness of 
breath with exercise, Shortness of breath at rest and 
Need to use oxygen 
Missing otherwise 
Eating and digestion subscore at Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
If at least 2 of the following items are answered, Scores 
are linearly transformed to a 0-100 scale where 0 
means all answered items were a “0” and “100” means 
that all answered items were a “4” 
 
Items: Difficulty swallowing solid foods, Difficulty 
swallowing liquids, Vomiting and Weight loss 
Missing otherwise 
Muscles and joints subscore at Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
If at least 2 of the following items are answered, Scores 
are linearly transformed to a 0-100 scale where 0 
means all answered items were a “0” and “100” means 
that all answered items were a “4” 
 
Items: Joint and muscle aches, Limited joint 
movement, Muscle cramps and Weak muscles 
Missing otherwise 


Statistical analysis plan 
Protocol: 2016-002358-18 
Version 3.0 
Date 21/12/2020 
 
SAP-GvHD-ATO Study PASL201637-V3.0 
Page 83 of 120 
 
Energy subscore at Vi 
Calculated for Vi = {W6, W14, M6, 
M9, M12} 
If at least 2 of the following items are answered, Scores 
are linearly transformed to a 0-100 scale where 0 
means all answered items were a “0” and “100” means 
that all answered items were a “4” 
 
Items: Loss of energy, Need to sleep more/take naps 
and Fevers 
Missing otherwise 
Mental and emotional subscore at Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
If at least 2 of the following items are answered, Scores 
are linearly transformed to a 0-100 scale where 0 
means all answered items were a “0” and “100” means 
that all answered items were a “4” 
 
Items: Depression, Anxiety and Difficulty sleeping 
Missing otherwise 
Global Lee symptom scale score at 
Vi 
Calculated for Vi = {Baseline, W6, 
W14, M6, M9, M12} 
The global score is defined as the average of 
subscores, if at least 4 are available. 
Missing otherwise 
Subscale score - Change from 
baseline at Vi 
Calculated for Vi = {W6, W14, M6, 
M9, M12} and for skin, eyes and 
mouth, breathing, eating and 
digestion, muscles and joints, 
energy, mental and emotional 
subscores 
Subscale score at Vi – Subscale score at baseline 
Missing if the subscore is missing at Vi and/or 
baseline 
Global Lee symptom scale score - 
Change from baseline at Vi 
Calculated for Vi = {W6, W14, M6, 
M9, M12} 
Global Lee score at Vi – Global Lee score at baseline 
Missing if the global Lee score is missing at Vi and/or 
baseline 
 


Statistical analysis plan 
Protocol: 2016-002358-18 
Version 3.0 
Date 21/12/2020 
 
SAP-GvHD-ATO Study PASL201637-V3.0 
Page 84 of 120 
 
 
The following table will be presented: 
 
Variable 
Visit 
Statistics / Modality 
FAS Population 
(N = XX) 
First subscore 
Baseline 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
W6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
W14 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
First subscore – Change 
from baseline 
W6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
W14 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 


Statistical analysis plan 
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Version 3.0 
Date 21/12/2020 
 
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CI 95%                             
[XX.X ; XX.X] 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
CI 95%                             
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
[XX.X ; XX.X] 
 
This table will be completed for: 
- 
Skin subscore 
- 
Eyes and mouth subscore 
- 
Breathing subscore 
- 
Eating and digestion subscore 
- 
Energy subscore 
- 
Mental and emotional subscore 
- 
Global Lee symptom scale score 
 
Global score and each subscore over time will be graphically represented by boxplots. 
The change from baseline over time of the global score and each subscore will be 
graphically represented by the mean and its associated CI 95%. 
11.4.2.5 Assessment of chronic GvHD 
activity post-ATO treatment 
Chronic GvHD activity (global and by organ) will be reported at 6 weeks, 14 weeks, 6, 9 and 
12 months after the first infusion of ATO. 
• 
Global chronic GvHD activity 
 
Variable 
Modality 
FAS Population 
(N = XX) 
Health care provider global ratings 
W6 
None 
Mild 
Moderate 
Severe 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
W14 
None 
Mild 
Moderate 
Severe 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 


Statistical analysis plan 
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Date 21/12/2020 
 
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Missing 
n 
M6 
None 
Mild 
Moderate 
Severe 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
M9 
None 
Mild 
Moderate 
Severe 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
M12 
None 
Mild 
Moderate 
Severe 
Missing 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n/N (XX.XX%) 
n 
 
Stacked bar graphs will be used for illustrating the percentage of patients in each score 
category at each time points (6 weeks, 14 weeks, 6, 9 and 12 months after the first infusion 
of ATO). 
• 
Chronic GvHD activity for each organ 
o Derivation 
Derived variables 
Definition 
Mouth score 
 
For each visit of interest, sum of the 3 following scores: 
- 
Erythema (MOUTH1) 
- 
Lichenoid (MOUTH2) 
- 
Ulcers (MOUTH3) 
Missing if at least one missing score 
 
Score to be calculated for the following visits: W6, W14, M6, M9 and M12 
 
 


Statistical analysis plan 
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Version 3.0 
Date 21/12/2020 
 
SAP-GvHD-ATO Study PASL201637-V3.0 
Page 87 of 120 
 
The following table will be presented: 
Organ score 
Visit 
Statistics / Modality 
FAS Population 
(N=XX) 
Organ 
– 
Abnormalities 
present but explained entirely 
by non-GvHD documented 
cause 
W6 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
Categorical score 
W6 
Modality 1 
… 
Modality n 
 
Missing 
n/N (XX.XX%) 
… 
n/N (XX.XX%) 
 
n 
 
Organ 
– 
Abnormalities 
present but explained entirely 
by non-GvHD documented 
cause 
W14 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
Categorical score 
W14 
Modality 1 
… 
Modality n 
Missing 
n/N (XX.XX%) 
… 
n/N (XX.XX%) 
n 
 
Organ 
– 
Abnormalities 
present but explained entirely 
by non-GvHD documented 
cause 
M6 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
Categorical score 
M6 
Modality 1 
… 
Modality n 
 
Missing 
n/N (XX.XX%) 
… 
n/N (XX.XX%) 
 
n 
 
Organ 
– 
Abnormalities 
present but explained entirely 
M9 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 


Statistical analysis plan 
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Date 21/12/2020 
 
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by non-GvHD documented 
cause 
Categorical score 
M9 
Modality 1 
… 
Modality n 
Missing 
n/N (XX.XX%) 
… 
n/N (XX.XX%) 
n 
 
Organ 
– 
Abnormalities 
present but explained entirely 
by non-GvHD documented 
cause 
M12 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
Categorical score 
M12 
Modality 1 
… 
Modality n 
Missing 
n/N (XX.XX%) 
… 
n/N (XX.XX%) 
n 
 
Liver – Abnormalities present 
but explained entirely by non-
GvHD documented cause 
W6 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
   Total bilirubin* 
W6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
   SGPT* 
W6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
   ALK* 
W6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Lung – Abnormalities present 
but explained entirely by non-
GvHD documented cause 
W6 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
   FEV1** 
W6 
N (N Missing) 
Mean ± SD 
XX (XX) 
XX.X ± XX.X 


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Date 21/12/2020 
 
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Page 89 of 120 
 
Median [Min ; Max] 
XX [XX ; XX] 
Liver – Abnormalities present 
but explained entirely by non-
GvHD documented cause 
W14 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
   Total bilirubin* 
W14 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
   SGPT* 
W14 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
   ALK* 
W14 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Lung – Abnormalities present 
but explained entirely by non-
GvHD documented cause 
W14 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
   FEV1** 
W14 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Liver – Abnormalities present 
but explained entirely by non-
GvHD documented cause 
M6 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
   Total bilirubin* 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
   SGPT* 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
   ALK* 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Lung – Abnormalities present 
but explained entirely by non-
GvHD documented cause 
M6 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
   FEV1** 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 


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Liver – Abnormalities present 
but explained entirely by non-
GvHD documented cause 
M9 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
   Total bilirubin* 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
   SGPT* 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
   ALK* 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Lung – Abnormalities present 
but explained entirely by non-
GvHD documented cause 
M9 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
   FEV1** 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Liver – Abnormalities present 
but explained entirely by non-
GvHD documented cause 
M12 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
   Total bilirubin* 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
   SGPT* 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
   ALK* 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Lung – Abnormalities present 
but explained entirely by non-
GvHD documented cause 
M12 
No 
 
Yes 
 
Missing 
n/N (XX.X%) 
 
n/N (XX.X%) 
 
n 
   FEV1** 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
* Chemistry associated to liver, ** Linked to lung function 
 


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This table will be completed for the following scores:  
Organ 
Score 
Skin 
Score 0: No BSA involved 
Score 1: 1-18% BSA 
Score 2: 19-50% BSA 
Score 3: > 50% BSA 
Skin features score 
Score 0: No sclerotic features 
 
Score 2: Superficial sclerotic features “not 
hidebound” (able to pinch) 
 
Score 3: Deep sclerotic features, 
“Hidebound” (unable to pinch), Impaired 
mobility, Ulceration 
 
Mouth - Erythema 
None 
Mild erythema or moderate erythema 
(<25%) 
Moderate (>=25%) or severe erythema 
(<25%) 
Severe erythema (>= 25%) 
Mouth - Lichenoid 
None 
Lichen-like changes (<25%) 
Lichen-like changes (25-50%) 
Lichen-like changes (>50%) 
Mouth - Ulcers 
None 
Ulcers involving (<=20%) 
Severe ulcerations (>20%) 
Eyes 
Score 0: No symptoms 
 
Score 1: Mild dry eye symptoms not 
affecting ADL 
 
Score 2: Moderate dry eye symptoms 
partially affecting ADL without new vision 
impairment due to KCS 
 
Score 3: Severe eye symptoms 
significantly affecting ADL or unable to 
work because of ocular symptoms of loss 
or vision due to KCS 
Gastro-intestinal (Esophageal) 
0 = No esophageal symptoms 
 


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1 = Occasional dysphagia or odynophagia 
with solid foods or pills during the past 
week 
 
2 = Intermittent dysphagia or odynophagia 
with solid foods or pills, but not for liquids 
or soft foods, during the past week 
 
3 = Dysphagia or odynophagia for almost 
all oral intake, on almost every day of the 
past week 
Gastro-intestinal (Upper) 
0 = No symptoms 
 
1 = Mild, occasional symptoms, with little 
reduction in oral intake during the past 
week 
 
2 = Moderate, intermittent symptoms, with 
some reduction in oral intake during the 
past week 
 
3 = More severe or persistent symptoms 
throughout the day, with marked reduction 
in oral intake, on almost every day of the 
past week 
Gastro-intestinal (Lower) 
0 = No loose or liquid stools during the 
past week 
 
1 = Occasional loose or liquid stools, on 
some days during the past week 
 
2 = Intermittent loose or liquid stools 
throughout the day, on almost every day of 
the past week, without requiring 
intervention to prevent or correct volume 
depletion 
 
3 = Voluminous diarrhea on almost every 
day of the past week, requiring 
intervention to prevent or correct volume 
depletion 
Joint and fascia  
Score 0: No symptoms 
 


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Score 1: Mild tightness of arms or legs, 
normal or mild decreased range of motion 
and not affecting ADL 
 
Score 2: Tightness of arms or legs OR 
joint contractures, erythema thought due 
to fasciitis, moderate decrease ROM AND 
mild to moderate limitation of ADL 
 
Score 3 : Contractures WITH significant 
decrease 
of ROM AND significant limitation of ADL 
(unable to tie shoes, button shirts, dress 
self, etc.) 
Lungs 
Score 0: No symptoms 
 
Score 1: Mild symptoms (shortness or 
breath after climbing one flight of steps) 
 
Score 2: Moderate symptoms (shortness 
of breath after walking on flat ground) 
 
Score 3: Severe symptoms (shortness of 
breath at rest, requiring O2) 
This table will be also presented on PP population. 
 
Stacked bar graphs will be used for illustrating the percentage of patients in each score 
category at each time points (6 weeks, 14 weeks, 6, 9 and 12 months after the first infusion 
of ATO). 
Continuous indicators will be represented by boxplots. 
• 
Physician assessment of current overall chronic GvHD severity  
 
Variable 
Statistics 
FAS Population 
(N = XX) 
Chronic GVHD severity from 0 (not at all) to 10 (the most severe) 
W6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
W14 
N (N Missing) 
Mean ± SD 
XX (XX) 
XX.X ± XX.X 


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Median [Min ; Max] 
XX [XX ; XX] 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Physician evaluations of current overall chronic GvHD severity over time will be graphically 
represented by boxplots. 
• 
Physician evaluations of chronic GvHD changes 
 
Variable 
Statistics 
FAS Population 
(N = XX) 
Over the time would you say that this patient’s GVHD is… 
W6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
W14 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Physician evaluations of chronic GvHD changes over time will be graphically represented 
by boxplots. 
 
  


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SAFETY EVALUATION 
12.1 ADVERSE EVENTS 
All treatment related toxicities and other AE and SAE occurring from the time of signed 
informed consent until the end of the study are recorded. They are coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) and classified according to the NCI common 
toxicity criteria (CTC), specification for stem cell transplantation. 
 
A SAE or serious adverse drug reaction is any untoward medical occurrence at any dose 
that:  
• 
Results in death;  
• 
Is life-threatening (immediate risk of death);  
• 
Requires inpatient hospitalization or prolongation of existing hospitalization for 
medical reasons (e.g. prolongation of hospitalization for social reasons is 
excluded);  
• 
Results in persistent or significant disability/incapacity;  
• 
Results in congenital anomaly/birth defect.  
 
The investigator will decide whether the serious adverse event is related to trial medication. 
The decision will be recorded on the serious adverse event report.  
The assessment of causality is made by the investigator as not related, unlikely, possibly 
related or definitely related. 
 
All AE not previously described in the Summary of Product Characteristics of TRISENOX® 
or in the Investigator Brochure of ARSCIMED® should be considered as unexpected AE. 
 
When calculating the incidence of AEs and SAEs, each subject will only be counted once 
and any repetitions of AEs will be ignored; the denominator will be the total population size. 


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Type of AE 
Safety Population 
(N=XX) 
N AEs 
AE 
n/N (XX.X%) 
n 
Serious AE 
n/N (XX.X%) 
n 
AE leading to death 
n/N (XX.X%) 
n 
AE leading to withdrawal 
n/N (XX.X%) 
n 
Related AE 
n/N (XX.X%) 
n 
 
Adverse events will be also presented by SOC and PT: 
SOC 
PT 
Safety Population 
(N=XX) 
N AEs 
SOC 1 
PT 1 
PT 2 
… 
n/N (XX.X%) 
n/N (XX.X%) 
… 
n 
n 
… 
… 
 
 
 
SOC n 
PT 1 
PT 2 
… 
n/N (XX.X%) 
n/N (XX.X%) 
… 
n 
n 
… 
 
 
 
 
This table will be presented for each type of AE. 
A list of all AEs will be produced in a table including the following items: 
- 
Patient number 
- 
Age at inclusion 
- 
AE names 
- 
AE grade  
- 
Seriousness 
- 
Date of onset first cycle ATO 
- 
Date of end first cycle ATO 
- 
Second cycle ATO (yes/no) 
- 
Date of onset second cycle ATO 
- 
Date of end second cycle ATO 


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- 
Relation (causality) 
- 
Action taken for AE 
- 
Date of onset of AE 
- 
Outcome of AE (Resolved without sequelae/ ongoing/ death) 
 
12.2 LABORATORY PARAMETERS 
Each laboratory parameter will be described at baseline, W6, W14, M6, M9 and M12 and 
presented as follows: 
Variable 
Visit 
Statistics / Modality 
Safety Population 
(N = XX) 
Laboratory parameter 1 
Baseline 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Not clinically significant 
Clinically significant 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
W6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Not clinically significant 
Clinically significant 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
W14 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Not clinically significant 
Clinically significant 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Not clinically significant 
Clinically significant 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 


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Not clinically significant 
Clinically significant 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
Not clinically significant 
Clinically significant 
Missing 
n/N (XX.X%) 
n/N (XX.X%) 
n 
… 
 
 
 
This table will be completed for the following parameters: 
- 
Leucocytes 
- 
Neutrophils 
- 
Lymphocytes 
- 
Monocytes 
- 
Eosinophils 
- 
Hemoglobin 
- 
Platelets 
- 
PR 
- 
aPTT 
- 
Glycaemia 
- 
Creatinine 
- 
Uric acid 
- 
Calcium 
- 
Potassium 
- 
Magnesium 
- 
Total protein 


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- 
Albumin 
- 
Total bilirubin 
- 
Alkaline phosphatases 
- 
SGOT (ASAT) 
- 
SGPT (ALAT) 
- 
LDH 
 
12.3 PHYSICAL EXAMINATION 
Each body system of the clinical examination will be described at baseline, W6, W14, M6, 
M9 and M12 and presented as follows: 
 
Variable 
Visit 
Statistics  
Safety Population 
(N = XX) 
Parameter 1 
Baseline 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
W6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
W14 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
M6 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
M9 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
M12 
N (N Missing) 
Mean ± SD 
Median [Min ; Max] 
XX (XX) 
XX.X ± XX.X 
XX [XX ; XX] 
… 
 
 
 


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This table will be completed for the following parameters: 
- 
Cardiac frequency 
- 
Systolic arterial pressure 
- 
Diastolic arterial pressure 
- 
Temperature 
- 
O2 saturation 
 


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DISCUSSION AND OVERALL CONCLUSIONS 
At the end of the study evaluation, the principle investigator presents a final report, 
containing the clinical report, single tables, and the final conclusions. Publication of the 
results is realized independently from the outcome of the study. The study or parts of the 
study should be published by the writing committee only which consists of the persons in 
charge of the study as mentioned on the front page. According to the EBMT rules, co-
authors will be offered to the local PI of participating centres, the order depending on the 
number of patients included by the respective centres, or depending on their contribution 
to the protocol or the realization of the study. Other investigators will be mentioned in the 
addendum. All publications and/or communications related to this study should at least 
mention the PI of the study and the sponsor. 


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TABLES, FIGURES AND GRAPHS 
14.1 TABLES 
 
Table 
Number 
Population 
Table Title / Summary 
 
14.1 Demographic and Baseline Data 
14.1.1 Disposition and Deviations 
14.1.1.1 
All Patients 
Study Disposition 
14.1.1.2 
All Patients 
Protocol Deviations 
14.1.1.3 
All Patients 
Analyses Populations 
14.1.2 Demographic Data and other baseline characteristics 
14.1.2.1 
Safety 
Demographic characteristics 
14.1.2.2 
Safety 
Baseline characteristics 
14.1.2.3 
Safety 
Signs and symptoms of cGvHD at baseline 
14.1.3 ATO and associated treatments 
14.1.3.1 
Safety 
Arsenic trioxide therapy 
14.1.4.1 
Safety 
Associated treatment 
14.1.4.2 
Safety 
Concomitant treatments 
14.1.4.3 
Safety 
Secondary immunosuppressive treatment 
14.2 Efficacy – Primary criterion 
14.2.1 Main analyses 
14.2.1.1 
FAS 
Complete or partial response at 6 months (PI response) – 
Overall 
14.2.1.2 
FAS 
Complete and partial response at 6 months (PI response) – 
Overall 
14.2.1.3 
FAS 
Complete or partial response at 6 months (PI response) – By 
sex 
14.2.1.4 
FAS 
Complete and partial response at 6 months (PI response) – By 
sex 
14.2.1.5 
FAS 
Complete or partial response at 6 months (PI response) – By 
center 
14.2.1.6 
FAS 
Complete and partial response at 6 months (PI response)  – By 
center 
14.2.1.7 
FAS 
Complete or partial response at 6 months (PI response) – By 
number of cycles of ATO 
14.2.1.8 
FAS 
Complete and partial response at 6 months (PI response) – By 
number of cycles of ATO 
14.2.1.9 
FAS 
Complete or partial response at 6 months (PI response) – By 
use of Ciclosporin or not 
14.2.1.10 
FAS 
Complete and partial response at 6 months (PI response)  – By 
use of Ciclosporin or not 
14.2.1.11 
FAS 
Complete or partial response at 6 months (PI response) – By 
number of organs involved in cGvHD 


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Table 
Number 
Population 
Table Title / Summary 
14.2.1.12 
FAS 
Complete and partial response at 6 months (PI response) – By 
number of organs involved in cGvHD 
14.2.1.13 
FAS 
Complete or partial response at 6 months (PI response) – By 
GvHD severity at baseline 
14.2.1.14 
FAS 
Complete and partial response at 6 months (PI response)  – By 
GvHD severity at baseline 
14.2.2 Sensitivity analyses 
14.2.2.1 
PP 
Complete or partial response at 6 months (PI response) – 
Overall 
14.2.2.2 
PP 
Complete and partial response at 6 months (PI response) – 
Overall 
14.2.2.3 
FAS 
Complete or partial response at 6 months (computed response)  
– Overall 
14.2.2.4 
FAS 
Complete and partial response at 6 months (computed 
response) – Overall 
14.2.2.5 
FAS 
Complete or partial response at 6 months (computed response) 
– By sex 
14.2.2.6 
FAS 
Complete and partial response at 6 months (computed 
response) – By sex 
14.2.2.7 
FAS 
Complete or partial response at 6 months (computed response) 
– By center 
14.2.2.8 
FAS 
Complete and partial response at 6 months (computed 
response) – By center 
14.2.2.9 
FAS 
Complete or partial response at 6 months (computed response) 
– By number of cycles of ATO 
14.2.2.10 
FAS 
Complete and partial response at 6 months (computed 
response) – By number of cycles of ATO 
14.2.2.11 
FAS 
Complete or partial response at 6 months (computed response)  
– By use of Ciclosporin or not 
14.2.2.12 
FAS 
Complete and partial response at 6 months (computed 
response) – By use of Ciclosporin or not 
14.2.2.13 
FAS 
Complete or partial response at 6 months (computed response) 
– By number of organs involved in cGvHD 
14.2.2.14 
FAS 
Complete and partial response at 6 months (computed 
response) – By number of organs involved in cGvHD 
14.2.2.15 
FAS 
Complete or partial response at 6 months (computed response)  
– By GvHD severity at baseline 
14.2.2.16 
FAS 
Complete and partial response at 6 months (computed 
response)  – By GvHD severity at baseline 
14.2.2.17 
FAS 
Complete or partial response at 6 months (PI response) without 
patients 06-07, 06-08 and 06-09  – Overall 
14.2.2.18 
FAS 
Complete and partial response at 6 months (PI response) 
without patients 06-07, 06-08 and 06-09  – Overall 
14.2.2.19 
FAS 
Complete or partial response at 6 months (computed response) 
without patients 06-07, 06-08 and 06-09   – Overall 


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Table 
Number 
Population 
Table Title / Summary 
14.2.2.20 
FAS 
Complete and partial response at 6 months (computed 
response) without patients 06-07, 06-08 and 06-09 – Overall 
14.3 Efficacy – Secondary criteria 
14.3.1 Response at 6 months by organ 
14.3.1 
FAS 
Response at 6 months by organ 
14.3.2 
PP 
Response at 6 months by organ 
14.3.2 Survival analyses 
14.3.2.1a 
FAS 
Failure free survival at M6 
14.3.2.1B 
PP 
Failure free survival at M6 
14.3.2.2a 
FAS 
Failure free survival at M12 
14.3.2.2b 
PP 
Failure free survival at M12 
14.3.2.3a 
FAS 
Progression free survival at M6 
14.3.2.3b 
PP 
Progression free survival at M6 
14.3.2.4a 
FAS 
Progression free survival at M12 
14.3.2.4b 
PP 
Progression free survival at M12 
14.3.2.5a 
FAS 
Overall survival at M6 
14.3.2.5b 
PP 
Overall survival at M6 
14.3.2.6a 
FAS 
Overall survival at M12 
14.3.2.6b 
PP 
Overall survival at M12 
14.3.3 Treatment by corticosteroids 
14.3.3.1 
FAS 
Treatment by corticosteroids by visit – Absolute values and 
change from baseline 
14.3.4 Quality of life assessment 
14.3.4.1 
FAS 
FACT-BMT by visit – Absolute values and change from baseline 
14.3.4.2 
FAS 
Lee symptom scale by visit – Absolute values and change from 
baseline 
14.3.5 Assessment of chronic GVHD activity post-ATO treatment 
14.3.5.1 
FAS 
Global chronic GVHD activity by visit 


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Table 
Number 
Population 
Table Title / Summary 
14.3.5.2 
FAS 
Chronic GVHD activity for each organ by visit 
14.3.5.3 
FAS 
Physician assessment of current overall chronic GVHD severity 
by visit 
14.3.5.4 
FAS 
Physician evaluations of chronic GVHD changes by visit 
14.4 Safety 
14.4.1 Adverse events 
14.4.1.1 
Safety 
AEs summary – During treatment (Cycle 1 and/or Cycle 2) 
14.4.1.2 
Safety 
AEs summary - After the last infusion of ATO until 6 months after 
the first infusion of ATO 
14.4.1.3 
Safety 
AEs summary - From 6 to 12 months after the first infusion of 
ATO 
14.4.1.4 
Safety 
AEs by SOC/PT 
14.4.1.5 
Safety 
SAEs by SOC/PT 
14.4.1.6 
Safety 
AEs leading to death by SOC/PT 
14.4.1.7 
Safety 
AEs leading to withdrawal by SOC/PT 
14.4.1.8 
Safety 
Related AEs by SOC/PT 
14.4.2: Laboratory parameters 
14.4.2.1 
Safety 
Laboratory parameters by visit – Absolute values 
14.4.3: Physical examination 
14.4.3.1 
Safety 
Physical examination by visit – Absolute values 
 
14.2 FIGURES AND GRAPHS 
 
Figure 
Number 
Population 
Figure Title / Summary 
14.2 Efficacy – Primary criterion 
14.2.1 Main analyses 
14.2.1.1 
FAS 
Forest plot of Complete and partial response at 6 months (PI 
response) 
14.2.2 Sensitivity analyses 
14.2.2.1 
PP 
Forest plot of Complete and partial response at 6 months (PI 
response) 


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14.2.2.2 
FAS 
Forest plot of Complete and partial response at 6 months 
(computed response) 
14.2.2.3 
FAS 
Forest plot of Complete and partial response at 6 months (PI 
response)  without patients 06-07, 06-08 and 06-09 
14.2.2.4 
FAS 
Forest plot of Complete and partial response at 6 months 
(computed response)  without patients 06-07, 06-08 and 06-09 
14.3 Efficacy – Secondary criteria 
14.3.1 Survival analyses 
14.3.1.1a 
FAS 
Kaplan-Meier survival plot of Failure free survival at M6 
14.3.1.1b 
PP 
Kaplan-Meier survival plot of Failure free survival at M6 
14.3.1.2a 
FAS 
Kaplan-Meier survival plot of Failure free survival at M12 
14.3.1.2b 
PP 
Kaplan-Meier survival plot of Failure free survival at M12 
14.3.1.3a 
FAS 
Kaplan-Meier survival plot of Progression free survival at M6 
14.3.1.3b 
PP 
Kaplan-Meier survival plot of Progression free survival at M6 
14.3.1.4a 
FAS 
Kaplan-Meier survival plot of Progression free survival at M12 
14.3.1.4b 
PP 
Kaplan-Meier survival plot of Progression free survival at M12 
14.3.1.5a 
FAS 
Kaplan-Meier survival plot of Overall survival at M6 
14.3.1.5b 
PP 
Kaplan-Meier survival plot of Overall survival at M6 
14.3.1.6a 
FAS 
Kaplan-Meier survival plot of Overall survival at M12 
14.3.1.6b 
PP 
Kaplan-Meier survival plot of Overall survival at M12 
14.3.2 Treatment by corticosteroids 
14.3.2.1 
FAS 
Stacked bars of Prednisone dose by visit 
14.3.2.2 
FAS 
Stacked bars of change from baseline of Prednisone dose by 
visit 
14.3.3 Quality of life assessment 
14.3.3.1.1a 
FAS 
Boxplot of FACT-BMT Physical well-being subscore by visit 
14.3.3.1.1b 
FAS 
Boxplot of change from baseline of FACT-BMT Physical well-
being subscore by visit 
14.3.3.1.2a 
FAS 
Boxplot of FACT-BMT Social/Family well-being subscore by 
visit 
14.3.3.1.2b 
FAS 
Boxplot of change from baseline of FACT-BMT Social/Family 
well-being subscore by visit 


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14.3.3.1.3a 
FAS 
Boxplot of FACT-BMT Emotional subscore by visit 
14.3.3.1.3b 
FAS 
Boxplot of change from baseline of FACT-BMT Emotional well-
being subscore by visit 
14.3.3.1.4a 
FAS 
Boxplot of FACT-BMT Functionnal subscore by visit 
14.3.3.1.4b 
FAS 
Boxplot of change from baseline of FACT-BMT Functionnal 
subscore by visit 
14.3.3.1.5a 
FAS 
Boxplot of FACT-BMT Other concerns subscore by visit 
14.3.3.1.5b 
FAS 
Boxplot of change from baseline of FACT-BMT Other concerns 
subscore by visit 
14.3.3.1.6a 
FAS 
Boxplot of global FACT-BMT score by visit 
14.3.3.1.6b 
FAS 
Boxplot of change from baseline of global FACT-BMT score by 
visit 
14.3.3.2.1a 
FAS 
Boxplot of Lee symptom scale skin subscore by visit  
14.3.3.2.1b 
FAS 
Boxplot of change from baseline of Lee symptom scale skin 
subscore by visit 
14.3.3.2.2a 
FAS 
Boxplot of Lee symptom scale eyes and mouth subscore by visit  
14.3.3.2.2b 
FAS 
Boxplot of change from baseline of Lee symptom scale eyes and 
mouth subscore by visit 
14.3.3.2.3a 
FAS 
Boxplot of Lee symptom scale breathing subscore by visit  
14.3.3.2.3b 
FAS 
Boxplot of change from baseline of Lee symptom scale 
breathing subscore by visit 
14.3.3.2.4a 
FAS 
Boxplot of Lee symptom scale eating and digestion subscore by 
visit  
14.3.3.2.4b 
FAS 
Boxplot of change from baseline of Lee symptom scale eating 
and digestion subscore by visit 
14.3.3.2.5a 
FAS 
Boxplot of Lee symptom scale energy subscore by visit  
14.3.3.2.5b 
FAS 
Boxplot of change from baseline of Lee symptom scale energy 
subscore by visit 
14.3.3.2.6a 
FAS 
Boxplot of Lee symptom scale mental and emotional subscore 
by visit  
14.3.3.2.6b 
FAS 
Boxplot of change from baseline of Lee symptom scale mental 
and emotional subscore by visit 
14.3.3.2.7a 
FAS 
Boxplot of Global Lee symptom scale subscore by visit  
14.3.3.2.7b 
FAS 
Boxplot of change from baseline of Global Lee symptom scale 
subscore by visit 
14.3.4 Assessment of chronic GVHD activity post-ATO treatment 
 
14.3.4.1 
FAS 
Stacked bars of Global chronic GVHD activity by visit 


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14.3.4.2 
FAS 
Stacked bars of Chronic GVHD activity for each organ by visit 
14.3.4.3 
FAS 
Boxplot of total bilirubin by visit 
14.3.4.4 
FAS 
Boxplot of ALT (SGPT) by visit 
14.3.4.5 
FAS 
Boxplot of PAL (ALK) by visit 
14.3.4.6 
FAS 
Boxplot of FEV1 by visit 
14.3.4.7 
FAS 
Boxplots of Physician assessment of current overall chronic 
GVHD severity by visit 
14.3.4.8 
FAS 
Boxplots of Physician evaluations of chronic GVHD changes by 
visit 


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REFERENCE LIST 
A’Hern R.P. Sample size tables for exact single-stage phase II designs. Statistics in  
Medicine. 2001; 20: 859-866). 
Gamble C et al. Guidelines for the Content of Statistical Analysis Plans in Clinical Trials 
JAMA December 19, 2017 Volume 318, Number 23 


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LISTINGS 
Listing 
Number 
Listing Title / Summary 
16.2.1 Discontinued patients 
16.2.1.1 
Study Completion  
16.2.1.2 
Visits and Dates of Visits 
16.2.2 Protocol Deviations 
16.2.2.1 
Protocol Deviations  
16.2.3 Patients Excluded from the Efficacy Analysis 
16.2.3.1 
Subject Eligibility 
16.2.3.2 
Populations 
16.2.4 Demographic Data 
16.2.4.1 
Demographic characteristics 
16.2.4.2 
History of GvHD 
16.2.4.3 
GvHD prophylaxis 
16.2.4.4 
Diagnostic of chronic GvHD 
16.2.4.5 
Ciclosporin therapy 
16.2.4.6 
Prednisone therapy 
16.2.4.7 
Concomitant treatments 
16.2.5 Efficacy Response Data 
16.2.5.1 
Clinical assessment at each visit 
16.2.5.2 
Scores with abnormalities present but explained entirely by non-GVHD 
documented cause at each visit 
16.2.5.3 
GvHD Chronic form A at each visit 
16.2.5.4 
Response at each visit 
16.2.6 Efficacy Response Data 
16.2.6.1 
All Adverse Events  
16.2.6.2 
Laboratory results 
16.2.6.3 
Physical examination 
 


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APPENDICES 
17.1 RESPONSE CALCULATION ALGORITHM 
Etude GMED_16_001 : Evaluation des réponses complètes et partielles – 19/10/2020 
 
Les réponses sont définies comme (règles de calcul basées sur le protocole et l’article Lee et al)  
- Complete response at a visit: Lorsque tous les scores de « cGVDH activity assessment form A » des 
organes suivants sont à 0 ou que la variable "abnormalities present but explained entirely by non-GVHD 
documented cause » soit égale à Oui.  
Détails : 
Si une valeur est manquante pour un des organes atteints lors de la visite V1, la réponse ne peut pas être 
considérée comme complète. le fait que la valeur est manquante sera documentée.  
Si une valeur à la visite d’intérêt est manquante sur un organe non atteint lors de la visite V1, la réponse 
complète peut être établie, car les réponses complètes ou partielles ne sont établies que sur les organes 
atteints à V1.  
Si « abnormalities present but explained entirely by non-GVHD documented cause » = Oui pour un organe à 
la visite considérée, le score de cet organe n’est pas corrigé et cet organe n’est pas considéré pour 
l’évaluation de la réponse complète. cela ne créera pas de valeur manquante pour cet organe et n’empêchera 
pas la réponse d’être considérée comme complète si les informations sur les autres organes sont disponibles. 
- BSA=0 ET skin features=0   
M6_GVHD_A_S (préfixe M6 ou C1W6, W14, M9 et M12 selon la visite considérée) 
M6_GVHD_A_S_F_S 
M6_GVHD_A_S_ABN 
 
- Eyes=0   
M6_GVHD_A_E 
M6_GVHD_A_E_ABN 
 
- Gastrointestinal=0 (pour chacun des 3 scores : Gastro-oesophageal, Gastro-upper, Gastro-lower) 
M6_GVHD_A_GASTRO1 
M6_GVHD_A_GASTRO2  
M6_GVHD_A_GASTRO3 
M6_GVHD_GAST_ABN 
 
 
- Mouth=0 (considérer la somme des 3 scores : Eythema, Lichenoid, Ulcers ) 


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M6_GVHD_A_MOUTH1 
M6_GVHD_A_MOUTH2  
M6_GVHD_A_MOUTH3  
M6_GVHD_MTH_ABN 
 
Joint and fascia =0 
M6_GVHD_A_J  
M6_GVHD_A_J_ABN 
 
 
Liver : les 3 valeurs (Bilirubine, ALAT et PAL) sont en dessous des ULN (Unité limite supérieure) si le 
score hépatique était >0 à V1 (table 1 et annexe du protocole)  
.<M6_GVHD_A_L_SGPT_V<=M6_GVHD_A_L_SGPT_U_V  
.<M6_GVHD_A_L_ALK_V<=M6_GVHD_A_L_ALK_U_V  
M6_GVHD_LIV_ABN 
 
Le score à V1 est calculé comme : 
 
Score = 0 : Bilirubine normale WITH ALAT AND PAL < 3 ULN 
(.<V1_GVHD_A_L_BILI_V<=V1_GVHD_A_L_BILI_U_V et 
.<V1_GVHD_A_L_SGPT_V<3* V1_GVHD_A_L_SGPT_U_V  et 
.<V1_GVHD_A_L_ALK_V<3* V1_GVHD_A_L_ALK_U_V ) 
 
Score = 1 : Bilirubine normale WITH 3 ULN<=ALAT < 5 UNL AND 3 ULN <=PAL<5 UNL 
Score = 2 : Bilirubine élevée (>1*ULN)  mais <= à 3 mg/dL OR ALAT >= 5 UNL OR PAL >=5 UNL (non 
mentionné dans article NIH). 
Score = 3 : Bilirubine élevée > à 3 mg/dL 
 
 
 
 
 
Lung :  si FEV1 >=80% et FEV1<70 à V1. et dans le cas où  la valeur de FEV1 est manquante, si le score est 
égal à 0 
M6_GVHD_A_LU_FEV1_V>= 80  
missing(M6_GVHD_A_LU_FEV1_V) and M6_GVHD_A_L=0 
M6_GVHD_A_L   
M6_GVHD_A_L_ABN  
 
Calcul de réponse par organe : 
Aucun calcul de réponse par organe (complète, partielle ou progression) n’est effectué si : 


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- 
« abnormalities present but explained entirely by non-GVHD documented cause » = Oui pour un 
organe à la visite considérée  
- 
CR_organe , PR_organe et PD_organe sont alors mis à . (manquant) 
Aucun calcul de réponse complète ou partielle par organe n’est effectué si : 
- 
l’organe n’est pas atteint à V1 ou abnormalities present but explained entirely by non-GVHD 
documented cause » = Oui pour un organe à la visite V1.  
- 
la progression est recherchée même si pas d’atteinte à V1 
- 
CR_organe et PR_organe sont alors mis à . (manquant) 
 
-  Partial response by organ: en se basant sur les mêmes scores et en s’intéressant aux diminutions (ou 
augmentations) entre V1 (mêmes variables qu’indiquées précédemment mais qui commencent par « V1 » au 
lieu de « M6 ») et la visite considérée (M6,W6, W14, M9 ou M12) 
- une diminution d’1 point pour les scores sur des échelles de 0 à 4 pour : Skin BSA, Skin features, Eyes, 
Joints, Gastro-oesophageal, Gastro-upper, Gastro-lower,  
- une diminution de 2 points pour la somme des 3 sous-scores pour Mouth 
- pour Lung, une augmentation entre V1 et la visite d’au moins 10% sur FEV1 avec FEV1 à V1 <70. Dans le 
cas de FEV1 manquants à V1 et ou M6, une diminution d’1 point sur le score ‘lungs’ 
- pour Liver, (Bilirubine, ALAT ou PAL), 
 
  
- si les valeurs à M6 sont en dessous des normales, la réponse est considérée Complète 
- sinon la recherche d’une réponse partielle est effectuée : diminution de 50% de la valeur initiale  
Le ratio est calculé ainsi : (M6-V1/V1)*100 et si le ratio est inférieur à -50 (mais pas de progression pour une 
des autres valeurs), il y a une réponse partielle 
 
Global Partial response: au moins une réponse partielle sur un organe et avec une absence de progression 
pour un autre site 
- Progressive disease by organ:  
- peau, yeux, œsophage, tractus gastro-intestinal supérieur et inférieur : augmentation 1 point ou plus sur 
échelle de 0 à 3 = progression SAUF si changement de 0 à 1 (progression non spécifique) 
- Joint: augmentation d’1 point ou plus = progression  
- bouche : changement de 2 points ou plus sur la somme des 3 sous-scores  


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- pour Lung, diminution de 10 % avec FEV1 à V1 < 75% . Dans le cas de FEV1 manquants, augmentation 
d’1 point ou plus SAUF si changement de 0 à 1 (progression non spécifique) 
- pour Liver, si l’une des valeurs à M6 est au-dessus de la normale pour Bilirubine, ALAT ou PAL, la 
recherche d’une progression est effectuée : la différence M6 – V1 est calculée et si la différence est 
supérieure à 2*ULN, il y a Progression. 
Global progressive disease : si au moins un site avec une progression 
Mixed response: si Progressive disease sur au moins un organe et Partial response sur au moins un autre  
 
 
Extraits du protocole :  
Table 4. Response determination for chronic GvHD (extrait du protocole) 
 
 
 
 
 
 


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Appendix 2: Organ scoring of cGvHD 
(NIH consensus criteria, Jagasia et al. Bone Marrow Transplant, 2015) 
 
 


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17.2 FACT-BMT  
17.2.1 
FACT-BMT items 
 
 
FACT-BMT (4ème Version) 
French (Universal) 
 
17 February 2010 
Copyright 1987, 1997 
Page 3 of 3 
 
Veuillez indiquer votre réponse en entourant un seul chiffre par ligne et en tenant compte des 
7 derniers jours. 
 
 
 
AUTRES SUJETS D’INQUIÉTUDE 
 
Pas du 
tout 
Un 
peu 
Moyen-
nement 
Beau-
coup 
Énormé-
ment 
 
BMT1 
Je m'inquiète de ne pas pouvoir continuer à travailler (y 
compris le travail à la maison) ................................ ...............
 
0 
 
1 
 
2 
 
3 
 
4 
 
BMT2 
Je me sens distant(e) des autres ................................ ..............
 
0 
1 
2 
3 
4 
 
BMT3 
J'ai peur que la greffe ne réussisse pas ................................ ...
 
0 
1 
2 
3 
4 
 
BMT4 
Les effets du traitement sont pires que ce que j'imaginais .....
 
0 
1 
2 
3 
4 
 
C6 
J'ai bon appétit ................................ ................................ ........
 
0 
1 
2 
3 
4 
 
C7 
Je suis satisfait(e) de mon apparence physique .......................
 
0 
1 
2 
3 
4 
 
BMT5 
Je peux me débrouiller seul(e) ................................ ...............
 
0 
1 
2 
3 
4 
 
BMT6 
Je me fatigue facilement ................................ ......................
0 
1 
2 
3 
4 
 
BL4 
Le sexe m'intéresse ................................ ................................ .
 
0 
1 
2 
3 
4 
 
BMT7 
J'ai peur de ne plus pouvoir avoir d'enfants ............................
 
0 
1 
2 
3 
4 
 
BMT8 
J'ai confiance en mes infirmières(iers) ................................ ...
 
0 
1 
2 
3 
4 
 
BMT9 
Je regrette d'avoir eu une greffe de la moelle osseuse ...........
 
0 
1 
2 
3 
4 
 
BMT 
10 
J’ai de la mémoire ................................ ................................ ..
 
0 
1 
2 
3 
4 
 
Br1 
Je suis capable de me concentrer ................................ ...........
 
0 
1 
2 
3 
4 
 
BMT 
11 
J’ai fréquemment des rhumes ou des infections......................
 
0 
1 
2 
3 
4 
 
BMT 
12 
Je vois trouble................................ ................................ .........
 
0 
1 
2 
3 
4 
 
BMT 
13 
Je suis gêné(e) par un changement de goût des aliments .......
 
0 
1 
2 
3 
4 
 
BMT 
14 
J’ai des tremblements ................................ ..............................
 
0 
1 
2 
3 
4 
 
B1 
J’ai le souffle court ................................ ................................ .
 
0 
1 
2 
3 
4 
 
BMT 
15 
Je suis gêné(e) par des problèmes de peau (éruptions 
démangeaisons) ................................ ................................ ......
 
0 
 
1 
 
2 
 
3 
 
4 
 
BMT 
16 
J’ai du mal à aller à la selle ................................ .....................
 
0 
1 
2 
3 
4 
 
BMT 
17 
Ma maladie est une lourde épreuve pour ma famille  
proche ................................ ................................ ......................
 
0 
 
1 
 
2 
 
3 
 
4 
 
BMT 
18 
Le coût du traitement est un fardeau pour moi et pour ma 
famille ................................ ................................ ......................
 
0 
 
1 
 
2 
 
3 
 
4 
 


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FACT-BMT (4ème Version) 
French (Universal) 
 
17 February 2010 
Copyright 1987, 1997 
Page 1 of 3 
 
Vous trouverez ci-dessous une liste de commentaires que d’autres personnes atteintes de la même 
maladie que vous ont jugés importants. Veuillez indiquer votre réponse en entourant un seul 
chiffre par ligne et en tenant compte des 7 derniers jours. 
 
 
 
BIEN-ÊTRE PHYSIQUE  
Pas du 
tout 
Un 
peu 
Moyen-
nement 
Beau-
coup 
Énormé-
ment 
 
 
GP1 
Je manque d’énergie ................................ ........................
 
0 
1 
2 
3 
4 
 
GP2 
J’ai des nausées ................................ ...............................
 
0 
1 
2 
3 
4 
 
GP3 
À cause de mon état physique, j’ai du mal à répondre 
aux besoins de ma famille ................................ ...............
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GP4 
J’ai des douleurs ................................ ..............................
 
0 
1 
2 
3 
4 
 
GP5 
Je suis incommodé(e) par les effets secondaires du 
traitement ................................ ................................ .........
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GP6 
Je me sens malade ................................ ...........................
 
0 
1 
2 
3 
4 
 
GP7 
Je suis obligé(e) de passer du temps allongé(e) ..............
0 
1 
2 
3 
4 
 
 
BIEN-ÊTRE FAMILIAL/SOCIAL  
Pas du 
tout 
Un 
peu 
Moyen-
nement 
Beau-
coup 
Énormé-
ment 
 
 
GS1 
Je me sens proche de mes amis ................................ .......
 
0 
1 
2 
3 
4 
 
GS2 
Ma famille me soutient moralement................................
 
0 
1 
2 
3 
4 
 
GS3 
Mes amis me soutiennent ................................ ................
 
0 
1 
2 
3 
4 
 
GS4 
Ma famille a accepté ma maladie ................................ ....
 
0 
1 
2 
3 
4 
 
GS5 
Je suis satisfait(e) de la communication avec ma 
famille au sujet de ma maladie ................................ ........
 
0 
 
1 
 
2 
 
3 
 
4 
 
GS6 
Je me sens proche de mon (ma) partenaire (ou de la 
personne qui est mon principal soutien) ..........................
 
0 
 
1 
 
2 
 
3 
 
4 
 
Q1 
 
 
 
 
 
 
 
Quel que soit votre degré d’activité sexuelle en ce 
moment, veuillez répondre à la question suivante.   
Si vous préférez ne pas y répondre, cochez cette case              
et passez à la section suivante. 
     
  
     
 
 
      
     
 
 
GS7 
Je suis satisfait(e) de ma vie sexuelle ..............................
0 
1 
2 
3 
4 
 
 


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17.2.2 
Details of FACT-BMT calculation 
doc35_ScoringFACT
-BMT v4-REVISED.do 
 
 
 
FACT-BMT (4ème Version) 
French (Universal) 
 
17 February 2010 
Copyright 1987, 1997 
Page 2 of 3 
 
Veuillez indiquer votre réponse en entourant un seul chiffre par ligne et en tenant compte des 
7 derniers jours. 
 
 
 
BIEN-ÊTRE ÉMOTIONNEL  
Pas du 
tout 
Un 
peu 
Moyen-
nement 
Beau-
coup 
Énormé-
ment 
 
GE1 
Je me sens triste ................................ ...............................
 
0 
1 
2 
3 
4 
 
GE2 
Je suis satisfait(e) de la façon dont je fais face à ma 
maladie ................................ ................................ ............
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GE3 
Je perds espoir dans le combat contre ma maladie ..........
 
0 
1 
2 
3 
4 
 
GE4 
Je me sens nerveux (nerveuse) ................................ ........
 
0 
1 
2 
3 
4 
 
GE5 
Je suis préoccupé(e) par l’idée de mourir ........................
 
0 
1 
2 
3 
4 
 
GE6 
Je  suis préoccupé(e) à l’idée que mon état de santé 
puisse s’aggraver ................................ .............................
 
0 
 
1 
 
2 
 
3 
 
4 
 
 
 
BIEN-ÊTRE FONCTIONNEL  
Pas du 
tout 
Un 
peu 
Moyen-
nement 
Beau-
coup 
Énormé-
ment 
 
 
GF1 
Je suis capable de travailler (y compris le travail  
à la maison) ................................ ................................ .....
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GF2 
Mon travail (y compris le travail à la maison) me 
donne de la satisfaction ................................ ...................
 
 
0 
 
1 
 
2 
 
3 
 
4 
 
GF3 
Je suis capable de profiter de la vie ................................ .
 
0 
1 
2 
3 
4 
 
GF4 
J’ai accepté ma maladie ................................ ...................
 
0 
1 
2 
3 
4 
 
GF5 
Je dors bien ................................ ................................ ......
 
0 
1 
2 
3 
4 
 
GF6 
J’apprécie mes loisirs habituels ................................ .......
 
0 
1 
2 
3 
4 
 
GF7 
 
Je suis satisfait(e) de ma qualité de vie actuelle ..............
 
0 
1 
2 
3 
4 
 
 


Statistical analysis plan 
Protocol: 2016-002358-18 
Version 3.0 
Date 21/12/2020 
 
SAP-GvHD-ATO Study PASL201637-V3.0 
Page 119 of 120 
 
17.3 LEE SYMPTOM SCALE 
 The Lee Chronic GVHD Symptom Scale is a 30 item instrument with 7 subscales (skin, 
eyes, mouth, lung, nutrition, energy and psych) containing 2-7 items. Response options for 
“let us know if you have been bothered by any of the following in the past month” range 
from 0-4 (Not at all, Slightly, Moderately, Quite a bit, Extremely). Some investigators have 
used the scale in reference to the past 7 days. (Lee SJ, Cook EF, Soiffer R, Antin JH. 
Development and validation of a scale to measure symptoms of chronic graft-versus-host 
disease. Biol Blood Marrow Transplant 2002; 8:444-452) 
Subscale 
name 
Number 
of items 
Items 
Skin 
5 
a. Abnormal skin color 
b. Rashes 
c. Thickened skin 
d. Sores on skin 
e. Itchy skin 
Eye 
3 
f. Dry eyes 
g. Need to use eyedrops frequently 
h. Difficulty seeing clearly 
Mouth 
2 
i. Need to avoid certain foods due to mouth pain 
j. Ulcers in mouth 
Lung 
5 
l. Frequent cough 
m. Colored sputum 
o. Shortness of breath at rest 
p. Need to use oxygen 
aa. Fevers 
Nutrition 
5 
k. Receiving nutrition from an intravenous line or feeding tube 


Statistical analysis plan 
Protocol: 2016-002358-18 
Version 3.0 
Date 21/12/2020 
 
SAP-GvHD-ATO Study PASL201637-V3.0 
Page 120 of 120 
 
q. Difficulty swallowing solid foods 
r. Difficulty swallowing liquids 
s. Vomiting 
t. Weight loss 
Energy 
7 
n. Shortness of breath with exercise 
u. Joint and muscle aches 
v. Limited joint movement 
w. Muscle cramps 
x. Weak muscles 
y. Loss of energy 
z. Need to sleep more/take naps 
Psych 
3 
bb. Depression 
cc. Anxiety 
dd. Difficulty sleeping 
 
Bold indicates items that are scored under a different subscale than where they are located 
Scoring rules: 
1. Note that the subscales do not conform exactly to the categories in the patient 
survey.  
2. Subscales may be scored if 50% of more of the items in the subscale are completed.  
3. Scores are linearly transformed to a 0-100 scale where 0 means all answered items 
were a “0” and “100” means that all answered items were a “4” 
4. Missing items are not included in the scoring. 
5. The summary score is the average of the subscale scores, as long as 4 or more 
subscales are available. 
6. Higher scores indicate more severe symptoms. 
7. A clinically meaningful difference for each subscale or the summary score is 
considered to be half a standard deviation of the baseline score for the population, 
based on the distribution method of determining clinically meaningful changes.