An International, Multi-centre, Non-interventional Retrospective Study to Describe Treatment Pathways, Outcomes, and Resource Use in Patients With Classical Hodgkin Lymphoma (B-HOLISTIC)
Conditions: Classical Hodgkin Lymphoma, Relapsed or Refractory Classical Hodgkin Lymphoma
Sponsor: Takeda

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
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Title: An international, multi-centre, non-interventional retrospective study to describe treatment 
pathways, outcomes, and resource use in patients with classical Hodgkin lymphoma (B-
HOLISTIC) 
NCT Number: NCT03327571
Protocol Approve Date: 04 May 2017
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

Protocol ID: CHL-5001 
Observational/non-interventional 
study protocol 
FINAL   Version  No. 1.0 
Page 1 of 62 
Non-interventional study protocol 
Short title: 
Classical Hodgkin lymphoma real world evidence study 
Title: 
An international, multi-centre, non-interventional retrospective study to 
describe treatment pathways, outcomes, and resource use in patients with 
classical Hodgkin lymphoma (B-HOLISTIC)   
Study ID: 
CHL-5001 
Sponsor: 
Takeda Pharmaceuticals International AG 
Thurgauerstrasse 130 
8152 Glattpark-Opfikon (Zurich) 
Switzerland 
Study phase:  Medical Affairs, Non-registration Company Sponsored (Observational) 
Date of final version of protocol:  04 May 2017 
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1 
Administrative information 
1.1 
Contacts 
A separate contact information list will be provided to each site. 
 
1.2 
Approval 
Representatives of Takeda 
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this clinical study protocol and also in 
accordance with the following: 
 The ethical principles that have their origin in the Declaration of Helsinki. 
 International Conference on Harmonisation E6 Good Clinical Practice: 
Consolidated Guideline. 
 Guidelines for good pharmacoepidemiology practices (GPP). 
 All applicable laws and regulations, including, without limitation, data privacy 
laws, clinical trial disclosure laws, and regulations. 
 
SIGNATURES  
Proper
se only and subject to the applicable Terms of Use
PPD

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2 
Summary 
Short title of study 
B-CD30 + HOdgkin Lymphoma International Multi-centre Retrospective Study of Treatment 
PractIces and OutComes (B-HOLISTIC) 
Study sites 
The study will be conducted across 13 countries within the emerging markets region. The 
number of sites needed to achieve the required sample size will be determined based on 
local feasibility within each country. 
Objectives 
Primary objective: 
To describe progression-free survival (PFS) in patients with relapsed or refractory classical 
Hodgkin lymphoma (RRHL), defined as the time from initiation of first treatment for RRHL to 
first documentation of relapse or disease progression, or death.  
Secondary objectives: 
To describe the following in two populations of patients with Hodgkin lymphoma (HL): in 
those receiving frontline treatment for high-risk stage IIb–IV classical Hodgkin lymphoma 
(cHL) (Group 1) and in those with RRHL (Group 2): 
1. Patient demographic and clinical characteristics. 
2. HL treatment pathways. 
3. Clinical outcomes: 
a) Overall survival (OS). 
b) 1- and 5-year survival rates. 
For each line of therapy: 
c) Best clinical response after completion of treatment, as defined by the 
International Working Group 2007 Revised Response Criteria for Malignant 
Lymphoma (1). 
d) Response duration. 
e) PFS (group 1). 
4. The adverse events associated with each line of therapy. 
5. The HL-related healthcare resource use associated with each line of therapy. 
6. The HL-related healthcare costs associated with each line of therapy. 
Methodology 
An international, multi-centre, retrospective, observational research study to be conducted 
across 13 countries in the emerging markets region. 
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This will be a retrospective review of medical records of patients with a diagnosis of high-risk 
stage IIb–IV cHL who have received frontline treatment with chemotherapy +/- radiotherapy 
(Group 1), and of patients with a diagnosis of RRHL (Group 2). 
Pseudonymised (anonymised-coded) data will be collected according to the agreed 
minimum dataset (see Appendix 1 and Table 4) using a standardised study case report form 
(CRF). A web-based electronic CRF will be employed. 
Pseudonymised data from all participating centres and countries will be provided to the 
appointed contract research organisation (CRO) for pooled analysis and reporting. 
Number of subjects 
To take account of different population sizes, approximately 50–200 patients with cHL 
(Group 1) and 50–200 patients with RRHL (Group 2) will be included in the study in each 
participating country. 
A sample of 50 patients will provide reasonably reliable country-level estimates of the mean 
and median PFS (for the primary endpoint), based on predicted confidence limits.  Whilst it is 
hoped that each country will be able to include 100 patients in each group (approximately 
1300 per group in total across all 13 countries) to allow description of PFS in different 
subgroups and for different treatments, it is recognised that this may not be possible in every 
country, and therefore oversampling may be performed in countries with larger populations 
of eligible patients to enable the overall sample to be achieved. 
Diagnosis/disease/condition and main criteria for inclusion 
Patients with cHL or RRHL who are managed in the participating centres and who meet the 
following eligibility criteria will be included in the study. 
Inclusion criteria: 
1. 
Patients newly diagnosed with high-risk stage IIb–IV cHL (for Group 1) or RRHL (for 
Group 2) between 01 January 2010 and 31 December 2013. 
2. 
Age ≥18 years at diagnosis of cHL (Group 1) or RRHL (Group 2). 
3. 
Alive or deceased. 
4. 
Written informed consent is obtained for study data collection, where necessary, 
according to local regulations. 
Exclusion criteria: 
1. 
Patients for whom the minimum study dataset (see Appendix 1 and Table 4) is not 
available from their hospital medical records. 
2. 
Patients who have participated in an interventional clinical trial at any stage of their 
cHL (Group 1) or RRHL (Group 2) management.  
In each country, a geographically dispersed sample of sites from different settings (hospitals, 
cancer institutes, and academic medical centres) will be employed.  
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Duration of data collection per subject 
For each patient included in the newly diagnosed cHL group (Group 1), data on treatments 
received for cHL and the associated adverse events and resource use will be collected from 
the date of cHL diagnosis until the date of first documented relapse or disease progression 
after frontline therapy. All relevant outcomes, including mortality, will be collected during the 
observation period until the date of death (or data collection, whichever occurs first).  
For patients in the RRHL group (Group 2), a summary of treatments received prior to 
diagnosis of RRHL will be collected; detailed data on treatment pathways, clinical outcomes, 
adverse events, and resource use will be collected from the date of RRHL diagnosis until the 
death of the patient or the date of data collection (whichever occurs first).  
In both groups, resource use data will be collected for periods when the patient is receiving 
active treatment for cHL or RRHL to enable the resource use [and costs] associated with 
each line of treatment to be determined. 
Criteria for evaluation 
Population descriptors: 
Data will be collected in relation to practice location, subject gender, age, ethnicity, diagnosis 
and staging/subtype of disease, relevant clinical laboratory results/procedures, and 
comorbidities. See Section 9 (Table 4) for full list of variables. 
Main outcome variables: 
Data will be collected in relation to treatment pathways, clinical outcomes, and adverse 
events. See section 9 (Table 4) for full list of variables. 
Health economics 
Data will be collected in relation to HL-related resource use. The granularity and source of 
reference costs will be agreed at country level and will be detailed in the statistical analysis 
plan (SAP).   
Statistical methods 
Descriptive analyses will be conducted to summarize patient demographics and clinical 
characteristics, treatment patterns, clinical outcomes, and healthcare resource utilisation. 
 
 
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Table of contents 
1 
Administrative information................................................................................................ 2 
1.1 
Contacts ................................................................................................................. 2 
1.2 
Approval ................................................................................................................. 2 
2 
Summary ......................................................................................................................... 3 
3 
List of abbreviations and definition of terms ..................................................................... 8 
4 
Introduction .................................................................................................................... 12 
5 
Study objective(s) .......................................................................................................... 16 
6 
Study administrative structure ........................................................................................ 17 
6.1 
Study sites ............................................................................................................ 17 
6.2 
Sponsor personnel ............................................................................................... 18 
6.3 
Contract research organisation ............................................................................. 18 
6.4 
Essential documents ............................................................................................ 18 
7 
Ethics ............................................................................................................................ 18 
7.1 
Ethical conduct of the study .................................................................................. 18 
7.2 
Independent Ethics Committee/Institutional Review Board and Authorities........... 19 
7.3 
Subject information and written informed consent................................................. 19 
8 
Study design and plan ................................................................................................... 20 
8.1 
Study schedule ..................................................................................................... 21 
8.2 
Discussion of study design ................................................................................... 21 
8.3 
Selection of study population ................................................................................ 22 
8.4 
Treatments ........................................................................................................... 24 
9 
Conduct ......................................................................................................................... 24 
10 Safety reporting ............................................................................................................. 31 
10.1 Definitions............................................................................................................. 31 
10.2 Classifications ...................................................................................................... 32 
10.3 Collection of Adverse Events, Special Situation Reports and Product Quality 
Issues ................................................................................................................... 33 
10.3.1 
Spontaneously reported events ............................................................... 33 
10.3.2 
Events identified from chart review ......................................................... 33 
10.4 Reporting of Adverse Drug Reactions and Special Situation Reports to Regulatory 
Agencies .............................................................................................................. 33 
11 Data quality control and assurance ................................................................................ 34 
11.1 Quality control ...................................................................................................... 34 
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11.2 Audit from Quality Assurance Unit ........................................................................ 34 
11.3 Inspection by Institutional Review Board/Independent Ethics Committee or 
competent authority .............................................................................................. 35 
11.4 Data management ................................................................................................ 35 
11.4.1 
Data collection tools and flow .................................................................. 36 
12 Statistical methods and determination of sample size .................................................... 36 
12.1 Statistical analysis plan......................................................................................... 36 
12.2 Interim and final analyses ..................................................................................... 37 
12.3 Determination of sample size................................................................................ 38 
13 Reports .......................................................................................................................... 40 
14 Publications ................................................................................................................... 40 
15 Archiving of study documentation .................................................................................. 41 
16 References .................................................................................................................... 42 
17 Appendices .................................................................................................................... 46 
Appendix 1: Minimum dataset .............................................................................................. 46 
Appendix 2: Spontaneous reporting to sponsor .................................................................... 48 
Appendix 3: Study endpoints ................................................................................................ 49 
 
 
 
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3 
List of abbreviations and definition of terms 
Abbreviation 
Definition 
ABVD 
Doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine 
ADR 
Adverse drug reaction 
AE 
Adverse event 
AIDS 
Acquired immune deficiency syndrome 
Allo-SCT 
Allogeneic haematopoietic stem cell transplantation 
ASCT 
Autologous stem cell transplantation 
ASHAP 
Doxorubicin (Adriamycin), methylprednisolone (Solu-Medrol), high-dose 
cytarabine (Ara-C), and cisplatin (platinum) 
ASR 
Age-standardized rate 
BEACOPP 
Bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, 
vincristine (Oncovin), procarbazine, and prednisone 
BMT 
Bone marrow transplant 
BV 
Brentuximab vedotin 
CA 
Competent authority 
cHL 
Classical Hodgkin lymphoma 
ChlVPP 
Chlorambucil, vinblastine, procarbazine, and  prednisolone 
CHOP 
Cyclophosphamide, doxorubicin (hydroxydaunomycin), and vincristine 
(Oncovin), prednisolone 
CI 
Confidence interval 
CL 
Confidence limits 
COPP 
Cyclophosphamide, vincristine (Oncovin), procarbazine, and prednisone 
CR 
Complete remission 
CRF 
Case report form 
CRO 
Contract research organisation 
CT 
Computerised tomography 
CVM 
Carboplatin, vinblastine, and methotrexate 
CVP 
Cyclophosphamide, vincristine, and prednisolone 
DHAC 
Dexamethasone, doxorubicin (doxorubicin hydrochloride), cytarabine 
(Ara-C), and carboplatin 
DHAP 
Dexamethasone, high-dose cytarabine (Ara-C), and cisplatin (platinum) 
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DMP 
Data management plan 
EBV 
Epstein–Barr virus 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic case report form 
ESHAP 
Etoposide, methylprednisolone (Solu-Medrol), high-dose cytarabine (Ara-
C), and cisplatin (platinum) 
FDG 
Fluorodeoxyglucose 
GCO 
Global Cancer Observatory 
G-CSF 
Granulocyte-colony stimulating factor 
GDP 
Gemcitabine, dexamethasone, cisplatin (platinum) 
GEM-P 
Gemcitabine, cisplatin, and methylprednisolone 
GHSG 
German Hodgkin Study Group 
GPP 
Good pharmacoepidemiology practices 
HDI 
Human development index 
High-risk stage 
IIb–IV cHL 
HL is staged using the Ann Arbor staging classification (2). Patients with 
stage IIb HL are classified as ‘high risk’ if they have a large mediastinal 
mass (measuring at least one-third of the transverse diameter of the 
thorax) or extranodal disease (any tumour spread involving other tissues 
than those of the lymph nodes, spleen, thymus, Waldeyer’s tonsillar ring, 
appendix, and Peyer’s patches) 
HIV 
Human immunodeficiency virus 
HL 
Hodgkin lymphoma 
HRU 
Healthcare resource utilization 
ICE 
Ifosfamide, carboplatin, and etoposide 
ICE±R 
Ifosfamide, carboplatin, and etoposide ± rituximab 
ICU 
Intensive care unit 
ID 
Identification 
IEC 
Independent Ethics Committee 
IFRT 
Involved-field radiotherapy 
IGEV 
Ifosfamide, gemcitabine, vinorelbine (and prednisolone) 
INRT 
Involved-node radiotherapy 
IPS 
International Prognostic Score 
IRB 
Institutional Review Board 
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ISRT 
Involved-site radiotherapy 
LCL 
Lower confidence limit 
LMIC 
Low- and middle-income countries 
LOC 
Local operating country 
MINE 
Mesna, ifosfamide, mitoxantrone (Novantrone), and etoposide 
MOPP 
Mustine, vincristine (Oncovin), procarbazine, prednisolone 
OPEC 
Vincristine (Oncovin), prednisolone, etoposide, and chlorambucil 
OS 
Overall survival 
PD 
Progressive disease 
PET 
Positron emission tomography 
PFS 
Progression-free survival 
PN 
Peripheral neuropathy 
PR 
Partial remission 
PSUR 
Periodic safety update report 
QA 
Quality assurance 
Risk factors for 
relapse 
Risk factors for relapse are defined using the International Prognostic 
Score for newly diagnosed advanced stage cHL (3) and the Josting score 
for RRHL (4) 
RR 
Relative risk 
RRHL 
Relapsed or refractory classical Hodgkin lymphoma. RRHL includes 
patients with primary refractory HL (those who have failed to achieve a 
complete remission [CR] with frontline therapy or relapse within 3 months 
after end of frontline therapy) and patients with relapsed HL (those who 
have a recurrence >3 months after end of frontline treatment [early 
relapsers: recurrence within 3–12 months; late relapsers: recurrence 
>12 months]) 
RT 
Radiotherapy 
RWE 
Real world evidence 
SADR 
Serious adverse drug reaction 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis system 
SCT 
Stem cell transplantation 
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SD 
Stable disease 
SSR 
Special situation report 
Stanford V 
Cyclophosphamide or ifosfamide, doxorubicin, vinblastine, vincristine, 
bleomycin, etoposide, prednisolone 
StDev 
Standard deviation 
TB 
Tuberculosis 
TLFs 
Tables, Listings, and Figures 
UCL 
Upper confidence limit 
 
 
 
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4 
Introduction 
Classical Hodgkin lymphoma (cHL) is the more common form of Hodgkin lymphoma (HL), 
characterised by the presence of Reed–Sternberg cells. The prevalence of all HL and hence 
cHL (which accounts for the majority of all HL cases) varies both between and within 
geographical regions, but the condition is typically more prevalent within economically 
developed countries. Global Cancer Observatory (GCO) data indicate that, in 2012, HL 
prevalence was four times higher in very high human development index (HDI) countries 
compared to those whose HDI was low (5). Despite the lower current prevalence of HL 
within developing countries, it is estimated by the GCO that, by 2030, there will be 12,392 
incident cases and 5951 deaths within 10 emerging market countries alone (see Table 1 for 
list of countries). This amounts to a 16% increase in incident cases and a 39% increase in 
deaths since 2012 (5).  
The incidence of HL by age also varies markedly according to countries’ development 
status, such that, in developing countries, the incidence is higher in childhood and decreases 
with age, while in developed countries the opposite applies (6). This has led many observers 
to postulate that regional differences may reflect differences in aetiology, potentially owing to 
variation in exposure to common infectious agents. Indeed, researchers have found causal 
associations between serological markers of Epstein–Barr virus (EBV) infection and EBV-
positive HL in young adults (relative risk [RR] 4.0; 95% confidence interval [CI] 3.4–4.5) (7). 
Others have noted that, as HL incidence varies between countries, so does exposure to 
EBV. In a dataset of 1566 HL patients, Glaser et al. found that patients who lived in 
developing countries were almost twice as likely to have EBV-positive HL compared to those 
who did not (63.4% versus 36%) (8). A higher incidence of HL has similarly been noted 
amongst those with AIDS-related immunosuppression: in a study linking AIDS and cancer 
registry data from 612 HL patients in the United States (US), the RR for HL among those 
with AIDS versus those without was 11.5 (95% CI 10.6–12.5) (9). In a study conducted 
amongst HL patients in South Africa, 46% were found to be HIV-positive (10). The authors 
argue that poor diagnostic capabilities and the absence of robust cancer registries in South 
Africa highlight the need to strengthen cancer registries in the region. 
 
 
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Table 1: Epidemiological data for HL in 13 emerging market countries   
Country  
Incidence per 
100,000 ASR 
Deaths per  
100,000 ASR 
Prevalence   
per 100,000 
ASR 
Male  Female  
Argentina* 
1.4 
0.3 
1.3 
1.8 
0.9 
Australia* 
1.7 
0.2 
2.3 
2.5 
2.1 
China* 
0.1 
0.1 
0.1 
0.2 
0.1 
Colombia* 
0.9 
0.3 
0.9 
1.1 
0.6 
Hong Kong∆ 
0.91 
0.1 
ND 
ND 
ND 
Mexico* 
1.3 
0.5 
1.2 
1.4 
1 
Republic of 
Korea* 
0.4 
0.1 
0.4 
0.7 
0.2 
Russia* 
1.8 
0.6 
1.8 
2 
1.7 
Saudi Arabia* 
1.6 
0.8 
1.3 
1.4 
1.1 
Singapore* 
0.9 
0.1 
0.8 
1 
0.6 
South Africa* 
0.9 
0.3 
0.8 
1 
0.6 
Taiwan 
ND 
ND 
ND 
ND 
ND 
Turkey* 
2.1 
1.1 
1.9 
2.6 
1.2 
Average 
1.27 
0.43 
1.24 
1.5 
0.99 
* Data from Global Cancer Observatory (5) 
∆ 2012 Data from Hong Kong Cancer Registry Cancer Statistics Query 
System (11)  
ND, no data available; ASR, age-standardised rate.  
 
Although once considered incurable, the prognosis for patients with cHL has improved 
markedly over recent decades. Today over 80% of newly diagnosed patients can be cured 
following treatment with chemotherapy either with, or without, involved-field radiotherapy 
(IFRT) (12). However, this improvement in patient outcomes is largely attributable to the 
outputs of several American and European cooperative study groups (13,14), as well as to 
notable improvements in salvage treatments for relapsed or refractory classical HL (RRHL). 
These include high-dose chemotherapy, autologous stem cell transplantation (ASCT) (15–
17), and targeted biological therapies (18). Despite these notable improvements in the 
standard of care, approximately 5–10% of cHL patients treated in economically developed 
countries are refractory to initial treatment, and a further 10–30% relapse following an initial 
positive response (12,15,19). High-quality, population-based, data concerning the underlying 
patterns of incidence and survival of HL are limited (20) or primarily derived from within 
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North America (21), western European study populations (20,22), or from developed 
emerging market countries such as Japan (23) and Australia (24). Population-based data 
from within emerging markets are scarce or are largely historical. Although global incidence, 
prevalence, and mortality data are available for most emerging market countries and types 
of cancer (GLOBOCAN & Global Cancer Observatory), these data are of variable quality and 
are limited to descriptive epidemiological parameters without linkage of interventional data to 
patient outcomes (5,25).  
Although various real world evidence (RWE) studies have been conducted within emerging 
market countries, these are typically small hospital-based studies that yield little, if any, 
generalisable results (16,26–28). As such, RWE on treatment patterns, clinical outcomes, 
and healthcare resource utilization (HRU) within the emerging market countries is limited. 
There have been very few RWE studies concerning RRHL and, of those that have been 
reported, most were conducted in Australia (29,30) or Turkey (18,31,32). With the exception 
of one multi-centre study (18), the remainder of these studies were one- or two-centre 
studies with limited sample sizes. While studies of this type generate detailed patient 
information, there remains a need for RWE, generated at the national level in emerging 
market countries, that would allow payers and policy-makers to more effectively plan for and 
deliver national services and to evaluate the impact of treatment interventions for cHL in real 
world clinical context. These limitations appear all the more relevant given that most 
randomised trials in oncology are conducted in socioeconomically advantaged subgroups of 
younger Caucasian patients with fewer comorbidities (33). Owing to potential environmental 
and patient-related differences between regions, extrapolation of these data from developed 
countries to emerging markets may be problematic (34). There are several national cancer 
registries that provide basic epidemiological data relating to HL in various emerging market 
regions, including Central and Southern America (35), South Africa (36), Taiwan (37), 
Singapore (38), and Turkey (39). However, as is commonplace with registry studies, 
individual level data concerning stage of disease, HRU, access to treatments, and outcomes 
are lacking.  
GCO data reveal no significant difference in HL-related mortality rates between developed 
and developing countries (5). This is unexpected given that patients residing within low- and 
middle-income countries (LMICs) may have limited access to cancer care services. While 
first-line chemotherapy regimens for HL are widely available, with reimbursement approval in 
most emerging market countries (see Table 2), the same may not be true for treatments for 
RRHL. Anecdotal evidence suggests that in certain LMICs (e.g. Mexico (40) and Argentina 
(41)), access to autologous and allogeneic stem cell transplants may be extremely limited.  
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Table 2: Access to HL treatment within 13 emerging market countries (42)1 
Country 
HL therapies with regulatory 
approval 
HL therapies with 
funding/reimbursement approval  
Argentina 
ABVD, BEACOPP, DHAP, ICE, 
MINE, RT 
ABVD, BEACOPP, DHAP, ICE, 
MINE, RT 
Australia 
ABVD, BEACOPP, BV, ChIVPP, 
COPP, cyclophosphamide, 
DHAP, ICE±R, MINE, MOPP, RT, 
Stanford V, SCT 
ABVD, BEACOPP, BV, ChIVPP, 
COPP, cyclophosphamide, DHAP, 
ICE±R, MINE, Stanford V 
China 
ABVD, BEACOPP, DHAP, ICE, 
MINE, RT 
ABVD, BEACOPP, DHAP 
Colombia 
ABVD, BEACOPP, BV, DHAP, 
ESHAP, ICE, MINE, RT 
ABVD, DHAP, ESHAP 
Hong Kong 
ND 
ND 
Mexico 
ABVD, BEACOPP, DHAP, ICE, 
MINE, RT 
ABVD, BEACOPP, DHAP, ICE 
Republic of 
Korea 
ND 
ND 
Russia 
ABVD, BEACOPP, DHAP, ICE, 
MINE, RT 
ABVD, BEACOPP, DHAP, ICE 
Saudi Arabia 
ND 
ND 
Singapore 
ABVD, ASHAP, BEACOPP, BV, 
DHAP, ICE, MINE, RT 
ABVD, BEACOPP, DHAP 
South Africa 
ABVD, ASHAP, BEACOPP, 
CHOP, CVP, cyclophosphamide,  
DHAP, ESHAP, GDP, GEM-P, 
ICE, IGEV, MINE, RT, SCT 
Private health insurance for: 
ABVD, ASHAP, BEACOPP, 
ChIVPP, CVM, cyclophosphamide, 
DHAC, DHAP, 
ESHAP, GDP, GEM-P, ICE, IGEV, 
MINE, OPEC, RT, SCT 
Government partially 
funds/reimburses: 
ABVD, BEACOPP 
Taiwan 
ND 
ND 
Turkey 
ABVD, BEACOPP, DHAP, ICE, 
MINE, RT 
ABVD, BEACOPP 
ND, no data available. 
1 Real time data are accessible at 
http://www.lymphomacoalition.org/lcinfo/globalTherapy.php 
                                               
 
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In view of the current lack of RWE from countries outside Europe and North America, the 
data collected in this study will be used to describe how patients with high-risk stage IIb–IV 
cHL and RRHL are treated across different countries in the emerging markets region and the 
associated clinical outcomes. This will contribute to a greater understanding of current 
treatment patterns, which will help to inform future clinical decision-making in these 
countries.  
There is a particular need for RWE on clinical outcomes for patients treated after ASCT 
relapse and in patients with RRHL who are not eligible for ASCT. Currently, the treatment of 
these patient groups is thought to be unstandardised and likely to vary not only between 
countries but from one centre to another within a country. This study will describe how 
patients are treated across regional and geographical boundaries in emerging market 
countries, and the clinical outcomes associated with treatment.  
The study will also provide evidence of the resource use associated with different treatment 
options, which will be of interest to funding and reimbursement bodies. 
5 
Study objective(s) 
Primary objective: 
To describe progression-free survival (PFS) in patients with RRHL, defined as the time from 
initiation of first treatment for RRHL to first documentation of relapse or disease progression 
or death.  
Secondary objectives: 
To describe the following in two populations of patients with HL: in those receiving frontline 
treatment for high-risk stage IIb–IV cHL (Group 1) and in those with RRHL (Group 2): 
1. 
Patient demographic and clinical characteristics (including known risk factors for 
relapse, prior therapies, and clinical staging). 
2. 
HL treatment pathways (treatments and treatment sequences received for cHL or 
RRHL and imaging tests used to evaluate response). 
3. 
Clinical outcomes: 
a) 
Overall survival (OS). 
b) 
1- and 5-year survival rates. 
For each line of therapy: 
c) 
Best clinical response after completion of treatment, as defined by the 
International Working Group 2007 Revised Response Criteria for Malignant 
Lymphoma (1). 
d) 
Response duration. 
e) 
PFS (group 1). 
4. 
The adverse events associated with each line of therapy. 
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5. 
The HL-related healthcare resource use associated with each line of therapy. 
6. 
The HL-related healthcare costs associated with each line of therapyϮ. 
ϮIt is expected that all participating countries will collect data on patient characteristics, 
treatment pathways, clinical outcomes, adverse events, and resource use (for the 
primary objective and secondary objectives 1–5). Allocation of costs (for secondary 
objective 6) is optional. Sections of the protocol that relate specifically to secondary 
objective 6 are shown in italics and may be deleted if the country is not participating in 
this part of the study. 
6 
Study administrative structure 
Takeda Pharmaceuticals International is the sponsor of this non-interventional study, and will 
engage the services of a contract research organisation (CRO) to operationalise the study 
globally. Takeda Pharmaceuticals International will retain overall responsibility for the study, 
but will delegate tasks as necessary to the CRO. A core protocol will be provided to the 
CRO, and they will be expected to identify/recruit study sites and manage subject 
recruitment. The data collection will be carried out by the local hospital staff. The appointed 
CRO will train the data collectors and provide support with data query management. 
Pseudonymised data from all participating centres and countries will be provided to the CRO 
for pooled analysis and reporting. 
6.1 
Study sites 
The plan is that the study will be conducted in approximately 100 sites across 13 countries 
within the emerging markets region (Argentina, Australia, China, Colombia, Hong Kong, 
Mexico, Republic of Korea, Russia, Saudi Arabia, Singapore, South Africa, Taiwan, and 
Turkey).  Sites in each country will be identified by the CRO in consultation with Takeda, 
ideally using a national database (where this is available) and will be pre-screened for 
eligibility using a customised feasibility questionnaire. Sites will be selected on the basis that: 
• 
They are specialist lymphoma treatment centres. 
• 
They have access to data throughout the whole patient pathway (either direct or 
through collaboration with previous treatment centres, including transplant centres). 
• 
There are appropriate and sufficient personnel available for abstracting medical 
records and data collection internally (after receiving appropriate training). 
• 
They have a means to identify eligible patients robustly and systematically for the 
study (database, department records or equivalent). 
• 
 Adequate numbers of eligible patients are available for inclusion in the study 
(minimum 5–10 patients in the RRHL group). 
In each participating country, a geographically dispersed sample of sites from different 
settings (hospitals, cancer institutes, and academic medical centres) will be included. The 
number of sites needed to achieve the required sample size and obtain good geographic 
coverage will vary between the participating countries; this will be determined by the CRO (in 
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consultation with Takeda), depending on the number, size, and geographic spread of 
potentially eligible study sites in each country.      
Global Research will keep a record of the individuals responsible for each participating Study 
Site, the Site Responsibles. 
6.2 
Sponsor personnel 
Takeda local operating country (LOC) will keep a record of all relevant sponsor personnel.  
6.3 
Contract research organisation 
The CRO will keep a record of all involved CRO personnel involved in any aspect of the 
study, e.g. site selection, study startup, data collection, query management, safety reporting, 
analysis, and study reporting. 
6.4 
Essential documents 
The following essential documents must be received by Global Research before the study is 
initiated at a site: 
 
Written agreement between Takeda and/or the CRO and the Study Site as locally 
applicable. 
 
Signed and dated protocol agreement and amendment agreements, if any, with the 
original signature of the Site Responsible.  
 
Subject information sheet and informed consent form in local language (notified 
to/approved by Independent Ethics Committees [IECs]/Institutional Review Boards [IRBs] 
as locally required). 
 
Written IEC/IRB approval/vote according to local regulations. 
 
Authority approval according to local regulations. 
 
Local insurance certificate as applicable. 
7 
Ethics 
This study is an observational study where the existence of the study has no impact on the 
subject except for collection of informed consent (where required as per country regulations) 
to use of the subject’s data.  
7.1 
Ethical conduct of the study 
This study will be conducted in accordance with the protocol, the current version of the 
Declaration of Helsinki (43), good pharmacoepidemiology practices (GPP) (44), ISPE GPP 
guideline, and any local regulations. Special attention will be paid to data protection. The 
CRO will ensure adherence to any country-specific requirements for data protection. 
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Takeda/the appointed CRO will ensure that the protocol, any amendments, and the subject 
information sheet/informed consent form are submitted to the relevant IECs/IRBs according 
to local requirements. 
As the sponsor, Takeda is responsible for meeting the ICH requirement for yearly updates to 
the IECs/IRBs, if applicable. 
7.2 
Independent Ethics Committee/Institutional Review Board and 
Authorities 
Independent Ethics Committee/Institutional Review Board 
According to applicable regulations, the appointed CRO or the Site Study Responsible will: 
 
Notify or obtain approval from the relevant IEC/IRB of the protocol, any amendments, 
and the subject information sheet/informed consent form.  
The appointed CRO or the Site Study Responsible will submit required documents to the 
IEC/IRB, such as: 
 
Periodic updates on the progress of the study. 
 
Notification of the end of the study. 
 
A summary of the study results. 
Global Research will keep an updated list of all submission and approval dates of all 
documents submitted to the IEC/IRB and will provide the Site Responsible with a copy of this 
list. Copies of the documents will be distributed upon request. 
Authorities 
Global Research or the appointed CRO will send required documents to the competent 
authority (CA) and/or other national or regional authorities. Global Research will keep an 
updated list of submission and approval dates and a copy of all documents submitted.   
7.3 
Subject information and written informed consent 
Eligible patients will be approached to provide written informed consent for their medical 
records to be reviewed for study data collection (if this is required by local laws and 
regulations). 
The Site Study Responsible must give the subject (and, if applicable, parent or legal 
guardian) oral and written information about the study in a form that the subject (parent or 
legal guardian) can understand, and obtain the subject’s (and, if applicable, the subject’s 
assent and the parent’s or legal guardian’s) written consent before collection of identifiable 
subject information (hereinafter referred to as personal data). Before consenting, the subject 
(and, if applicable, parent or legal guardian) must be left with ample time to consider and to 
pose questions. Since the study is observational the consent only concerns the data 
collection per se and is not consent to any interventional procedure or treatment.  
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The subject must agree that sponsor personnel, their representatives, or IEC/IRB or CA 
personnel (national or other) may require direct access to the subject’s data/personal 
records that were collected, processed, and stored in an anonymous form.   
The subject must agree that his/her data will be processed and stored in an anonymous form 
for evaluation of this study and any later overviews. Data may also be transferred in 
anonymous form to third parties, e.g. other companies or authorities, that may be located in 
other countries with potentially different regulations for data.  
The subject or legal guardian, if applicable, has the right to withdraw his/her consent at any 
time without prejudice. In the informed consent form it is stated that, if consent is withdrawn, 
any data collected before withdrawal of consent will be kept. The original, signed informed 
consent forms must be kept on the Site. 
For details, see the subject information sheet and informed consent form. 
8 
Study design and plan 
This study is a ‘non-interventional study’ as defined in: G-STND-PV-006, Directive 
2001/20/EC (45), and will follow the guidelines for GPP (44).  
This means that: 
 
The assignment of a subject to a particular therapeutic strategy is not decided in 
advance by the study protocol but falls within current practice. 
 
No additional diagnostic or monitoring procedures shall be applied to the subjects. 
 
Epidemiological methods shall be used for the analysis of collected data. 
The study is an international, multi-centre, retrospective observational research study 
involving retrospective review of medical records (paper and/or electronic, as applicable 
locally) of patients with a diagnosis of high-risk stage IIb–IV cHL who have received frontline 
treatment with chemotherapy with or without radiotherapy (Group 1) and/or patients with a 
diagnosis of RRHL (Group 2). Patients who are diagnosed with high-risk stage IIb–IV 
classical HL and/or RRHL between 2010 and 2013 will be included. 
Pseudonymised data will be collected according to the agreed minimum dataset (see 
Appendix 1 and Table 4) using a standardised study case report form (CRF). Key variables 
will include those related to patient characteristics, diagnosis, treatment information, 
resource use, clinical outcomes, and adverse events.   
A web-based electronic CRF will be employed. 
For each patient included in the newly diagnosed cHL group (Group 1), data on treatments 
received for cHL and the associated adverse events and resource use will be collected from 
the date of cHL diagnosis until the date of first documented relapse or disease progression 
after frontline therapy. Patients will continue to be observed until the date of death (or data 
collection, whichever occurs first) for collection of overall survival data.  
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For patients in the RRHL group (Group 2), a summary of treatments received prior to 
diagnosis of RRHL will be collected; detailed data on treatment pathways, clinical outcomes, 
adverse events, and resource use will be collected from the date of RRHL diagnosis until the 
death of the patient or the date of data collection (whichever occurs first).  
In both groups, resource use data will be collected for periods when the patient is receiving 
active treatment for cHL or RRHL, to enable the resource use [and costs] associated with 
each line of treatment to be determined.  
The data collection will be carried out by local hospital staff. The appointed CRO will provide 
support with data query management. Pseudonymised data from all participating centres 
and countries will be provided to the CRO for pooled analysis and reporting.  
It is expected that data collection for the study will last approximately 12 months. 
8.1 
Study schedule 
The study report should be signed within 12 months after the collection of the last datapoint. 
Global Research will ensure that end-of-study notification is submitted to the concerned 
authorities and IEC/IRB for each site, for each country, and for the complete study, as locally 
required. 
Global Research will ensure that results are posted on ‘clinicaltrials.gov’ and as required by 
local authorities.  
Based on upcoming knowledge, Takeda might choose to terminate the study prematurely. In 
such case the Committee(s), study sites, IECs/IRBs, and authorities will be informed 
promptly. 
8.2 
Discussion of study design   
A retrospective chart review is an appropriate and scientifically robust method of collecting 
data that currently exists in patients’ medical records. By including both living and deceased 
patients, bias of excluding patients with more severe disease is avoided. 
Including 13 countries in the study with multiple sites in each country ensures a 
geographically dispersed sample of sites from different settings (hospitals, cancer institutes, 
and academic medical centres) is included, which ensures the data is representative of the 
emerging markets region.   
A prospective study design would not be practical with this patient population owing to the 
relatively low incidence of HL in some emerging markets countries and the length of follow-
up that would be required to determine the study endpoints. The sampling period chosen for 
this study provides a relatively recent review of clinical practice while also providing sufficient 
follow-up for the PFS and OS endpoints. 
Study limitations: 
 
 
Patients may have received some or part of their treatment in outlying hospitals 
separate from the participating centres, and the available summary of treatment 
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received there may not be as detailed as that from the participating hospital itself. 
This may limit the completeness of the details of treatment reported in the study 
results. 
 
Retrospective studies rely on the quality of the data routinely recorded in patients’ 
medical records; it is acknowledged that not all of the data fields will be available for 
every patient. 
 
The data collected will represent the practices of individual physicians/centres and 
may vary with non-participating physicians (e.g. those who refused study 
participation, failed to complete the study requirements on time and were excluded 
from the study, or were unresponsive to the screening invitation). Patients of non-
participating physicians may have profiles, treatments, and outcomes that differ from 
those of study patients; thus, the generalisability of study results may be limited. 
 
Adverse events are likely to be underreported or underdocumented in a routine 
clinical setting compared to what would be expected from a controlled trial or 
prospective study.  
 
Assessment of treatment response may be different in a routine clinical setting as 
compared to the monitoring that would be expected in a controlled trial setting or 
prospective study. 
 
Within each country’s sample of 50–200 patients with RRHL, the number of patients 
who relapse after ASCT, and who receive each treatment option after ASCT relapse, 
may be small, limiting the possibility of subgroup analyses related to ASCT. 
 
The definition of completion of therapy will differ based on country, therapy, and local 
guidelines. 
 
The sampling period for the study (2010–2013) and consecutive selection of patients 
according to the date of cHL or RRHL diagnosis was chosen to provide sufficient 
follow-up for the PFS and OS endpoints. However, it is acknowledged that this may 
bias the data collection towards older practices, especially in centres where there are 
many eligible patients. 
8.3 
 Selection of study population 
To take account of different population sizes, approximately 50–200 patients with cHL 
(Group 1) and 50–200 patients with RRHL (Group 2) will be included in the study in each 
participating country. 
Patients will be identified at each centre using hospital central management information 
systems, local department databases, pharmacy databases, or multidisciplinary team 
records (as applicable locally), and screened for eligibility by a member of the direct care 
team at each site. Physicians will be asked to select patients for inclusion in the study, 
according to study-specific inclusion/exclusion criteria (see below) consecutively, according 
to the date of cHL or RRHL diagnosis, until the target sample size has been met. Written 
informed consent will be obtained from each patient prior to participation (where required by 
local regulations).  
Inclusion criteria: 
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1. 
Patients newly diagnosed with high-risk stage IIb–IV cHL (for Group 1) or 
RRHL (for Group 2) between 01 January 2010 and 31st December 2013. 
2. 
Age ≥18 years at diagnosis of cHL (Group 1) or RRHL (Group 2). 
3. 
Alive or deceased. 
4. 
Written informed consent is obtained for study data collection, where 
necessary according to local regulations. 
Exclusion criteria: 
1. 
Patients for whom the minimum study dataset (see Appendix 1 and ) is not 
available from their hospital medical records. 
2. 
Patients who have participated in an interventional clinical trial at any stage of 
their cHL (Group 1) or RRHL (Group 2) management.  
A minimum of 50 patients in each group is required to give reasonably reliable country-level 
estimates of the mean and median PFS (see Section 12.3). Whilst it is hoped that each 
country will be able to include 100 patients in each group (approximately 1300 per group in 
total across all 13 countries) to allow description of PFS in different subgroups and for 
different treatments, it is recognized that this may not be possible in every country, and 
therefore oversampling may be performed in countries with larger populations of eligible 
patients to enable the overall sample to be achieved.  
The maximum number of patients to be collected in any one country will be determined by 
the CRO in consultation with Takeda, which will monitor recruitment on an ongoing basis 
and notify sites when patient recruitment should cease. 
The number of patients to be collected at each site (including site-specific recruitment 
targets and maximum number of patients per site) will also be decided by the CRO, in 
consultation with Takeda depending on the size of the local patient population and expected 
number of eligible patients. Patients diagnosed with high-risk stage IIb–IV cHL between 
2010 and 2013, who are subsequently diagnosed with RRHL, can be included in both 
groups, provided that the RRHL diagnosis was also between 2010 and 2013. Examples of 
study eligibility are shown in Table 3. 
 
 
 
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Table 3: Patient eligibility for study Group 1 (cHL) and Group 2 (RRHL) – examples 
Example 
Date of HL 
diagnosis 
Date of RRHL 
diagnosis 
Study eligibility 
1 
01 March 2013 
01 March 2014 
Include in cHL group (Group 1) only 
2 
01 May 2008 
01 May 2010 
Include in RRHL group (Group 2) 
only 
3 
01 February 2011 
01 February 2013 
Include in both cHL and RRHL 
groups 
4 
01 November 
2009 
01 November 
2014 
Exclude – patient not eligible 
8.4 
Treatments 
Non-interventional/observational – no treatments/pharmacotherapy are required as part of 
this study. 
9 
Conduct 
Written informed consent will be obtained prior to any patient-specific data collection, where 
this is required according to country regulations. The patient level data to be collected from 
the medical records is shown in Table 4 below. 
 
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Table 4: Variables and data  
Minimum dataset indicated by * and bold, underlined text and is also provided in Appendix 1. 
Variables 
Patients diagnosed with high-risk stage IIb–IV cHL 
between 01 January 2010 and 31 December 2013, 
who received frontline treatment with 
chemotherapy ± radiotherapy (Group 1) 
Patients diagnosed with RRHL between 01 January 
2010 and 31 December 2013 (Group 2) 
Patient and 
disease 
characteristics 
 
Practice location (country)* 
 
Gender* 
 
Month and year of birth* 
 
Date of cHL diagnosis* 
 
Ethnicity 
 
Clinical stage at diagnosis* 
 
Body weight at diagnosis 
 
Histological subtype of cHL 
 
Albumin at diagnosis (g/L)  
 
White blood cell count at diagnosis (×109/L)  
 
Haemoglobin at diagnosis (g/L)  
 
Lymphocyte count (×109/L and percentage of 
differential) at diagnosis 
 
Presence of B symptoms (Yes/No) at diagnosis 
 
Relevant comorbid conditions (lung disease 
[including 
tuberculosis, 
TB], 
cardiovascular 
disease, human immunodeficiency virus [HIV], 
hepatitis B and C) 
 
Positron emission tomography 
(PET)/computerised tomography (CT) scan results 
 
Date of most recent follow-up/contact* 
 
 
Practice location (country)* 
 
Gender* 
 
Month and year of birth* 
 
Date of HL and RRHL diagnosis* 
 
Histological subtype of cHL 
 
Date of start and end of frontline treatment* 
 
Date of first relapse after start of frontline 
treatment (date of scan confirming relapse)* 
 
Ethnicity 
 
Body weight at first diagnosis and at relapse 
 
Prior therapies for HL (including frontline* and pre-
relapse) 
 
Clinical stage at first diagnosis and at relapse 
 
Presence of B symptoms (Yes/No) at diagnosis  
 
Haemoglobin at relapse (g/L) 
 
Relevant 
comorbid 
conditions 
(lung 
disease 
[including TB], cardiovascular disease, HIV, hepatitis 
B and C) 
 
Date of most recent follow-up/contact* 
 
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Treatment 
pathways 
Details of treatments received for cHL from the date of 
diagnosis until the date of first documented relapse or 
disease progression after frontline therapy 
 
For frontline treatment and each subsequent line 
of treatment: 
 
Treatment 
modality 
(chemotherapy, 
RT, 
chemotherapy + RT, other treatment [specify])* 
 
Clinical stage at initiation 
 
Start and end dates* 
 
Therapy regimen* 
 
Total doses/cycles administered 
 
For RT: 
o Type (whole body, IFRT, ISRT, INRT, 
other)* 
o Anatomical site* 
o Number of fractions 
o Total dose 
o Whether given as pre-planned frontline 
treatment or for residual FDG-avid disease 
 
PET/CT scan details (from date of cHL diagnosis until 
date 
of 
first 
documented 
relapse 
or 
disease 
progression after frontline therapy): 
 
Dates* 
 
Deauville rating (1–5) 
 
Response 
category 
recorded 
(complete 
remission [CR], partial remission [PR], stable 
disease [SD], progressive disease [PD])* 
ASCT eligibility details: 
 
Considered eligible for ASCT (Yes/No) 
 
If no, reasons for ASCT ineligibility (advanced age, 
comorbid 
conditions, 
chemoresistant 
disease, 
cumulative toxicities, other) 
 
If patient initially considered ineligible for ASCT (due 
to chemoresistant disease), did they subsequently 
become eligible? (Yes/No)  
 
Was ASCT undertaken (Yes/No)* 
 
Reasons ASCT not undertaken, if patient eligible 
(patient refusal, inability to mobilise stem cells, loss 
of response to chemotherapy, toxicity, other) 
 
Details of treatments received for RRHL from the date of 
RRHL diagnosis until the date of the patient’s death or 
the date of data collection (whichever occurs first)  
 
For each line of treatment:  
 
 
Treatment 
modality 
(chemotherapy, 
RT, 
chemotherapy + RT, ASCT, allo-SCT, other 
treatment [specify])* 
 
Clinical stage at initiation 
 
Start and end dates* 
 
Therapy regimen* 
 
Total doses/cycles administered 
 
Palliative treatment (Yes/No) 
 
For RT: 
o Type (whole body, IFRT, ISRT, INRT, 
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other)* 
o Anatomical site* 
o Number of fractions 
o Total dose 
o Intent of treatment (obliterate single site of 
bulky disease as part of original treatment 
plan/control of disease when other treatments 
have failed) 
 
For ASCT:  
o Salvage regimen 
o Chemotherapy conditioning regimens used 
o Source of ASCT (bone marrow/peripheral) 
o CD34+ count administered 
o Presence of known risk factor for ASCT 
relapse 
(time 
to 
first 
relapse 
≤3 months/<12 months, stage IV disease at 
relapse, bulky disease ≥5 cm at relapse, 
extranodal disease, inadequate response to 
salvage chemotherapy (<PR or PET positivity 
at end of salvage therapy), performance 
status (ECOG) ≥1)   
 
For allo-SCT: 
o Type 
of 
allo-SCT 
(matched, 
related, 
unrelated) 
 
PET/CT scan details (from date of RRHL diagnosis until 
date of the patient’s death or the date of data collection 
(whichever occurs first): 
 
Dates* 
 
Deauville rating (1–5) 
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 
Response category recorded (CR, PR, SD, PD)* 
 
Clinical 
outcomes 
Occurrence of relapse/disease progression after 
start of frontline treatment (Yes/No)* 
 
Date of first documented relapse or disease 
progression after start of frontline therapy* 
 
Date and cause of death*, if patient died (HL-
related/adverse event/treatment-related/other) 
 
Assessments of response to frontline therapy: 
 
Date of assessment* 
 
Response (CR, PR, SD, PD)* 
 
All date(s) of documented relapse or disease 
progression during the study observation period*  
 
Date and cause of death*, if patient died (HL-
related/adverse event/treatment-related/other) 
 
Assessments of response to each line of therapy 
(including ASCT, each treatment received by non-ASCT 
patients, and each post-ASCT treatment regimen): 
 
Date of assessment* 
 
Response (CR, PR, SD, PD)* 
 
Adverse 
events 
Adverse events during frontline HL treatment: 
 
Date 
 
Description 
 
Clinician 
assessment 
of 
treatment-
related/unrelated 
 
Type (serious/non-serious) 
Adverse events during each therapy (including ASCT, 
each treatment received by non-ASCT patients, and 
each post-ASCT treatment regimen): 
 
Date 
 
Description 
 
Clinician assessment of treatment-related/unrelated 
 
Type (serious [as previously defined]/non-serious) 
HL-related 
resource use 
From start of frontline treatment until date of first 
documented relapse or disease progression after 
frontline treatment. Only for periods when the patient 
is receiving active treatment for HL. For each type of 
resource, indicate (Yes/No) whether visit was for 
adverse event management 
 
From the date of RRHL diagnosis until the date of the 
patient’s death or the date of data collection (whichever 
occurs first) 
Only for periods when the patient is receiving active 
treatment for RRHL. For each type of resource, indicate 
(Yes/No) 
whether 
visit 
was 
for 
adverse 
event 
management 
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Inpatient hospital admissions with overnight stay: 
 
Admission and discharge dates 
 
Elective or emergency 
 
Reason for admission 
 
Length of stay (overall and by unit/ward – general, 
high dependency/intermediate, intensive care unit 
[ICU], bone marrow transplant [BMT] unit) 
 
Emergency room visits: 
 
Visit dates 
 
Outpatient visits: 
 
Visit dates 
 
New appointment or follow-up 
 
Healthcare professional seen 
 
Face-to-face or telephone 
 
Scans and procedures: 
 
Date of scan or procedure 
 
Scan or procedure type 
 
RT episodes: 
 
Episode dates 
 
Treatment with granulocyte-colony stimulating factor 
(G-CSF) or other high cost medicines (to be defined): 
 
Start and stop dates 
 
Name of treatment 
 
Dose 
 
Inpatient hospital admissions with overnight stay: 
 
Admission and discharge dates 
 
Elective or emergency 
 
Reason for admission 
 
Length of stay (overall and by unit/ward – general, 
high dependency/intermediate, ICU, BMT unit) 
 
Emergency room visits: 
 
Visit dates 
 
Outpatient visits: 
 
Visit dates 
 
New appointment or follow-up 
 
Healthcare professional seen 
 
Face-to-face or telephone 
 
Scans and procedures: 
 
Date of scan or procedure 
 
Scan or procedure type 
 
RT episodes: 
 
Episode dates 
 
Treatment with G-CSF or other high cost medicines (to 
be defined): 
 
Start and stop dates 
 
Name of treatment 
 
Dose 
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 
For G-CSF, specify whether pegylated (Yes/No) 
 
For G-CSF, specify whether pegylated (Yes/No) 
HL-related 
costs 
The granularity and source of costs will be agreed at 
country level and will be detailed in the SAP   
The granularity and source of costs will be agreed at 
country level and will be detailed in the SAP   
 
 
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10 Safety reporting 
10.1 
Definitions 
Adverse event 
An adverse event (AE) is any untoward medical occurrence in a subject administered a 
medicinal product and which does not necessarily have to have a causal relationship with 
this treatment. An adverse event can therefore be any unfavourable and unintended sign 
(e.g. an abnormal laboratory finding), symptom, a new disease, or worsening in severity or 
frequency of a concomitant disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product. 
Adverse drug reaction  
An ADR is any response to a medicinal product that is noxious and unintended and that 
occurs at doses normally used in man for the prophylaxis, diagnosis, or therapy of diseases 
or for the restoration, correction, or modification of physiological function.  
Response in this context means that a causal relationship between a medicinal product and 
an adverse event is at least a reasonable possibility. 
Adverse reaction also includes adverse clinical consequences associated with use of the 
product outside the terms of the Summary of Product Characteristics or other conditions laid 
down for the marketing and use of the product (including prescribed doses higher than those 
recommended, overdoses, or abuse).  
As this study is a secondary analysis of medical records, an AE will only be considered as 
an ADR if there is an explicit statement in the medical record that the adverse event was 
caused by the medicinal product. 
Special situation reports and product quality issues 
A special situation report (SSR) includes any of the following events: 
 
Pregnancy: any case in which a pregnancy patient is exposed to a Takeda product or in 
which a female patient or female partner of a male patient becomes pregnant following 
treatment with Takeda product. Exposure is considered either through maternal 
exposure or via semen following paternal exposure. 
 
Breastfeeding: infant exposure from breast milk. 
 
Overdose: all information of any accidental or intentional overdose. 
 
Drug abuse, misuse, or medication error: all information on medicinal product abuse, 
misuse, or medication error (potential or actual). 
 
Suspected transmission of an infectious agent: all information on a suspected (in the 
sense of confirmed or potential) transmission of an infectious agent by a medicinal 
product.  
 
Lack of efficacy of Takeda product. 
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 
Occupational exposure. 
 
Use outside the terms of the marketing authorisation, also known as ‘off-label’. 
 
Use of falsified medicinal product. 
A Product Quality Issue refers to defects related to the safety, identity, strength, quality, or 
purity of the product or with the physical characteristics, packaging, labelling, or design of 
the product. 
10.2 
Classifications 
Seriousness 
A serious ADR or AE (SADR/SAE) is any ADR or AE which results in death, is life-
threatening, requires inpatient hospitalisation, or prolongation of existing hospitalisation, 
results in persistent or significant disability or incapacity, or is a congenital anomaly or birth 
defect. 
Life-threatening in this context refers to a reaction/event in which the subject was at risk of 
death at the time of the reaction/event. It does not refer to a reaction/event that 
hypothetically might have caused death if more severe. 
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious, such as important medical events that might not be 
immediately life-threatening or result in death or hospitalisation, but which might jeopardise 
the subject or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalisation, 
or development of dependency or abuse.  
Any suspected transmission of an infectious agent via a medicinal product is considered a 
serious adverse reaction. 
Causality  
 
Related: 
A reasonable temporal relationship between the medicinal product 
administration and the event where there is no other obvious explanation 
for the occurrence of the event. 
 
Not related: There is evidence for (an) alternative explanation(s) for the event, e.g. the 
event is explained by one or more of the following: a) the subject’s medical 
condition (medical history, disease progress, indication); b) a concomitant 
medication for which the event is labelled; or c) AE occurrence prior to the 
introduction of the medicinal product. 
Outcome  
 
Fatal:  
The subject died due to the event. If the subject died due to other 
circumstances than the event the outcome should be stated as ‘not 
recovered’ or ‘recovering’. 
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 
Recovered/resolved: The subject has fully recovered from the event or the condition has 
returned to the level observed at baseline. 
 
Recovering/resolving: The event is improving but the subject is still not fully recovered. 
 
Not recovered/not resolved: The event is ongoing at the time of reporting and the subject 
has still not recovered. 
 
Recovered with sequelae/resolved with sequelae: As a result of the event, the subject 
suffered persistent and significant disability/incapacity (e.g. became blind, 
deaf, or paralysed). 
 
Unknown: 
If outcome is not known or not reported. 
 
10.3 
Collection of Adverse Events, Special Situation Reports and 
Product Quality Issues 
10.3.1 Spontaneously reported events  
If, during the conduct of the study, a member of the research team is spontaneously 
informed of other AEs or SSRs that are not study endpoints, and the event pertains to a 
Takeda product (or unbranded generic), such information should be reported to the Sponsor 
or regulatory agency in the country in which the event occurred (spontaneous reporting 
contacts are provided in Appendix 2). As such reports are spontaneously notified, causality 
of any AEs should be assumed unless there is evidence to the contrary.  
10.3.2 Events identified from chart review  
AEs that are study endpoints (all AEs during treatment) and SSRs, as defined in Table 4, 
should be systematically identified, abstracted, and summarized as part of any interim 
analysis and in the final study report.  
 
10.4 
Reporting of Adverse Drug Reactions and Special Situation 
Reports to Regulatory Agencies 
The Sponsor shall notify regulatory agencies in accordance with local regulatory 
requirements or Sponsor’s post-marketing commitments. 
 
 
 
 
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11 Data quality control and assurance 
11.1 
Quality control 
All CRFs will be field-tested for reliability and validity with a minimum of two or three 
physicians, and their recruited HL patients. 
As this study will involve recruitment and participation of multiple investigators (with their site 
staff) in multiple countries across the emerging markets region, ensuring that understanding 
of questions, terms, and guidelines is uniform across physicians is essential to the quality of 
the data collected and the minimisation of biases in interpretation. A research brief and 
detailed data collection instructions, including clear, concise definitions of questions, terms, 
and guidelines, will be provided by the CRO.  
Data cleaning and validation will be conducted prior to the conduct of statistical analyses.  
Database lock will occur at the end of the study (i.e. completion of the data collection 
described in this protocol), unless otherwise specified (refer to Section 11.4 on Data 
management for more details). Data validation for key datapoints will be conducted on 10% 
of the completed CRFs via telephone or queries in the electronic CRF (eCRF). This will 
include the translation of data from local language into the CRF (where relevant). Physicians 
will be asked to be re-abstract or provide key datapoints based on the original source 
document, i.e. the medical record. Physicians should not share patients’ confidential 
information when providing key datapoints. 
In the case where certain datapoints are missing from patients’ medical records, the method 
for the handling of this missing data (e.g. imputation of missing values or complete case 
analysis) will be detailed in the SAP.  
Data-related quality controls 
The data management processes employed will ensure strict oversight of data entry to 
ensure the appropriate quality control measures, e.g. CRF review for data logic, data 
inconsistency, data query and discrepancy resolution, and documentation are conducted.  
All work will be subject to quality control and documentation procedures to ensure that the 
study reporting is accurate and thorough, and the analyses can be reproduced. If the data do 
not permit an analysis as planned (e.g. through insufficient sample size in a stratified 
analysis), or if clarifying analyses are required (e.g. an unexpected result that could be 
explained by a subgroup analysis), the CROs will inform the client and include the additional 
information and results in reporting. 
11.2 
Audit from Quality Assurance Unit 
The Quality Assurance (QA) Unit may audit the study to ensure that study procedures 
comply with the protocol and standard operating procedures, and that collected data is 
correct and complete. 
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11.3 
Inspection by Institutional Review Board/Independent Ethics 
Committee or competent authority 
Representatives from IRB/IEC or competent authority may in rare cases wish to inspect the 
study on site. Upon receiving notification of such inspection, the Study Site Responsible 
must immediately contact Global Research and must make the records available as 
requested.  
11.4 
Data management 
Data management will be the responsibility of the appointed CRO. Data management will be 
carried out according to a data management plan (DMP), which will identify the location of 
the CRO’s data management facility. The DMP must be written and approved before the 
design of the study database is finalised. The data management provider should approve all 
data formats before the data collection tools are made available to the sites. 
If the written informed consent of a subject is known not to be available in spite of it being 
required, data for this subject is not entered into or is deleted from the database. 
Data management processes   
To include detailed processes for the following activities:  
• 
Pilot study. 
• 
Study instruction handouts/materials.   
• 
Internal staff training. 
• 
Study monitoring and physician follow-up. 
• 
CRF editing and online review. 
• 
Data validations.  
• 
Documentation of missing and anomalous data and resolution directly with 
investigators. 
Data tabulations and statistical analyses will be conducted using SAS version 9.4 (this 
applies to tabulations i.e. data analysis, and statistical analyses, i.e. Tables, Listings, and 
Figures [TLFs]). 
At the conclusion of the study, final, locked datasets will be delivered in a format acceptable 
to the sponsor, e.g. statistical analysis system (SAS). A detailed format and label program 
containing a description of each study variable and associated format will accompany their 
delivery. 
Data handling 
Data collection, processing, storage, and usage will follow data protection/privacy guidelines 
in each country. All results will be reported in a de-identified, aggregate manner. Physicians 
will be identified only by assigned identifiers and patients will be distinguished by assigned 
identifiers. At the end of data collection, physicians will be instructed to maintain the master 
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links between patient IDs for the study and the patient ID on site for a time period that is 
consistent with the study Sponsor’s standard operating procedures.   
If a subject is erroneously included in the study more than once, only the data relating to the 
first inclusion will be kept in the database and be available for analysis. Data from later 
inclusions will be transferred to the first dataset when relevant, i.e. if collected within the 
timeframe of the first follow-up period.  
The current Standard Coding Instructions for coding of medical history, concomitant illness 
(MedDRA), concomitant medication (WHO-Drug), and adverse events/reactions (MedDRA) 
must be followed. 
The subjects will be identified in the database only by study ID, site ID, subject number, 
gender, and month and year of birth. 
11.4.1 Data collection tools and flow 
The study site will receive data collection tools (CRFs, access to electronic data capture, 
etc.) from Takeda. Whenever possible, complete datasets should be entered.  
The Study Site Responsible must sign off the complete dataset for each subject, confirming 
the collected data. ADR data reported according to Section 10 should be signed off 
separately by a physician who may or may not be involved in the study.  
A web-based electronic CRF will be employed. The data entry site will be password-
protected and physicians/site staff  completing the study online will receive a password to 
access the study portal and perform data entry.  Further details can be found in the DMP. 
12 Statistical methods and determination of sample size 
Statistical analyses will be performed by the appointed CRO. 
12.1 
Statistical analysis plan 
For full details of the statistical analyses please refer to the SAP. 
This study is observational and epidemiological methods will be employed for data analyses. 
Descriptive analysis will be performed of all collected data except data collected only for the 
purpose of data cleaning, i.e. all data listed in Section 9. Below is the overall approach to the 
analyses for this study. 
All analyses will be conducted separately for Group 1 (cHL) and Group 2 (RRHL). Within 
each group (for the descriptive and outcomes analyses), endpoints will be presented for the 
overall sample (aggregated across all countries), at regional level (e.g. South America, Asia–
Pacific), and separately for each participating country. 
Descriptive analyses will be used to summarize patient demographics and clinical 
characteristics, treatment patterns, clinical outcomes, and healthcare resource utilisation. 
 
 
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Continuous endpoints  
Key continuous endpoints (e.g. duration of treatment, healthcare resource utilisation) will be 
summarised using the summary statistics of mean and standard deviation, median and 
range. 
Categorical endpoints  
Key categorical endpoints will be summarised using both the number and percentage in 
each category. Only patients with data available for a particular variable will be included in 
the calculation of a percentage. 
Time to event endpoints 
Key time to event endpoints (e.g. OS, PFS) will be summarised in terms of the total number 
of events observed and the proportion of patients who have died/progressed at a given 
milestone after accounting for censoring using Kaplan–Meier curves. 
In addition to the descriptive analyses, multivariate analyses will be included, adjusting for 
differences in patient demographic, clinical, and treatment characteristics, as well as risk 
factors that will be conducted for key time to event analyses, when treatment cohorts will be 
compared within the RRHL or frontline setting.  
Objectives-based analysis plan 
The endpoints relating to each study objective are listed in Appendix 3. Specific statistical 
analyses will be discussed in more detail in the SAP, which will also include table shells.  
Safety endpoints 
ADRs reported in the study as well as ADRs reported directly to authorities and to Takeda 
International Drug Safety according to Section 10.3 and not captured in the study database 
will be extracted from the overall safety database and the study database, and listed or 
tabulated in the final report in the standard way of presenting such data in a periodic safety 
update report (PSUR). 
12.2 
Interim and final analyses 
An interim analysis is planned, based on all patients’ data collected up to a specified 
timepoint.The interim analysis will include results for key variables and will be discussed 
further in the SAP along with proposed timeline. 
The final analysis will include the full study population and all analyses outlined above, to be 
delivered in the form of populated data tables and a final clinical study report. Any known 
deviations from the planned analyses, the reason for such deviations, and all 
alternative/additional statistical analyses that may be performed, as well as the final 
statistical analysis, must be described in a revised SAP before completion of data collection. 
All later deviations and/or alterations will be summarised in the clinical study report. 
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12.3 
Determination of sample size 
The aim of this study is to describe the treatments and associated clinical outcomes for 
patients with high-risk stage IIb–IV cHL and RRHL in different countries in the emerging 
markets region. This will contribute to a greater understanding of current treatment patterns, 
which will help to inform future clinical decision-making. 
The primary endpoint is to describe PFS in patients with RRHL, defined as the time from 
initiation of first treatment for RRHL to first documentation of relapse or disease progression 
or death. Although the results from different countries will be combined, it is important that, 
for the primary endpoint, the sample is sufficient to provide reasonably reliable results for 
each participating country separately. It is also intended that subgroup analyses will be 
performed to describe the outcomes in different patient groups (e.g. those with HIV or 
hepatitis and early versus late relapsers) and for different treatment regimens (including 
ASCT versus non-ASCT and brentuximab vedotin versus other treatments). 
There are no comparable studies from the emerging markets region that can be used to 
inform calculation of the required sample size. A recent phase III clinical trial of patients with 
HL with risk factors for relapse or progression after ASCT observed a median PFS of 
42.9 months (for brentuximab vedotin) and 24.1 months (for placebo) (46). However, the 
study was conducted in the US and Europe and did not include patients who were unsuitable 
for ASCT (for whom PFS is expected to be lower); it is acknowledged therefore that the 
results may not be directly applicable to this study. The reliability of a range of mean and 
median PFS estimates for various sample/subgroup sizes are shown in Table 5 and Table 6. 
Table 5: Reliability of the mean progression-free survival at various sample sizes 
95% Confidence limits (CLs) 
n = 25 
n = 50 
n = 100 
n = 200 
Observed mean PFS 
(months) 
LCL 
UCL 
LCL 
UCL 
LCL 
UCL 
LCL 
UCL 
18 
15.6  
20.4  16.3  
19.7  
16.8  
19.2  
17.2  18.8  
21 
18.2  
23.8  19.0  
23.0  
19.6  
22.4  
20.0  22.0  
24 
20.8 
27.2 
21.7 
26.3 
22.4 
25.6 
22.9 
25.1 
 
27 
23.4 
30.6 
24.5 
29.5 
25.2 
28.8 
25.7 
28.3 
 
30 
26.0 
34.0 
27.2 
32.8 
28.0 
32.0 
28.6 
31.4 
 
33 
28.6 
37.4 
29.9 
36.1 
30.8 
35.2 
31.4 
34.6 
 
36 
31.2  
40.8  32.6  
39.4  
33.6  
38.4  
34.3  37.7   
LCL, Lower confidence limit; UCL, upper confidence limit. 
 
 
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Table 6: Reliability of the median progression-free survival at various 
sample sizes 
95% CLs 
n = 25 
n = 50 
n = 100 
n = 200 
Observed 
median PFS 
(months) 
LCL 
UCL 
LCL 
UCL 
LCL 
UCL 
LCL 
UCL 
18 
14.3 
21.7 
15.0 
21.0 
15.4 
20.6 
15.7 
20.3 
20 
15.9 
24.1 
16.6 
23.4 
17.1 
22.9 
17.4 
22.6 
24 
19.1  
28.9  
20.0  
28.0  
20.5  
27.5  
20.9  
27.1  
27 
21.5  
32.5  
22.5  
31.5  
23.1  
30.9  
23.5  
30.5  
30 
23.8  
36.2  
25.0  
35.0  
25.6  
34.4  
26.1  
33.9  
33 
26.2  
39.8  
27.5  
38.5  
28.2  
37.8  
28.7  
37.3  
36 
28.6 
43.4  
30.0  
42.0  
30.8  
41.2  
31.3  
40.7  
LCL, Lower confidence limit; UCL, upper confidence limit. 
For both the mean and median PFS time outcomes, samples of 50 or more give reliable 
outcomes as they generate reasonably reliable estimates of the standard deviation of the 
PFS distribution. Therefore, a sample of at least 50 (50–200) patients with cHL and at least 
50 (50–200) patients with RRHL per country will be used in this study. Whilst it is hoped that 
each country will be able to include 100 patients in each group (approximately 1300 per 
group in total across all 13 countries) to allow description of PFS in different subgroups and 
for different treatments, it is recognised that this may not be possible in every country and 
therefore oversampling may be performed in countries with larger populations of eligible 
patients to enable the overall sample to be achieved.  
For PFS rates, a previous study of patients receiving salvage therapy for RRHL who were 
followed up for a median of 45 months showed a variation in the freedom from second 
treatment failure rate from approximately 30% to 80%, depending on the stage of disease, 
time to recurrence, and frontline treatment received (4). The reliability of different PFS rate 
outcomes for various sample/subgroup sizes is shown in Table 7. 
 
 
 
 
 
 
 
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Table 7: Reliability of progression-free survival rates for various sample 
sizes 
 
95% CLs 
n = 50 
n = 100 
n = 200 
n = 300 
Observed 
PFS rate 
LCL 
UCL 
LCL 
UCL 
LCL 
UCL 
LCL 
UCL 
20% 
11% 
33% 
13% 
29% 
15% 
26% 
16% 
25% 
30% 
19% 
44% 
22% 
40% 
24% 
37% 
25% 
36% 
40% 
27% 
54% 
31% 
50% 
33% 
47% 
35% 
46% 
50% 
36% 
64% 
40% 
60% 
43% 
57% 
44% 
56% 
60% 
46% 
73% 
50% 
69% 
53% 
67% 
54% 
65% 
70% 
56% 
81% 
60% 
78% 
63% 
76% 
64% 
75% 
80% 
67% 
89% 
71% 
87% 
74% 
85% 
75% 
84% 
LCL, Lower confidence limit; UCL, upper confidence limit. 
While the reliability of the PFS rates is limited with samples of 200 or less, they are 
reasonable for 300 or more. It would thus be possible to give estimates at a regional level for 
this outcome, combining the results of two or more countries.  
Secondary endpoints include patient demographic and clinical characteristics, HL treatment 
pathways, adverse events, and resource use for both the cHL and RRHL groups. Outcomes 
that are simply counted (e.g. presence or absence of risk factors, use of specific treatments) 
will have reliability similar to the PFS rates, while those that are measured (e.g. age and 
measurable risk factors) and healthcare resource use of both hospital visits, inpatient 
admission, and their respective costs, will be more reliable, similar to the mean PFS. It is 
acknowledged that, for some analyses (e.g. patients receiving each treatment after ASCT), 
the number of patients in each country with data available is likely to be small. It will be 
possible to give reliable estimates at a regional level for these outcomes by combining the 
results of two or more countries. 
13 Reports 
A non-interventional study report based on the results obtained will be prepared and 
submitted to Global Research for distribution. The final study report should be available 
within 1 year of collection of the last datapoint, and the participating sites should be informed 
about the results when the report is finalised. 
14 Publications 
It is planned that results of this study may be presented at an upcoming conference (venue 
to be determined based on timing of results availability) or submitted for publication in 
appropriate peer-reviewed medical journal(s). 
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Takeda has the right to use the data and results for regulatory purposes and for internal 
presentation within the company and to partners. 
Publication requests from individual sites will need to be considered and approved by 
Takeda and the study Steering Committee.  
15 Archiving of study documentation 
During the course of the study the Site Responsible must, as a minimum, file the essential 
documents (Section 6.4), the protocol, any amendments, the list of participating subjects, the 
written informed consents, the CRFs, and the progress reports in the study site file. After 
final database lock, the Site Responsible must, as a minimum, store the list of participating 
subjects and the signed informed consent forms on site for 5 years. The Site Responsible 
should store additional study documentation for a longer period of time, as required by any 
local regulations and/or hospital requirement. 
 
 
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16 References 
1.  
Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. 
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Crowther D, Lister TA. The Cotswolds report on the investigation and staging of 
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Hasenclever D, Diehl V, Armitage JO, Assouline D, Björkholm M, Brusamolino E, et al. 
A Prognostic Score for Advanced Hodgkin’s Disease. N Engl J Med. 1998 Nov 
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4.  
Josting A, Franklin J, May M, Koch P, Beykirch MK, Heinz J, et al. New prognostic 
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Thomas RK, Re D, Zander T, Wolf J, Diehl V. Epidemiology and etiology of Hodgkin’s 
lymphoma. Ann Oncol. 2002 Oct 1;13(suppl 4):147–52.  
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Hjalgrim H, Askling J, Rostgaard K, Hamilton-Dutoit S, Frisch M, Zhang J-S, et al. 
Characteristics of Hodgkin’s Lymphoma after Infectious Mononucleosis. N Engl J Med. 
2003 Oct 2;349(14):1324–32.  
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Glaser SL, Lin RJ, Stewart SL, Ambinder RF, Jarrett RF, Brousset P, et al. Epstein-Barr 
virus-associated Hodgkin’s disease: Epidemiologic characteristics in international data. 
Int J Cancer. 1997;70(4):375–82.  
9.  
Frisch M, Biggar RJ, Engels EA, Goedert JJ, for the AIDS-Cancer Match Registry 
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11.  Hong Kong Hospital Authority. Hong Kong Cancer Registry Query System (CanSQS) 
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16.  Ramirez P, Ocqueteau M, Rodriguez A, Garcia MJ, Sarmiento M, Ernst D, et al. 
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Bras Hematol E Hemoter. 2015 May;37(3):184–9.  
17.  Majhail NS, Weisdorf DJ, Defor TE, Miller JS, McGlave PB, Slungaard A, et al. Long-
Term Results of Autologous Stem Cell Transplantation for Primary Refractory or 
Relapsed Hodgkin’s Lymphoma. Biol Blood Marrow Transplant. 2006 Oct 
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18.  Salihoglu A, Elverdi T, Karadogan I, Paydas S, Ozdemir E, Erdem G, et al. 
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Turkey. Ann Hematol. 2015;94:415–20.  
19.  Younes A, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Savage KJ, et al. Results of 
a Pivotal Phase II Study of Brentuximab Vedotin for Patients With Relapsed or 
Refractory Hodgkin’s Lymphoma. J Clin Oncol. 2012 Jun 20;30(18):2183–9.  
20.  Smith A, Crouch S, Lax S, Li J, Painter D, Howell D, et al. Lymphoma incidence, 
survival and prevalence 2004-2014: sub-type analyses from the UK’s Haematological 
Malignancy Research Network. Br J Cancer. 2015 Apr 28;112(9):1575–84.  
21.  Shenoy P, Maggioncalda A, Malik N, Flowers CR. Incidence Patterns and Outcomes 
for Hodgkin Lymphoma Patients in the United States. Adv Hematol. 2011;2011:725219.  
22.  Smith A, Roman E, Howell D, Jones R, Patmore R, Jack A, et al. The Haematological 
Malignancy Research Network (HMRN): a new information strategy for population 
based epidemiology and health service research. Br J Haematol. 2010;148(5):739–53.  
23.  Chihara D, Ito H, Izutsu K, Hattori M, Nishino Y, Ioka A, et al. Advance and stagnation 
in the treatment of patients with lymphoma and myeloma: Analysis using population-
based cancer registry data in Japan from 1993 to 2006. Int J Cancer. 
2015;137(5):1217–23.  
24.  Roder DM, Kearney B, To LB, Kearney DJ, Luke C, Lewis ID, et al. Outcomes of 
lymphoma in South Australia, 1977-2007. Vol. 196. Australia: Australasian Medical 
Publishing Company; 2012.  
25.  International Agency for Research on Cancer. GLOBOCAN 2012: Estimated cancer 
incidence, mortality and prevalence worldwide in 2012 [Internet]. 2012 [cited 2017 Mar 
13]. Available from: http://globocan.iarc.fr/Default.aspx 
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26.  Law MF, Ng TY, Chan HN, Lai HK, Ha CY, Leung C, et al. Clinical features and 
treatment outcomes of Hodgkin’s lymphoma in Hong Kong Chinese. Arch Med Sci 
AMS. 2014 Jun 29;10(3):498–504.  
27.  Jaime-Pérez JC, Heredia-Salazar AC, Cantú-Rodríguez OG, Gutiérrez-Aguirre H, 
Villarreal-Villarreal CD, Mancías-Guerra C, et al. Cost Structure and Clinical Outcome 
of a Stem Cell Transplantation Program in a Developing Country: The Experience in 
Northeast Mexico. The Oncologist. 2015 Apr;20(4):386–92.  
28.  Omer Al-Sayes FM, Sawan A. Clinico-Pathological Study of Hodgkin’s Disease in King 
Abdulaziz University Hospital, Jeddah. J Taibah Univ Med Sci. 2006;1(1):48–56.  
29.  Cheah CY, Chihara D, Horowitz S, Sevin A, Oki Y, Zhou S, et al. Patients with classical 
Hodgkin lymphoma experiencing disease progression after treatment with brentuximab 
vedotin have poor outcomes. Ann Oncol. 2016 Jul 1;27(7):1317–23.  
30.  Thompson PA, Perera T, Marin D, Oran B, Popat U, Qazilbash M, et al. Double 
umbilical cord blood transplant is effective therapy for relapsed or refractory Hodgkin 
lymphoma. Leuk Lymphoma. 2016 Jul 2;57(7):1607–15.  
31.  Suyanı E, Sucak GT, Akı ŞZ, Yeğin ZA, Özkurt ZN, Yağcı M. Gemcitabine and 
vinorelbine combination is effective in both as a salvage and mobilization regimen in 
relapsed or refractory Hodgkin lymphoma prior to ASCT. Ann Hematol. 
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32.  Abalı H, Ürün Y, Öksüzoğlu B, Budakoğlu B, Yıldırım N, Güler T, et al. Comparison of 
ICE (Ifosfamide-Carboplatin-Etoposide) Versus DHAP (Cytosine Arabinoside-Cisplatin-
Dexamethasone) as Salvage Chemotherapy in Patients with Relapsed or Refractory 
Lymphoma. Cancer Invest. 2008 Jan 1;26(4):401–6.  
33.  Mohd Noor A, Sarker D, Vizor S, McLennan B, Hunter S, Suder A, et al. Effect of 
Patient Socioeconomic Status on Access to Early-Phase Cancer Trials. J Clin Oncol. 
2013 Jan 10;31(2):224–30.  
34.  EMEA: Committee for Medicinal Products for Human Use. Reflection Paper on the 
Extrapolation of Results from Clinical Studies Conducted Outside the EU to the EU-
Population [Internet]. 2009 [cited 2017 Mar 13]. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/11/
WC500013468.pdf 
35.  Kusminsky G, Abriata G, Forman D, Sierra MS. Hodgkin lymphoma burden in Central 
and South America. Suppl Cancer Cent S Am. 2016 Sep;44, Supplement 1:S158–67.  
36.  Schonfeld SJ, Erdmann F, Wiggill T, Singh E, Kellett P, Babb C, et al. Hematologic 
malignancies in South Africa 2000–2006: analysis of data reported to the National 
Cancer Registry. Cancer Med. 2016 Apr;5(4):728–38.  
37.  Chiang C-J, You S-L, Chen C-J, Yang Y-W, Lo W-C, Lai M-S. Quality assessment and 
improvement of nationwide cancer registration system in Taiwan: a review. Jpn J Clin 
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38.  National Registry of Diseases Office. National Cancer Disease Registry, Singapore 
[Internet]. 2015 [cited 2017 Mar 13]. Available from: 
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39.  European Society for Blood and Marrow Transplantation (EBMT). National BMT 
Registries - Turkish Transplant Registry [Internet]. 2009 [cited 2017 Mar 13]. Available 
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40.  Espinosa-Bautista Karla A, Armengol-Alonso Alejandra, Castro-Sánchez Andrea, 
Pérez-Álvarez Sandra I, León Eucario. Autologous Transplant in Lymphoma: 
Experience in a Limited Resource Mexican Reference Center. J Blood Disord Transfus. 
2015;6(2):266.  
41.  Claudia Shanley. An Update on the Current State of Hodgkin Lymphoma Care in 
Argentina [Internet]. 2015 [cited 2017 Mar 13]. Available from: 
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series-asia/17-expert-interview-series/92-an-update-on-the-current-state-of-hodgkin-
lymphoma-care-in-argentina 
42.  Lymphoma Coalition. 2015 LeIP Report card on Lymphomas: A Focus on Hodgkin and 
Mantle Cell Lymphomas [Internet]. 2015 [cited 2017 Mar 13]. (Lymphoma eInformation 
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43.  WMA. WMA Declaration of Helsinki - Ethical Principles for Medical Research Involving 
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44.  Epstein M, International Society of Pharmacoepidemiology. Guidelines for good 
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Aug;14(8):589–95.  
45.  The European Parliament and the Council of the European Union. Directive 
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directive-04-april-01.pdf 
46.  Moskowitz CH, Nademanee A, Masszi T, Agura E, Holowiecki J, Abidi MH, et al. 
Brentuximab vedotin as consolidation therapy after autologous stem-cell 
transplantation in patients with Hodgkin’s lymphoma at risk of relapse or progression 
(AETHERA): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 
Lond Engl. 2015 May 9;385(9980):1853–62.  
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17 Appendices 
Appendix 1: Minimum dataset  
Variables 
cHL (Group 1) 
RRHL (Group 2) 
Patient and 
disease 
characteristics 
 
Practice location (country) 
 
Gender 
 
Month and year of birth 
 
Date of cHL diagnosis 
 
Clinical stage at diagnosis 
 
Date of most recent follow-up/contact 
 
 
Practice location (country) 
 
Gender 
 
Month and year of birth 
 
Date of HL and RRHL diagnosis 
 
Date of start and end of frontline treatment 
 
Date of first relapse after start of frontline treatment (date 
of scan confirming relapse) 
 
Frontline therapy for HL 
 
Date of most recent follow-up/contact 
Treatment 
pathways 
Details of treatments received for cHL from the date of 
diagnosis until the date of first documented relapse or 
disease progression after frontline therapy  
 
For frontline treatment and each subsequent line of 
treatment: 
 
Treatment modality (chemotherapy, RT, chemotherapy 
+ RT, other treatment [specify]) 
 
Start and end dates 
 
Therapy regimen 
 
For RT: 
o 
Type (whole body, IFRT, ISRT, INRT, other) 
o 
Anatomical site 
PET/CT scan details (from date of cHL diagnosis until date 
of first documented relapse or disease progression after 
frontline therapy): 
 
Dates 
 
Response category recorded (CR, PR, SD, PD) 
 
Was ASCT undertaken (yes/no) 
 
Details of treatments received for RRHL from the date of 
RRHL diagnosis until the date of the patient’s death or the date 
of data collection (whichever occurs first)  
 
For each line of treatment:  
 
Treatment modality (chemotherapy, RT, chemotherapy + 
RT, ASCT, allo-SCT, other treatment [specify]) 
 
Start and end dates 
 
Therapy regimen 
 
For RT: 
o 
Type (whole body, IFRT, ISRT, INRT, other) 
o 
Anatomical site 
PET/CT scan details (from date of RRHL diagnosis until date 
of the patient’s death or the date of data collection (whichever 
occurs first): 
 
Dates 
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 
Response category recorded (CR, PR, SD, PD) 
Clinical 
outcomes 
Occurrence of relapse/disease progression after start of 
frontline treatment (yes/no) 
 
Date of first documented relapse or disease progression 
after start of frontline therapy 
 
Date of death, if patient died 
 
Assessments of response to frontline therapy: 
 
Date of assessment 
 
Response (CR, PR, SD, PD) 
 
All date(s) of documented relapse or disease progression 
during the study observation period 
 
Date of death, if patient died 
 
Assessments of response to each line of therapy (including 
ASCT, each treatment received by non-ASCT patients and 
each post-ASCT treatment regimen): 
 
Date of assessment 
 
Response (CR, PR, SD, PD) 
 
 
 
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Appendix 2: Spontaneous reporting to sponsor 
 
COUNTRY 
DRUG SAFETY EMAIL 
Argentina 
Australia 
China 
Colombia 
Hong Kong 
Mexico 
Russia 
Saudi Arabia 
Singapore 
South Africa 
South Korea 
Taiwan 
Turkey 
 
 
 
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Appendix 3: Study endpoints  
Endpoints will be presented for the overall sample, at regional level (e.g. South America, Asia–Pacific), and separately for each 
participating country. 
Clinical outcomes may also be presented separately for the following subgroups:    
 
Patients with HIV/hepatitis B or C. 
 
Patients who receive PET CT versus CT only for evaluation of treatment response. 
 
In the RRHL group (Group 2):  
o Patients with primary refractory HL (those who have failed to achieve a CR with frontline therapy or relapse within 
3 months after end of frontline therapy) versus patients with relapsed HL (relapse >3 months after end of frontline 
therapy). 
o Early versus late relapsers (early: relapse within 3–12 months after end of frontline therapy; late: relapse >12 months after 
end of frontline therapy). 
o ASCT versus no ASCT. 
o Patients who receive brentuximab vedotin versus other treatments in the non-ASCT setting. 
o Patients who receive brentuximab vedotin versus other treatments in the post-ASCT setting.  
Patient characteristics will be presented overall and by:  
 
ASCT status (yes/no). 
 
Non-ASCT patients receiving brentuximab vedotin (yes/no). 
 
Post-ASCT patients receiving brentuximab vedotin post-relapse (yes/no).  
Primary endpoint 
PFS in patients with RRHL, defined as the time from initiation of first treatment for RRHL to first documentation of relapse or disease 
progression or death, censored at date of most recent follow-up/contact. 
Secondary endpoints 
Secondary study endpoints include patient characteristics (Table 8), treatment pathways (Table 9), clinical outcomes (Table 10), 
adverse events (Table 11), resource use (Table 12), and costs (Table 13). Endpoints will be reported separately for cHL (Group 1) 
and RRHL (Group 2) patients. Patients diagnosed with high-risk stage IIb–IV cHL between 2010 and 2013, who are subsequently 
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diagnosed with RRHL (between 2010 and 2013 inclusive), will be included in the analysis for both groups, as described in Section 
8.3 (see examples in Table 3). 
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Table 8: Endpoints relating to secondary objective 1 (patient characteristics) 
Secondary 
objective 1 
Patients diagnosed with high-risk stage IIb–IV cHL 
between 01 January 2010 and 31 December 2013, 
who received frontline treatment with 
chemotherapy ± radiotherapy (Group 1) 
Patients diagnosed with RRHL between 01 January 
2010 and 31 December 2013 (Group 2) 
Patient 
characteristics 
 
Gender distribution 
 
Distribution and mean (StDev) age at cHL 
diagnosis 
 
Distribution of ethnicity 
 
Distribution of clinical staging at diagnosis 
 
Distribution and mean (StDev) body weight at 
diagnosis 
 
Distribution of histological subtype of cHL 
 
Distribution of known risk factors for relapse (IPS 
factors) at diagnosis: 
o Age ≥45 years 
o Male sex 
o Stage IV disease 
o Albumin <4 g/L 
o WBC ≥15 × 109/L 
o Haemoglobin <10.5 g/L 
o Lymphocyte count <0.6 × 109/L or <8% of 
differential 
 
Distribution of IPS score 
 
Proportion of patients with B symptoms at 
diagnosis 
 
Distribution of comorbid conditions (lung disease 
[including TB], cardiovascular disease, HIV, 
hepatitis B and C) 
 
Gender distribution 
 
Distribution and mean (StDev) age at diagnosis 
 
Distribution of ethnicity 
 
Distribution of histological subtype of cHL 
 
Distribution and mean (StDev) body weight at first 
diagnosis and at relapse 
 
Distribution of clinical staging at first diagnosis, at 
relapse, at ASCT (if performed), and at start of 
treatment with brentuximab vedotin (if used) 
 
Distribution of known risk factors for relapse (Josting 
factors (4): 
o Time to recurrence within 3–12 months after 
end of frontline treatment 
o Stage III or IV relapse  
o Haemoglobin at relapse <10.5 g/dL for 
females and <12 g/dL for males 
 
Distribution of Josting score (0, 1, 2, 3) 
 
Proportion of patients with B symptoms at RRHL 
diagnosis 
 
Distribution of comorbid conditions (lung disease 
[including TB], cardiovascular disease, HIV, hepatitis 
B and C) 
 
Distribution of prior therapies for HL at each line of 
treatment 
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 
Distribution of PET/CT scan status if available 
 
Median (range) number of previous treatment 
regimens 
 
Mean (StDev) and median (range) time from end of 
frontline treatment to first relapse 
 
 
 
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Table 9: Endpoints relating to secondary objective 2 (treatment pathways) 
Secondary 
objective 
2 
Patients diagnosed with high-risk stage IIb–IV 
cHL between 01 January 2010 and 31 
December 2013, who received frontline 
treatment with chemotherapy ± radiotherapy 
(Group 1) 
Patients diagnosed with RRHL between 01 January 2010 and 
31 December 2013 (Group 2) 
Treatment 
pathways 
 
Distribution of frontline treatment regimens 
 
Median (range) number of doses or treatment 
cycles associated with each regimen 
 
Frequency of PET/CT assessment and when 
used (e.g. baseline/after first treatment) 
 
Distribution of treatments received for HL 
after completion of frontline therapy (but 
before relapse, if this occurred) 
 
Distribution of type, site, and dosing of RT (if 
used), 
when 
used 
(before/during/after 
chemotherapy) and whether used for pre-
planned frontline treatment or for residual 
FDG-avid disease 
All patients with RRHL 
 
Proportion of patients who were considered eligible/ineligible 
for ASCT 
 
Proportion of patients initially considered ineligible for ASCT 
(e.g. owing to chemoresistant disease) who subsequently 
became eligible and received ASCT: 
o Treatment received, including median (range) number 
of doses or treatment cycles associated with each 
regimen 
o Frequency of PET/CT assessment and when used 
(e.g. interim and/or end of treatment 
 
Proportion of eligible patients who received/did not receive 
ASCT 
 
Non-ASCT patients: 
 
Distribution of reasons for not undergoing ASCT in patients 
who were ASCT-eligible (patient refusal, inability to mobilise 
stem cells, loss of response to chemotherapy, toxicity, other) 
 
Distribution of reasons for ASCT ineligibility (advanced age, 
comorbid conditions, chemoresistant disease, cumulative 
toxicities, other) 
 
Distribution of treatment regimens received at each line of 
treatment and proportion of patients for whom treatment is 
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palliative 
 
Median (range) number of doses or treatment cycles received 
at each line of treatment, for each treatment regimen 
 
Mean (StDev) and median (range) duration of each line of 
treatment 
 
Proportion of patients with dose delays at each line of 
treatment for each treatment regimen 
 
Mean (StDev) and median (range) time from relapse (after 
frontline treatment) to first treatment post-relapse 
 
Mean (StDev) and median (range) time to initiation of each 
subsequent treatment, both from relapse and from completion 
of previous treatment  
 
Mean (StDev) and median (range) duration of each line of 
treatment 
 
Proportion of patients receiving PET/CT at each line of the 
treatment pathway and frequency of assessment 
 
Proportion of patients receiving radiotherapy at each stage of 
the treatment pathway 
 
Distribution of type, site, and dosing of radiotherapy, if used 
 
Patients undergoing ASCT: 
 
Distribution of chemotherapeutic salvage regimens used pre- 
and post-ASCT 
 
Median (range) number of doses or cycles associated with 
each salvage regimen 
 
Distribution of chemotherapy conditioning regimens used 
 
Proportion of patients receiving consolidation therapy post-
ASCT 
 
Distribution of consolidation therapies used and mean (StDev) 
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and median (range) duration of treatment 
 
Time from relapse (after end of frontline treatment) to ASCT 
 
Source of ASCT (bone marrow, peripheral) 
 
Mean (StDev) and median (interquartile range) CD34+ count 
administered 
 
Distribution of known risk factors for relapse after ASCT (time 
to first relapse ≤3 months, stage IV disease at relapse, bulky 
disease ≥5 cm at relapse, extranodal disease, inadequate 
response to salvage chemotherapy (<PR or PET positivity), 
performance status (ECOG) ≥1)  
 
Patients who relapse after ASCT: 
 
Mean (StDev) and median (range) time from ASCT to first 
relapse post-ASCT 
 
Distribution of post-ASCT regimens received at each line of 
treatment and proportion of patients for whom treatment is 
palliative  
 
Median (range) number of doses or cycles received at each 
line of treatment, for each treatment regimen 
 
Mean (StDev) and median (range) duration of each line of 
treatment 
 
Mean (StDev) and median (range) time from ASCT to first 
treatment after relapse 
 
Mean (StDev) and median (range) time to initiation of each 
subsequent treatment, both from ASCT and from completion 
of previous treatment 
 
Proportion of patients receiving PET/CT at each stage of the 
treatment pathway, frequency of assessment, and when 
assessed 
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 
Proportion of patients receiving radiotherapy at each stage of 
the treatment pathway 
 
Distribution of type, site, intent, dosing, and frequency of 
radiotherapy, if used 
 
Proportion of patients undergoing subsequent ASCTs and 
median (range) number of ASCTs per patient 
 
Proportion of patients undergoing allogeneic stem cell 
transplantation (allo-SCT) 
 
 
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Table 10: Endpoints relating to secondary objective 3 (clinical outcomes) 
Secondary 
objective 
3 
Patients diagnosed with high-risk stage IIb–IV cHL 
between 01 January 2010 and 31 December 2013, who 
received frontline treatment with chemotherapy ± 
radiotherapy (Group 1) 
Patients diagnosed with RRHL between 01 January 
2010 and 31 December 2013 (Group 2) 
Clinical 
outcomes 
 
Median PFS, defined as time from initiation of frontline 
regimen to first documentation of relapse or disease 
progression or death, censored at date of most recent 
follow-up/contact 
 
Distribution of best clinical response after completion of 
frontline treatment (CR, PR, SD, PD), as defined by the 
International Working Group 2007 Revised Response 
Criteria for Malignant Lymphoma (1) 
 
Mean (StDev) and median (range) time to best 
response 
 
Proportion of patients with documented relapse or 
disease progression at any point after completion of 
frontline treatment 
 
Median (range) duration of best response, defined as 
the time from when the criteria for response (CR or PR) 
are met to first documentation of relapse or disease 
progression 
 
1-, 3-, and 5-year* PFS rates 
 
Median OS, defined as the time from diagnosis of cHL 
to death, censored at date of most recent follow-
up/contact 
 
Proportion of patients alive at 1 and 5 years* after 
diagnosis 
 
For deceased patients: 
Clinical outcomes to be presented for ASCT, each 
salvage regimen used pre- and post-ASCT, each 
treatment regimen received by non-ASCT patients, 
and each post-ASCT regimen in patients who 
relapse: 
 
Median PFS, defined as time from initiation of 
treatment to first documentation of relapse or 
disease progression or death, censored at date of 
most recent follow-up/contact 
 
Distribution 
of 
best 
clinical 
response 
after 
completion of each line of treatment (CR, PR, SD, 
PD) 
 
Mean (StDev) and median (range) time to best 
response 
 
For ASCT patients: proportion of patients in 
response who are assessed as high risk of relapse 
pre-ASCT (risk factors defined in Table 4 (above). 
 
Proportion of patients with documented relapse or 
disease progression at any time after completion of 
treatment 
 
Median (range) duration of best response (as 
previously defined) 
 
1-, 3-, and 5-year* PFS rates 
 
Median OS, defined as the time from first relapse 
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o Mean (StDev) and median (range) time to death 
(from diagnosis and from completion of frontline 
therapy) 
o Distribution of cause of death (HL-
related/adverse event/treatment-related/other) 
 
 
 
 
 
 
after frontline therapy to death, censored at date of 
most recent follow-up/contact 
 
Proportion of patients alive at 1 and 5 years* after 
first relapse 
 
For deceased patients: 
o Mean (StDev) and median (range) time to 
death (from initial diagnosis, from first 
relapse, from ASCT, and from relapse after 
ASCT) 
o Distribution of cause of death (HL-
related/adverse event/treatment-
related/other) 
* 5 year PFS and OS rates will be reported only for patients with >5-year observation periods. 
 
 
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Table 11: Endpoints relating to secondary objective 4 (adverse events) 
Secondary 
objective 
4 
Patients diagnosed with high-risk stage IIb–IV cHL 
between 01 January 2010 and 31 December 2013, who 
received frontline treatment with chemotherapy ± 
radiotherapy (Group 1) 
Patients diagnosed with RRHL between 01 January 
2010 and 31 December 2013 (Group 2) 
Adverse 
events 
To be presented overall and separately for adverse events 
considered by the treating clinician as treatment-related:  
 
Distribution of adverse events associated with frontline 
treatment, including haematological malignancies, and 
peripheral neuropathy (PN) 
 
Distribution of adverse event seriousness (serious [as 
previously defined]/non-serious) 
 
To be presented overall and separately for adverse 
events 
considered 
by 
the treating clinician 
as 
treatment-related:  
 
Distribution 
of 
adverse 
events 
(including 
haematological malignancies and PN) associated 
with: 
o ASCT 
o Each treatment regimen received by non-
ASCT patients 
o Each post-ASCT treatment regimen 
 
Distribution of adverse event seriousness (serious 
[as previously defined]/non-serious)  
 
 
 
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Table 12: Endpoints relating to secondary objective 5 (resource use) 
Secondary 
objective 
5 
Patients diagnosed with high-risk stage IIb–IV cHL 
between 01 January 2010 and 31 December 2013, who 
received frontline treatment with chemotherapy ± 
radiotherapy (Group 1) 
Patients diagnosed with RRHL between 01 January 
2010 and 31 December 2013 (Group 2) 
Resource 
use 
Resource use will be reported for: 
 
Frontline chemotherapy ± RT treatment (per patient per 
cycle) 
 
Overall HL-related resource use will be reported, as well as 
the 
resource 
use 
associated 
with 
adverse 
event 
management  
 
The following resource use parameters will be reported: 
 
Distribution and mean (StDev) number of inpatient 
hospital admissions and reasons (if available) 
 
For inpatient hospital admissions; mean (StDev) length 
of stay, overall and by unit/ward (general, high 
dependency/intermediate, ICU, BMT unit) 
 
Distribution and mean (StDev) number of emergency 
room visits 
 
Distribution and mean (StDev) number of outpatient 
visits by healthcare professional seen 
 
Distribution and mean (StDev) number of episodes of 
radiotherapy received 
 
Distribution and mean (StDev) number of each type of 
scan/procedure 
 
Distribution and mean (StDev) number of days of 
treatment with G-CSF/pegylated G-CSF or other high-
Resource use will be reported for: 
 
Salvage therapy (per patient per cycle) 
 
ASCT (per patient per procedure [from start of stem 
cell mobilization to reinfusion of cells]) 
 
Allo-SCT (per patient per procedure) 
 
Brentuximab vedotin in the non-ASCT setting (per 
patient per cycle) 
 
Brentuximab vedotin in the post-ASCT setting (per 
patient per cycle) 
 
Each post-ASCT chemotherapy regimen (per 
patient per cycle) 
 
For each treatment, overall HL-related resource use will 
be reported, as well as the resource use associated 
with adverse event management  
 
The following resource use parameters will be reported: 
 
Distribution and mean (StDev) number of inpatient 
hospital admissions and reasons (if available) 
 
For inpatient hospital admissions; mean (StDev) 
length of stay, overall and by unit/ward (general, 
high dependency/intermediate, ICU, BMT unit) 
 
Distribution 
and 
mean 
(StDev) 
number 
of 
emergency room visits 
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cost medicines 
 
Distribution and mean (StDev) number of courses of 
treatment with G-CSF/pegylated G-CSF or other high-
cost medicines 
 
 
Distribution and mean (StDev) number of outpatient 
visits by healthcare professional seen 
 
Distribution and mean (StDev) number of episodes 
of radiotherapy received 
 
Distribution and mean (StDev) number of each type 
of scan/procedure 
 
Distribution and mean (StDev) number of days of 
treatment with G-CSF/pegylated G-CSF or other 
high-cost medicines 
 
Distribution and mean (StDev) number of courses of 
treatment with G-CSF/pegylated G-CSF or other 
high-cost medicines 
 
 
 
 
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Table 13: Endpoints relating to secondary objective 6 (costs) 
Secondary 
objective 
6 
Patients diagnosed with high-risk stage IIb–IV cHL 
between 01 January 2010 and 31 December 2013, 
who received frontline treatment with 
chemotherapy ± radiotherapy (Group 1) 
Patients diagnosed with RRHL between 01 January 2010 
and 31 December 2013 (Group 2) 
Costs 
Costs will be reported for: 
 
Frontline chemotherapy ± RT treatment (per patient 
per cycle) 
 
Overall HL-related costs will be reported, as well as the 
costs associated with adverse event management 
 
The costs associated with each frontline treatment will 
be calculated from the resource use parameters (listed 
in Table 12 [above]) using country-specific reference 
costs 
Costs will be reported for: 
 
Salvage therapy (per patient per cycle) 
 
ASCT (per patient per procedure [from start of stem cell 
mobilization to reinfusion of cells]) 
 
Allogeneic stem cell transplantation (per patient per 
procedure) 
 
Brentuximab vedotin in the non-ASCT setting (per 
patient per cycle) 
 
Brentuximab vedotin in the post-ASCT setting (per 
patient per cycle) 
 
Each post-ASCT chemotherapy regimen (per patient per 
cycle) 
 
For each treatment, overall HL-related costs will be reported, 
as well as the costs associated with adverse event 
management  
  
Allocation of costs (as for patients receiving frontline HL 
treatment) 
 
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