Drug Use Surveillance for ADCETRIS Intravenous Infusion "Untreated CD30-Positive Hodgkin's Lymphoma"
Conditions: Untreated CD30-Positive Hodgkin's Lymphoma
Sponsor: Takeda

 
 
Clinical Study Protocol 
 
NCT Number: NCT03729609 
Title: General Drug Use Surveillance Protocol General Drug Use Surveillance for 
ADCETRIS Intravenous Infusion 50 mg “ Untreated CD30-Positive Hodgkin's 
Lymphoma” 
Study Number: C25018 
Document Version and Date: Version 8.0 / 12-Sep-2023 
 
Certain information within this document has been redacted (ie, specific content is 
masked irreversibly from view) to protect either personally identifiable information or 
company confidential information. 
 
A summary of changes to previous protocol versions is appended to the end of the 
document. 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

 
 
 
 
General Drug Use Surveillance Protocol 
General Drug Use Surveillance for ADCETRIS 
Intravenous Infusion 50 mg 
“Untreated CD30-Positive Hodgkin's 
Lymphoma” 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Survey sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
C25018  
Edition 
Version 8.0 
Date of preparation 
September 12, 2023 
 
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Table of Contents 
1.0 
BACKGROUND ........................................................................................................................................... 1 
2.0 
PURPOSE ...................................................................................................................................................... 1 
3.0 
SCHEDULED NUMBER OF CASES AND RATIONALE ......................................................................... 1 
 
SCHEDULED NUMBER OF CASES ...................................................................................................... 1 
 
RATIONALE ............................................................................................................................................. 1 
4.0 
PATIENTS TO BE SURVEYED ................................................................................................................... 2 
 
INCLUSION CRITERIA .......................................................................................................................... 2 
 
EXCLUSION CRITERIA ......................................................................................................................... 2 
5.0 
DOSAGE AND ADMINISTRATION ........................................................................................................... 2 
6.0 
SCHEDULED NUMBER OF MEDICAL INSTITUTIONS BY CLINICAL DEPARTMENT ................... 2 
7.0 
METHOD ...................................................................................................................................................... 2 
 
OBSERVATION PERIOD ......................................................................................................................... 2 
 
REQUEST TO AND CONTRACT WITH MEDICAL INSTITUTIONS ................................................. 3 
 
PATIENT CONSENT ................................................................................................................................ 3 
 
PATIENT ENROLLMENT METHOD ...................................................................................................... 3 
 
PREPARATION AND SUBMISSION OF SURVEY SHEETS ................................................................ 4 
8.0 
SCHEDULED PERIOD OF SURVEY ......................................................................................................... 4 
9.0 
SURVEY ITEMS ........................................................................................................................................... 4 
 
PATIENT REGISTRATION ...................................................................................................................... 4 
 
PATIENT CHARACTERISTICS .............................................................................................................. 4 
 
TREATMENT............................................................................................................................................ 5 
 
TUMOR RESPONSE ................................................................................................................................ 5 
 
OBSERVATION ITEMS ........................................................................................................................... 5 
 
ADVERSE EVENTS ................................................................................................................................. 5 
10.0 
ANALYSIS ITEMS AND METHOD............................................................................................................ 8 
 
ITEMS RELATED TO CASE STRUCTURE ........................................................................................... 8 
 
PATIENT CHARACTERISTICS .............................................................................................................. 8 
 
TREATMENT............................................................................................................................................ 8 
 
ITEMS RELATED TO SAFETY .............................................................................................................. 8 
 
INCIDENCE OF ADVERSE EVENTS ............................................................................................ 8 
 
FACTORS THAT MAY AFFECT THE SAFETY ............................................................................. 8 
 
ITEMS RELATED TO EFFICACY .......................................................................................................... 8 
11.0 
REGISTRATION OF SURVEY INFORMATION ........................................................................................ 8 
12.0 
ORGANIZATIONAL STRUCTURE ............................................................................................................ 9 
 
SUPERVISOR ........................................................................................................................................... 9 
 
MEDICAL ADVISOR ............................................................................................................................... 9 
13.0 
CONTRACT RESEARCH ORGANIZATION ............................................................................................. 9 
14.0 
OTHER NECESSARY MATTERS ............................................................................................................... 9 
 
REVISION OF THE PROTOCOL ............................................................................................................ 9 
 
ACTIONS TO BE TAKEN IF PROBLEMS AND QUESTIONS ARISE ................................................ 9 
 
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1.0 
BACKGROUND 
Information about the safety of ADCETRIS intravenous infusion 50 mg (hereinafter, 
ADCETRIS) in combination with doxorubicin hydrochloride, vinblastine sulfate and 
dacarbazine (hereinafter, AVD) in Japanese patients is limited.  Compared to ADCETRIS 
monotherapy, the incidences of neutropenia and febrile neutropenia are higher with 
combination therapy with ADCETRIS plus these agents.  Therefore, it was decided that 
additional pharmacovigilance activities for neutropenia and febrile neutropenia were necessary 
in order to confirm the occurrence status in actual setting of use in Japan. 
Thus, a drug use survey (hereinafter, this survey) was planned in patients with untreated 
CD30-positive Hodgkin lymphoma in daily clinical practice. 
This survey is conducted in accordance with relevant regulatory requirements including the 
GPSP Ordinance. 
 
2.0 
PURPOSE 
Evaluate the occurrence status of neutropenia and febrile neutropenia with ADCETRIS used in 
combination with AVD in patients with untreated CD30-positive Hodgkin's lymphoma in daily 
clinical practice. 
 
3.0 
SCHEDULED NUMBER OF CASES AND RATIONALE 
 
SCHEDULED NUMBER OF CASES 
100 (as Safety Analysis Set) 
 
 
RATIONALE 
The global phase 3 study in patients with untreated advanced classical Hodgkin's lymphoma 
(C25003 study) indicated that the incidence of the adverse event of febrile neutropenia in 
patients who received G-CSF for primary prevention was 11%, and the incidence of the adverse 
event of neutropenia of Grade 3 or higher was 29%. 
In the special drug use-result survey of ADCETRIS in patients with relapsed or refractory 
CD30-positive Hodgkin’s lymphoma and anaplastic large cell lymphoma, the number of 
Hodgkin’s lymphoma patients with the adverse event of febrile neutropenia was 6.  It is 
therefore considered necessary to collect at least 6 cases of the adverse event of febrile 
neutropenia in this survey. 
Assuming that the incidence of the adverse event of febrile neutropenia is 11%, a sample size 
of 93 patients is required to detect at least 6 cases of the adverse event of febrile neutropenia at 
a ≥95% probability.  The sample size was thus determined to be 100.  On the assumption that 
the incidence of the adverse event of neutropenia of Grade 3 or higher is 29%, ≥22 cases of 
neutropenia of Grade 3 or higher will be observed at a ≥95% probability if 100 cases are 
collected. 
 
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4.0 
PATIENTS TO BE SURVEYED 
Patients with Hodgkin's lymphoma will be included in this survey.  However, patients must 
meet the following inclusion criteria and none of the exclusion criteria.  The Precautions listed 
in the package insert should be referred. 
 
INCLUSION CRITERIA 
Patients who meet the following criteria will be included in this survey. 
[1] Untreated patients
[2] CD30-positive patients
[3] Patients on concomitant ADCETRIS and AVD
 
EXCLUSION CRITERIA 
Patients who meet the following criteria will be excluded from this survey. 
Patients contraindicated for ADCETRIS 
5.0 
DOSAGE AND ADMINISTRATION 
In combination therapy with AVD, the usual adult dosage for intravenous administration is 
1.2 mg/kg (weight) as brentuximab vedotin (genetical recombination) once every 2 weeks for 
up to 12 doses.  The dose may be reduced appropriately according to the patient's condition.  
The Precautions listed in the package insert should be referred for details. 
6.0 
SCHEDULED NUMBER OF MEDICAL INSTITUTIONS BY CLINICAL 
DEPARTMENT 
Department of hematology etc. 
Approximately 100 medical institutions 
7.0 
METHOD 
 
OBSERVATION PERIOD 
Period from the start of ADCETRIS to 2 weeks after the completion of 12 doses (once every 2 
weeks)note) 
Note) If a patient receives less than 12 doses of ADCETRIS, the period will be up to 2 weeks 
after the discontinuation of ADCETRIS. 
*
Rationale for observation period
In the ADCETRIS + AVD group in C25003 study, the number of patients with the event of
neutropenia, neutrophil count decreased and febrile neutropenia after the initial dose and the
number of patients with the initial onset in each Cycle were highest in Cycle 1 for both of all
Grades and Grade 3 or higher, which decreased over time as the cycles went on.  However,
still in Cycle 6 (period between 11th dose and 2 weeks after the 12th dose), the number of
patients with the initial onset was 2 for neutropenia and 5 for febrile neutropenia.  The number
of patients with the event of Grade 3 or higher was 64 for neutropenia, 8 for febrile neutropenia,
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and 18 for neutrophil count decreased. 
Based on the above, it was considered necessary to observe the occurrence status of 
myelosuppression (neutropenia, febrile neutropenia) set as safety specification for this survey 
until 2 weeks after the completion of 12 doses, the maximum number of doses specified in the 
DOSAGE AND ADMINISTRATION. 
 
 
REQUEST TO AND CONTRACT WITH MEDICAL INSTITUTIONS 
The person in charge from Takeda Pharmaceutical Company Limited (hereinafter, “Takeda’s 
person in charge”) should, when requesting a medical institution and physician to conduct this 
survey, conclude a written contract with the medical institution. 
 
 
PATIENT CONSENT 
The investigator should, before registering patients, explain the details of the informed consent 
form to patients (or their legal representatives) and obtain oral or written consent from patients 
(or their legal representatives) to provide information to this survey. 
For written consent, patients (or their legal representatives) should sign and date the informed 
consent form.  The investigator should retain the original signed and dated informed consent 
form. 
The informed consent form should include information on the outline of this survey and 
patient’s personal information as well as its handling, and explain that patients may discontinue 
the participation in this survey at any time without explaining the reason and suffering any 
therapeutic disadvantage. 
Patients who have provided consent will be assigned an identification number. 
 
 
PATIENT ENROLLMENT METHOD 
The “Central Registration Method” by post should be used. 
The investigator or a person appointed by the investigator* should send “Patient Registration 
Sheet” via post to the Central Registration Center by 30 days after the start of treatment with 
ADCETRIS (the day of the first dose is counted as “Day 0” and the following day as “Day 1”). 
The day of the postmark is deemed the day of patient enrollment. 
* The “person appointed by the investigator” refers to those who belong to the relevant medical 
institution (including those who are contracted with the medical institution for assignments, 
such as contracted CRC) and who have been designated beforehand by the investigator to 
execute assignments relating to this survey under the instruction of the investigator.  The 
physician responsible for the survey conduct (one person per medical institution or clinical 
department, to be determined at the time of concluding a contract) will prepare documentation 
that indicates the designation and the date of designation (in any form), sign or seal and submit 
it to the Takeda’s person in charge before a person appointed by the investigator starts the 
assignments such as patient enrollment. 
 
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PREPARATION AND SUBMISSION OF SURVEY SHEETS 
Paper-based survey sheets should be used to collect information. 
The investigator or a person appointed by the investigator should prepare a survey sheet for all 
the enrolled patients promptly after completion of the observation period of each patient, and 
the investigator should sign or print his/her name on and seal the sheet to submit to Takeda 
Pharmaceutical Company Limited. 
For patients in whom ADCETRIS has been discontinued due to some reasons in the middle of 
the observation period, the investigator or a person appointed by the investigator should prepare 
a survey sheet promptly after the completion of necessary observation, and submit to Takeda 
Pharmaceutical Company Limited. 
 
8.0 
SCHEDULED PERIOD OF SURVEY 
Survey period 
: November 2018 to December 31, 2022 
Patient registration period : November 2018 to December 31, 2021note) 
Survey Completion date (Estimated completion date of Statistical Analysis): planed as October 
30, 2023 
 
Note) No patients will be registered after January 1, 2022 even if the patient has started treatment 
with ADCETRIS before December 31, 2021. 
If it is estimated that the overall number of patients registered to this survey reaches the 
planned sample size (as Safety Analysis Set) before December 30, 2021, the patient 
registration will be closed before the end of patient registration period.  If the patient 
registration period is shortened, this survey period will be changed according to the 
shortened duration. 
 
9.0 
SURVEY ITEMS 
The investigator or a person appointed by the investigator should include the following items in 
the Patient Registration Sheet and Survey Sheet.  The schedule of this survey is indicated in 
Appendix 1. 
 
 
PATIENT REGISTRATION 
1) Survey items 
The start date of treatment with ADCETRIS, patient identification number, gender, age, 
presence/absence of (verbal or written) consent, assessment results of the inclusion and 
exclusion criteria 
2) Survey period 
At the time of patient registration 
 
 
PATIENT CHARACTERISTICS 
1) Survey items 
Time of diagnosis of Hodgkin’s lymphoma, lesion, clinical stage (Ann Arbor Staging), 
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presence/absence of B symptoms, ECOG Performance Status, therapeutic category, 
complications (presence/ absence and details), medical history (presence/absence and 
details), height, weight, presence/absence of pregnancy/lactation (for women only) 
2) Survey period 
At the start of ADCETRIS 
 
 
TREATMENT 
1) Survey items 
Administration status of ADCETRIS and AVD, reason for the discontinuation of 
ADCETRIS, administration status of medications other than ADCETRIS and AVD to the 
underlying disease (presence/absence and name of the drug, duration of administration), 
administration status of drugs used to prevent infections (presence/absence and name of the 
drug, duration of administration), administration status of G-CSF (presence/absence and 
name of the drug, duration and purpose of administration) 
2) Survey period 
Period from the start of ADCETRIS to 2 weeks after the completion of 12 doses or the 
discontinuation of ADCETRIS 
 
 
TUMOR RESPONSE 
1) Test items 
Best response should be assessed as CR, CRu (if no PET is performed), PR, SD or PD in 
accordance with the Revised response criteria (see Appendix 2) based on the result of CT 
and PET scan of the neck, chest, abdomen, and pelvis. 
2) Survey period 
Period from the start of ADCETRIS to 2 weeks after the completion of 12 doses or the 
discontinuation of ADCETRIS (but until before the start of subsequent treatment) 
 
 
OBSERVATION ITEMS 
1) Observation items 
Presence/absence of pregnancy during the observation period (for women only) 
2) Survey period 
Period from the start of ADCETRIS to 2 weeks after the completion of 12 doses or the 
discontinuation of ADCETRIS 
 
 
ADVERSE EVENTS 
1) Events subject to survey 
The following event is determined as the safety specification. Information of those of Grade 
3 or higher will be collected. 
 
 
Myelosuppression (neutropenia, febrile neutropenia) 
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* Rationale 
Among the important identified risks in the Risk Management Plan, myelosuppression 
(neutropenia, febrile neutropenia) was determined as safety specification based on the 
following reasons: The global phase 3 study in patients with untreated advanced classical 
Hodgkin's lymphoma (C25003 study) indicated that the incidence of febrile neutropenia 
was higher in the concomitant ADCETRIS and AVD group than the comparator ABVD 
group.  In light of this fact, the (draft) important precautions of ADCETRIS describe 
that use of G-CSF including prophylactic administration (primary prevention) should be 
considered in using ADCETRIS in combination with AVD.  Control of neutrophil count 
is important to continue administration of ADCETRIS (including resumption after 
interruption).  The profile of this event (administration status of ADCETRIS, status of 
neutrophil count control, prophylactic administration status of G-CSF) occurring in 
Japanese patients in clinical practice will be collected/evaluated. 
 
2) Survey items 
Presence/absence of adverse events (see Table 1 and “1) Events subject to survey”), name of 
the adverse event, date of onset, CTCAE Grade* (worst grade and its date), seriousness and 
its reasons (see Table 2), change in dosage and administration of ADCETRIS and AVD 
(presence/absence and details), treatment for the event (presence/absence and details), 
outcome assessment date, outcome, causal relationship with ADCETRIS** (see Table 3), 
over-time related changes in laboratory tests (neutrophil count etc.). 
If the outcome has been assessed to be not recovered/not resolved or unknown, follow-up 
surveillance should be conducted as far as possible. 
* This should be assessed in accordance with the U.S. National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE). 
** If ADCETRIS is assessed to be not related, the rationale for assessment should be collected. 
 
3) Survey period 
Period from the start of ADCETRIS to 2 weeks after the completion of 12 doses or the 
discontinuation of ADCETRIS 
 
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10.0 
ANALYSIS ITEMS AND METHOD 
 ITEMS RELATED TO CASE STRUCTURE 
The number of enrolled patients, number of patients whose survey sheets have been collected, 
number of cases subject to safety evaluation, number of cases subject to efficacy evaluation, 
number of patients excluded from evaluation, and reasons for exclusion should be aggregated. 
 
 PATIENT CHARACTERISTICS 
Patient characteristics including the gender, age, duration of Hodgkin’s lymphoma, lesion, and 
clinical stage should be aggregated. 
 
 TREATMENT 
The administration status of ADCETRIS, administration status of AVD, and administration 
status of G-CSF, etc. should be aggregated. 
 
 ITEMS RELATED TO SAFETY 
The following items should be aggregated in patients subject to safety evaluation.  Adverse 
events should be rephrased using MedDRA/J and summarized in Preferred Term (PT) and 
System Organ Class (SOC). 
 INCIDENCE OF ADVERSE EVENTS 
The frequencies of adverse events (neutropenia and febrile neutropenia) which occurred 
during the observation period should be aggregated according to the time of onset, severity 
(CTCAE grade), seriousness, and causal relationship with ADCETRIS. 
 
 FACTORS THAT MAY AFFECT THE SAFETY 
The frequencies of adverse reactions (neutropenia and febrile neutropenia) which occurred 
during the observation period should be aggregated according to the classification, such as 
patient characteristic factors (gender, age, presence/absence of concurrent renal dysfunction, 
presence/absence of concurrent hepatic dysfunction, etc.) and the details of treatment 
(administration status of G-CSF, etc.). 
 
 ITEMS RELATED TO EFFICACY 
The tumor response (best response) through the discontinuation or completion of ADCETRIS 
should be aggregated in patients subject to efficacy evaluation. 
 
11.0 
REGISTRATION OF SURVEY INFORMATION 
Information about this survey should be registered to the following public website before the 
start of this survey: 
 
Japan Pharmaceutical Information Center- Clinical Trials Information: 
Japan Pharmaceutical Information Center-Clinical Trials Information 
 
U.S. National Institute of Health, clinical trial registration system: ClinicalTrials.gov 
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12.0 
ORGANIZATIONAL STRUCTURE 
 SUPERVISOR 
Takeda Pharmaceutical Company Limited 
 
 
13.0 
MEDICAL ADVISOR 
 
 
 
14.0 
CONTRACT RESEARCH ORGANIZATION 
(1) 
 
 
 
 
Assignment:Registration center, data management operations, storage of records, medical 
writing, and support operations related to post-marketing surveys  
 
(2) 
 
 
Assignment: Database construction 
 
(3) 
 
 
Assignment: Statistical analysis 
 
(4) 
 
 
Assignment: Monitoring 
 
15.0 
OTHER NECESSARY MATTERS 
 REVISION OF THE PROTOCOL 
During the survey period, the progress of survey, occurrence of adverse reactions and serious 
adverse reactions that cannot be predicted from the Precautions, presence/absence of elevated 
frequency of specific adverse reactions, and appropriateness of survey items should be 
understood, and if necessary, this Protocol should be reviewed and revised.  Additionally, 
approval for a partial change in the Dosage and Administration or Indications is obtained 
during the survey period, the necessity to revise this Protocol should be discussed and the 
Protocol should be revised, where necessary. 
 
 ACTIONS TO BE TAKEN IF PROBLEMS AND QUESTIONS ARISE 
If any problem is found in the safety and efficacy, data should be reviewed to take actions. 
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Document History 
 
Version 
Date 
Comments 
original version 
2018/10/22 
New document 
2nd version 
2018/12/25 
To add the period when patients could be registered 
3rd version 
2019/06/01 
For minor changes in “13.0 CONTRACT RESEARCH 
ORGANIZATION” 
4th version 
2020/06/30 
Because of the extension of the scheduled period of survey as 
well as addition and minor changes in “13.0 CONTRACT 
RESEARCH ORGANIZATION” 
5th version 
2021/01/15 
For 
addition 
in 
“13.0 
CONTRACT 
RESEARCH 
ORGANIZATION” 
6th version 
2022/05/11 
For 
minor 
changes 
in 
“12.0 
ORGANIZATIONAL 
STRUCTURE” 
7th version 
2023/04/06 
For minor changes in “14.0 CONTRACT RESEARCH 
ORGANIZATION” 
8th version 
2023/09/12 
In order to add the date of completion of the survey (date of 
completion of final analysis) to “8.0 SCHEDULED PERIOD OF 
SURVEY” 
 
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