NUCALA ® Subcutaneous Injection Special Drug Use Investigation (EGPA, Long-term）
Conditions: Churg-Strauss Syndrome, Eosinophilic Granulomatosis With Polyangiitis
Sponsor: GlaxoSmithKline

For re-examination 
 
Protocol No. 208505 
 
 
 
 
 
 
 
 
 
NUCALA Subcutaneous Injection  
Special Drug Use Investigation  
（EGPA, Long-term） 
 
Protocol 
 
 
 
 
 
 
 
GlaxoSmithKline K.K. 
 
 
 
 
Revised: 23 July 2024 (Ver. 3.2) 
 
 
 
 
 

 
 
 
 
TABLE OF CONTENTS 
Page 
1. 
Objectives ..................................................................................................... 1 
2. 
Safety Specification .................................................................................... 1 
3. 
Target Population ........................................................................................ 1 
4. 
Target Sample Size and Rationale ............................................................. 1 
5. 
Planned Number of Medical Institutions by Department ........................ 1 
6. 
Study Period................................................................................................. 1 
7. 
Study Methods ............................................................................................. 2 
8. 
Study Items .................................................................................................. 3 
9. 
Analysis Items and Methods ...................................................................... 6 
10. Organizational Structure ............................................................................ 7 
11. Name, Address of the Outsourcees, and the Scope of Outsourced 
Operations .................................................................................................... 7 
12. Scheduled Timing to Be a Milestone for Assessing the Status and 
Results in the Study or Reporting to the Pharmaceuticals and Medical 
Devices Agency (PMDA) and Rationale .................................................... 8 
13. Additional Measures that Have a Potential to Be Taken Depending to 
the Study Results and the Decision Criteria for the Start ....................... 8 
14. Publication of the Study Results ............................................................... 8 
15. Other Requirements .................................................................................... 8 
16. Attachments ................................................................................................. 9 
 
 

For re-examination 
 
Protocol No. 208505 
1 
1. Objectives 
The objective of this study is to collect and assess information on the safety and effectiveness 
of the long-term use of Nucala subcutaneous injection (hereinafter referred to as “Nucala”) in 
daily clinical practice in patients with Eosinophilic Granulomatosis with Polyangiitis (EGPA). 
 
［Conditions for Approval］As the number of EGPA patients who are inadequate responders 
to existing therapies in Japanese clinical trials is extremely limited, it is required to conduct a 
drug use investigation (DUI) after the market launch in all patients until the data are 
accumulated from an adequate number, thereby enabling the early collection of data regarding 
safety and effectiveness, and taking necessary measures needed for the proper use of the drug, 
along with getting a grasp of the characteristics of patients receiving Nucala for EGPA. 
 
2. Safety Specification 
In this study, the safety specifications are as follows, and the occurrence, etc. will be monitored. 
• 
Hypersensitivity including Anaphylaxis 
• 
Infections 
• 
Malignant Tumors 
 
3. Target Population 
All patients* administered Nucala for the treatment of EGPA after its approval of indication 
will be included in the study. In addition, after the approval, patients who had already received 
Nucala for EGPA prior to the conclusion of the contract will also be included. 
It also covers patients who had been registered to a special drug use investigation, SDUI 
(Protocol No.204524) for bronchial asthma, but had a change in treatment purpose from 
bronchial asthma to EGPA during the observation period. 
*：Irrespective of whether patients have a history of Nucala treatment for bronchial asthma or 
not 
 
4. Target Sample Size and Rationale 
Target number of patients: 300 patients (as a safety analysis population) 
Rationale: 
In a phase Ⅲ international joint study conducted in EGPA patients (mepolizumab 
group: 68 patients), the incidence of serious infection defined as the important potential 
risk was 5.88% (4/68 patients). On the assumption that the incidence used as a 
threshold is 6%, to confirm that the lower bound of the two-sided 95% CI exceeds the 
6% threshold when the real risk exists two times or more, 277 patients are required as a 
safety analysis population. Accordingly, the target number of patients was set at 300 in 
consideration of the dropouts. 
 
5. Planned Number of Medical Institutions by Department 
All medical institutions where Nucala is administered to EGPA patients 
 
6. Study Period 
1. Study conduct 

 
 
 
 
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Study period: from the approval of EGPA indication to three months after termination of the 
observation period in patients eligible for case report form (CRF) collection 
(period of the follow-up investigation, if conducted) or the lifting of approval 
conditions, whichever comes later 
Observation period: The observation period per patient is up to 96 weeks (2 years) from the 
start of Nucala administration for EGPA at a maximum. If a patient has 
withdrawn from/terminated administration of Nucala, it will be until the 
withdrawal/termination. Additionally, to consider the safety and effectiveness 
of Nucala administration in patients who had withdrawn from/terminated due to 
“symptom improvement”, the 48-week (1-year) follow-up investigation should 
be conducted as much as possible. 
Scheduled enrolment period: from the approval of EGPA indication to the lifting of approval 
condition 
Patients are eligible for CRF collection when starting Nucala administration for 
EGPA by 31 October, 2019, and CRFs will be collected as required when 
patients start the administration since 1 November, 2019. Further, patients are 
eligible for enrolment when starting the administration by the acknowledgment 
of the report at a committee meeting, where the all-case investigation-related 
conditions for approval are lifted, and enrolment will continue. 
2. Study end 
Final analysis completion: July 2025 
Final report preparation completion: December 2025 
 
7. Study Methods 
1. 
Requirements for physicians 
For use of Nucala, confirm that physicians meet any of the following requirements; 
1) 
Experienced in the treatment of EGPA, certified as a specialist and an instructor in every 
kind of relevant academic societies 
2) 
Experienced in the treatment of EGPA, certified as a physician and cooperating 
physician designated for intractable diseases 
3) 
Sufficiently experienced in the treatment of EGPA, providing the treatment of EGPA in 
proper cooperation with physicians who correspond to the above-mentioned 
4) 
Providing the treatment of EGPA under direct supervision of physicians who correspond 
to 1 and 2 
2. 
Request and contract for the study 
1) 
The person in charge of this study (medical representative or monitoring outsourcee) 
will explain the objectives, target population, study items, study methods, etc. and 
request cooperation to the planned physicians for the study, etc. at the medical 
institutions where Nucala had been adopted/delivered for the treatment for bronchial 
asthma but also have plans to administer the drug to EGPA patients. 
2) 
If cooperation to the study has been obtained, the Written Contract should be concluded 
with the heads (e.g. directors, etc.) of the medical institutions before the start of the 
study. 
3. 
Enrolment of target population 
The study will be conducted using an all-case investigation method. 

 
 
 
 
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1) 
The investigator will record the patient information, etc. on the Enrolment Form 
regarding all patients eligible for enrolment after the conclusion of the contract, and will 
fax it to the Enrolment Centre immediately after the start of administration. The 
personally identifiable information, such as the name, address, date of birth, initials of 
patients, should not be recorded in the Enrolment Form. 
<Enrolment Centre> 
2) 
After the approval of EGPA indication, the Written Contract should be concluded before 
the start of administration in principle, however, patients to whom Nucala has 
unavoidably been administered before the conclusion of the contract will also be 
enrolled as a retrospective patient. 
4. 
Data collection and case report form (CRF) completion 
1) 
The investigator will confirm the study items, such as the characteristics of patients 
eligible for CRF collection. 
2) 
During the observation period, the investigator will monitor the information about safety 
and effectiveness, etc.  
3) 
At the end of the observation period of patients eligible for CRF collection (or at 
withdrawal/termination, if a patient has withdrawn from/terminated administration of 
Nucala), the investigator will record the obtained information on the CRF and submit the 
completed CRF to the person in charge of this study . The personally identifiable 
information, such as the name, address, date of birth, initials of patients, should not be 
recorded in the CRF. 
5. 
Confirmation of all-case investigation implementation 
Annually and after the end of the study period, the investigator will confirm whether or not 
enrolled patients are all receiving Nucala, affix his/her signature or name/seal to the 
“Confirmation Letter of All-Case Investigation” and submit it to the person in charge of this 
study.  
6. 
Obtaining Informed Consent 
The investigator will provide a patient eligible for CRF collection (and/or, his/her substitute) 
with a full explanation on the publication of the study results either verbally, or in writing 
using an informed consent form and obtain informed consent. 
 
8. Study Items 
The investigator will collect the information about the following items, etc. as far as possible 
and record it on the CRF. 
1. 
Information on medical institution 
Name of a medical institution, department, investigator 
2. 
Patient characteristics (at the start of Nucala administration for EGPA (hereinafter referred to 
as “at the start of Nucala administration”)) 
Identification number, gender, year of birth or age at the start of Nucala administration, start 
date of Nucala administration, presence and absence of obtained informed consent regarding 
study result publication, body weight, reasons for use of Nucala, date (month, year) of EGPA 
diagnosis, severity classification of EGPA*1 at the start of Nucala administration, presence or 
absence of hospitalization due to EGPA in 48 weeks before the start of Nucala administration 
and number of times patient experienced hospitalization, presence and absence of past 
CCI

 
 
 
 
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medical history/comorbidity (bronchial asthma, renal impairment, hepatic function abnormal, 
others) and name of disease, presence or absence of history of Nucala use for bronchial 
asthma if a patient has comorbid bronchial asthma. 
To protect the confidentiality regarding identification of an individual patient, the 
identification number should be a unique number assigned to an individual patient by the 
investigator, etc. 
In this study, any disease, symptom, and allergy history other than EGPA which is present 
before the start of administration of Nucala but has recovered/resolved by the start of Nucala 
administration will be handled as a “past history”. Meanwhile, any disease, symptom, and 
allergy other than EGPA which is present at the start of Nucala administration will be 
handled as a “comorbidity”. 
*1：Severity Classification of EGPA defined by Japan Intractable Diseases Information 
Center (Japan Intractable Diseases Research Foundation) 
3. 
Administration status of Nucala 
Single dose during the observation period (mg/dose), daily dose frequency (X times per day), 
administration date, reasons for revision of dosage and administration  
4. 
Pre-treatment medications (during 4 weeks before the start of Nucala administration) and 
concomitant medications (adrenal cortical steroid (including medications for bronchial 
asthma), immune-suppressive agent and immunoglobulin preparations only) 
Presence or absence of adrenal cortical steroid (including medications for bronchial asthma), 
immune-suppressive agent and immunoglobulin preparations during 4 weeks before the start 
of Nucala administration and during the observation period, name of drugs, daily dose, start 
date of administration, end date of administration, reasons for administration 
5. 
Concomitant medications (other than adrenal cortical steroid, immune-suppressive agent and 
immunoglobulin preparations) 
Presence or absence of concomitant medications other than adrenal cortical steroid (including 
medications for bronchial asthma), immune-suppressive agent and immunoglobulin 
preparations) during the observation period, name of medications, reasons for use 
6. 
Pre-treatment for EGPA 
Presence or absence of pre-treatment for EGPA before the start of administration, name of 
treatment  
7. 
Concomitant therapies for EGPA 
Presence or absence of concomitant therapies other than medications during the observation 
period, name of therapies 
8. 
Hematological Tests Parameters (Number of white blood cell count, eosinophils in the blood, 
CRP) 
Test date and results of hematological test at the start of Nucala administration (during 0-4 
weeks before the start of Nucala administration), Weeks 12, 24, 36, 48, 60, 72, 84, and 96 
after the first dose, or at withdrawal/termination (if test performed) 
9. 
Hematological Tests Parameters (MPO-ANCA* (myeloperoxidase), PR3*-ANCA 
(proteinase3)) 
Test date and results of hematological test at the start of Nucala administration (during 0-4 
weeks before the start of Nucala administration), Weeks 24, 48, 72, and 96 after the first 
dose, or at withdrawal/termination (if test performed) 
*: antineutrophil cytoplasmic antibody, ANCA (antineutrophil cytoplasmic antibody) 

 
 
 
 
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10. Clinical symptoms (only disease activity relevant to EGPA in systemic vasculitis*assessed)  
(9 organ-system (General, Cutaneous, Mucous membranes/eyes, ENT, Chest, 
Cardiovascular, Abdominal, Renal, Nervous system) and 56 items) 
Presence or absence of clinical symptoms and findings (any of 9 organ systems) at the start 
of Nucala administration (during 0-4 weeks before the start of administration), Weeks 12, 24, 
36, 48, 60, 72, 84, and 96 after the first dose, or at withdrawal/termination, date of 
assessment. 
If EGPA-related clinical symptoms or clinical findings in any of the 9 organ-systems were 
detected, items which corresponds to in each organ-systems will be selected from a total of 
56 items. 
Additionally, if a sign of exacerbation was observed in above mentioned clinical symptoms 
or clinical findings when compared to the assessment performed 12 months before this (or 
more than 12 months before if no assessment was performed within the period), 
"exacerbation" will also be selected.*: excerpt from BVAS（Birmingham Vasculitis Activity 
Score）(Vers.3) 
11. Exacerbation of bronchial asthma 
If a patient has bronchial asthma as a comorbidity, frequency of exacerbation of bronchial 
asthma which corresponds to the either types defined below and a total number of days 
patient hospitalized for bronchial asthma treatment from 48 weeks prior to the initiation of 
Nucala treatment to Weeks 12, 48 and 96 after the administration (or to the time point of 
withdrawal/termination); 
・exacerbation of bronchial asthma which requires hospitalization 
・exacerbation of bronchial asthma which requires emergency room visit 
・exacerbation of bronchial asthma which requires usage of systemic steroids* 
*The standard definitions for the usage of systemic steroids are as follows; 
When a patient requires continuous administration of steroids systemically, in 
concrete terms, orally, intravenously or intramuscularly, for ≥three days. However, as 
for intramuscular injection, it must also include a continuous administration of 
dexamethasone phosphate acid ester sodium or betamethazoneline acid ester sodium for 
≥three days, or one or more dose of triamcinolone acetonide. 
When a patient requires administering systemic steroids double the existing 
maintenance dose for ≥three days in patients receiving the maintenance therapy of 
systemic steroids requiring dose increase associated with exacerbation of bronchial 
asthma. 
Multiple exacerbation of asthma for which steroids are administered at an interval of 
<seven days will be handled as continuation of exacerbation of the same asthma.  
12. Hospitalization for EGPA treatment 
Presence or absence of hospitalization for EGPA treatment 96 weeks after the administration 
(or to the time point of withdrawal/termination) during the observation period, date of 
hospitalization and discharge if patient experienced hospitalization 
13. Global assessment of effectiveness 
Effectiveness will be comprehensively assessed by any of “effective” or “not effective” at 
Weeks 12, 48 after the start of Nucala administration, end of the observation period, or at 
withdrawal/termination, based on the course of subjective symptoms, course of clinical 
symptoms, etc. from the start date of administration to the end of the observation period. If 

 
 
 
 
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effectiveness cannot be determined for some reasons, it should be assessed as 
“indeterminable” and its reasons should be recorded on the CRF. 
14. Continuation status of Nucala 
Continuation status of Nucala at Weeks 12, 48 after the start of administration, end of the 
observation period, the reason if a patient has withdrawn from/terminated administration 
15. Pregnancy 
Whether Nucala is administered to a pregnant woman or not, the presence or absence of 
pregnancy during the observation period, and the expected delivery date (if a patient is 
female) 
In addition, the follow-up investigation should be conducted for a mother and her foetus as 
far as possible regarding the course of delivery, spontaneous abortion, elective abortion, and 
AEs, etc.  
16. Adverse events (AEs) 
Presence or absence of AEs after the start of Nucala administration, diagnosis or symptoms, 
occurrence date, outcome of AEs, outcome date, seriousness, reason for assessing as serious, 
relationship to Nucala, factors suspected of being related to AEs other than Nucala  
1）In this study, the safety specifications matters are defined as follows; 
・Hypersensitivity including Anaphylaxis, Infections, Malignant tumor 
2）To grasp the safety specifications and ADRs, the investigator will collect the information 
about all AEs (e.g., a disease, symptom, abnormal laboratory value) occurring after the 
start of Nucala administration on the CRF, regardless of whether or not Nucala is related 
to an AE. Considering whether or not the possibility of a reasonable relationship to 
Nucala is present, etc., the relationship to Nucala will be assessed on any of “related” or 
“not related”. 
3）The AEs assessed as “related” to Nucala will be handled as an “ADR” suspected of being 
caused by Nucala. 
17. Follow-up investigation (only in patient who has withdrawn from/terminated due to 
“symptom improvement”) 
Assessment date after the end of follow-up period, presence or absence of AEs leading to 
death, serious infections, PML, and MT, diagnosis or symptoms, occurrence date, outcome of 
AEs, outcome date, seriousness, reasons for assessing as serious, relationship to Nucala, 
factors suspected of being related to AEs except Nucala 
 
9. Analysis Items and Methods 
1. 
Analysis items 
1) 
Patient disposition-related matters 
i). 
Number of enrolled patients and number of patients whose CRF is collected and 
fixed 
ii). Number of patients included in the safety analysis set and number of patients 
included in the effectiveness analysis set, number of patients excluded from 
analysis and the reason for exclusion 
iii). Number of patients included in the analysis sets regarding remission and 
recurrence, number of patients excluded from the analysis sets and the reason for 
exclusion 
2) 
Safety-related matters 
i). 
Occurrence of ADRs/infections (type, severity and incidence of ADRs, etc.) 

 
 
 
 
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ii). Factors that potentially affect safety (occurrence of ADRs and infections by 
patient characteristics, etc.) 
iii). Occurrence of events defined as a priority study matters 
3) 
Effectiveness-related matters 
i). 
Responder rate based on global assessment of effectiveness 
The responder rate is the proportion of patients assessed as “effective”. 
ii). Factors that potentially affect effectiveness (responder rate by patient 
characteristics, etc.) 
iii). Time to EGPA remission and recurrence 
The remission and recurrence are defined as follows; 
 
Remission: BVAS=0 in the assessment of disease activity in systemic 
vasculitis assessed by 9 organ-system, 51 items. 
 
Recurrence: If any of the following occurs during the observation period 
 
Initiation/increased dose of adrenal cortical steroid 
 
Initiation/increased dose of immune-suppressive agent 
 
Hospitalization in association with the EGPA treatment 
2. 
Analysis methods  
Concerning the items associated with safety and effectiveness, etc., the odds ratio and 95% 
confidence interval will be calculated for factors that potentially affect them. These will be 
graphically presented using a forest plot, etc., as appropriate. For comparison of the scores, 
etc., the mean values and quartile points, etc. for values at the time of measurement and 
changes from baseline will be calculated. 
 
10. Organizational Structure 
Refer to the Attachment 1. 
 
11. Name, Address of the Outsourcees, and the Scope of Outsourced 
Operations 
CCI

 
 
 
 
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12. Scheduled Timing to Be a Milestone for Assessing the Status and 
Results in the Study or Reporting to the Pharmaceuticals and 
Medical Devices Agency (PMDA) and Rationale 
• 
At the time of Periodic Safety Reports: consideration will be comprehensively given to 
the safety and effectiveness information. 
• 
At the time of re-examination application: the final report will be prepared/submitted, 
based on the results of tabular analysis obtained from the fixed data of all collected 
CRFs. 
 
13. Additional Measures that Have a Potential to Be Taken Depending 
to the Study Results and the Decision Criteria for the Start 
The RMP, including the following, will be reviewed at the timings to be a milestone. 
• 
Regarding hypersensitivity including anaphylaxisthe, if the proportion of occurrence, 
peak occurrence period and risk factors become visible as an ADR caused by Nucala, 
the necessity for revising the Package Insert and study materials will be considered as 
appropriate. 
• 
Including whether or not a new concern in the safety specification is present, the 
necessity for changes in the content of plan in the study will be considered. 
• 
The necessity for creation of the Risk Minimization Plan for a new concern in the safety 
specification will be considered. 
 
14. Publication of the Study Results 
The information regarding the results of the study will be provided to clinical sites as an interim 
report and a final report as appropriate for the purpose of “proper use” and “safety assurance”, 
considering a proper timing and the number of patients whose CRF is collected, etc., by means of 
presentation at academic conferences and papers.  
In addition, the summaries of the plan and results in the study will be disclosed in GSK Clinical 
Study Register. 
 
15. Other Requirements 
1. 
Protocol revision 
The progress in the study, the number of patients excluded from analysis, occurrence of 
unexpected/serious ADRs, large increase in occurrence of specific ADRs and validity of the 
study items, etc. will be timely grasped during the study period, and the Protocol will be 
reviewed and revised if required. 
If the content of the Protocol in the study has been changed, the Change Notification should 
be submitted to the PMDA in advance, except for minor changes. 
2. 
Measures to be taken in detecting issues or concerns 
CCI

 
 
 
 
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If issues, etc. have been detected from the results of assessment/analysis during the study 
period or after the completion of the study, consideration will be given on whether or not the 
SDUI or Post-marketing Clinical Study should be newly conducted, as appropriate. 
 
16. Attachments 
1) Organizational structure for post-marketing surveillance operations  
 
AT1 
2) NUCALA Subcutaneous Injection Special Drug Use Investigation (EGPA, long-term) 
Written Contract 
 
 
 
 
 
 
 
AT2 
3) NUCALA Subcutaneous Injection Special Drug Use Investigation (EGPA, long-term) 
Implementation Guidance 
 
 
 
 
 
 
AT3 
4) NUCALA Subcutaneous Injection Special Drug Use Investigation (EGPA, long-term) 
Enrolment Form 
 
 
 
 
 
 
 
AT4 
5) NUCALA Subcutaneous Injection Special Drug Use Investigation (EGPA, long-term) Case 
Report Form 1（From the start of Nucala administration to Week 12） 
 
AT5 
6) NUCALA Subcutaneous Injection Special Drug Use Investigation (EGPA, long-term) Case 
Report Form 2（Week 13 to Week 48） 
 
 
 
 
AT6 
7) NUCALA Subcutaneous Injection Special Drug Use Investigation (EGPA, long-term) Case 
Report Form 3（Week 49 to Week 96） 
 
 
 
 
AT7 
8) NUCALA Subcutaneous Injection Special Drug Use Investigation (EGPA, long-term) Case 
Report Form 4（Follow-up investigation） 
 
 
 
 
AT8