Nucala® Subcutaneous Injection Special Drug Use Investigation (Long-Term)
Conditions: Asthma
Sponsor: GlaxoSmithKline

For re-examination 
 
Protocol No. 204524 
 
 
 
 
 
 
 
 
 
Nucala® Subcutaneous Injection 
Special Drug Use Investigation 
(Long-Term) 
 
Protocol 
 
 
 
 
 
 
 
GlaxoSmithKline K.K. 
 
 
 
 
Revised: 8 December 2022 (Vers.3.1) 
 
 

For re-examination 
 
Protocol No.202026 
 
<Contents> 
 
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 .............................................................. 5 
10. 
Organizational Structure .................................................................... 6 
11. 
Name, Address of the Outsourcees, and the Scope of Outsourced 
Operations ........................................................................................... 6 
12. 
Planned 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 ............................. 6 
13. 
Additional Measures that Have a Potential to Be Taken Depending 
on the Study Results and the Decision Criteria for the Start ......... 6 
14. 
Publication of the Study Results ....................................................... 7 
15. 
Other Requirements ............................................................................ 7 
16. 
Attachments ......................................................................................... 7 
 
 
 

 
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1. Objectives 
The objective of the study is to collect and assess information regarding the safety and 
effectiveness of long term use of Nucala® for subcutaneous injection (hereinafter referred to as 
“Nucala”) in asthma patients in daily clinical practice. 
 
2. Safety Specification 
In the study, the occurrence of safety specification and the priority investigation matter will be 
monitored. They will be defined as follows; 
 
Hypersensitivity reaction including anaphylaxis 
 
Infections 
 
Malignant tumour 
  
3. Target Population 
The study will include patients receiving Nucala for the first time for treatment of bronchial 
asthma (a refractory asthma whose symptoms are inadequately controlled despite receiving 
standard asthma medications), for which Nucala is indicated. 
 
4. Target Sample Size and Rationale 
1) 
Target number of subjects : 1,000 subjects (as enrolled subjects) 
2) 
Rationale : 
In the Phase III Global Trial (385 subjects), the incidence of adverse drug reactions (ADRs) 
occurring in one patient was 0.26%. Since 885 subjects are required to detect an ADRs 
including unexpected ADRs occurring at an incidence of ≧0.26% in at least one patient 
with a probability of 90%, the target number of subjects was set at 1,000 in consideration of 
withdrawal and dropouts. 
In addition, in the placebo-controlled trial targeting severe asthma patients, the incidence of 
“allergic reaction/hypersensitivity”, one of the “hypersensitivity reaction including 
anaphylaxis” defined as the important potential risk, was 1.14% (3/263 subjects). On the 
assumption that the incidence used as a threshold is assumed to be 1.2%, to confirm the 
incidence in the post-marketing surveillance with the estimation accuracy which detects the 
1.2% of threshold with a statistical power of ≧80% when the real risk exists two times or 
more of the threshold, 827 subjects are required as a safety analysis set. Accordingly, it is 
thought to be possible to examine the incidence in the study with 1,000 subjects. 
5. Planned Number of Medical Institutions by Department 
Approximately 200, mainly the departments of respiratory medicine  
 
6. Study Period 
1. 
Study conduct 
Study period : January 2017 - September 2023 
Observation period: The observation period per subject will be 1 year (52 weeks) from the 
initiation of Nucala treatment. 
In addition, the follow-up investigation will be conducted for 2 years after 
the observation period (or after the withdrawal/termination, if a subject has 
withdrawn from/ terminated the administration of the drug) to examine the 
occurrence of malignant tumour. 

 
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Planned enrollment period : January 2017 - June 2020 
However, if the number of enrolled subjects has reached the target sample size, enrollment may 
be terminated even before completing the above-mentioned planned enrollment period. 
2. 
Study end 
Completion of final analysis: January 2024 
Completion of final report writing : June 2024 
 
7. Study Methods 
  In the study, the electronic data capture (EDC) system will be used for case registration and data 
collection. 
1) 
Request and contract for the study 
(1) The person in charge of the study (medical representative or monitoring 
outsourcee) will explain the objectives, target population, study items, study 
methods, etc. to the planned physicians for the study, etc. at the medical 
institutions where Nucala is adopted/delivered, and will request them to 
cooperate with the study.  
(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 
starting the study. 
2) 
Enrollment of target population 
The study will be conducted using a central enrollment method. 
(1) The investigator will enter and enroll subject information, etc. in the EDC 
system within 14 days from the initiation of Nucala treatment regarding “3. 
Target Population” who started administration of Nucala after the conclusion of 
the contract (the start date of the administration will be regarded as Day 1). 
(2) If the number of enrolled subjects has reached the number of contracted 
subjects, enrollment into the study will be terminated. 
3) 
Collection of data and entry in the EDC system 
(1) 
The investigator will confirm the study items, such as the characteristics of 
enrolled subjects. 
(2) 
If asthma control test (ACT) is conducted to an enrolled subject at the initiation 
of Nucala treatment, and at Week 12, 24 and 52 after the administration (or at 
the time point of withdrawal/termination if a subject has withdrawn 
from/terminated the administration), the investigator will check the content, and 
enter the test score in the EDC system. 
(3) 
During the observation period, the investigator will monitor the information 
regarding the safety and effectiveness, etc. If an enrolled subject does not visit 
the hospital/clinic during the observation period, the investigator will monitor 
the information regarding AEs and others by telephone, etc. as far as possible. 
(4) 
The investigator will enter the information of the enrolled subjects obtained at 
the end of the observation period, and send it. 
(5) 
During the follow-up period of 2 years after the observation period (or after the 
withdrawal/termination if a subject has withdrawn from/terminated the 
administration), the information regarding the onset of malignant tumour will be 
monitored. The investigator will enter the information of an enrolled subject 
obtained at the time point when the onset of malignant tumour has been 
monitored or at the end of the follow-up period in the EDC system, and send it. 

 
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In case other ADR (AE suspected of being related to Nucala), has been 
monitored, the investigator will contact the person in charge of the study. If an 
enrolled subject does not visit the hospital/clinic during the follow-up period, the 
investigator will confirm the presence/absence of onset of malignant tumour by 
telephone, etc. as far as possible. 
8. Study Items 
The investigator will collect the information regarding the following items, etc. as far as 
possible and enter it in the EDC system. 
1) 
Information regarding medical institutions 
Name of medical institution, department, investigator 
2) 
Subject characteristics (at the initiation of Nucala treatment) 
Identification number, gender, year of birth, start date of administration, hospitalization 
status, reason for use, presence/absence and name of complications (renal impairment, 
hepatic impairment, allergy, others), history of smoking, duration of asthma, pre-
administration severity and type of asthma 
To protect the confidentiality regarding identification of an individual subject, the 
identification number should be a unique number assigned to an individual subject by the 
investigator, etc. 
In this study, any disease/symptom except for asthma which is present before the initiation 
of Nucala treatment will be handled as a “complication”. 
3) 
Pretreatment medications for asthma (during 4 weeks prior to the initiation of Nucala 
treatment) 
Presence or absence of pretreatment medications for asthma during 4 weeks prior to the 
initiation of Nucala treatment, category and product name of medication, single dose and 
dose unit (as for inhaled steroids and oral steroids)  
4) 
Administration status of Nucala 
Single dose and dose unit, daily dose frequency, date of administration  
5) 
Concomitant medications 
Presence or absence of concomitant medications, name of medications, route of 
administration, reason for administration, single dose and dose unit of inhaled steroids and 
oral steroids during the observation period 
6) 
Concomitant therapies for asthma (except for medications) 
Presence or absence of concomitant therapies for asthma, name of therapies during the 
observation period. 
7) 
Blood test item 
Presence or absence of eosinophils count ≧300/μL during 52 weeks prior to the Nucala 
treatment, eosinophils count and examination date at the initiation of Nucala treatment, at 
Week 12, 24 and 52 after the administration or at the time point of withdrawal/termination 
(only if examination is performed), administration history of Omalizumab, serum total IgE 
levels* and examination date 
* In subject with Omalizumab history, the serum total IgE levels measured before the 
treatment start of Omalizumab or, on and after 1 year post last dose will be entered. 
8) 
Exacerbation of asthma 
Frequency of exacerbation of asthma from 52 weeks prior to the initiation of Nucala 
treatment to 52 weeks after the administration (or to the time point of 
withdrawal/termination), frequency of exacerbation of asthma and number of days of 
hospitalization from 52 weeks prior to the initiation of Nucala treatment to 52 weeks after 

 
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the administration (or to the time point of withdrawal/termination) which corresponds to the 
either types of exacerbation defined below; 
・exacerbation of asthma which requires hospitalization 
・exacerbation of asthma which requires emergency room visit 
・exacerbation of asthma which requires usage of systemic steroids* 
*The definitions for use of systemic steroids are as follows; 
When administering steroids (e.g., prednisolone) orally and intravenously (or 
intramuscularly) for a total of ≧three days are required. 
When in subject receiving the maintenance therapy of systemic steroids, who requires 
administering double the existing maintenance dose for≧three days. 
Multiple exacerbation of asthma for which steroids are administered at a interval of ＜ 
seven days will be handled as continuation of exacerbation of the same asthma. 
9) 
Respiratory Function Test (Peak Expiratory Flow (PEF)) 
Morning/evening PEF score measured at the nearest time point of 1 week before and after 
the initiation of Nucala treatment, and at Week12, 24, and 54 after the administration, or at 
the withdrawal/termination* (only if PEF is conducted), measurement date, measurement 
time of the day, presence and absence of use of short-acting beta 2 agonist (SABA) within 4 
hours before measuring PEF score 
* All PEF score obtained during this period will be entered in the EDC system 
10) Asthma Control Test (ACT) 
The information of ACT recorded by a subject at the initiation of Nucala treatment, at Week 
12, 24 and 52 after the administration, or at the time point of withdrawal/termination if a 
subject has withdrawn from/terminated administration. (only if ACT is conducted) 
11) Global assessment of effectiveness 
Effectiveness will be comprehensively assessed by any of “effective” or “not effective” at 
52 weeks after the initiation of Nucala treatment or at the time point of withdrawal 
from/termination of administration, based on the course of subjective symptoms, and course 
of clinical symptoms, etc. from the initiation of Nucala treatment to the end of the 
observation period. If effectiveness cannot be determined for some reasons, it should be 
assessed as “indeterminable”, and the reason should be entered in the EDC system. 
12) Administration of the drug at the end of the observation period 
Administration of the drug at the end of the observation period, the reason if a subject has 
withdrawn from/terminated administration 
13) Occurrence of malignant tumour during 2 years after the observation period (follow-up 
investigation) 
Presence or absence of onset of malignant tumour during 2 years after the observation 
period (or during 2 years after the withdrawal/termination if a subject has withdrawn 
from/terminated administration of the drug), diagnosis or symptoms, onset date, outcome of 
malignant tumour, outcome date, seriousness, relationship to Nucala and factors suspected 
of being related to AEs except for Nucala 
14) Pregnancy 
 (For female subjects) whether or not the drug is administered to a pregnant woman, 
whether or not a subject is pregnant during the observation period and expected delivery 
date 

 
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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. 
15) Adverse Events (AEs) 
Presence or absence of AEs after initiation of Nucala treatment, diagnosis or symptoms, 
onset date, outcome of AEs, outcome date, seriousness, reason for assessing as serious, 
relationship to the drug, factors suspected of being related to AEs except for Nucala 
(1)  In this study, the priority study matters are defined as follows; 
・ Hypersensitivity reaction including anaphylaxis, infections and malignant tumour 
(2) To grasp the priority study matters and ADRs, the investigator will enter the 
information regarding all AEs (e.g., a disease, symptom, abnormal laboratory value) 
occurring after the initiation of Nucala treatment in the EDC system, regardless of 
whether or not the Nucala is related to an AE. Considering whether or not the 
possibility of a reasonable relationship to the drug is present, etc., the relationship to 
the drug will be assessed on a scale of two categories, any of “related” or “not related”, 
and it will be entered in the EDC system. 
(3) AEs assessed as “related” to Nucala will be handled as suspected “ADRs” that are 
caused by the product. 
9. Analysis Items and Methods 
1) 
Analysis items 
(1) Subject disposition-related matters 
① Number of enrolled subjects and number of subjects whose data is entered in the 
EDC system and fixed 
② Number of subjects included in the safety and effectiveness analysis sets, number 
of subjects excluded from analysis and the reason for exclusion 
③ Number of subjects included in the analysis sets regarding exacerbation of 
asthma, number of subjects excluded from the analysis sets and the reason for 
exclusion  
④ Number of subjects included in the analysis sets regarding ACT, number of 
subjects excluded from the analysis sets and the reason for exclusion 
(2) Safety-related matters 
① Occurrence of ADRs and infections (type, severity and incidence of ADRs, etc.) 
② Occurrence of events defined as a priority investigation matter 
(3) Effectiveness-related matters 
① Response rate based on the global assessment of effectiveness 
The response rate is the proportion of subjects assessed as “effective”. 
② Frequency of exacerbation of asthma 
③ Total score of ACT 
④ PEF score 
2) 
Analysis methods 
(1) Safety 
① The incidence of ADRs and 95% confidence interval will be calculated. 
(2) Effectiveness 
① The response rate and its 95% confidence interval will be calculated. 
② For comparison of the scores, etc., the summary statistics for values at the time of 
measurement and changes from baseline will be calculated. 
(3) Consideration of covariates 

 
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① The covariate that affects safety (incidence of ADRs) will be considered by 
calculating the odds ratio and its 95% confidence interval. 
② The covariate that affects effectiveness (response rate) will be considered by 
calculating the odds ratio and its 95% confidence interval (It will be graphically 
presented using a forest plot, etc., as appropriate). 
 
10. Organizational Structure 
See Attachment 1. 
 
11. Name, Address of the Outsourcees, and the Scope of Outsourced 
Operations  
1) 
Enrollment 
Outsourcee : CMIC Co., Ltd. (1-1-1, Shibaura, Minato-ku, Tokyo) 
Scope : patient enrollment and other related operations 
2) 
Data management 
Outsourcee : CMIC Co., Ltd. (1-1-1, Shibaura, Minato-ku, Tokyo) 
Scope : patient enrollment and other related operations 
3) 
Statistical analysis 
Outsourcee : CMIC Co., Ltd. (1-1-1, Shibaura, Minato-ku, Tokyo) 
Scope : statistical analysis and other related operations  
4) 
EDC system operarions 
Outsourcee : FUJITSU FIP Corporation (1-2-1, Shibaura, Minato-ku, Tokyo) 
Scope : development and operation of EDC system, and other related operations 
5) 
Monitoring 
Outsourcee: CMIC Co., Ltd. 
            Shibaura1-1-1, Minato-ku, Tokyo 
Scope : contract with medical institutions, payment to medical institutions, promotion of 
enrolment and CRF collection, other related operations 
 
12. Planned 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 in the EDC. 
 
13. Additional Measures that Have a Potential to Be Taken Depending on 
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 anaphylaxis, if the proportion, the peak onset period 
and risk factors become visible as an ADR caused by the drug, the necessity for revision 
to the Package Insert and study materials will be considered as appropriate. 
• 
Including the presence or absence of a new issue in the safety specification, the necessity 
for changes in the content of plan in this study will be considered. 

 
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∙ 
The necessity for creation of Risk Minimization Plan for a new issue 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 subjects whose data is collected, etc., 
by means of presentation at an academic conference and papers. 
In addition, the summaries of plan and results in this study will be disclosed in GSK Clinical 
Study Register. 
 
15. Other Requirements 
1) 
Protocol Revision 
The progress in the study, the number of subjects 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. 
<Examples of minor changes> 
(1) 
Change of the organization or the person in charge for the conduct of the study 
(2) 
Change of the planned number of medical institutions (by department) 
(3) 
EDC system 
[1] 
Modifications to the layout of items (relocation of items, enlargement or reduction of 
sections) 
[2] 
Change in the explanation of items 
[3] 
Inclusion of additional examples of ADRs, in association with a revision of the 
Precautions or inclusion of noteworthy ADRs 
(4) 
Addition, change, and deletion of items that have no impact on the entire study, 
particularly efficacy and safety analyses 
(5) 
Study period 
[1] 
Change of the start day of the study due to a delay in the product launch 
[2] 
Prolongation of the study period to correspond to a short-term (within 3 months) 
prolongation, if necessary, of the registration period 
[3] 
Reduction of the study period in case no change has been made to the planned sample 
size 
2) 
Handling of problems or questions detected 
If any problem is found during the study period or in the evaluation and analysis results, etc. after 
completion of the study, implementation of an additional special drug use investigation 
or post-marketing clinical study will be considered according to need. 
 
16. Attachments 
1) 
Organizational Structure for Post-marketing Surveillances                  AT 1 
2) 
Nucala® for Subcutaneous Injection SDUI Written Contract  
 
AT 2 
3) 
Nucala® for Subcutaneous Injection SDUI Implementation Guidance  
AT 3 
4) 
Nucala® for Subcutaneous Injection SDUI Enrolment Form  
 
AT 4 

 
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5) 
Nucala® for Subcutaneous Injection SDUI Case Report Form (CRF)  
AT 5 
6) 
Nucala® for Subcutaneous Injection SDUI Asthma Control Test (ACT) 
AT 6