NINLARO Capsules Drug Use-Results Survey (All-Case Surveillance) "Relapsed/Refractory Multiple Myeloma"
Conditions: Relapsed/Refractory Multiple Myeloma
Sponsor: Takeda

 
 
Title: NINLARO Capsules Drug Use-Results Survey (All-Case Surveillance) 
“Relapsed/Refractory Multiple Myeloma” 
 
NCT Number: NCT03169361 
Protocol Approve Date: 23-Jun-2020 
 
Certain information within this protocol has been redacted (ie, specific content is 
masked irreversibly from view with a black bar) to protect either personally identifiable 
information or company confidential information. 
 
 
Note; This document was translated into English as the language on original version 
was Japanese. 

 
Drug Use-Results Survey Protocol 
NINLARO Capsules Drug Use-Results Survey 
(All-Case Surveillance) 
“Relapsed/Refractory Multiple Myeloma” 
Survey sponsor 
Takeda Pharmaceutical Company Limited 
Protocol No. 
C16025 
Edition 
Version 6 
Date of preparation June 23, 2020 
 
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Table of Contents 
1.0 
BACKGROUND ............................................................................................................................................ 1 
2.0 
PURPOSE ...................................................................................................................................................... 1 
3.0 
SCHEDULED NUMBER OF CASES AND RATIONALE .......................................................................... 1 
3.1 
SCHEDULED NUMBER OF CASES ....................................................................................................... 1 
3.2 
RATIONALE ............................................................................................................................................. 1 
4.0 
PATIENTS TO BE SURVEYED .................................................................................................................... 1 
5.0 
DOSAGE AND ADMINISTRATION ........................................................................................................... 2 
6.0 
SCHEDULED NUMBER OF MEDICAL INSTITUTIONS BY CLINICAL DEPARTMENT .................... 2 
7.0 
METHOD ....................................................................................................................................................... 2 
7.1 
OBSERVATION PERIOD .......................................................................................................................... 2 
7.2 
REQUEST TO AND CONTRACT WITH MEDICAL INSTITUTIONS .................................................. 2 
7.3 
PATIENT ENROLLMENT METHOD ...................................................................................................... 3 
7.4 
PREPARATION AND SUBMISSION OF SURVEY SHEETS ................................................................. 3 
7.5 
CONFIRMATION OF ALL-CASE SURVEILLANCE ............................................................................. 3 
8.0 
SCHEDULED PERIOD OF SURVEY .......................................................................................................... 4 
9.0 
SURVEY ITEMS ........................................................................................................................................... 4 
9.1 
ITEMS TO BE INCLUDED IN THE PATIENT REGISTRATION SHEET ............................................. 4 
9.2 
ITEMS TO BE INCLUDED IN THE SURVEY SHEET ........................................................................... 5 
9.2.1 
Survey sheet cover.............................................................................................................................. 5 
9.2.2 
Patient characteristics ......................................................................................................................... 5 
9.2.3 
Treatment ............................................................................................................................................ 5 
9.2.4 
Observation items ............................................................................................................................... 5 
9.2.5 
Adverse events ................................................................................................................................... 5 
10.0 
ANALYSIS ITEMS AND METHOD ............................................................................................................ 9 
10.1 
ITEMS RELATED TO CASE STRUCTURE ............................................................................................ 9 
10.2 
PATIENT CHARACTERISTICS ............................................................................................................... 9 
10.3 
TREATMENT ............................................................................................................................................ 9 
10.4 
ITEMS RELATED TO SAFETY ............................................................................................................... 9 
10.4.1 
Incidence of adverse events ................................................................................................................ 9 
10.4.2 
Factors that may affect the safety ....................................................................................................... 9 
10.5 
INTERIM ANALYSIS ............................................................................................................................... 9 
11.0 
REGISTRATION OF SURVEY INFORMATION ...................................................................................... 10 
12.0 
ORGANIZATIONAL STRUCTURE........................................................................................................... 10 
12.1 
SUPERVISOR .......................................................................................................................................... 10 
12.2 
MEDICAL ADVISOR ............................................................................................................................. 10 
12.3 
CENTRAL REGISTRATION CENTER .................................................................................................. 10 
13.0 
CONTRACT RESEARCH ORGANIZATION ............................................................................................ 10 
14.0 
OTHER NECESSARY MATTERS ............................................................................................................. 11 
14.1 
REVISION OF THE PROTOCOL ........................................................................................................... 11 
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14.2 
ACTIONS TO BE TAKEN IF PROBLEMS AND QUESTIONS ARISE ............................................... 11 
 
 
 
 
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1.0 
BACKGROUND 
Information about the safety of NINLARO capsules (hereinafter, “NINLARO”) in Japanese 
patients at the time of marketing approval is limited. Therefore, it is important to swiftly collect 
post-marketing safety information and provide the field of clinical practice with such 
information. 
Having this as a background, all-case surveillance (hereinafter, “this survey”) is conducted in all 
cases administered NINLARO as an additional pharmacovigilance activity from the time of 
marketing, in order to evaluate the safety of the drug in patients with relapsed/refractory multiple 
myeloma in daily clinical practice. 
This survey is conducted in accordance with relevant regulatory requirements including the 
GPSP Ordinance. 
2.0 
PURPOSE 
To evaluate the safety of NINLARO in patients with relapsed/refractory multiple myeloma in 
daily clinical practice. 
3.0 
SCHEDULED NUMBER OF CASES AND RATIONALE 
3.1 
SCHEDULED NUMBER OF CASES 
Total of 480 cases with relapsed/refractory multiple myeloma 
3.2 
RATIONALE 
The clinical study results of NINLARO suggested that the incidence of skin disorder of Grade 3 
or higher may be high in Japanese and clinical management such as dose adjustment may be 
crucial. It was therefore decided that a certain number of cases should be collected to evaluate 
skin disorder of Grade 3 or higher. 
The second interim analysis result of a global Phase 3 clinical study (C16010 study) revealed that 
skin disorder of Grade 3 or higher occurred in 17 cases (4.7%) in the NINLARO group in up to 6 
cycles. For similar examination in the all-case surveillance, 15 or more cases with skin disorder 
of Grade 3 or higher are required. To observe 15 or more cases with skin disorder of Grade 3 or 
higher in up to 6 cycles with a 95% probability, approximately 462 cases are required for this 
survey. Hence, the scheduled number of cases was set to be 480. 
It is estimated that, if 480 cases are collected, it will be possible to observe 48 or more cases with 
thrombocytopenia (Grade 3 or higher), 21 or more cases with severe gastrointestinal disorder 
(Grade 3 or higher), 64 or more cases with peripheral nerve disorder (3 or more cases of Grade 3 
or higher), and 44 or more cases with infections (Grade 3 or higher) in up to 6 cycles with a 95% 
probability. 
4.0 
PATIENTS TO BE SURVEYED 
All the multiple myeloma patients on whom NINLARO has been administered should be 
surveyed. 
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5.0 
DOSAGE AND ADMINISTRATION 
In combination therapy with lenalidomide and dexamethasone, the usual adult dosage for oral 
administration is 4 mg as ixazomib, in the fasting state, once a day, once a week for 3 weeks 
(Days 1, 8, and 15), with a 13-day washout period (Days 16 through 28). This 4-week cycle will 
be repeated. The dose may be reduced appropriately according to the patient's condition. When 
administering the drug, refer to the Precautions listed in the package insert. 
6.0 
SCHEDULED NUMBER OF MEDICAL INSTITUTIONS BY CLINICAL DEPARTMENT 
The survey should be conducted at all the medical institutions (including hematology department) 
in which NINLARO is used (estimated to be approximately 300 medical institutions). 
7.0 
METHOD 
7.1 
OBSERVATION PERIOD 
Period from the start of NINLARO to after 6 cycles (4 weeks per cycle) 
* Rationale for observation period 
The second interim analysis (with the median number of treatment cycles in the NINLARO 
group: 17.0) of a global Phase 3 clinical study (C16010 study) revealed that adverse events had 
occurred in up to 6 cycles in 94% of the subjects in the NINLARO group who had continued 12 
or more treatment cycles. Based on these results, it is considered that a number of subjects 
experienced some sort of adverse events in up to 6 cycles after the start of NINLARO and that, in 
relation to the events defined as important survey item, the initial onset of the event was 
generally observed in up to 6 cycles and the adverse events showed no tendency to increase in 
long-term administration of more than 6 cycles. Thus, the observation period was set to be the 
period from the start of NINLARO to after 6 cycles, considering that the safety profile of 
NINLARO should be confirmed generally in up to 6 cycles. 
7.2 
REQUEST TO AND CONTRACT WITH MEDICAL INSTITUTIONS 
Paper-based survey sheets should be used. The person in charge from Takeda Pharmaceutical 
Company Limited (hereinafter, “Takeda’s person in charge”) should request medical institutions 
to conduct the survey on the premise that a written contract should be concluded with the 
institution. It is determined that Takeda’s person in charge should preliminary obtain a written 
agreement from the investigator which ensures the following (2) has been fully understood, and 
in principle deliver NINLARO after the contract is concluded. However, in case NINLARO is 
delivered/administered out of necessity before the contract is concluded, such cases should be 
retrospectively investigated and all cases that NINLARO is going to be administered should be 
surveyed. 
(1) REQUEST FOR COOPERATION WITH THIS SURVEY 
Takeda’s person in charge should request the investigator to cooperate with this survey by 
explaining the purpose, contents, and method of this survey (all-case surveillance, etc.) as well 
as information including proper use of NINLARO to him/her, in accordance with the “Request 
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for cooperation with the Drug Use-Results Survey,” “Outline of Survey,” “Patient Registration 
Sheet (sample),” “Survey Sheet (sample),” “Precautions and Instructions for Use,” “Proper Use 
Guide,” etc. 
(2) PRELIMINARY UNDERSTANDING OF THE INVESTIGATOR 
1) The medical institution has already decided to adopt NINLARO or intends to adopt 
NINLARO. 
2) The medical institution should promptly conclude the contract for this survey. 
3) The investigator should enroll patients before prescription of NINLARO or on the day of 
the prescription in compliance with the Outline of Survey for this survey. 
4) The investigator should prepare the survey sheet for all cases administered NINLARO in 
compliance to the Outline of Survey for this survey. 
(3) CONTRACT FOR THE SURVEY 
Takeda’s person in charge should, promptly after obtaining a written agreement from the 
investigator, conclude a written contract with the medical institution. Takeda’s person in charge 
should bring the “Patient Registration Sheet” to the investigator. 
7.3 
PATIENT ENROLLMENT METHOD 
The “Central Registration Method” using FAX should be used. 
In this survey, the investigator prepares the “Patient Registration Sheet” for the patient to be 
surveyed and register the patient by sending it by FAX to the Central Registration Center (see 
Section 12.3) in principle before prescription of NINLARO or on the day of the prescription. 
7.4 
PREPARATION AND SUBMISSION OF SURVEY SHEETS 
The investigator should prepare a survey sheet for the enrolled cases requiring survey sheet 
preparation promptly after completion of the observation period of each case, and the investigator 
should sign or print his/her name on and seal the sheet to submit to Takeda’s person in charge. In 
case it cannot be confirmed that the patient has taken NINLARO, this should be included in the 
sheet. (Other items are not necessary.) 
For cases in which NINLARO was discontinued due to some reasons in the middle of the 
observation period, the investigator should prepare a survey sheet promptly after the completion 
of necessary observation, and the investigator should sign or print his/her name on and seal the 
sheet to submit to Takeda’s person in charge. However, for cases in which NINLARO was 
discontinued due to adverse events, they should be continuously observed even after the 
discontinuation as much as possible until the events are recovered/resolved or 
recovering/resolving. Then, the investigator should include the observation results in the survey 
sheet, and the investigator should sign or print the name on and seal the sheet. 
7.5 
CONFIRMATION OF ALL-CASE SURVEILLANCE 
After transition to a period where preparation and submission of survey forms is not required, the 
physician in charge of the survey should, upon confirmation that the cases for which survey 
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sheets have been submitted are all those on whom NINLARO was started during the period 
requiring preparation and submission of the survey sheet, sign or print his/her name on and seal 
the “All-Case Surveillance Confirmation Form” to submit to Takeda’s person in charge. 
8.0 
SCHEDULED PERIOD OF SURVEY 
Survey period: from the date of marketing NINLARO to the time of lifting of approval 
conditions for all-case surveillance (planned in around March 2021) 
Patient enrollment period: from the date of marketing NINLARO to the time of lifting of 
approval conditions for all-case surveillance Note) 
Note) Time to transition from the period requiring preparation and submission of the survey sheet 
to the patient enrollment only period (not requiring preparation and submission of the 
survey sheet) should be determined with consultation with the Pharmaceuticals and 
Medical Devices Agency when the number of enrolled cases is estimated to reach the 
scheduled number of cases, based on the collection status of survey sheets and on 
confirmation that the targeted information can be obtained. 
The number of enrolled cases is estimated to reach 480 in May 2018. 
 
Since the number of patients enrolled has reached the planned number of 480 patients, for 
enrolled cases who started NINLARO by September 24, 2017 are required preparation and 
submission of survey sheet.  Enrolled cases who started NINLARO from September 25, 
2017 are not required preparation and submission of survey sheet. 
 
 
Enrollment should continue until the approval conditions for all-case surveillance are lifted 
so that a system is maintained where survey sheets can be collected as necessary to obtain 
appropriate information. 
9.0 
SURVEY ITEMS 
The investigator should include the following items in the Patient Registration Sheet and Survey 
Sheet. The schedule of this survey is indicated in
 
9.1 
ITEMS TO BE INCLUDED IN THE PATIENT REGISTRATION SHEET 
1) Survey items 
Name of the medical institution, name of the physician who filled out the Patient Registration 
Sheet, prescription date of NINLARO, patient identification number, patient’s initials, gender, 
age, name of diagnosis, condition 
2) Survey period 
At the time of patient enrollment 
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9.2 
ITEMS TO BE INCLUDED IN THE SURVEY SHEET 
9.2.1 
Survey sheet cover 
Last entry date (month day, year) of the survey sheet, name of the physician who filled out 
the survey sheet 
9.2.2 
Patient characteristics 
1) Survey items 
Time of diagnosis of multiple myeloma (time of initial onset), type of multiple myeloma, 
clinical stage (ISS), IMWG diagnostic criteria, ECOG Performance Status, therapeutic 
category, virus testing, hepatic function disorder (presence/absence and details), renal 
function disorder (presence/absence and details), complications (presence/absence and 
details), medical history (presence/absence and details), height, weight, treatment of multiple 
myeloma before the start of NINLARO (presence/absence and details: pharmacotherapy, 
radiotherapy, hematopoietic stem cell transplant) 
2) Survey period 
At the start of NINLARO 
9.2.3 
Treatment 
1) Survey items 
Administration status of NINLARO/lenalidomide, and dexamethasone (date of starting the 
cycle, single dose, presence/absence of adjustment of single dose, treatment compliance 
status), confirmation of continuation/discontinuation of NINLARO, administration status of 
drugs used to prevent recurrence of infections and herpes zoster (presence/absence and name 
of the drug, duration of administration) 
2) Survey period 
Period from the start of NINLARO to after 6 cycles (or to the discontinuation of NINLARO) 
9.2.4 
Observation items 
1) Observation items 
Presence/absence of pregnancy during the observation period (for women only) 
2) Survey period 
Period from the start of NINLARO to after 6 cycles (or to the discontinuation of NINLARO) 
9.2.5 
Adverse events 
1) Survey items 
Presence/absence of adverse events (see Table 1), name of the adverse event*, date of onset, 
CTCAE Grade (worst grade and its date), seriousness and its reasons (see Table 2), treatment 
for the event (presence/absence and details), outcome assessment date, outcome, causal 
relationship with NINLARO** (see Table 3), changes in laboratory tests related to adverse 
events 
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Not related 
An adverse event in which there is no temporal relationship with the 
drug or which can be very likely caused by other factors such as 
underlying diseases, complications, concomitant drugs, and 
concomitant treatment. 
 
 
 
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2) Important survey items 
Detailed information on the following events, considered as important survey items, will be 
collected as much as possible if they occur. 
• Thrombocytopenia 
• Severe gastrointestinal disorder 
• Skin disorder 
• Peripheral nerve disorder 
• Infections 
* Rationale for important survey items 
Among the important identified risks, important potential risks, and their related events 
listed in the Risk Management Plan, the events above were determined as important 
survey items based on the following reasons: 
a) Thrombocytopenia 
The profile (incidence, severity, actions to be taken, etc.) of this event occurring in Japanese 
patients in clinical use will be confirmed because the incidence of event related to 
thrombocytopenia was higher in the ixazomib group than that of the placebo group in a 
global Phase 3 clinical study [C16010 study]. 
b) Severe gastrointestinal disorder 
The profile (incidence, severity, actions to be taken, etc.) of this event occurring in Japanese 
patients in clinical use will be confirmed because the incidence of gastrointestinal disorder 
was higher in the ixazomib group than that of the placebo group, and particularly severe 
gastrointestinal disorder was observed in many subjects in the ixazomib group in a global 
Phase 3 clinical study [C16010 study]. 
c) Skin disorder 
The profile (incidence, severity, actions to be taken, etc.) of this event occurring in Japanese 
patients in clinical use will be confirmed because the incidence of skin disorder was higher in 
the ixazomib group than that of the placebo group and severe skin disorder was observed in 
many subjects in the ixazomib group in a global Phase 3 clinical study [C16010 study]. 
d) Peripheral nerve disorder 
The profile (incidence, severity, etc.) of this event occurring in Japanese patients in clinical 
use will be confirmed because the incidence of peripheral nerve disorder was higher in the 
ixazomib group than that in the placebo group and the event more frequently led to 
withdrawal, dose-reduction, and discontinuation of the investigational drug in the global 
Phase 3 clinical study [C16010 study]. 
e) Infections 
Infections were highly frequently observed in a global Phase 3 clinical study (C16010 study). 
The incidence of herpes infections was higher in the ixazomib group than in the placebo 
group. Therefore, the incidence of this event occurring in Japanese patients in clinical use 
and the administration status of prophylactic drugs will be confirmed. 
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3) Survey period 
Period from the start of NINLARO to after 6 cycles (or to the discontinuation of NINLARO) 
10.0 ANALYSIS ITEMS AND METHOD 
10.1 ITEMS RELATED TO CASE STRUCTURE 
The number of enrolled patients, number of cases whose survey sheets were collected, number of 
cases subject to safety evaluation, number of cases excluded from evaluation, and reasons for 
exclusion should be aggregated. 
10.2 PATIENT CHARACTERISTICS 
Patient characteristics including the gender, age, duration of multiple myeloma, and 
complications should be aggregated. 
10.3 TREATMENT 
The administration status of NINLARO, lenalidomide and dexamethasone, and administration 
status of drugs used to prevent recurrence of infections or herpes zoster should be aggregated. 
10.4 ITEMS RELATED TO SAFETY 
The following items should be aggregated in cases subject to safety evaluation. Adverse events 
should be rephrased using MedDRA/J and summarized in Preferred Term (PT) and System Organ 
Class (SOC). 
10.4.1 
Incidence of adverse events 
The frequencies of adverse events which occurred during the observation period should be 
aggregated according to the type, time of onset, seriousness, causal relationship with 
NINLARO. 
10.4.2 
Factors that may affect the safety 
The frequencies of adverse reactions which occurred during the observation period should be 
aggregated according to the classification, such as patient characteristic factors, (age, 
presence/absence of renal complications, presence/absence of hepatic complications, etc.) and 
the administration status of NINLARO. 
10.5 INTERIM ANALYSIS 
In order to swiftly evaluate, analyze, and if necessary, publish the safety information obtained 
from this survey, cases on which safety evaluation can be conducted among those whose survey 
sheets were collected up to 1 year after the start of this survey will be analyzed in the same 
manner as Sections 10.1 through 10.4. 
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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 
12.0 ORGANIZATIONAL STRUCTURE 
12.1 SUPERVISOR 
Supervisor of post-marketing surveys, etc., 
Takeda Pharmaceutical Company Limited 
12.2 MEDICAL ADVISOR 
Provides advice on preparation and revision of study protocols, preparation and revision of 
clinical study reports, and the conduct of the survey with medical judgment. 
 
 
12.3 CENTRAL REGISTRATION CENTER 
 
 
13.0 CONTRACT RESEARCH ORGANIZATION 
(1) 
 
 
 
(2) 
  
 
(3) 
 
 
Contracted services: Data management services, “storage of records, etc.” and 
“conversion of adverse events, etc. into a PDF format and support 
for provision of related information” 
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14.0 OTHER NECESSARY MATTERS 
14.1 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. 
14.2 ACTIONS TO BE TAKEN IF PROBLEMS AND QUESTIONS ARISE 
If any problem is found in the safety, data should be reviewed to take actions. 
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