DRUG USE INVESTIGATION FOR HIV INFECTION PATIENTS OF MARAVIROC (REGULATORY POST MARKETING COMMITMENT PLAN).
Conditions: CCR5-tropic HIV-1 Infection
Sponsor: ViiV Healthcare

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宐室宵室容宬宵宲宦
宄孷孳孳孴孳孼孶季季季宑宒宑孰完宑宗守宕宙守宑宗完宒宑宄宏季宖宗官宇宜季宓宕宒宗宒宆宒宏季季
安宬宱室宯孯季宍官宑孱季孵孳孴學季

 
 
Drug Use-results Survey of Celsentri Tablets 150 mg – HRD Cooperative investigation – 
Protocol 
 
 
1. Objectives 
To understand the following matters and to examine whether or not a special drug use-results 
survey and/or postmarketing clinical study is needed: 
 Unknown adverse drug reactions (ADRs) 
 Occurrence of ADRs under actual conditions of use 
 Factors that are likely to affect safety, efficacy and other relevant matters 
In addition, effects on immune competence, liver function and the cardiovascular system will be 
also evaluated as priority investigation items. 
 
 
2. Planned Sample Size of the Survey and Rationale of Determination 
Based on an approval condition, the drug use-results survey of Celsentri will be conducted in all 
patients treated with this drug at survey sites to the extent possible. 
For the drug use-results survey implemented as part of the HRD cooperative investigation in 
which Celsentri is included, however, consideration will be paid by setting the upper limit of the 
number of patients to be enrolled at sites where there are many survey subjects for eliminating 
the influence of the present survey on routine medical practice at the sites and maintaining the 
quality of the survey due to this acute increase in the number of patients. When paying 
consideration, approximately 40 patients per investigator should be enrolled in the HRD 
cooperative investigation while taking account of time points for collecting case report forms 
(CRFs) and for case review by the investigator. If it is necessary of select subjects from all patients, 
consideration should be given so that there is no arbitrarily bias in efficacy or safety. 
 
 
3. Subjects 
The indication of Celsentri is as follows: 
CCR5-tropic HIV-1 infection 
The subjects of this survey will be patients who are prescribed with Celsentri (including 
retrospective patients). 
 
 
4. Planned Number of Survey Sites by Medical Department 
Institutions with which many physicians with a lot of experience in treatment are affiliated and 
which have many target patients (27 sites; Appendix 1). 
 
 
5. Methods 
A cooperative investigation (HRD cooperative investigation) by companies marketing drugs for 
the treatment of HIV infectionNote 1) will be conducted using a common CRF. The implementation 
of this survey will be outsourced to CMIC PMS Co., Ltd. (hereinafter referred to as the CRO). 
For the survey method, a central registration system will be adopted for sequentially 
understanding and controlling patients who used Celsentri. 
In this survey, patient enrollment, input of data in survey items and data verification will be carried 
out using an Electronic Data Capture (EDC) system on the Internet from April 2009. 
Some of the HRD cooperative investigation sites cannot connect to the external network so that 
the concerned sites shall lend a stand-alone computer (hereinafter referred to as the SPC), of which 
use is limited to the HRD cooperative investigation, and perform the survey. 
1 
 

 
 
5.1 Request for the Survey 
(1) Request for the survey to physicians and conclusion of a contract 
The CRO should request institutions collaborating in the survey to conduct the survey in 
writing and conclude a written contract. 
(2) Request for the survey at the institutions concluded the contract 
The CRO should fully explain physicians at institutions where the contract has been concluded, 
about the gist of the survey using the outline of the implementation of the HRD cooperative 
investigation, and given them a user’s ID and password for the HRD cooperative investigation. 
 
5.2 Patient Enrollment 
(1) For patients who have been on drugs subject to the HRD cooperative investigation at the time 
of the contract or will start to receive them during the survey period, the 
investigator/subinvestigator should enter required information (medical record number or 
identification number, patient’s initials [as necessary], gender, birth date [as necessary, age; 
e.g., age group], pregnancy status, inpatient/outpatient status, name of the drug surveyed and 
start date of treatment) on the enrollment screen of the EDC system, and send it using the 
user’s ID and password issued for each investigator/subinvestigator. The patients’ enrollment 
numbers will be issued by the EDC system. The sites that cannot connect to the external 
network should send or collect the data after inputting them in the SPC. 
Patients who have been continuously on the drugs subject to the HRD cooperative 
investigation will be automatically continued to be enrolled based on data of the previous 
CRFs. 
(2) The CRO should, as necessary, report the status of patient enrollment to the applicable 
companies using an HRD cooperative investigation control chart. 
(3) Sites having a markedly high number of patients should first understand an expected number 
of new patients and then enroll new patients in the order of the re-enrollment of new patients 
on the day of enrollment in the HRD cooperative investigation among continuing patients 
and patient verification by the sites. The ratio of the number of re-enrolled continuing 
patients and newly enrolled patients should be adjusted. Overall, approximately 40 patients 
per investigator should be enrolled. 
 
5.3 Progress Control of the Drug Use-results Survey 
(1) The CRO should be aware of the progress of the survey at the study sites in charge to 
systematically promote it using the HRD cooperative investigation control chart. 
(2) The Postmarketing Surveillance Control Manager should investigate whether or not the HRD 
cooperative investigation has smoothly progressed and, as necessary, give appropriate 
instructions to the CRO and relevant departments in the company. 
 
5.4 Data Input/Sending and Reinvestigation 
The investigator/subinvestigator should enter results up to the end of March of each year, in 
principle, between April and July and send them (Data will be collected using a USB memory 
device at sites where Internet communication is not available.). The CRO should request the 
investigator to perform a reinvestigation by gathering reinvestigations from each company. 
The CRO should print out the inputted and corrected CRFs from the EDC system. The 
investigator should check the contents and sign/seal them. These CRFs should be defined as 
the originals, and the CRO should send their copies to the applicable companies. 
 
5.5 Statement of Confirmation on All-case Surveillance 
The CRO should prepare a statement of confirmation collectively for enrolled patients by 
investigator and drug. The CRO should bring the statement of confirmation at the time of 
signing/sealing the originals of the CRFs, and the investigator should sign/seal the statement 
2 
 

 
of confirmation to ensure that the enrolled patients are all the treated patients. The CRO should 
send a copy (including fax) of the statement of confirmation signed/sealed by the investigator 
to the applicable company, and the CRO should retain the original. 
 
5.6 Collection of Safety Information 
The “HRD Cooperative investigation: Spontaneous Reporting Form for ADRs, etc.” should be 
distributed to all medical institutions where drugs for the treatment of HIV infection are used 
to collect safety information from physicians by fax. 
(1) At the time when the CRO visits the HRD cooperative investigation sites, safety information 
should be continuously collected even for patients who completed the patient enrollment 
period of the drug use-results survey using means such as the “HRD Cooperative 
investigation: Spontaneous Reporting Form for ADRs, etc.” 
(2) At institutions other than the HRD cooperative investigation sites, medical representatives 
(MRs) of each manufacturer should actively collect safety information. 
 
5.7 Handling of Patients with ADRs 
(1) When ADRs, etc. (including those for which the causal relationship is unknown) suspected to 
be caused by the drug occurred, the investigator/subinvestigator should immediately notify 
them to the CRO or complete required information in the “HRD Cooperative investigation: 
Spontaneous Reporting Form for ADRs, etc.,” which has been provided beforehand, and fax 
it to the CRO. 
(2) When learning the onset of ADRs, etc. (including those for which the causal relationship is 
unknown) associated with Celsentri from healthcare professionals, an MR should 
immediately fill out the “HRD Cooperative investigation: Spontaneous Reporting Form for 
ADRs, etc.” and directly fax it to the CRO. When receiving a Spontaneous Reporting Form, 
it should be immediately faxed to the CRO. 
(3) When an anti-HIV infection drug, for which the causal relationship cannot be ruled out, was 
concomitantly used, an MR should obtain prior consent of the investigator for reporting ADR 
information to a company related to the concerned drug. 
(4) When identifying ADR information in data sent from the investigator, the CRO should notify 
it to the applicable company. 
(5) The applicable company should assess and analyze this ADR information and, as necessary, 
instruct a detailed investigation to the CRO. The CRO should request the investigator to input 
and send the latest information using the EDC system and inform it to the applicable company 
after receiving the said information. 
 
 
6. Planned Period of the Survey 
The survey will be started in April 2009. The patient enrollment period will be until the end of 
the 8th year. 
Enrollment period: April 1, 2009 to March 31, 2017 
 
 
7. Investigation Items 
7.1 Identification Characteristics of the Investigators/Subinvestigators 
Names of the site, department and investigator/subinvestigator, date of completing the form, 
and patient enrollment number 
 
<HRD cooperative investigation: CRF> 
7.2 Patient Background Characteristics 
Medical record number, inpatient/outpatient status, patient’s initials, birth date, history of HIV 
infection treatment, race, gender, pregnancy status, infection route, underlying disease, date of 
3 
 

 
infection, past history, presence or absence of allergy, and presence or absence and details of 
complications 
 
7.3 Prescribed Anti-HIV Drugs 
Name of the drug, daily dose, duration of treatment and treatment continuation/discontinuation 
status 
 
7.4 Prescribed Concomitant Medications (including drugs for the treatment of HIV-related diseases) 
Presence or absence of prescribed concomitant medications, name of the drug, dose, duration 
of treatment, treatment continuation/discontinuation status and reason for use 
 
7.5 Concomitant Therapies 
Presence or absence of concomitant therapies, details of therapy, duration of therapy and reason 
for therapy 
 
7.6 Patient Outcome (at discontinuation of the survey) 
Date of outcome and details of outcome 
 
7.7 HIV-RNA, CD4, CDC Classification, Time-course of Body Weight and Tropism 
Date of test, number of HIV-RNA copies, CD4 count, CDC classification, body weight and 
tropism 
 
7.8 Abnormal Changes in Laboratory Values 
(i) Presence or absence of abnormal changes in laboratory values 
(ii) Date of test 
(iii) Hematology 
White blood cell count, red blood cell count, hemoglobin, hematocrit, platelet count, 
differential white blood count, partial thromboplastin time (PTT), activated partial 
thromboplastin time (APTT), fibrinogen and fibrin degradation products (FDP) 
(iv) Blood biochemistry 
Total protein, albumin, total bilirubin, aspartate aminotransferase (AST) (glutamic-
oxaloacetic transaminase, GOT), alanine aminotransferase (ALT) (glutamic pyruvic 
transaminase, GPT), lactic dehydrogenase (LDH), alkaline phosphatase (Al-P), gamma 
glutamyl transpeptidase (γ-GTP), creatine phosphokinase (CPK), blood urea nitrogen (BUN), 
creatinine, uric acid, total cholesterol, triglyceride, electrolytes, amylase, lipase, fasting blood 
glucose, C-reactive protein (CRP) and β2-microglobulin 
(v) Urinalysis 
Protein, sugar, occult blood and sediment 
(vi) Abnormal ocular findings 
 
7.9 Adverse Events (including ADRs, abnormal changes in laboratory values, new onset of 
opportunistic infection, etc.) 
Presence or absence of adverse events (AEs), date of onset, diagnosis or name of specific 
symptom, details of symptoms/course and therapeutic action, seriousness, reason for assessing 
the event as serious, date of outcome, outcome, and relationship between disease and the drug 
used 
(In the case of death) Presence or absence of autopsy, date of autopsy, autopsy findings and 
examination 
 
7.10 Priority Investigation Items 
In this survey, the occurrence of the following items will be defined as the priority investigation 
items: 
4 
 

 
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cooperative investigation. Also, when approval for partial changes in the dosage and 
administration or indication is granted during the reexamination period (excluding the case 
where a reexamination period is newly designated), whether or not the protocol needs to be 
revised should be reviewed, and the protocol should be, as necessary, revised. 
 
(2) Actions in the case where there are problems or questions 
In the cases, for example, where the onset of serious and unknown ADRs was suggested, where 
the incidence of ADRs largely increased, where any efficacy or safety issues are identified 
compared with pre-approval data, and where the onset of different ADRs was suggested, the 
conduct of a special drug use-results survey and/or postmarketing clinical study to detect or 
confirm their causes and validate estimations made from the results of examination should be 
considered. 
 
 
Note 1) Companies that developed drugs for the treatment of HIV infection (in random order); companies participating in the HRD 
cooperative investigation (as of January, 2014) 
ViiV Healthcare K.K. 
MSD K.K. 
GlaxoSmithKline K.K. 
Mitsubishi Tanabe Pharma Corporation 
Japan Tobacco Inc. 
Pfizer Japan Inc. 
Janssen Pharmaceutical K.K. 
Bristol-Myers Squibb 
 
 
 
 
 
Prepared on June 1, 2015 
 
 
 
7 
 

 
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Celsentri PMS_HRD Cooperative investigation Protocol 
 Appendix 4 
 
The procedure of communication regarding adverse drug reactions, etc. 
 
Healthcare 
facility 
 
CRO 
 
Company related to 
the suspected drug 
 
 
 
 
 
Physician 
Sending of “Communication sheet for 
spontaneous report of adverse drug 
reactions, etc. in HRD cooperative 
investigation” by fax 
CRO and EDC 
system 
 
 
PMS 
division 
or direct contact by phone, etc. 
Contacting the related 
company 
 
 
 
 
 
 
Request for input into case report 
formsNote 1) 
Contacting the related company 
 
 
Input and sending to EDC system 
 
 
 
Request for resurvey where necessary 
Request for resurvey where 
necessary 
 
 
 
Input and sending of resurvey content 
Contacting the related company 
 
 
Request for completion of detailed case 
report formNote 2) in cases of occurrence of 
adverse drug reaction 
 
 
Collection of detailed case report form 
Request for detailed investigation 
in cases of occurrence of adverse 
drug reaction where necessary 
 
 
Contacting the related company 
 
 
Note 1) EDC system for case report forms for the HRD cooperative investigation 
Note 2) Detailed case report form for adverse drug reaction, etc. in the HRD cooperative investigation