PASQol Protocol ver 3.2, March 20, 2019

PAlliative medicine Steroid intervention Quality Of Life trial team (PASQol)

Multicenter Randomized, Placebo-controlled, Double-blind Clinical Trial Assessing theEffects of Corticosteroid Administration on Fatigue and QOL in Advanced Cancer
Patients

ProtocolJune 17, 2014, ver. 1.0
January 25, 2016, ver. 2.0
December 20, 2016, ver. 3.0
December 4, 2017, ver. 3.1
March 20, 2019, ver. 3.2

Lead principal investigator: Kikuko Miyazaki PhD
Kyoto University School of Public Health,
Department of Health Informatics
Address: Yoshida Konoe-cho, Sakyo-ku
Kyoto, 606-8501
E-mail: miy@plum.ocn.ne.jp
Associate principal investigator: Takeo Nakayama MD, PhD
E-mail: nakayama.takeo.4a@kyoto-u.ac.jp

Trial period:

1/59

June 2014 to June 2019

PASQol Protocol ver 3.2, March 20, 2019

Table of Contents
0

SUMMARY

0.1

Study Design

0.2

Objectives

0.3

Study Hypothesis

0.4

Endpoints

0.5

Study Population

0.6

Target Sample Size and Trial Period

0.7

Contact List

1

BACKGROUND2OBJECTIVES

2.1

Target Disease Name

2.2

Study Hypothesis

3

STUDY POPULATION

3.1

Inclusion Criteria

3.2

Exclusion Criteria

4

PROTOCOL

4.1

Study Design

4.2

Target Sample Size and Trial Period

4.3

Selection of Potential Subjects

4.4

Informed Consent

4.5

Eligibility Confirmation

4.6

Enrollment

4.7

Blinding

4.8

Emergency Code Breaking

4.9

Baseline Survey and Study Treatment Initiation

4.10

Study Treatment

4.11

Concomitant Therapies

4.12

Study Treatment Discontinuation

4.13

Study Completion

4.14

Completion of the Overall Study

4.15

Information Subject to Reporting Requirements during Trial and Observation Periods and

Schedules
4.16

Information on the Survey Period

4.17

Information on Report Categories

5

ADVERSE EVENT ASSESSMENT AND REPORTING

5.1

Adverse Event Definition
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5.2

Adverse Event Assessment

5.3

Survey Items

5.4

Adverse Event Reporting

5.5

Expected Adverse Events

6

ENDPOINTS

6.1

Primary Endpoints

6.2

Secondary Endpoints

6.3

Exploratory Endpoints

7

STATISTICAL CONSIDERATIONS

7.1

Approach to the Analysis of the Primary Endpoint

7.2

Analysis Populations

7.3

Interim Analyses

8

DATA COLLECTION

8.1

Forms and Due Dates

8.2

Preparation for Input

8.3

Input Method

8.4

Data Transmission Method

8.5

Confirmation of and Inquiry about Information in Case Report Forms

9

ETGICS

9.1

Protection of Study Subjects

9.2

Writing and Revising Written Information/Informed Consent From

9.3

Obtaining Permissions from Study Sites for Study Conduct

9.4

Protection of Personal Information

9.5

Informed Consent

9.6

Independent Enrollment Audit Committee

10

QUALITY CONTROL

10.1

Study Monitoring

10.2

Data Check

10.3

Record Retention

10.4

Data Lock Announcement

11

STUDY PARTICIPANTS’ EXPENSES AND ACTIONS TO TAKE IN RESPONSE TO STUDY-RELATED INJURIES
11.1

Study Participants’ Expenses

11.2

Actions to Take in Response to Study-related Injuries

12

CONFLICTS OF INTEREST AND SOURCES OF STUDY FUNDING

12.1

Conflicts of Interest

12.2

Sources of Study Funding3

PASQol Protocol ver 3.2, March 20, 2019

13

PUBLICATION OF STUDY RESULTS AND ASSIGNMENT OF RIGHTS

13.1

Clinical Trial Registration

13.2

Publication of Study Results

13.3

Data Attribution and Access Rights

14

PROTOCOL REVISIONS

14.1

Revisions of This Protocol

14.2

Recording and Reporting Revisions

14.3

Reporting Revisions

15

STUDY COMPLETION AND EARLY TERMINATION

15.1

Study Completion

15.2

Early Study Termination

16

STUDY ORGANIZATIONAL STRUCTURE

16.1

Lead Principal Investigator

16.2

Associate Principal Investigator

16.3

Study Secretatiat

16.4

Steering Committee

16.5

Independent Data Monitoring Committee

16.6

Independent Enrollment Audit Committee

16.7

Protocol Author

16.8

Statistical Analysis Manager

16.9

Study Drug Manager

16.10

Allocation Manager

16.11

Data Center

17

STUDY SITES18

REFERENCES

Appendices
Package Insert (Betamethasone Tablets)
Written Information/Informed Consent FormPatient Screening Form
Enrollment Form/Survey Form and Other Reports
EORTC QLQ-C15-PAL
NRS
Medication Log
Kyoto University Graduate School of Medicine and Faculty of Medicine and Kyoto University Hospital
Medical Ethics Committee Operating Procedure 11 (Reporting of Serious Adverse Events/Safety
Information in Medical Research Involving Human Subjects)
4PASQol Protocol ver 3.2, March 20, 2019

Flow of Reporting/Responding to Serious Adverse Events
Independent Enrollment Audit Committee Bylaw
Independent Enrollment Audit Committee Inquiry Form
Manual on Obtaining Informed Consent

5PASQol Protocol ver 3.2, March 20, 2019

0 SUMMARY
0.1

Study Design
Multicenter randomized, placebo-controlled, double-blind, parallel group study
PS2/3 Terminal-Stage Patients with Advanced Cancer-Related Fatigue

Enrollment
Randomization

Corticosteroid Group

Placebo Group

Betamethasone Capsules (2 mg)
Twice Daily, Morning and Noon,
Per Oral for 1 Week (7 Days)

Placebo Capsules
Twice Daily, Morning and Noon,
Per Oral for 1 Week (7 Days)

Observations and Assessments for up to 7 Days after Enrollment(Follow-Up on Outcome Until Death)

0.2

Objectives
The objective is to evaluate the effectiveness of oral corticosteroid administration (2 mgbetamethasone, twice daily, total of 4 mg a day) in alleviating fatigue in PS2/3 terminal-stage patientswith advanced cancer-related fatigue. Secondary objectives are to evaluate the quality of life (QOL)
improvement by corticosteroid administration and to assess safety by obtaining information on theseverity and frequency of adverse events. An additional objective is to exploratorily assess therelationship between fatigue and blood test values.

0.3

Study Hypothesis
When the study treatment (1 week of corticosteroid or placebo administration) is given to PS2/3
terminal-stage patients with advanced cancer-related fatigue, the alleviation of fatigue, as indicated by
the FA (fatigue) score in EORTC QLQ-C15-PAL, in the corticosteroid group is superior to that in theplacebo group.

0.4
0.4.1

Endpoints
Primary endpoint
The FA (fatigue) score in EORTC QLQ-C15-PAL

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PASQol Protocol ver 3.2, March 20, 2019

0.4.2

Secondary endpoints(1) Efficacy endpoints
1)

Non-FA QOL scores in EORTC QLQ-C15-PAL

2)

Numeric rating scale (NRS)

3)

Survival time(2) Safety endpoint
Adverse events
0.4.3

Exploratory endpoint
Blood tests (C-reactive protein [CRP], white blood cell count, hemoglobin, platelet count, blood

glucose level)
0.5

Study Population
The study population in this trial will be PS2/3 terminal-stage patients with advanced cancer-related
fatigue. Eligible subjects may be outpatients, inpatients, or someone receiving treatment at home.

0.6

Target Sample Size and Trial Period(1) Target sample size: 210 patients (corticosteroid group, 105; placebo group, 105)
(2) Planned trial period: June 17, 2014 (after ethics committee approval) to June 16, 2019

0.7

Contact List

0.7.1

Lead principal investigator
Kikuko Miyazaki
Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501
Kyoto University School of Public Health
TEL: 090-2421-6077
E-mail: miyazaki@hi.med.kyoto-u.ac.jp

0.7.2

Secretariat
Yoshida Konoe-cho, Sakyo-ku, Kyoto 606-8501
Kyoto University School of Public Health
TEL: 075-753-9477 (department main line); FAX: 075-753-9478
E-mail: pasqol@hi.med.kyoto-u.ac.jp

0.7.3

Data center
54 Shogoin-Kawahara-cho, Sakyo-ku, Kyoto 606-8507
Department of Data Science, Institute for Advancement of Clinical and Translational Science, Kyoto

University Hospital
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PASQol Protocol ver 3.2, March 20, 2019

TEL: 075-751-4760; FAX: 075-761-2670
E-mail: pasqol@mail2.adm.kyoto-u.ac.jp

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PASQol Protocol ver 3.2, March 20, 2019

List of Abbreviations and Definition of Terms
Abbreviation

Expanded Term

Explanation

CRC
CRF

Clinical Research Coordinatorcase report form

CRP

C-reactive protein

EAPC

European Association for Palliative Care

ECOG PS

Eastern Cooperative Oncology Group
Performance Status

EDC

Electronic Data Capture

EORTC QLQC15-PAL

European Organisation for Research andTreatment of Cancer quality of life
questionnaire core 15 palliative

FA
PF
AP
QL
FAS
IC
ID

fatigue
physical functioning
appetite loss
overall quality of life
Full analysis set
Informed consent
Identification

IRB
JCOG
JMDC
MID

Institutional review board
Japan Clinical Oncology Group
Japan Medical Data Center
Minimally Important Difference

NCCN
NRS

National Comprehensive Cancer Network
numeric rating scale

PPS

Per protocol set

QOL
UMIN-CTR

Quality of Life
University Hospital Medical Information
Network Clinical Trials Registry

WHO

World Health Organization

Clinical research coordinator
Case report form
In this study, it mainly refers to apaper-based patient questionnaire
C-reactive protein, an indicator used tomeasure inflammatory responses anddestruction of body tissue
European Association for Palliative
Care
A scale by the Eastern Cooperative
Oncology Group (ECOG) used toassess the patient’s general condition
Electronic Data Capture
In this study, it mainly refers to
information input on a computer
Palliative patients’ quality of life
questionnaire compiled by theEuropean Organisation for Research
and Treatment of Cancer
QOL fatigue subscale
QOL physical functioning subscale
QOL appetite-loss subscale
QOL overall-quality-of-life subscale
Full analysis set
Informed consent
A unique number that identifies anindividual
Institutional review board
Japan Clinical Oncology Group
Japan Medical Data Center
Minimal difference that is still clinicallysignificant
A U.S. cancer network
A method for measuring intensity on
an 11-point scale from 0 to 10
A population of participants deemed to
be protocol compliant without protocol
violations
Quality of life
University Hospital Medical
Information Network Clinical Trials
Registry
World Health Organization

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PASQol Protocol ver 3.2, March 20, 2019

1 Background
Cancer has been the leading cause of death in Japan since 1981 and accounted for 29.5% of alldeaths in 2010. The number of deaths from cancer has been on a rising trend1). Given the large numberof deaths from cancer at present, even if no complete cure is available, medical interventions areneeded to alleviate as much as possible the discomfort of terminally ill patients2). In Japan, the Cancer
Control Act went into effect in April 2007, and the Basic Plan to Promote Cancer Control Programs
drawn up in the following year clearly focused on addressing three issues, including palliative care3)4).
The Basic Plan to Promote Cancer Control Programs was revised in April 2012 to further promote suchprograms, and the revised basic plan still continues to list the promotion of palliative care as one of the
key issues that should be addressed5).
The World Health Organization (WHO) defines palliative care as an approach that improves thequality of life (QOL) of patients and their families facing the problems associated with life-threatening
illness, through the prevention and relief of suffering by means of early identification and meticulous
assessment and treatment of pain and other physical, psychosocial, and spiritual issues6). There isalso a report indicating that early palliative care aimed at improving QOL resulted in prolonging
survival7). Since the goal of palliative care is to improve patients' QOL, assessing QOL allows theoutcome of palliative care to be obtained.
Fatigue, along with the perception of pain and dyspnea, is one of the discomforts affecting the QOLof terminal cancer patients. Fatigue is the most frequent physical condition in terminal cancer patientsand is reportedly experienced by 66% to 100% of patients8-11). Fatigue in cancer patients mainly
includes the fatigue associated with the cancer treatment and that stemming from the cancer itself.
The National Comprehensive Cancer Network (NCCN) defined cancer-related fatigue as “a subjective
perception of physical, mental, and cognitive weariness and/or exhaustion, relative to daily activities,
that is related to cancer with persistent pain and cancer treatment and hinders normal functioning”12).
The Research Steering Committee of the European Association for Palliative Care (EAPC) defines
fatigue in terminally ill patients as “a subjective perception of weariness, weakness, and lack ofenergy"13). While both definitions consider fatigue as a "subjective perception," there has been noconsensus on a unified definition.
Corticosteroids are often used in palliative care in Japan to treat fatigue in terminal cancer
patients14)15). However, there have been no high evidence-level studies focusing on the relationshipbetween corticosteroid administration and fatigue16). Methylphenidate, one of the therapeuticmodalities for treating cancer-related fatigue, has been reported to be slightly more effective thanplacebo, but not enough for it to be recommended as treatment for fatigue17-19). The effectiveness ofthalidomide, another therapeutic modality, in treating fatigue has been controversial, but most of thereports involve patients undergoing chemotherapy rather than terminal-stage patients20). Given thissituation, at the 2012 American Society of Clinical Oncology (ASCO) conference, the MD Anderson
Cancer Center in the United States stated that corticosteroid therapy intervention for patients with10

PASQol Protocol ver 3.2, March 20, 2019advanced cancer is effective in alleviating fatigue and reported in July 2013 that a randomized
controlled trial comparing a corticosteroid (Decadron® 8 mg/day) group and a placebo group21)22)
showed the efficacy of corticosteroid in alleviating fatigue in patients with advanced cancer. However,Decadron® 8 mg/day is a very high dose compared with the clinical doses commonly used in Japanfor palliative care, thus raising a concern about the potential of overdose in Japanese due to theirsmaller body size23).
At present, there is no established standard treatment with respect to corticosteroid administration
to alleviate fatigue in terminal-stage patients. Corticosteroids have been administered to terminal
cancer patients based on the experience of palliative care clinicians with the aim of improving apatient’s general condition, even though there is no evidence of their effectiveness14). However, there
are no reports on how fatigue is treated in most terminal cancer patients in Japan who die without
palliative care. Accumulating evidence, which can be passed on to clinical practice, showing thebenefits of corticosteroids as a treatment for fatigue in terminal-stage patients will contribute to theestablishment of a standard treatment. We believe the establishment of a standard treatment for
fatigue in the terminal stage of cancer will also allow many cancer patients, who currently die without
treatment from a palliative care specialist, to receive treatment for fatigue. Clinical research in Japanis needed on corticosteroid doses that can be used to treat fatigue in terminal cancer patients.
[The number of cancer patients in Japan who die without treatment from a palliative care specialist]
There are sporadic regional or institutional reports but no nationwide reports on the number of cancer
patients who received treatment from a palliative care specialist before their death. The applicant
performed an estimation using the insurance claim database of a health insurance union (Japan
Medical Data Center [JMDC])24) with about one million enrollments. Approximately 15% of the patients
who died of lung, stomach, colorectal, pancreatic, breast, or prostate cancer between 2005 and June2012 received treatment from a palliative care specialist before their death either as an inpatient in a
palliative care ward or through a palliative care team. The efficacy evaluation of corticosteroid
administration for treating fatigue in this study is expected to lead to the identification of an effective
treatment regimen to alleviate fatigue for the nearly 85% of cancer patients who are not expected toreceive any treatment from a palliative care specialist before their death.

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PASQol Protocol ver 3.2, March 20, 2019

2 Objectives
The primary objective is to evaluate the effectiveness of oral corticosteroid administration (2 mgbetamethasone, twice daily, total of 4 mg a day) in alleviating fatigue in PS2/3 terminal-stage patientswith advanced cancer-related fatigue. Secondary objectives are to evaluate the quality of life (QOL)
improvement by corticosteroid administration and to assess safety by obtaining information on theseverity and frequency of adverse events.
2.1

Target Disease Name
In this study, the target disease is broadly defined cancer, including leukemia, malignant lymphoma,
carcinoma, and sarcoma of epithelial, hematopoietic, or non-epithelial origin.

2.2

Study Hypothesis
When the study treatment (1 week of corticosteroid or placebo administration) is given to PS2/3
terminal-stage patients with advanced cancer-related fatigue, the alleviation of fatigue, as indicated by
the FA (fatigue) score in EORTC QLQ-C15-PAL, in the corticosteroid group is superior to that in theplacebo group.

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3 Study Population
The study population in this trial will be PS2/3 terminal-stage patients with advanced cancer-related
fatigue. Eligible subjects may be outpatients, inpatients, or someone receiving treatment at home whomeet all of the following inclusion criteria and none of the exclusion criteria. Unless otherwise specified,determinations will be made based on the medical data obtained on the eligibility confirmation date or
those obtained within 2 weeks before eligibility confirmation.
3.1

Inclusion Criteria(1) A diagnosis of stage 4 cancer, for which surgery aimed at complete recovery is impossible, and adecision has been made to prioritize palliative care over cancer treatment with the aim ofmaintaining/improving QOL(2) A determination by two medical staff members that the cancer is in the terminal stage
The two medical staff members must have a good understanding of the patient's symptoms andinclude at least one physician.
(3) Aged 20 to 89 years at the time of informed consent(4) Someone whose responses at the time of examination to any of the two questions below in
EORTC QLQ-C15-PAL on the fatigue (FA) subscale is “quite a bit” or “very much,” from among
the following response options: “not at all,” “a little,” “quite a bit,” and “very much”
1)

Have you felt weak?

2)

Were you tired?

(5) An ECOG PS score of 2 or 3 at the time of examination
Japanese translation of the ECOG Performance Status (PS) scale25)
Score
0
1
2
3
4

Definition
Able to carry out activities without any problems. Able to carry on daily living just as
before the disease without restriction.
Restricted in physically strenuous activity but ambulatory and able to carry out work of
a light or sedentary nature, e.g., light housework, office work.
Ambulatory and capable of all self-care but unable to carry out any work activities.
Up and about more than 50% of waking hours.
Capable of only limited self-care. Confined to bed or chair more than 50% of waking
hours.
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair.

(6) Able to take the investigational product (capsules) orally(7) Approval from the independent enrollment audit committee to carry out informed consent(8) A patient who has given written informed consent personally to participate in this study(9) A patient whose family has given written informed consent for the patient to participate in this
study

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PASQol Protocol ver 3.2, March 20, 2019

[Rationales](1) and (2) The criteria were established to identify suitable study participants.
(2) The definition of the term “end stage” varies and refers to a time period anywhere within 6 monthsof expected death, depending on the corresponding period specified by the respective treatment. In
this study, the term “end-stage” refers to the last 1 to 2 months before the expected death of a subject
to be treated, during which time fatigue is reported to occur frequently26) 27).
(3) The criterion was established in consideration of the legal age at which individuals can give valid
consent.
(4) through (6) The criteria were established to identify subjects eligible to participate in this study.
(7) The criterion was established in consideration of the study subjects’ circumstance of having an endstage disease.
(8) The criterion was established for ethical considerations.
(9) The criterion was established in consideration of the study subjects’ circumstance of having an endstage disease.
3.2

Exclusion Criteria(1) Use of a corticosteroid by injection or orally within 1 week before enrollment(2) Use of a synthetic corpus luteum preparation within 4 weeks before enrollment(3) Undergoing surgery within 4 weeks before enrollment(4) Undergoing radiation therapy (excluding symptom-alleviating radiation therapies) at the time ofenrollment(5) Chemotherapy within 4 weeks before enrollment or within the regimen period(6) A history of diabetes that was treated with drugs (excluding diabetes that is well controlled or notexpected to exacerbate with betamethasone administration)(7) An apparent comorbidity with infection(8) A comorbidity with peptic ulcer that was treated with drugs(9) Presence of a mental illness related to cognitive function (including delirium)(10) Someone for whom any of the contraindications listed on the package insert of Betamethasone
Tablets applies(11) Any other patients whom the attending physician deems inappropriate for inclusion as a subject inthis study[Rationales](1) and (2) The criteria were established in consideration of a potential impact on the evaluation of thestudy treatment.
(3) through (8) The criteria were established in consideration of the participants’ safety.
(9) and (10) The criteria were established to identify subjects eligible to participate in this study.
14

PASQol Protocol ver 3.2, March 20, 2019(11) The criterion was established to exclude patients whom the attending physician deems
inappropriate for inclusion as a subject in this study for reasons that could not be anticipated at theplanning stage.

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PASQol Protocol ver 3.2, March 20, 2019

4 Protocol
4.1

Study Design
A multicenter, placebo-controlled, double-blind (attending physicians and patients), randomized,
parallel-group comparative study.
The present trial is a clinical trial that compares alleviation of fatigue (systemic conditions), an
approved indication of betamethasone, between betamethasone- and placebo-treated groups of
performance status 2 or 3 (PS2/3) terminal-stage patients with advanced cancer-related fatigue. The
study treatment period for individual participants begins on the day (Day 1) after the enrollmentbaseline date (Day 0) and ends at study treatment discontinuation or completion (Day 7). During thetrial period, the randomly allocated study treatment (with steroid or placebo) will be administered to allparticipants under blinded conditions. Furthermore, in the present trial, an outcome survey on death ofindividual participants after the end of their study treatment will be conducted.
[Rationales for the choice of study design](1) The multicenter design of the present trial was chosen to 1) increase the likelihood of obtaining
generalized findings by recruiting diverse study sites, given the impacts from factors intrinsic to aparticular study site, and 2) ensure a sufficient number of enrolled patients.
(2) The placebo-controlled design was chosen for the following reasons. 1) The study intends toprovide patients appropriate palliative care regardless of whether intervention with a steroid is given
and to determine the efficacy of the steroid’s effect. Thus, to accurately assess the steroid’s effect,
placebo is needed as a comparator. The appropriate palliative care mentioned above refers toalleviation (or spiritual care in some facilities) of various distressing physical symptoms (e.g., treatment
for dyspnea, in the case of lung cancer, or for nausea, vomiting, and constipation/diarrhea, in the caseof gastrointestinal cancer) related to certain types of incipient cancer; pain, insomnia, and otherphysical symptoms associated with many end-stage cancers; and psychological and social issues. 2)
Given that a placebo has the potential to provide a certain effect (placebo effect) in terms of alleviating
fatigue, a subjective symptom, it is necessary to assess whether treatment with a steroid in theintervention group provides an added effect over and above the placebo effect. 3) We had the following
discussion with collaborating physicians involved in palliative care about whether it is ethical to use aplacebo control fatigue in PS2/3 terminal-stage patients with advanced cancer-related fatigue. Basedon empirical knowledge derived from clinical practice, unlike pain therapy and other treatments thatmust be rendered promptly, no standard therapeutic intervention has yet been established to improve
the quality of life (QOL) of fatigued patients, and the time to commence such a therapy may vary by
about a week in normal clinical practice. Unlike therapies to treat pain, nausea, and dyspnea, whichmust be rendered promptly based on a specified procedure to determine when to commence treatment
in clinical practice, a delay of about a week in giving the placebo group treatment with a steroid for
fatigue in the present trial is not considered a material deviation from current clinical practice.
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Nevertheless, for reference purposes, a placebo-controlled, double-blind clinical trial has been
conducted in Japan to confirm the effect of a drug in pain therapy28). As for fatigue therapy, an interim
report of a clinical trial on a steroid (Decadron®, 8 mg/day) conducted in advanced cancer patients by
the MD Anderson Cancer Center in the U.S. was presented at the annual meeting of the American
Society of Clinical Oncology (ASCO) held in June 2012. The report indicated that a steroid has efficacy
in the treatment of fatigue associated with cancer21), and detailed results from the study were publishedon July 29, 201322). While the duration of placebo treatment was two weeks in the U.S. study, a durationof one week was selected for the present trial based on the clinical practice experience describedabove.
(3) The double-blind design was chosen with consideration given to the following: 1) influence from theattending physician; for instance, consideration of the degree of mutual trust built between physicians
and patients; 2) an assumption that influence from the attending physician tends to be greater in PS2/3
terminal-stage patients with advanced cancer-related fatigue, the subjects of the present trial; and 3)
minimization of influence on participants’ subjective assessment, as the primary endpoint is the fatigue
subscale in QOL assessment (a subjective assessment by participants) to be recorded by theparticipants.
(4) The choice of a randomized comparative study was to minimize the influence from all biases due
to known and unknown factors when making a comparative analysis of the primary endpoint.
(5) A study treatment period of 7 days was chosen in consideration of participants who are outpatients
receiving home care.
(6) The choice of betamethasone tablets among oral steroids was made for the following reasons. 1)
A preliminary survey of collaborating hospitals and facilities that will be participating in this study
showed that except for two facilities that use Decadron®, all have been using betamethasone tablets.
2) Its small dosage form makes handling easy when preparing a capsular formulation of the study drug.
(7) The package insert for betamethasone, the study drug in the present trial, provides the following
dosage and administration: “Usually, for adults, administer orally 0.5 to 8 mg as betamethasone perday, divided into 1 to 4 doses.” Dosages appropriate for end-stage cancer patients have yet to be
determined29). Given that the lowest maximum dose of betamethasone was 4 mg according to apreliminary survey of collaborating hospitals and facilities that will be participating in this study, adosage of 4 mg/day was selected for the study drug.
4.2

Target Sample Size and Trial Period(1) Target sample size: 210 patients (corticosteroid group, 105; placebo group, 105)
(2) Trial period, planned: June 17, 2014 (after ethics committee approval) to June 16, 2019
[Rationale for the choice of sample size]
Our earlier study in palliative care patients showed that the change in the fatigue (FA) scale on the17

PASQol Protocol ver 3.2, March 20, 2019

Quality of Life Questionnaire - Core 15 Palliative (QLQ-C15-PAL) was −15.3 in the group of patients
whose answer was “better” and 0.0 in those whose answer was either “no change” or “worse.”
Assuming an intergroup difference of −15.5 for the detected change, the standard deviation for thechange was 30.2, thus giving an effective size of 0.51. To detect an intergroup difference of 0.5 SD at
a two-sided significance level of 5% and a statistical power of ≥90%, 168 patients in two groups (84patients per group) are needed. Assuming a patient dropout rate of 20% during the trial, 210 patientsin two groups (105 patients per group) are to be enrolled.
The assumption of a patient dropout rate of 20% during the trial is based on the following factors,
which are unique to terminal-stage patients.
1)

The QOL questionnaire is a survey form self-administered by patients. As cancer symptoms
progress, some patients may not be able to self-administer the questionnaire a week after study
commencement.

2)

As the survey respondents are terminal-stage cancer patients, some of them may die.

3)

Pain therapy and cancer progression may lower cognitive level.

4)Some of the patients may switch to home care during the end-stage of their lives.

5)

Some of the end-stage patients may transfer to a hospital facility near their home for the remaining
part of their lives.

[Rationale for the choice of trial period]
Given the target sample size of 210 patients and the number of study sites (24), an enrollment periodof three years was chosen, as such a duration is needed to ensure the target sample size is reached.
Although each participant is to receive the study treatment for one week, the subsequent outcome
survey is expected to last for at least three to seven weeks. Meanwhile, with no reliable way of
predicting expected survival durations available at present and a report that QOL improvements can
extend patient survival7), it is necessary to anticipate a survival period longer than that predicted atenrollment. Thus, a follow-up survey period of up to four months after enrollment (after 16 weeks) of
the last patient was chosen, with the trial to end at the same time.
4.3

Screening of Candidate Subjects(1) The investigator (attending physician) selects candidate patients based on information available inroutine medical practice.
(2) The investigator, upon determining that a patient is potentially eligible to participate in this study(3.1 and 3.2), shall record on the Patient Screening Form (Appendix) an arbitrary symbol ornumber that is linkable within the study site. No patient screening forms linkable within the site will
be submitted anywhere outside of the facility.
(3) The investigator shall communicate the information of a potentially eligible candidate on the IC
Inquiry Forma (Appendix) to the independent enrollment supervisory board (16.6) by email
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PASQol Protocol ver 3.2, March 20, 2019

(audit@hi.med.kyoto-u.ac.jp).
(4) For candidates who are not enrolled, record on the Patient Screening Form “did not meet theinclusion criteria,” “declined to participate,” or “other reason.”[Rationale for the choice of Patient Screening Form]
The Patient Screening Form was selected because it provides the information necessary to identify“did not meet the inclusion criteria,” “declined to participate,” or “other reason” in the process of
preparing a flowchart for screening patients to be included in the analysis30).
[Rationale for the choice of IC Inquiry Form]
Inquiries to the independent enrollment supervisory board require information that aids theverification of eligibility and the assessment of the justification for obtaining’ informed consent. Thus,
the form gives the investigator the discretion to freely record information. Furthermore, with regard to
the exclusion criterion, “presence of a mental illness related to cognitive function (including delirium),”the investigator is to inquire about “the patient’s overall condition (e.g., disease recognition, decisionmaking ability, relationship with the medical care team, and interest in the clinical trial).”
4.4

Informed Consent(1) Inform patients after confirming approval has been granted by the independent enrollment
supervisory board to administer informed consent.
(2) Inform patients as instructed in the Manual for Obtaining Informed Consent (Appendix), with thepatient’s right to decide whether to participate or not fully respected(3) When presenting information to a patient, pay due attention to the patient’s physical condition.
(4) The investigator (attending physician) shall use the Written Information (Appendix) to provide an
explanation about the present trial to patients who are candidates for inclusion in the study anduse the Informed Consent Form (Appendix) to obtain voluntary consent directly from the patient.
(5) Meanwhile, the investigator shall also obtain the signature of a family member of the patient tosignify that the family has also consented to the patient’s inclusion in the trial.
(6) In cases where no consent could be obtained from a patient and his or her family member, theinvestigator shall indicate this on the Patient Screening Form.

4.5

Eligibility Verification(1) The investigator (attending physician) shall verify the eligibility of participants who gave consent toparticipate in the study.
(2) Assess eligibility based on clinical data available on the day of eligibility verification or clinical dataobtained within 2 weeks before the eligibility verification.
(3) In cases where a patient is deemed ineligible, indicate this on the Patient Screening Form.
(4) In cases where a patient is potentially eligible (3.1 and 3.2), the investigator shall communicate
19

PASQol Protocol ver 3.2, March 20, 2019

this to the independent enrollment supervisory board by email promptly once the patient becomesa candidate for informed consent. (4.3 (3)).
4.6Enrollment(1) To enroll a participant, the investigator (attending physician) shall fill out a hard copy of theenrollment form with the required information, which is to be verified by two individuals: theinvestigator (attending physician) and another clinician.
(2) The investigator shall enter the eligibility criteria-related information in the data center-provided
enrollment form (electronic data capture [EDC]) on a computer and inform the secretariat throughits mailing list (PASQol@umin.ac.jp).
(3) In the present trial, for outpatients, carry out the procedures from informed consent to enrollment
on the same day and commence treatment with the study drug on the following day (Day 1).

4.6.1

Enrollment Procedure
The investigator (attending physician) shall enter on the Enrollment Form, the date of enrollment,

the name of the study site and a predetermined symbol for the study site, a serial number (participant
enrollment number) assigned within the study site, participant’s information (date of birth or age, sex,
date on which the independent enrollment supervisory board gave approval, date of informed consent,
date of treatment commencement, name of the primary cancer diagnosed, date of diagnosis, andEastern Cooperative Oncology Group Performance Status [ECOG PS]), and the result of eligibility
verification (a check list of inclusion and exclusion criteria).
(1) The investigator (attending physician) shall ask a clinician other than an investigator (attending
physician) to verify the information provided on the Enrollment Form.
(2) The investigator, after the information on the Enrollment Form has been verified, shall verify theallocation number without changing the study drug’s serial number that has been distributed inadvance to the study site and enter the number on the Enrollment Form.
(3) The investigator (attending physician) shall ask a clinician other than another investigator(attending physician) to verify the allocation number of the study drug concerned. The individual
who verifies the information shall sign and date the verification section of the Enrollment Form.
(4) The investigator (attending physician) shall enter the allocation number on the Patient Screening
Form (Appendix), which is used as a reference table for anonymized numbers within the study
site.
(5) The investigator (attending physician) shall retain the Enrollment Form and the Patient Screening
Form, which is used as a reference table for anonymized numbers.
4.6.2

Participant Enrollment Numbers
A participant enrollment number (XX-YY) comprises the following parts.
XX: the study site number
YY: a serial number assigned within a study site to a participant enrolled in the present trial
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PASQol Protocol ver 3.2, March 20, 2019

4.6.3

Random Drug Allocation(1) Randomly allocate drugs according to the allocation schedule prepared by the allocation manager(16.9 and 16.10 below).
(2) Allocate drug numbers so that the ratio of corticosteroid group to placebo group is 1:1.
(3) Allocation is to be carried out by the variable block randomization method at the pharmacy
department of the study drug manager.
(4) The allocation manager shall supervise the variable block allocation and verify the drug allocationaccording to the operating procedure for allocation (16.9 and 16.10 below).
[Rationale for the choice of variable block allocation]
The present trial is to be conducted in both outpatients receiving home care and inpatients. The wait
time during office visits should be minimized as much as possible for PS2/3 terminal-stage patientswith advanced cancer-related fatigue. Thus, we chose block allocation, which allows the study drug tobe prepared in advance. Given the need to blind the study drug in block allocation, variable block
allocation was selected.
4.7

Blinding

4.7.1

Allocation Concealment
The present trial is a placebo-controlled, double-blind, comparative study.
The allocation is carried out by the variable block randomization method based on a written

specification for creating allocation schedules prepared by the allocation manager, who keeps the
allocation schedule confidential to conceal the allocation.
4.7.2

Ensuring Blindness(1) Confirming indistinguishability between the investigational product and placebo
Before blinding the study drug, the allocation manager shall check the study drug to be allocatedto confirm that the investigational product and placebo are indistinguishable.
(2) Generating and retaining allocation numbers
The allocation manager shall generate allocation numbers based on the written specification for
creating allocation schedules and retain the numbers under seal until the declaration of data lockby the principal investigator (10.4 below) after the completion of data check following thecompletion of the trial in all patients (10.2 below).
(3) Review of blindness
The allocation manager, after the declaration of data lock, shall review the blindness of the study
drugs that have been stored in random order as opposed to the enrollment numbers and verify
whether the study drugs were allocated based on the allocation schedule (16.9 and 16.10 below).
4.8

Emergency Code Breaking
In the event a participant develops a serious adverse event during the study treatment period that is21

PASQol Protocol ver 3.2, March 20, 2019

life-threatening or requires emergency treatment and the information on whether betamethasone wasadministered is deemed necessary to make a treatment decision for the participant, the investigator(attending physician) shall follow the following procedures to have the participant’s allocation number
disclosed.
4.8.1

Procedures for Emergency Disclosure of Allocation Numbers(1) In the event the conditions described above for disclosure of allocation numbers are deemed met,
the investigator (attending physician) shall take actions according to one of the two procedures
below.
(2) Procedure 1: The investigator (attending physician) shall unseal the envelope marked “Procedurefor Emergency Code Breaking of Allocation Numbers” that has been prepared in advance by thehead of the independent data monitoring board and sealed and distributed by the secretariat, andfollow the instructions provided therein.
(3) Procedure 2: The investigator (attending physician) shall contact the secretariat by phone andfollow the procedures as instructed.
(4) When contacted by the investigator (attending physician) per Procedure 2, if the secretariat alone
is unable to take actions in response, he/she shall promptly contact the allocation manager toconfirm the study drug group and contact the investigator (attending physician) by phone or email.
4.9

Baseline Survey and Study Treatment Commencement
The investigator (attending physician) shall present information to the patient, obtain informed
consent, and carry out baseline observations and assessments immediately after completing thepatient’s enrollment. After contacting the secretariat by email, commence the study treatment on themorning of the next day (Day 1) after the baseline survey (Day 0).
In the event the study treatment cannot be commenced as a participant is found to be ineligible after
his/her enrollment or cannot participate for some other reason, discontinue the study for the participant,record the reason for doing so on the case report form (CRF), and contact the secretariat promptly byemail or phone.

4.10 Study Treatment
4.10.1

Definition of Study Treatment
The study treatment is defined as the randomly allocated treatment as described for the two groups

below.
(1) Steroid group
Administer orally a steroid (2 mg of betamethasone tablets 0.5 mg “SAWAI” twice daily in the22

PASQol Protocol ver 3.2, March 20, 2019morning and noon) for one week (until Day 7).
(2) Placebo group
Administer orally placebo capsules (twice daily in the morning and noon) for one week (until Day
7).
4.10.2Administration of Study Treatment(1) The investigator (attending physician) shall administer the study treatment prepared as allocatedstarting from the day following enrollment (Day 1).
(2) Dispense the study drug without changing the order of packaging.
(3) The study drug is provided to outpatient participants by the investigator (attending physician) andto inpatient participants by the investigator (attending physician) or a clinician instructed by theinvestigator (attending physician).
4.10.3

Study Drugs(1) In the present trial, patients in the control group will be treated with placebo. Thus, prepare
capsules by filling JP-conforming capsules with betamethasone drug product and lactose, andprepare placebo in a similar manner by filling the capsules with lactose alone.
(2) An opinion issued on January 7, 2013 by officials of the Compliance and Narcotics Division,
Pharmaceutical and Food Safety Bureau, Ministry of Health, Labour and Welfare on the
preparation of the study drug for the present trial indicated that this protocol does not violate thePharmaceutical Affairs Law31)32).
(3) A study drug manager appointed by the allocation manager shall prepare and label the study drug
according to the allocation schedule generated by the allocation manager in a formulation roomthat meets class 10,000 clean room standards.
(4) The packaging form of the study drug is as follows. Dispense a total of 14 doses (for 7 days), witheach dose wrapped in a piece of powder wrapping paper and labeled with the allocation number
on the exterior. Place the required number of packets for one participant into an aluminum zipper
bag containing a desiccant to remove moisture. Place security tape over the opening of the zipper
bag to allow identification of any bags that have been opened.
4.10.4

Investigational Product (steroid)
Capsules containing a 2-mg betamethasone tablet, a synthetic adrenocortical hormone, per capsule
Nonproprietary name: Betamethasone
Chemical name: 9-Fluoro-11β,17,21-trihydroxy-16β-methylpregna-1,4-diene-3,20-dione
See the package insert of Betamethasone Tablets (Appendix) for details. Always obtain the latest

version of the package insert to verify information.
4.10.5Control Drug (placebo)
Capsules containing lactose that are superficially indistinguishable from the investigational product23

PASQol Protocol ver 3.2, March 20, 2019

4.10.6

Method of Study Drug Administration(1) Administer orally one capsule twice daily, morning and noon.
(2) There shall be no dose increase or reduction during study treatment.
(3) In the event the treatment is interrupted (dose interruption) after study commencement, continue
to carry out the study and perform assessments as specified. The term “interruption” in thepresent trial means an interruption (dose interruption) of the study treatment for some unspecified
reason followed by treatment resumption.
(4) In the event the administration of the study drug is discontinued after study commencement,
perform assessments promptly after discontinuation of the study treatment. The term “study
treatment discontinuation” in this study means discontinuation of the study treatment followed by
no resumption of the study treatment.
(5) Survey the drug compliance status by asking the participants to mark a verification check box on
the dosing diary (Appendix) each time the participant takes a dose during the study treatment
period.
(6) Instruct the participants to always drink water before taking a capsule.
(7) In cases where there is leftover study drug after the study treatment, check the dosing diary andcollect any leftover study drug.
4.10.7

Study Drug Management(1) The study drug manager shall create a standard operating procedure to ensure quality control ismaintained in the conduct of the study and establish a standard operating procedure for study
drug management.
(2) Document distribution, storage, control, and collection of the study drug each time the study drug
is transferred or delivered/received.
(3) The study drugs shall be managed as directed in the standard operating procedure to ensure
quality control is maintained in the conduct of the study.
4.11 Concomitant Therapies
4.11.1

Administration and Documentation of Concomitant Therapies(1) During the study period, follow the provisions provided below under “Prohibited Concomitant
Therapies.”(2) Treat adverse events appropriately, at the discretion of the investigator (attending physician) at
the study site where the event occurred.
(3) Survey and document any concomitant therapies administered between eligibility verification andstudy treatment completion or discontinuation.
4.11.2

Prohibited Concomitant Therapies
During the study period, the administration for the first time of any of the medications or therapies

described below is prohibited. In cases where a prohibited concomitant therapy cannot be discontinued
24

PASQol Protocol ver 3.2, March 20, 2019or must continue, withdraw the participant concerned from the study.
(1) Oral or injectable adrenocortical hormone preparations other than the therapeutic agent used in
the study(2) Oral administration of a synthetic corpus luteum hormone preparation(3) Surgery(4) Radiation therapy (except radiation therapy to alleviate symptoms)(5) Chemotherapy[Rationales](1), (2) Such hormone preparations can affect efficacy evaluations(3) Postoperative healing of surgical wounds is affected(4), (5) Decreased white blood cell count affects susceptibility to infections
4.12 Study Treatment Discontinuation
4.12.1

Study Treatment Discontinuation and Study Discontinuation
The investigator (attending physician) shall promptly discontinue the study treatment in a participant

if any of the following apply after his/her enrollment and discontinue the study in the participant.
(1) When the investigator (attending physician) concludes that a participant is unable to continue thestudy treatment due to the occurrence of an adverse event(2) When a participant must receive a prohibited concomitant therapy(3) When a participant expresses the wish to discontinue the study treatment or to discontinue or
withdraw consent for study participation(4) When a participant is found to be ineligible after his/her enrollment(5) When the independent enrollment supervisory board requests a discontinuation(6) When a participant stops making office visits after relocation or transferring to another hospital(7) When a blood test other than those scheduled during the trial period is required(8) When a participant is deemed by the investigator (attending physician) as unable to continue thestudy due to a reason other than those described in items (1) through (7) above
4.12.2

Data Related to Study Treatment Discontinuation
Perform observations, tests, and assessments required at discontinuation as soon as possible. If 3

days’ worth of data before study treatment discontinuation are available, such data may be used as
the data at study treatment discontinuation.
Record the reason for discontinuing study treatment on the CRF.
4.13 Completion of Study
4.13.1

Study Completion and Assessments
The investigator (attending physician), after performing the study treatment in a patient for one week
25

PASQol Protocol ver 3.2, March 20, 2019

starting from the day of commencement, shall conclude the study treatment and complete the study inthe participant.
On the day of study completion (Day 7), perform the observations, tests, and assessments required
at study completion.
4.13.2

Outcome Survey after Study Completion
After study completion, conduct an outcome survey on deaths of participants.

4.14 Completion of Study in All Participants
After the study is completed in all participants, the principal investigator shall declare a data lockaccording to the procedures below and then perform unblinding.
(1) After completion of the trial in all participants, the data center shall send a notice of data-checkcompletion to the principal investigator.
(2) The principal investigator, after verifying the notice of completion, shall sign and date the data lockdeclaration (under 10.4 below).
(3) The allocation manager, after verifying the data lock declaration issued by the principal
investigator, shall disclose the allocation numbers.
(4) There is no potential for data obtained in the present trial to be used for other purposes.

26

PASQol Protocol ver 3.2, March 20, 2019

Observations, Tests, Assessments
4.15 Information Subject to Reporting Requirement during Study/Observation Period and Reporting
Schedule

Item

Time

Day
Inclusion/exclusion criteria
verification
Approval from the independent
enrollment supervisory board
Consent acquisition

At
Eligibility
Verificati
on

Enro
llme
nt
Alloc
ation

Baseline

0

0

0

1

2

3

4

5

6

Study
Treatment
Discontinuati
on orCompletion(Day 7)

○

○

○

○

○

○

○

○

○

○

○

○

○

○

During Study Treatment

Outco
me
Survey〇〇〇Patient characteristics: sex, date ofbirth or age, name of the diagnosed〇

primary cancer
Allocation (study drug) number
Body height and weight)〇〇

Study drug compliance
Administration of concomitanttherapies〇

ECOG PS〇○QOL assessment

〇

○

NRS

〇

○

○a)

○b)

Blood tests: CRP, white blood cellcount, hemoglobin, platelet count,blood glucose test dateOccurrence of adverse event
If discontinued: date of and reason○

for discontinuation
Outcome survey: date of death orverification of final outcome, reason○

for ending triala) Data obtained within the two weeks immediately prior to Day 0 may be referenced.
b) Data obtained within one week from Day 7 may be referenced.

27

PASQol Protocol ver 3.2, March 20, 2019

Information Subject to Reporting Requirement at Enrollment on Day 0 (baseline)
Have at least two individuals check all categories of information in the following enrollment reportand promptly enter the information in the EDC according to the operating procedure for EDC inputs
prepared by the data center.
(1) Participant enrollment number(2) Name of study site(3) Name of investigator(4) Date of enrollment(5) Date on which the independent enrollment supervisory board issued an approval to administer IC(6) Sex(7) Date of birth or age(8) Name of the diagnosed primary cancer(9) Date of primary cancer diagnosis(10) Inclusion criteria verification(11) In cases where the exclusion criteria verification resulted in the patient as “otherwise deemed by
the attending physician as inappropriate for inclusion in the present trial,” document the basis forsuch a determination.
(12) Verification of the status of informed consent (IC) acquisition(13) Date of IC acquisition(14) Allocation (drug) number(15) Name of the individual who reports the double-check(16) Date of the double-check4.16 Information on Survey Period(1) In the present trial, out of consideration for participants receiving outpatient palliative care while
undergoing home care, conduct the eligibility verification, enrollment, allocation, and baseline
survey on the same day (Day 0).
(2) On the day following enrollment and the baseline survey is defined as Day 1 of the study
treatment, which continues until Day 7.
(3) Out of consideration for participants receiving outpatient palliative care while undergoing homecare, the study treatment is to conclude on Day 7.
1)

If the next visit of an outpatient participant is postponed due to a holiday/weekend, givethe participant an envelope containing a QOL questionnaire and an NRS form on Day 0
and ask the participant to fill out the forms on Day 7, place the forms in the envelope, andbring them to the next outpatient visit.

2)

If the next visit of an outpatient participant is postponed due to a holiday/weekend, theinvestigator (attending physician) is to conduct the ECOG PS survey on the outpatient28

PASQol Protocol ver 3.2, March 20, 2019

visit that is closest to Day 7.
(4) Conduct an outcome survey on death of participants after discontinuation or completion of thestudy treatment.
4.17 Information on Data to be Reported
4.17.1Baseline and Day-0 Data to be Reported(1) Enrollment number(2) Name of study site(3) Name of investigator(4) Date of report(5) Date of assessment(6) Body height and weight(7) The ECOG PS assessment is to be performed by the investigator (attending physician).
(8) Concomitant therapies are defined as the therapies administered on Day 0.
(9) Assess QOL using the Japanese version of EORTC QLQ-C15-PAL by requesting participants tofill out the form.
(10) EORTC QLQ-C15-PAL was developed for cancer patients receiving palliative care, and publishedresults of a validation of its Japanese version by the principal investigator of the present trial,
among others, are available33)34). Registration with EORTC will take place before use.
Upon collecting a QOL questionnaire that has been filled out by a participant, check for any
missing information immediately.
(11) Ask participants to rate their fatigue on a numeric rating scale (NRS) of 0 to 10.
(12) The NRS has been included as a fatigue screening tool in the U.S. National Comprehensive
Cancer Network (NCCN) Fatigue Practice Guidelines 201312) and used in earlier studies on
fatigue.
The “NRS score by NCCN for rating severity of fatigue” is shown below.
NRS Score

Severity of Fatigue

0

No fatigue

1 to 3

Mild fatigue

4 to 6Moderate fatigue

7 to 10

Severe fatigue

10

The most severe fatigue imaginable(13) Do not collect blood samples for a blood test for the sole purpose of collecting data for thepresent trial.
(14) Report data from a blood test performed as part of the usual medical care within the two weeks
immediately prior to Day 0, along with the date of the test.
(15) The blood test shall include parameters subject to substantial variations as a result of the study
29

PASQol Protocol ver 3.2, March 20, 2019drug treatment, including C-reactive protein (CRP), white blood cell count, hemoglobin, platelet
count, and blood glucose.
4.17.2

Information to be Reported during Trial Period (Days 1 to 7)(1) Ask participants receiving outpatient care to record study drug compliance by making entries in a
drug compliance diary (Appendix). Participants who are inpatients may make entries in the drug
compliance diary personally or have a clinician (physician, nurse, or pharmacist) do so on theirbehalf.
(2) With regard to the administration of concomitant therapies, the investigator (attending physician)is to record any drugs prescribed other than the study drug.
(3) With regard to occurrence of adverse events, see “5. Adverse Events Assessment andReporting.”(4) An interruption of study treatment is defined as a temporary discontinuation (dose interruption)
after one or more doses of the study drug followed by resumption of study drug use. The specificperiod of and the reason for the interruption of study drug treatment shall be provided.
4.17.3

Information to be Reported at Discontinuation of Study Treatment(1) Discontinuation of study treatment is defined as no resumption of the study drug on or before Day
7 after one or more doses of the study drug.
(2) Upon discontinuing the study treatment, conduct the observations and tests required at
discontinuation as soon as possible.
(3) Ask patients to fill out the QOL questionnaire and NRS form.
(4) If 3 days’ worth of data before study treatment discontinuation are available, use such data as thedata at study treatment discontinuation.
4.17.4

Information to be Reported at Completion of Study Treatment (Day 7)(1) With regard to the administration of concomitant treatments, the investigator (attending physician)is to record any drugs prescribed other than the study drug.
(2) The investigator (attending physician) shall perform the ECOG PS assessment.
(3) Ask participants to assess QOL by filling out the Japanese version of the EORTC QLQ-C15-PAL.
Upon collecting a QOL questionnaire that has been filled out by a participant, check for any
missing information immediately.
(4) Ask participants to rate the severity of their fatigue on a scale from 0 to 10 on the NRS form forassessing the level of fatigue.
(5) Perform a blood test, in principle, on Day 7 (acceptable range Days 8 to 14). However, dependingon the patient’s condition, it is acceptable to report data from a test conducted within one weekfrom Day 7 on a day that is nearest to Day 7. The reported data are to include the date of theblood test, CRP, white blood cell count, hemoglobin, platelet count, and blood glucose.
(6) For occurrence of adverse events, see “5. Adverse Events Assessment and Reporting.”(7) Participants shall record study drug compliance in the drug compliance diary (Appendix) and
30

PASQol Protocol ver 3.2, March 20, 2019submit the diary to the investigator (attending physician) on Day 7. The investigator (attending
physician) shall check the drug compliance diary and transcribe the information into the CRF.
4.17.5

Information to be Reported from the Outcome Survey(1) Date of confirmation of death outcome or the final outcome(2) Outcome(3) Cause of death31

PASQol Protocol ver 3.2, March 20, 2019

5 Adverse Events Assessment and Reporting
5.1

Definition of Adverse Event
In the present trial, all adverse events occurring during the study treatment are subject to evaluation.
An adverse event for which a causal relationship to the study treatment cannot be ruled out is defined
as an adverse drug reaction (ADR) to the study treatment. Of the ADRs occurring in the steroid group,
those described in the package insert of Betamethasone Tablets (Appendix) are defined as known
ADRs, and those not described in the package insert or those described but inconsistent in nature or
severity are defined as unknown ADRs (unexpected ADRs)35).

5.2

Adverse Events Assessment
In the present trial, adverse events are assessed based on the Common Terminology Criteria for
Adverse Events (CTCAE) v4.0, Japanese Clinical Oncology Group (CTCAE v4.0-JCOG)36).

5.3

Information Investigated

5.3.1

In the event the investigator (attending physician) confirms the occurrence of an adverse event,he/she shall investigate the following.

(1) Name of event (in principle, the name of the diagnosis)(2) Date of occurrence(3) Seriousness(4) Grade (1, mild; 2, moderate; 3, severe or medically significant but not immediately life-threatening;
4, life-threatening; 5, death related to adverse event)(5) Disposition of study treatment (continued, interrupted, discontinued)(6) Action (action taken [if any action is taken, explain], no action taken)(7) Outcome (resolved, resolving, unchanged, worsened, death, unknown [if the investigation ends
with the outcome remaining unchanged, worsened, or unknown, provide a reason])(8) Date of outcome confirmation(9) Causal relationship to the study treatment (related, not related [basis for determining
presence/absence of a causal relationship])
5.3.2

Definition of Seriousness
A serious adverse event is defined as any untoward medical occurrence associated with the use of

the study drug that(1) results in death(2) is life-threatening(3) requires inpatient hospitalization or causes prolongation of existing hospitalization(4) results in persistent or significant disability or incapacity(5) is a congenital anomaly, or(6) other event or reaction deemed a medically significant condition
32

PASQol Protocol ver 3.2, March 20, 2019

5.3.3

Grade
Determine the grade of an adverse event according to the following criteria based on the most severe

condition during the time period the adverse event was observed.
Grade
1
2
3

Condition

Intervention

Mild; asymptomatic or presence of a mild

Clinical finding or laboratory test

symptom(s)finding only; no treatment required

Moderate; requiring

Limitation in age-appropriate

minimal/localized/noninvasive treatment

instrumental activities of daily living

Severe or medically significant but not

Requiring inpatient hospitalization or

immediately life-threatening

prolongation of existing
hospitalization; disability/incapacity;
limitation in activities of daily living

5.3.4

4

Life-threatening

5

Death related to adverse event

Requiring emergency treatment

Outcome
Outcomes are classified into any one of the following six categories: resolved, resolving, unchanged,

worsened, death, and unknown.
The day of outcome confirmation, in cases where the adverse event resolved, was resolving, or
resulted in death, is considered the day on which the outcome was actually confirmed. In cases where
the follow-up ended with the outcome of unresolved or unknown, the day of the last confirmation ofoutcome by the investigator (attending physician) is considered the day of outcome confirmation, andthe reason for ending the follow-up or why the outcome was unknown shall be described in the spacefor comments.
5.3.5

Causal Relationship to Study Treatment
The investigator at each study site shall determine whether an event is causally related to the study

treatment based on the following criteria and describe the basis for such a determination in the spacefor comments.
(1) Not causally related: in cases where no temporal relationship exists between the occurrence of an
adverse event and the study treatment or where the occurrence of the event can be explained bya medically appropriate reason other than the study treatment(2) Causally related: in cases where the above does not apply
5.4

Adverse Events Reporting
In the present trial, upon occurrence of a serious adverse event during the study treatment period,
the treatment approach for the participant concerned shall be reviewed, and, if obtaining the study drug
33

PASQol Protocol ver 3.2, March 20, 2019

information is deemed necessary, communications shall be appropriately carried out according to theprocedure established at each study site.
5.4.1

Serious Adverse Events Reporting(1) Upon occurrence of a serious adverse event, the investigator shall promptly notify the director, theinstitutional review board, and the secretariat of the hospital facility according to the Kyoto
University Graduate School of Medicine and Faculty of Medicine and Kyoto University Hospital
Medical Ethics Committee Operating Procedure 11 (Reporting of Serious Adverse Events/Safety
Information in Medical Research Involving Human Subjects)(Appendix).

(2) Complete a “Serious Adverse Event Reporting Form” on the data center’s electronic data capture(EDC) system within 72 hours.
(3) The secretariat, upon receiving a notification that a serious adverse event has occurred, shallnotify the independent data monitoring board.
(4) In cases where the serious adverse event is unexpected and associated with invasive medical
intervention/research, the principal investigator shall publicly disclose information on the course of
the event under the name of the hospital director and report to the Ministry of Health, Labour andWelfare periodically as the information becomes available using the form specified in the
notification by the Research and Development Division of the Health Policy Bureau according to
the Institutional Review Board Operating Procedure 11 for Kyoto University Graduate School of
Medicine and Faculty of Medicine/Kyoto University Hospital (Reporting of Serious Adverse
Events/Safety Information in Medical Research in Humans) (Appendix).
(5) The principal investigator shall report, as appropriate, occurrences of any adverse drug reactions,
infections, or problems due to the use of a pharmaceutical or medical device that has been
approved for marketing in accordance with the “Pharmaceuticals and Medical Devices Safety
Information Reporting System” provided in Paragraph 2 of Article 77-4-2 of the Pharmaceutical
Affairs Law.
5.4.2

Emergency Reporting(1) In the present trial, serious adverse events that meet the following description are subject to theemergency reporting requirement: any event occurring in the study treatment period that is lifethreatening, requires emergency intervention, and for which information on whether theadministration of betamethasone should be allowed is deemed necessary to review the treatment
approach for the participant concerned.
(2) Upon occurrence of an adverse event that is deemed “life-threatening and requiring emergency
intervention as well as information on whether the administration of betamethasone should beallowed in order to review the treatment approach,” the attending physician shall promptly notify
the investigator. In the event the investigator cannot be contacted, the physician shall assume theresponsibility of the investigator.
(3) If an event is deemed “life-threatening and requiring emergency intervention as well as
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PASQol Protocol ver 3.2, March 20, 2019

information on whether the administration of betamethasone should be allowed in order to review
the treatment approach,” the investigator shall report the event immediately to the director of thehospital facility.
(4) The investigator shall follow the procedures provided in 4.8 for emergency code breaking andreporting.
(5) The investigator (attending physician) shall record what transpired that led to the disclosure of thestudy drug allocation number and the disclosed information following Procedure 1 of 4.8(emergency code breaking) or Procedure 2 (contacting the secretariat) on the Emergency
Allocation Number Code Breaking Request Reporting Form, send it by email attachment or
facsimile transmittal to the secretariat within 72 hours from the day of such a request, and retain
the allocation number. The investigator shall also retain the sent file.
5.4.3

Routine Reporting
Adverse events subject to the routine reporting requirement are shown in “5.1 Definition of Adverse

Event.” If an adverse event subject to the routine reporting requirement occurs, the investigator(attending physician) shall record the required information on the CRF corresponding to the time period
during which the event occurred and the Adverse Event Reporting Form and enter the information on
the data center’s EDC by the deadlines for submitting each survey form.
In addition, wherever possible, the investigator (attending physician) shall follow up and document
the outcome of the adverse event during the trial period on the survey form.
5.5

Expected Adverse Events
See the package insert of Betamethasone Tablets (Appendix).

5.5.1

Adverse events that have been reported in association with the terminal-stage use ofcorticosteroids, particularly during long-term use, include oral candidiasis, subcutaneous
hemorrhage, moon face, mood elevation, hyperglycemia, and gastrointestinal hemorrhage.
Nevertheless, a wide variety of drugs are used in the terminal stage, making it unclear whether
the adverse events are attributable to corticosteroids or other drugs such as nonsteroidal antiinflammatory drugs (NSAIDs)37-39).

5.5.2

In a previous study of Decadron®, a 2-week randomized controlled trial with placebo, no significant
difference in frequency of adverse events was reported between the active-drug group and theplacebo group (41/62 vs. 44/58; P = .14)20).

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PASQol Protocol ver 3.2, March 20, 2019

6 Endpoints
6.1

Primary Endpoints
Fatigue (FA) score of EORTC QLQ-C15-PAL
The primary endpoint selected is the fatigue (FA) score, which represents a participant’s QOL, on
the EORTC QLQ-C15-PAL used to evaluate QOL on Day 7 after study commencement.
[Rationale for the choice of primary endpoint]
In the present trial, the subscale fatigue (FA) score as part of the assessment of patient QOL isconsidered the representative parameter of QOL and selected as the primary endpoint.
Palliative medicine is an approach aimed at improving QOL in patients and their families facing theissues related to a life-threatening disease2). PS2/3 terminal-stage patients with advanced cancerrelated fatigue who participate in the present trial share the treatment goal of QOL improvement. Thus,
the QOL in participants will be assessed, with the score serving as an endpoint for assessing theefficacy of palliative medicine. The QOL questionnaire, however, is based on a multi-dimensional scale.
The subscale fatigue (FA) has the greatest effect on QOL and is considered a representative parameter.
To reduce the load from EORTC on the patients receiving palliative care, the number of questions
has been reduced from 30 in the EORTC QLQ-C30 used routinely to assess QOL in cancer patientsto 15 in the disease-specific EORTC QLQ-C15-PAL for palliative care patients used to assess QOL in
the present trial33). Its Japanese version has been validated, with the validation results published34).
Registration with EORTC will take place before use.

6.2

Secondary Endpoints

6.2.1

Efficacy Endpoints(1) QOL-related scores other than the FA score on EORTC QLQ-C15-PAL
The efficacy of the steroid is confirmed if the EORTC QLQ-C15-PAL subscales of physicalfunctioning, emotional functioning, appetite loss, and overall QOL showed improvements on Day
7 after study commencement.
(2) NRS (numeric rating scale)
The efficacy is confirmed if the fatigue NRS on Day 7 after study commencement showed an
improvement.
(3) Survival time
Assess time to death with the day of enrollment (randomization) as the starting point. The efficacy
is confirmed if the survival time is extended.
[Rationales for the choices of secondary endpoints (efficacy endpoints)](1) To assess improvements in the EORTC QLQ-C15-PAL subscales of physical functioning,
emotional functioning, appetite loss, and overall QOL that are related to fatigue, in addition to the36

PASQol Protocol ver 3.2, March 20, 2019

fatigue subscale.
(2) To use the fatigue NRS, which is used by NCCN for screening fatigue, as one of the efficacy
endpoints in the present trial.
(3) To ascertain in this 1-week study if the corticosteroid has efficacy in extending survival time.
6.2.2

Safety Endpoint
Adverse events
See “5. Adverse Events Assessment and Reporting.”[Rationale for the choice of secondary endpoint (efficacy endpoints)]
To assess the study drug’s safety by comparing the occurrences of adverse events between thesteroid group and the placebo group.
6.3

Exploratory Endpoints
Blood test (CRP, white blood cell count, hemoglobin, platelet count, blood glucose)
To investigate changes in the results of the blood tests (CRP, white blood cell count, hemoglobin,platelet count, blood glucose) between the most recent data on or before Day 0 and the most recent
data on or after Day 7.
[Rationale for the choice of exploratory endpoint]
Several potential causes including anemia, psychologic problems, and cytokines have been
proposed for the fatigue in terminal-stage cancer patients, but the causes are yet to be elucidated.
Comparing CRP, white blood cell count, hemoglobin, platelet count, and blood glucose between theintervention group and the placebo group may provide data that indicate what the causes of fatigue
might be.

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PASQol Protocol ver 3.2, March 20, 2019

7 Statistics
7.1

Approach in Analysis of Primary Endpoint
The approach in the analysis of the primary endpoint is to be specified in the statistical analysis plan
prepared by a biostatistician before data lock.
The approach in the analysis of endpoints is as follows. The EORTC QLQ-C15-PAL fatigue (FA)subscale, the primary endpoint, will be scored from 0 to 100 in accordance with the scoring algorithm
formulated by EORTC; differences between the two groups at baseline and one week post-treatment
will be determined; and tests of differences will be carried out. The null-hypothesis is defined as “nodifference in change of QLQ-C15-PAL fatigue (FA) score between the steroid-treated group and theplacebo group.”

7.2

Analysis Sets
Analysis sets are defined below. Details on handling of cases and procedures for handling missing
and excluded cases and abnormal data are provided in the statistical analysis plan prepared before
data lock. The efficacy endpoint analyses are to be performed on the full analysis set (FAS) and, forreference purpose, on the per protocol set as well. The safety endpoint analysis is to be performed on
the safety analysis set.
(1) Full analysis set (FAS)
The population of participants consisting of all enrolled patients after excluding (1) ineligible
patients, (2) patients who were never exposed to the study drug (steroid or placebo) after
allocation, and (3) patients for whom the data required for major assessments are not available(2) Per protocol set (PPS)The population of participants consisting of those in the FAS who were deemed protocol
compliant with no protocol deviations(3) Safety analysis set
The population of participants who received at least one or more doses of the study drug (steroid
or placebo)

7.3

Interim Analysis
No interim analysis will be conducted. However, information on safety will be reported periodicallyto the independent data monitoring board for review.

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PASQol Protocol ver 3.2, March 20, 20198 Data Collection
8.1

Forms and Submission Deadlines(1) Report data for all participants for whom written informed consent was submitted.
(2) In the present trial, all data are to be collected using the EDC created by the data center.
(3) The deadline for submitting patient enrollment forms is the day of enrollment.
(4) The deadline for submitting the baseline and the end-of-study patient survey forms (CRFs) is two
weeks after the end of the study treatment.
(5) The deadline for submitting outcome reporting forms is two weeks after a participant’s death.
(6) The deadline for submitting adverse events reporting forms is two weeks after the end of thestudy treatment.
(7) The deadline for submitting serious adverse events survey forms is within 72 hours of theinvestigator becoming aware of such an event.

8.2

Data Entry Preparation(1) The investigator shall enter the relevant information in the blanks and check the corresponding
items provided in the CRF (hard copy)(2) The information entered by the investigator is to be double-checked by a clinician other than theindividual who entered the information.
(3) The clinician who double-checked the information on the CRF shall affix his/her signature and thedate in the space for signature.

8.3

Data Entry Procedure(1) The investigator shall insert the USB flash drive provided by the data center into a computer.
(2) Enter the ID and password provided.
(3) Enter the information on a hard copy of the CRF prepared in advance as instructed in the data
entry operating procedure prepared by the data center.

8.4

Data Transmission Procedure(1) The investigator (attending physician), after entering data into the EDC, shall save, recheck, andthen transmit the data to the data center.
(2) The investigator shall retain the original copy of the CRF for a period of five years after study
completion.

8.5

Verification of and Inquiries about Information in CRFs
The data center may question the investigator (attending physician) regarding any ambiguities in thereport forms.
The secretariat shall inquire about cases for which no outcome survey form has been submitted four39

PASQol Protocol ver 3.2, March 20, 2019

months after all enrollments have been completed in the study. The investigator shall enter informationin the EDC as instructed by the data center.
The term “data lock” refers to the finalization of data after the information in the case reports for allparticipants has been verified.

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PASQol Protocol ver 3.2, March 20, 2019

9 Ethics
9.1

Protection of Study Participants

9.1.1

Compliance(1) The conduct of the present trial is in compliance with the World Medical Association Declaration of
Helsinki41)42) and the Ethical Guidelines for Medical and Health Research Involving Human
Subjects issued by the Ministry of Health, Labour and Welfare, and the Ministry of Education43).
(2) Given that participants in the present trial are PS2/3 terminal-stage patients with advanced
cancer-related fatigue, in addition to providing routine palliative care from the time when they
become a candidate for enrollment until the study is completed the investigator shall also afford
these patients special attention.
9.1.2

Relationship to the Pharmaceutical Affairs Law
The present trial is considered to be consistent with the Pharmaceutical Affairs Law based on the

explanation given below.
[Basis for claiming consistency with the Pharmaceutical Affairs Law]
The Compliance and Narcotics Division of the Pharmaceutical and Food Safety Bureau of the
Ministry of Health, Labour and Welfare was requested to review a draft protocol of the present trial(office communication dated December 14, 2012). We received an email reply that there are no issues
with the conduct of the present trial as the review found the study does not violate the Pharmaceutical
Affairs Law, which clinical trials must comply with, because the study is a clinician (investigator)initiated clinical study that does not involve any pharmaceutical manufacturer (last officecommunication dated January 7, 2013).

9.2

Preparation and Revision of Written Information and Consent Form
The Written Information (Appendix) is a document written by the investigator (attending physician)or a staff member appointed by the investigator in easy-to-understand language and given to patients.
The document contains information about the clinical trial, including background information,
significance, objectives, and methodology. It is used when providing explanatory information about thetrial to patients and their families.
The Consent Form (Appendix) is a document on which patients and their families express their
willingness to participate in and cooperate with the present trial.

[Definition of the term “family”]
The definition of the term “family,” given the diversity in today’s society, is not limited to the so-called blood
relationship as defined by laws. The following adopted by WHO in 1990 applies: The term family refers to41

PASQol Protocol ver 3.2, March 20, 2019individuals related by blood to the patient or other individuals who play an important key role for the patient.”
9.2.1

Preparation and Revision
The Written Information and Consent Form is to be prepared by the principal investigator after

consultation with the investigators (attending physicians) who will be providing information to patients,
and to be used after approvals from the institutional review board (IRB) of Kyoto University and the
IRB at each study site. Revisions shall be proposed for review by the steering committee, theindependent enrollment supervisory board, or the independent data monitoring board according to theprocedures established by the IRB of Kyoto University and the IRB at each study site.
9.2.2

Written Information and Consent Form
The Written Information shall include the following information: study objectives; study methodology

including the information that it is a placebo-controlled, randomized, double-blind study; expected
benefits and disadvantages of the drug and treatment method; other therapies available; that the study
results will be helpful to patients in the future; that refusal to take part will involve no disadvantages tothe patient; that the patient may request withdrawal from the study at any time after submitting his/herConsent Form; that the patient’s privacy will be protected when the information obtained in the study
is published; costs and payment; contact information for inquiries about the study; and the name of theindividual who provided the information.
The Consent Form, to be prepared in duplicate, shall include the contents of the information
presented, the fact that consent was given voluntarily by the patient and his/her family, and a space
for the patient and his/her family to sign and date the form.
9.3

Obtaining Permission at Study Sites to Conduct the Study(1) First, the conduct of the study is subject to approval by the IRB of Kyoto University, which theprincipal investigator is affiliated with.
(2) Thereafter, it is subject to approval by the IRB at each study site based on the approved protocol
and the documents submitted to each study site as required by the rules and regulations set forthat the facility.
(3) Annual renewals of the IRB’s approval for the study shall follow the rules and regulations set forthat each study site.

9.4

Protection of Personal Information
Points to consider regarding the participants’ personal information are as follows.
(1) Names of participants at study sites shall be anonymized in a linkable fashion within the study
site.
(2) In the anonymization process, assign the letter designated by the secretariat for each facility and42

PASQol Protocol ver 3.2, March 20, 2019a number in the order of enrollment to each participant.
(3) Within a study site, the investigator shall create a list showing the anonymized names ofparticipants and corresponding patient IDs and keep the list in a locked location under strict
safeguard.
(4) The data center shall strictly safeguard the transmitted data in a room that is locked at all times.
9.5

Informed Consent(1) The investigator (attending physician) shall provide the Written Information that has received
approval from the institutional review board (IRB) at his/her study site and give a comprehensive
oral explanation to a patient and his/her family before his/her participation in the study.
(2) The Written Information shall include the following information: 1) study objectives; 2) information
about the drug; 3) information about the treatment method; 4) expected benefits anddisadvantages; 5) benefits and disadvantages to the patient (you) personally; 6) whether any
other therapies are available and information on such therapies; 7) information on participating inthe study; 8) the fact that privacy will be protected; and 9) costs and payment as well as
information on making inquiries regarding the study.
(3) After providing the explanatory information, confirm that the patient and his/her family have agood understanding about the study, request participation in the study, and obtain voluntary
written consent using the Consent Form (Appendix).
(4) The Consent Form shall include the following information: 1) study objectives; 2) information
about the drug; 3) information about the treatment method; 4) expected benefits anddisadvantages; 5) benefits and disadvantages to the patient (you) personally; 6) whether any
other therapies are available and information on such therapies; 7) information on participating inthe study; 8) the fact that privacy will be protected; and 9) costs and payment as well as
information on making inquiries regarding the study.
(5) Participation in the study is allowed only if both the patient and his/her family gave consent.
(6) Upon consent to participate in the study, the patient and his/her family shall sign and date theConsent Form. In addition, the investigator (attending physician) who provided the explanatory
information and the clinical research coordinator (CRC), among others, who provided
supplementary information, if any, shall each sign and date the form at the time such information
was given.
(7) The Consent Form shall be prepared in duplicate, with one copy retained by the patient personallywhile the study site shall strictly safeguard a second copy.

9.6

Independent Enrollment Supervisory Board(1) Establish an independent enrollment supervisory board to confirm whether consent by
participants was voluntary from the administration of informed consent to enrollment and43

PASQol Protocol ver 3.2, March 20, 2019

throughout the trial period. (See 16.6 below)(2) The independent enrollment supervisory board shall respond to inquiries from patients during thetrial period, and its contact information shall be provided in the written information about the study.

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PASQol Protocol ver 3.2, March 20, 201910 Quality Control
10.1 Study Monitoring
Study monitoring is carried out to confirm whether the present trial is conducted safely and inaccordance with the protocol and whether the data collected are accurate.
Confirm protocol compliance through central monitoring based on the patient enrollment forms,
CRFs, outcome report forms, among other records, collected by the data center.
10.2 Data Check
10.2.1The data center shall check the following data.

(1) The data center shall install a logical check function in advance in the EDC.
(2) Confirm the eligibility and theoretical consistency of the main data.
10.3 Record Retention
The investigator shall retain records related to consent by participants, documents related to patient
screening forms, basic data (e.g., laboratory data) used to generate reports, written approvals from the
IRB, and archival records generated at his/her medical institution.
Such records shall be retained until at least 10 years have elapsed since publication of the study
results.
Such records shall be disposed of by a method that safeguards confidentiality.
10.4 Data Lock Declaration
The term “data lock declaration” refers to a declaration by the principal investigator, after receiving
a communication from the data center of data check completion, that all data in the present trial havebeen locked; the declaration shall include the date of data lock. (4.14)

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PASQol Protocol ver 3.2, March 20, 201911 Support for Costs and Study-related Injuries to Study Participants
11.1 Costs to Study Participants
The medical care provided in the present trial, as in normal practice, is to be covered by theparticipant’s health insurance plan and co-payments.
In the present trial, no insurance claims will be filed for reimbursement of the cost of the study drug
used in the study period; instead the cost will be covered by the budget for the study.
There will be no monetary compensation provided to participants for participation and cooperatingin the present trial.
11.2 Support in the Event of Study-related Injuries
Treatments for any injury to health attributable to the study will be provided using the participant’s
health insurance plan just as in routine medical care.
Four insurance companies were asked to provide quotes for clinical study insurance coverage, but
all four companies “declined” to provide a quote. Thus, there will be no subscription for insurance
coverage. Given that the study drug is an approved drug, any study-related injuries to the participants
and any necessary compensation arising from a causal relationship to the study treatment will becovered by the Adverse Drug Reaction Relief System40) of the Pharmaceuticals and Medical Devices
Agency.

46

PASQol Protocol ver 3.2, March 20, 201912 Conflict of Interest and Research Funding Sources
12.1 Conflict of Interest
The conflict of interest will be properly reviewed and managed by the “Kyoto University Conflict ofInterest Review Committee” in accordance with the “Kyoto University Conflict of Interest Policy” and“Kyoto University Regulations for Conflict of Interest Management.”
12.2 Research Funding Sources
The present trial will be funded by a scientific research grant, Basic Research (B) “Research with a
New Perspective on Palliative Care: Clinical Practice Guidelines and Patients’ Perception of
Value/QOL Challenges,” and “Standardization of treatment for advanced-cancer fatigue,” department
administrative budgets, and donations.

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PASQol Protocol ver 3.2, March 20, 201913 Publication of Research Results and Assignment of Rights
13.1 Clinical Trial Registry
The present trial will be registered with UMIN-CTR (http://www.umin.ac.jp/ctr/index-j.htm), where
information will be publicly disclosed. The principal investigator shall complete the task of clinical trial
registration before the first participant is enrolled.
13.2 Publication of Research Results
In accordance with the authorship qualification requirements46) provided in the Uniform
Requirements for Manuscripts Submitted to Biomedical Journals by the International Committee ofMedical Journal Editors, the principal investigator and the person responsible for writing the protocol
shall determine the authorship of papers and presentations at academic conference.
A group of authors appointed by the principal investigator and the person responsible for writing theprotocol shall write the manuscripts. Individuals who are not in the group of authors but meet theauthorship qualification requirements46) will be credited as an author by group name, with a note
indicating that group members meet the authorship qualification. Names of individuals in such a groupwill be mentioned in an acknowledgement.
Individuals who publish the trial results shall seek a review and approval by the principal investigator,
the person responsible for writing the protocol, and the steering committee before doing so.
13.3 Assignment of Data and Access Rights
Data collected in the present trial shall be assigned to the principal investigator and the person
responsible for writing the protocol. The principal investigator, the person responsible for writing theprotocol, the steering committee, the data center, and the statistical analysis manager in the present
trial may access the collected data for the purpose of conducting the present trial.

48

PASQol Protocol ver 3.2, March 20, 201914 Protocol Revision
14.1 Revision of This Protocol
Revisions shall be carried out by the person responsible for writing the protocol, and applications forchange shall be filed in accordance with the procedure set forth by the IRB at each site.
14.2 Record Keeping and Reporting of Revisions
The principal investigator shall record the history of revisions in writing and report to the investigators.
14.3 Reporting Revisions
The investigator shall report revisions to the person responsible at his/her medical institution andproceed with the process of revisions. For minor changes, follow the rules and regulations set forth byeach medical institution.
If a proposed revision will affect the patient enrollment form or the CRF and EDC forms, the principal
investigator shall ask the data center to revise the patient enrollment form or the CRF and EDC forms.

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15 Study Completion and Premature Termination
15.1 Study Completion
This study is complete when the deaths of all enrolled participants have been confirmed or when 16
weeks (four months) have elapsed since the last enrollment, whichever is earlier. Upon study
completion, the investigator shall check the quantity of the leftover study drug that had been distributed
and its allocation number and return the leftover study drug promptly to the study drug manager.
15.2 Premature Termination of Study
The term “premature termination of study” refers to termination of the study earlier than scheduled
due to any of the reasons below. Under the following circumstances, the independent data monitoringboard shall advise the principal investigator to terminate the study prematurely.
(1) When the study treatment is deemed to have safety issues based on any report of serious
adverse events or any safety information including information available outside of the study(2) When completion of the study is deemed difficult due to delays in patient enrollment or frequent
protocol deviations, among other reasons

50

PASQol Protocol ver 3.2, March 20, 201916 Organizational Structure of the Trial
The present trial is an investigator-initiated clinical trial conducted by the principal investigator andthe steering committee.
The organizational structure of the trial is as described below.
16.1 Principal Investigator
The principal investigator shall oversee the trial.
Kikuko Miyazaki
Kyoto University School of Public Health, Department of Health Informatics
Yoshidakonoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
Phone: 090-2421-6077
E-mail: miy@plum.ocn.ne.jp
16.2 Vice Principal Investigator
The vice principal investigator shall play the role of assisting the principal investigator and be
appointed by the principal investigator as necessary.
Takeo Nakayama
Kyoto University School of Public Health, Department of Health Informatics
Yoshidakonoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
Phone: 080-1432-5322、075-753-9477
FAX: 075-753-9478
E-mail: nakayama.takeo.4a@kyoto-u.ac.jp
16.3 Trial Secretariat
The trial secretariat shall be responsible for clerical work related to the operation and managementof the present trial.
(1) Responsible for clerical work related to the operation and management of the present trial(2) To liaise with relevant departments and study sites(3) To send documents to relevant parties as requested by the principal investigator or the steeringcommittee(4) To sort and retain documents related to the present trial(5) To make preparation for and manage the convening of meetings
Secretary Office
Kyoto University School of Public Health, Department of Health Informatics
Yoshidakonoe-cho, Sakyo-ku, Kyoto, 606-8501, Japan
Phone: 075-753-9477
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PASQol Protocol ver 3.2, March 20, 2019

FAX: 075-753-9478
E-mail: pasqol@hi.med.kyoto-u.ac.jp
16.4 Steering Committee(1) The steering committee shall convene upon the call of the principal investigator.
(2) The steering committee shall support the principal investigator to oversee the trial and, upon her
request, shall hold consultations over the planning, implementation, and operation of the trial,
interpretation of results, coordination with publications, and ascertaining issues related to the
conduct of the trial and countermeasures.
(3) The principal investigator shall take and maintain minutes of the steering committee meetings.

Masayuki Ikenaga

Yodogawa Christian Hospital

Kenji Ueshima

Kyoto University Hospital, Patient Support Center

Hiroi Kasai

Kyoto University Hospital, Institute for Advancement of Clinicaland Translational Science

Takashi Kawamura

Kyoto University Health Service

Tosiya Sato

Kyoto University School of Public HealthYoshimi Suzukamo

Tohoku University Graduate School of Medicine

Takahiro Horimatsu

Kyoto University School of Medicine

16.5 Independent Data Monitoring Board(1) The independent data monitoring board shall assess the progress and safety of the present trial atappropriate intervals and advise the principal investigator whether to continue the trial, modify the
protocol, or discontinue the trial, according to the provisions of the independent data monitoringboard.
(2) Upon receiving a report from the secretariat on the occurrence of a serious adverse event, theboard shall determine the relationship of the event to the study treatment and examine
countermeasures.
(3) The board shall make a decision on and respond to the secretariat’s request for emergency code
breaking.
(4) The principal investigator shall take and maintain minutes of the independent data monitoringboard meetings.

Shinya Saito

Okayama University Graduate School of Health Sciences

Fumihiko Wakao

National Cancer Center, Center for Cancer Control andInformation Service

Mariko Naito

Hiroshima University School of Dentistry52

PASQol Protocol ver 3.2, March 20, 201916.6 Independent Enrollment Supervisory Board(1) The independent enrollment supervisory board shall verify on an ongoing basis the proper
administration of informed consent (see 4.3), the eligibility of enrolled participants, and theparticipation in the trial by participants during the trial period, according to the provisions of the
independent enrollment supervisory board.
(2) The chairperson of the independent enrollment supervisory board shall elect independent
enrollment supervisory board members; however, the opinions of cancer patients should bereflected, and the board members shall include at least one individual who has had cancer.
(3) The chairperson of the independent enrollment supervisory board shall take and maintain minutesof the board meetings.

Shigemi Matsumoto

Kyoto University Graduate School of Medicine

Keiko Sato

Kyoto University Hospital, Patient Safety Unit

Ikuko Yamaguti

Non-Profit Organization, COML

16.7 Person Responsible for Writing the Protocol
This person shall be responsible for writing and revising Protocol v1.0.

Kikuko Miyazaki

Kyoto University School of Public Health16.8 Statistical Analysis Manager
As a statistician, the statistical analysis manager shall be responsible for overseeing statistics in thepresent trial, creating a statistical analysis plan, and performing data analyses.

Tosiya Sato

Kyoto University School of Public HealthYoshimi Suzukamo

Tohoku University School of Medicine

16.9 Study Drug Manager
The study drug manager shall create an operating procedure for preparation of the study drug andan operating procedure for delivery and acceptance of the study drug, and control the preparation of
the study drug (betamethasone and placebo).
Shuichi Nawata

Showa University Northern Yokohama Hospital53

PASQol Protocol ver 3.2, March 20, 201916.10 Allocation Manager
The allocation manager shall create specifications for preparing allocation schedules, generate an
allocation schedule based on the specifications, and keep it under seal until the data lock declaration.
Furthermore, the allocation manager shall also create an operating procedure for allocation and verify
whether the study drug was properly allocated based on the operating procedure. In addition, theallocation manager shall review the blinding after the data lock declaration.

Takashi Kawamura

Kyoto University Health Service

Keiichi Matsuzaki

Kyoto University Health Service

16.11 Data Center
Kyoto University Hospital, Institute for Advancement of Clinical and Translational Science54, Shogoin Kawahara-cho, Sakyo-ku, Kyoto, 606-8507, Japan
Phone: 075-751-4760
Fax: 075-761E-mail: pasqol@mail2.adm.kyoto-u.ac.jp
16.11.1 EDC System(1) The data center shall construct an EDC system for data collection.
(2) The data center shall create an EDC manual.
(3) The data center shall be responsible for the maintenance of the EDC.
16.11.2 Enrollment Reception(1) The data center, upon receiving a patient enrollment form transmitted by the investigator(attending physician), shall verify eligibility criteria.
(2) The center shall communicate the enrollment status to the secretariat twice monthly.
16.11.3 Data Management
The data center shall compile data, process the compiled data, and generate a dataset for statisticalanalysis.
(1) The data center shall compile only clinical information that has been anonymized using
identification codes.
(2) It shall check for inconsistencies in the eligibility of enrolled patients and perform the operation ofenrollment.
(3) It shall check the eligibility of the data collected.
(4) It shall properly retain the anonymized data and keep the anonymized clinical information on the
CRFs in the form of electronic data strictly safeguarded in a server.
(5) It shall generate a dataset for statistical analysis.

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17 Study Sites
Study Site

Investigator

Yodogawa Christian Hospital

Masayuki Ikenaga

Yokohama University City Medical Center

Mari Saito

Kyoto University Hospital

Taro Funakoshi

Yokohama Municipal Citizen’s Hospital

Hirotsugu Kunikane

Toho University Ohashi Medical Center

Yoichi Nakamura

Kumamoto University HospitalAtushi Yoshitake

Japan Baptist Hospital

Tetsuya Yamagiwa

Tokai Central Hospital

Kunihiro Kawabata

Kyoto Min-iren Chuo Hospital

Akira Nozaki

Tokyo Medical and Dental University Medical Hospital

Satoshi Miyake

Suzuki Clinic of Internal Medicine

Hiroshi Suzuki

National Hospital Organization Kinki Chuo Chest Center

Akihiro Tokoro

Okayama University Hospital

Naruto Taira

Kyoto City HospitalToshihiko Kirishima

Kyoto Okamoto Memorial Hospital

Yoshihiro Shimizu

Mitsubishi Kyoto Hospital

Akira Yoshioka

National Hospital Organization Kyoto Medical Center

Akira Nozaki

Kishiwada City Hospital

Masahiro Kawashima

Momotaro Home Visit Clinic

Eisaku Komori

Kitano Hospital

Yuko Katayama

Kaedenokaze Home Visit Clinic

Hiroshi Miyaki

Kansai Electric Power Hospital

Tooru Kajiyama

Watanabe Home Visit Clinic

Tsuyoshi Watanabe

55

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