Clinical trial NCT03280264
Conditions: Parathyroid Carcinoma Primary Hyperparathyroidism
Sponsor: Kyowa Kirin Co., Ltd.
Start date: 2017-08-30; Completion date: 2019-04-09
Enrollment: 18 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
To evaluate the efficacy of KHK7580 orally administered up to 24 weeks for hypercalcemia in patient with parathyroid carcinoma or primary hyperparathyroidism who are unable to undergo parathyroidectomy or relapse after parathyroidectomy.

Detailed description:

Arms: arm 1: oral administration
Interventions: intervention 1: KHK7580
Intervention descriptions: intervention 1: oral administration

Protocol documents:
Prot_SAP_000.pdf: 
Phase 3 Clinical Study of KHK7580 
(An Intra-Subject Dose-Adjustment Study of 
KHK7580 for the Treatment of Hypercalcemia in 
Patients with Parathyroid Carcinoma or Primary 
Hyperparathyroidism Who Are Unable to 
Undergo Parathyroidectomy or Relapse After 
Parathyroidectomy) 
Protocol 
Sponsor: Kyowa Hakko Kirin Co., Ltd. 
Protocol No.: 7580-101 
Version: 
Created on:  July 30, 2018


Protocol No.: 7580-101 
  
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Handling of this Protocol 
The information in this protocol is owned by the sponsor, Kyowa Hakko Kirin Co., Ltd., and is provided 
only to those directly involved in the study, such as the investigator and subinvestigator (including clinical 
study collaborators and other staff), the head of the study site, the study drug administrator, the study 
administration office, and the IRB. 
Therefore, the information in this protocol should not be disclosed or leaked to third parties who are not 
involved in this study. 
The information in this protocol cannot be copied, cited, or published without the permission of Kyowa 
Hakko Kirin Co., Ltd. 


Protocol No.: 7580-101 
  
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List of Abbreviations and Definitions of Terms 
List of abbreviations 
Abbreviation 
Unabbreviated term 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
PHPT 
Primary hyperparathyroidism 
PTH 
Parathyroid hormone 
PTx 
Parathyroidectomy 
SHPT 
Secondary hyperparathyroidism 
List of definitions of terms 
Term 
Definition and explanation of term 
Study AMG 073 
20000204 
A Phase 2 Clinical Study of Cinacalcet Hydrochloride at Doses of 30 to 90 mg/day in 
Patients with Parathyroid Carcinoma or Refractory PHPT 
AUC 
Area under the plasma drug concentration-time curve 
AUC0-t 
Area under the plasma drug concentration-time curve up to t hours after administration 
AUC0-∞ 
Area under the plasma drug concentration-time curve up to infinity 
Cmax 
Maximum plasma drug concentration 
CYP 
Cytochrome P450 
EDTA-2K 
Dipotassium ethylenediaminetetraacetate 
EQ-5D 
EuroQol 5 Dimension 
EQ-5D-5L 
5-level EQ-5D version 
F 
Bioavailability 
FAS 
Full analysis set 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use (ICH) 
IRB 
Institutional review board 
Study KRN1493-101 
A Phase 3 Clinical Study of Cinacalcet Hydrochloride for the Treatment of 
Hypercalcemia in Patients with Parathyroid Carcinoma or PHPT Who Are Unable to 
Undergo PTx or Relapse After PTx 
LC/MS/MS 
Liquid chromatography / tandem mass spectrometry 
M1 
KHK7580 metabolite: Taurine conjugate of KHK7580 
M2 
KHK7580 metabolite: Glycine conjugate of KHK7580 
MedDRA/J 
Medical Dictionary for Regulatory Activities, Japanese version 
mRNA 
Messenger RNA 
PT 
Preferred terms in MedDRA/J 
QOL 
Quality of life 
QT 
Time from the start of the Q wave to the end of the T wave on the electrocardiogram 
QTc 
QT interval corrected for heart rate 
RNA 
Ribonucleic acid 
SOC 
System organ class in MedDRA/J 
t1/2 
Plasma elimination half-life 
tmax 
Time to peak plasma drug concentration 
Pharmaceuticals and 
Medical Devices Act 
Act on Securing Quality, Efficacy and Safety of Products Including Pharmaceuticals 
and Medical Devices 
Study drug 
KHK7580 
Adverse drug reaction 
An adverse event whose causal relationship to the study drug has been judged to be 
“related” or “possibly related.” 


Protocol No.: 7580-101 
  
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List of items investigated (hematology, blood biochemistry, vital signs, and electrocardiogram) 
Item investigated 
Abbreviation 
Term used in case report forms 
Red blood cell count 
RBC 
Erythrocytes 
White blood cell count 
WBC 
Leukocytes 
Hematocrit level 
Ht level 
Hematocrit 
Hemoglobin concentration 
Hb concentration 
Hemoglobin 
Platelet count 
PLT 
Platelets 
Basophil 
Baso 
Basophils/Leukocytes 
Eosinophil 
Eosino 
Eosinophils/Leukocytes 
Neutrophil 
Neutro 
Neutrophils/Leukocytes 
Monocyte 
Mono 
Monocytes/Leukocytes 
Lymphocyte 
Lymph 
Lymphocytes/Leukocytes 
Gamma-glutamyltransferase 
γ-GTP 
Gamma Glutamyl Transferase 
Aspartate aminotransferase 
AST 
Aspartate Aminotransferase 
Alanine aminotransferase 
ALT 
Alanine Aminotransferase 
Alkaline phosphatase 
ALP 
Alkaline Phosphatase 
Albumin 
Alb 
Albumin 
Potassium 
K 
Potassium 
Calcium 
Ca 
Calcium 
Chloride 
Cl 
Chloride 
Creatinine 
Cr 
Creatinine 
Creatine kinase 
CK 
Creatine Kinase 
Corrected serum calcium 
Corrected serum Ca 
Calcium Corrected 
Blood urea nitrogen 
BUN 
Blood Urea Nitrogen 
Total cholesterol 
T-Cho 
Cholesterol 
Total bilirubin 
T-Bil 
Bilirubin 
Total protein 
TP 
Protein 
Triglycerides 
TG 
Triglycerides 
Sodium 
Na 
Sodium 
Lactate dehydrogenase 
LDH 
Lactate Dehydrogenase 
Uric acid 
UA 
Urate 
Magnesium 
Mg 
Magnesium 
Phosphorus 
P 
Phosphate 
intact PTH 
Intact PTH 
Parathyroid Hormone, Intact 
whole PTH 
Whole PTH 
Parathyroid Hormone, Whole 
Urine specific gravity 
− 
Specific Gravity 
Urine pH 
− 
pH 
Urinary glucose 
− 
Glucose 
Urinary protein 
− 
Protein 
Urinary urobilinogen 
− 
Urobilinogen 
Occult blood 
− 
Occult Blood 
Pregnancy test 
− 
− 
Height 
− 
Height 
Body weight 
− 
Weight 
Diastolic blood pressure 
− 
Diastolic Blood Pressure 
Systolic blood pressure 
− 
Systolic Blood Pressure 
Body temperature 
− 
Temperature 
Pulse rate 
− 
Pulse Rate 
Basic waveform 
− 
− 


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Time from the start of the Q wave to the end 
of the T wave on the electrocardiogram 
QT interval 
QT Duration 
QT interval corrected for heart rate 
QTc 
QTc Correction Method Unspecified 
Study participation period 
The duration of participation in this study for each subject is from the date of obtaining informed 
consent to the end of the prespecified final examination or withdrawal extermination. The evaluation 
period is up to 24 weeks, and the period following the end of the evaluation period is defined as the 
extended administration period. The total duration of study drug administration is 52 weeks, consisting of 
the evaluation period and the extended administration period combined. 
Timing of study drug administration, observation, and examination 
Week 0 is defined as the day on which study drug administration is started (Day 1), and Week X is 
defined as the examination day X weeks after the start of study drug administration. 
Baseline 
Baseline values are defined as test values obtained before the start of study drug administration (Week 
0). 


Protocol No.: 7580-101 
  
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Protocol Summary 
I 
Study Title 
An Intra-Subject Dose-Adjustment Study of KHK7580 for the Treatment of Hypercalcemia in Patients 
with Parathyroid Carcinoma or Primary Hyperparathyroidism Who Are Unable to Undergo 
Parathyroidectomy or Relapse After Parathyroidectomy 
II  Study Objectives 
II-I  Primary Objective 
To evaluate the efficacy of KHK7580 orally administered for up to 24 weeks to patients with 
hypercalcemia in parathyroid carcinoma or PHPT who are unable to undergo PTx or relapse after PTx 
II-II  Secondary Objective 
To evaluate the long-term safety and efficacy of KHK7580 orally administered to patients with 
hypercalcemia in parathyroid carcinoma or PHPT who are unable to undergo PTx or relapse after PTx 
III  Study Phase 
Phase 3 
IV  Endpoints 
IV-I 
Efficacy Evaluation 
Primary endpoint 
• Number and percentage of subjects whose corrected serum Ca level was maintained at ≤ 10.3 mg/dL
for 2 weeks in the evaluation period
Secondary endpoints 
• Number and percentage of subjects whose corrected serum Ca level was decreased by ≥ 1.0 mg/dL
from baseline and remained decreased for 2 weeks in the evaluation period
• Corrected serum Ca level at each time point
• Intact PTH level at each time point
• Whole PTH level at each time point
IV-II  Safety Evaluation 
• Presence or absence of adverse events and adverse drug reactions, and the details thereof
• Laboratory values
• Vital sign
IV-III  Pharmacokinetic Evaluation 
• Plasma KHK7580 concentration
• Pharmacokinetic parameters (tmax and Cmax)


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IV-IV  Other Evaluation 
• QOL assessment (EQ-5D-5L)
V 
 Target Disease 
Patients with hypercalcemia in parathyroid carcinoma or PHPT who are unable to undergo PTx or 
relapse after PTx 
VI  Inclusion Criteria 
1） 
Personally submitted written voluntary informed consent to participate in the study 
2） 
Aged ≥ 20 years at the time of consent 
3） 
A diagnosis of parathyroid carcinoma or PHPT who are unable to undergo PTx or relapse after 
PTx 
4） 
Corrected serum Ca level > 11.3 mg/dL at screening 
VII  Exclusion Criteria 
1） 
Treatment with cinacalcet hydrochloride (e.g., Regpara®) within 2 weeks before screening 
2） 
Start of treatment with denosumab (e.g., Ranmark® and Pralia®), bisphosphonates* and 
calcitonins for the treatment of hypercalcemia, and zoledronic acid hydrate (e.g., Reclast®) for the 
treatment of osteoporosis; change in dose or dosing regimen of such drugs; or change in type of 
such drugs within 12 weeks before screening 
*: Alendronate sodium hydrate (e.g., Teiroc®), zoledronic acid hydrate (e.g., Zometa® and 
zoledronic acid), and pamidronate disodium hydrate (e.g., Aredia®) 
3） 
Start of treatment with an active vitamin D preparation or its derivative, Ca preparation, 
bisphosphonates* for the treatment of osteoporosis, or calcitonins for purposes other than the 
treatment of hypercalcemia; change in dose or dosing regimen of such drugs; or change in type of 
such drugs within 2 weeks before screening 
*: Alendronate sodium hydrate (e.g., Fosamac®), ibandronate sodium hydrate (e.g., Bonviva®), 
etidronate disodium (e.g., Didronel®), minodronic acid hydrate (e.g., Recalbon®), and sodium 
risedronate hydrate (e.g., Benet®) 
4） 
Current or history of serious drug allergy. Drug dependence or alcohol dependence and/or their 
past history 
5） 
Severe heart disease (e.g., Class ≥ III per New York Heart Association classification; see 
Attachment 5 of the protocol [supplementary volume]) 
6） 
Severe hepatic impairment (e.g., treatment with antiviral therapy) 
7） 
Uncontrolled hypertension or diabetes 
8） 
History of diagnosis and treatment of malignant tumor within 5 years before screening (excluding 
parathyroid carcinoma, basal cell carcinoma, or surgically resected intraepithelial carcinoma of 
uterine cervix) 
9） 
Treatment with another investigational product (drug or unapproved medical device) in a clinical 
study or any study equivalent to clinical study within 12 weeks before screening 
10） Pregnant, lactating, possibly pregnant female subject (subjects who have been amenorrheic for at 
least 12 months after the last menstrual period without an alternative medical cause are to be 
considered to have no childbearing potential) with positive pregnancy test at screening or with 


Protocol No.: 7580-101 
  
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negative pregnancy test at screening who is unwilling to use adequate contraception according to 
the physician’s instructions or wishes to become pregnant during participation in the study 
11） Diagnosis of hypercalcemia induced by malignant tumor other than parathyroid carcinoma 
12） History of participating in a study of KHK7580 and prior exposure to KHK7580 
13） Other subjects unfit for participation in this study in the judgment of the investigator or 
subinvestigator 
VIII 
Target Number of Subjects 
At least 10 subjects receiving study treatment 
IX  Study Drug 
Identification code: KHK7580 
Generic name: Evocalcet (JAN), evocalcet (INN) 
Chemical nomenclature: 
2-{4-[(3S)-3-{[(1R)-1-(Naphthalen-1-yl)ethyl]amino}pyrrolidin-1-yl]phenyl}acetic acid 
Molecular formula: C24H26N2O2
Molecular mass: 374.48 
X 
 Study Design 
This study is a multicenter, intra-subject dose adjustment study. It consists of the screening period (from 
the time of consent to the start of study drug administration), the evaluation period (up to 24 weeks from 
the start of study drug administration), and the extended administration period (until Week 52 after the 
evaluation period). 
The investigator or subinvestigator will conduct the screening after obtaining the written consent. 
Subsequently, eligible subjects will be enrolled before the start of study drug administration. 
The design of this study is outlined below. 
After enrollment, the date of the start of study treatment (Day 1) will be defined as Week 0, and the 
subjects will start to receive study drug at the starting dose of 2 mg once daily (daily dose: 2 mg). However, 
the starting dose may be 2 mg twice daily (daily dose: 4 mg) for subjects with a corrected serum Ca level of 
> 12.5 mg/dL at screening. Subsequently, the dose level will be adjusted for each subject in accordance 


Protocol No.: 7580-101 
  
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with Section XI “Dose, Mode of Administration, and Dosing Period” so that corrected serum Ca level can 
be controlled at ≤ 10.3 mg/dL, and the study drug will be orally administered at each dose level 1 to 4 times 
daily. 
Subjects whose corrected serum Ca level have been maintained at ≤ 10.3 mg/dL for 2 weeks will be 
transferred to the extended administration period at the time even before Week 24. Other subjects will be 
transferred to the extended administration period at Week 24 if the investigator or subinvestigator has 
confirmed that there are no problems with their transfer to the extended administration period. The study 
treatment period will be 52 weeks consisting of the evaluation period and the extended administration 
period. The time of transition to the extended administration period (starting week of prolongation) will be 
recorded in the electronic case report form (eCRF). Subjects will be withdrawn from the study at the end of 
the evaluation period if, at the discretion of the investigator or subinvestigator, they will not be transferred 
to the extended administration period. If a subject did not enter the extended administration period, the 
reason will be recorded in the eCRF. 
Subjects will visit the hospital once every 2 weeks during the evaluation period. In the extended 
administration period following the evaluation period, subjects should visit the hospital to undergo 
scheduled tests at Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52. If the dose is increased or 
administration is resumed after an interruption, the date 2 weeks after the dose increase or resumption will 
be designated as the date of post-dose-increase (or post-resumption) visit, on which the subject should visit 
the hospital to undergo scheduled tests. 
XI. Dose, Mode of Administration, and Dosing Period
Dose and mode of administration 
Study treatment will start with once-daily administration of KHK7580 2 mg (daily dose: 2 mg). 
However, the starting dose of KHK7580 may be 2 mg twice daily (daily dose: 4 mg) for subjects with a 
corrected serum Ca level of > 12.5 mg/dL at screening. Thereafter, the dosage will be adjusted in 
accordance with Section XII “Dose Adjustment Criteria” until completion or discontinuation of the study. 
KHK7580 will be administered orally every day at any dosage and administration specified in (1) to (6), 
and administration at any other dosage and administration will not be allowed. 
(1) 2 mg once daily (daily dose: 2 mg) 
(2) 2 mg twice daily (daily dose: 4 mg) 
(3) 4 mg twice daily (daily dose: 8 mg) 
(4) 6 mg twice daily (daily dose: 12 mg) 
(5) 6 mg three time daily (daily dose: 18 mg) 
(6) 6 mg four times daily (daily dose: 24 mg) 
Dosing period 
52 weeks (the evaluation period [up to 24 weeks] and the extended administration period combined) 


Protocol No.: 7580-101 
  
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XII Dose Adjustment Criteria 
XII-I  Criteria for Dose Increase 
In principle, dose increase will be performed on the day of scheduled visit. If all of the following criteria 
are met, the dose will be increased on a step-by-step basis in accordance with the dose and mode of 
administration specified in (1) to (6), Section XI. 
• Corrected serum Ca level > 10.3 mg/dL at the time of hospital visit.
• The current dose has been administered for at least 2 weeks.
• There are no safety problems with dose increase in the subject in the judgment of the investigator or
subinvestigator.
XII-II  Dose Reduction 
The dose will be reduced if the investigator or subinvestigator determines that the dose should be 
reduced due to the occurrence of an adverse event, etc. In principle, the dose of the study drug will be 
reduced on a step-by-step basis; however, if the investigator or subinvestigator deems it necessary, the 
dose may be reduced by two or more levels at a time. In that case, the lowest possible dose is 2 mg once 
daily (daily dose: 2 mg). If it is judged that the dose should be reduced further while once-daily 
administration at a dose of 2 mg is performed (daily dose: 2 mg), study treatment will be interrupted. 
XII-III  Dose Increase After Dose Reduction 
In principle, the first dose increase after dose reduction will be performed on the day of scheduled visit. 
Dose increase may be performed when the investigator or subinvestigator determines that the dose can be 
increased. In principle, dose increase will be performed on a step-by-step basis; however, if the 
investigator or subinvestigator deems it necessary, the dose may be increased by two or more levels at a 
time, provided that the post-increase dose matches the dosage and administration immediately before dose 
reduction. 
XII-IV  Criteria for Treatment Interruption 
Study drug administration will be interrupted if any of the following criteria is met. 
• Corrected serum Ca level ≤ 7.5 mg/dL.
• The investigator or subinvestigator has determined that study drug administration should be
interrupted due to the occurrence of an adverse event, etc.
• The investigator or subinvestigator has determined that the dose should be reduced while the study
drug is administered at a dose of 2 mg once daily (daily dose: 2 mg).
XII-V  Resumption of Study Drug Administration After Interruption 
In principle, study drug administration will be resumed on the day of scheduled visit. Administration 
will be resumed after the corrected serum Ca level has reached or exceeded 8.4 mg/dL and the investigator 
or subinvestigator has judged that administration can be resumed in consideration of the safety of the 
subject. The dosage and administration at the time of resumption of administration will be the same as 
those immediately before interruption or the dosage and administration at a lower level. 


Protocol No.: 7580-101 
  
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The duration of an interruption should not exceed 8 consecutive weeks; if the investigator or 
subinvestigator has judged that it is impossible to resume administration, the subject will be withdrawn 
from the study. 
XIII  Planned Study Period 
August 2017 - October 2019 


Protocol No.: 7580-101 
  
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Table of Contents 
Handling of this Protocol ........................................................................................................... 2 
List of Abbreviations and Definitions of Terms ........................................................................ 3 
Protocol Summary ...................................................................................................................... 6 
Table of Contents ..................................................................................................................... 12 
1 
HISTORY AND BACKGROUND OF THE STUDY ..................................................... 17 
1.1 
Background .................................................................................................................................. 17 
1.2 
KHK7580 ..................................................................................................................................... 18 
1.3 
Non-Clinical Study Results .......................................................................................................... 18 
1.3.1 
Pharmacological Action ........................................................................................................... 18 
1.3.2 
Pharmacokinetics and Drug Metabolism .................................................................................. 19 
1.3.2.1 
Absorption ............................................................................................................................ 19 
1.3.2.2 
Distribution ........................................................................................................................... 19 
1.3.2.3 
Metabolism ........................................................................................................................... 20 
1.3.2.4 
Excretion .............................................................................................................................. 20 
1.3.3 
Toxicology................................................................................................................................ 20 
1.3.3.1 
Repeated-Dose Toxicity Studies .......................................................................................... 20 
1.3.3.2 
Carcinogenicity Studies ........................................................................................................ 21 
1.3.3.3 
Reproductive and Developmental Toxicity Studies ............................................................. 22 
1.4 
Clinical Study Results .................................................................................................................. 22 
1.4.1 
Clinical Studies in Healthy Adult Men..................................................................................... 22 
1.4.2 
Clinical Pharmacology Study in Patients with Hepatic Dysfunction ....................................... 24 
1.4.3 
Clinical Studies in Patients with Secondary Hyperparathyroidism (SHPT) on 
Hemodialysis ............................................................................................................................ 24 
1.4.4 
Clinical Studies in SHPT Patients on Peritoneal Dialysis ........................................................ 26 
1.5 
Background to This Study ............................................................................................................ 27 
2 
COMPLIANCE WITH GCP, ETC. .................................................................................. 27 
3 
STUDY OBJECTIVES AND ENDPOINTS .................................................................... 28 
3.1 
Study Objectives........................................................................................................................... 28 
3.1.1 
Primary Objective ..................................................................................................................... 28 
3.1.2 
Secondary Objective ................................................................................................................. 28 
3.2 
Endpoints ...................................................................................................................................... 28 
3.2.1 
Efficacy Evaluation .................................................................................................................. 28 
3.2.1.1 
Primary Endpoint ................................................................................................................. 28 
3.2.1.2 
Secondary Endpoints ............................................................................................................ 28 
3.2.2 
Safety Evaluation ..................................................................................................................... 28 
3.2.3 
Pharmacokinetic Evaluation ..................................................................................................... 28 
3.2.4 
Other Evaluation ....................................................................................................................... 28 


Protocol No.: 7580-101 
  
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4 
STUDY DESIGN .............................................................................................................. 29 
4.1 
Study Design ................................................................................................................................ 29 
4.2 
Type of Study ............................................................................................................................... 30 
5 
STUDY DRUG ................................................................................................................. 30 
5.1 
Investigational Drug (Investigational Therapy or Treatment) ...................................................... 30 
5.2 
Contained Amount and Formulation ............................................................................................ 30 
5.3 
Packaging ..................................................................................................................................... 30 
5.4 
Labeling ........................................................................................................................................ 30 
5.5 
Storage Method ............................................................................................................................ 30 
5.6 
Procedures for Delivery, Storage, Management, and Recovery of Study Drugs ......................... 30 
6 
CRITERIA FOR SUBJECT ENROLLMENT .................................................................. 32 
6.1 
Target Disease (Diagnosis Group) ............................................................................................... 32 
6.2 
Inclusion Criteria .......................................................................................................................... 32 
6.3 
Exclusion Criteria ......................................................................................................................... 32 
7 
REGIMEN AND CONCOMITANT THERAPY ............................................................. 34 
7.1 
Dose, Mode of Administration, and Dosing Period ..................................................................... 34 
7.1.1 
Dose and Mode of Administration ........................................................................................... 34 
7.1.1.1 
Dosage and Administration (Dose per Administration and Dosing Frequency) .................. 34 
7.1.1.2 
Dose Adjustment Criteria ..................................................................................................... 34 
7.1.2 
Dosing Period (Study Length) .................................................................................................. 35 
7.2 
Concomitant Drugs and Therapies (Concomitant Medications) .................................................. 35 
7.2.1 
Prohibited Concomitant Medication ......................................................................................... 36 
7.2.2 
Restricted Concomitant Medications........................................................................................ 36 
8 
REGISTRATION IN THE STUDY ................................................................................. 37 
8.1 
Method of Subject Registration .................................................................................................... 37 
8.1.1 
Assignment of Subject Identifiers ............................................................................................ 37 
8.2 
Registration Procedure ................................................................................................................. 37 
8.3 
Re-registration .............................................................................................................................. 38 
8.4 
Contact for Registration ............................................................................................................... 38 
9 
OBSERVATION, INVESTIGATION, AND EXAMINATION ITEMS AND 
SCHEDULE ...................................................................................................................... 39 
9.1 
Schedule ....................................................................................................................................... 39 
9.2 
Subject Demographics .................................................................................................................. 43 
9.3 
Observation and Investigation Items and the Timing Thereof ..................................................... 43 
9.3.1 
Exposure ................................................................................................................................... 43 
9.3.2 
QOL Assessment (EQ-5D-5L) ................................................................................................. 44 
9.4 
Examination Items and the Timing Thereof ................................................................................. 44 
9.4.1 
Laboratory Tests ....................................................................................................................... 44 
9.4.1.1 
Hematology .......................................................................................................................... 44 
9.4.1.2 
Blood Biochemistry 1 ........................................................................................................... 45 


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9.4.1.3 
Blood Biochemistry 2 ........................................................................................................... 45 
9.4.1.4 
Urinalysis ............................................................................................................................. 45 
9.4.2 
Vital Signs and Other Tests ...................................................................................................... 45 
9.4.2.1 
Height ................................................................................................................................... 46 
9.4.2.2 
Weight .................................................................................................................................. 46 
9.4.2.3 
Vital Signs ............................................................................................................................ 46 
9.4.3 
Standard 12-Lead Electrocardiogram (ECG) ........................................................................... 46 
9.4.4 
Pregnancy Test ......................................................................................................................... 46 
9.4.5 
Drug Concentration Measurement ........................................................................................... 47 
9.4.5.1 
Plasma KHK7580 Concentrations ........................................................................................ 47 
9.4.5.2 
Blood Collection Method and Sample Processing Method .................................................. 47 
9.4.5.3 
Blood Collection Time Points .............................................................................................. 47 
9.4.5.4 
Measurement Method and Test Plan .................................................................................... 47 
9.4.5.5 
Method for Transportation of Plasma Samples .................................................................... 48 
9.4.5.6 
Reporting of Measurement Results ...................................................................................... 48 
9.5 
Adverse Events ............................................................................................................................. 49 
9.5.1 
Definition of Adverse Events ................................................................................................... 49 
9.5.2 
Definition of Serious Adverse Events ...................................................................................... 49 
9.5.3 
Definition of Other Significant Adverse Events ....................................................................... 49 
9.5.4 
Items to Be Investigated ........................................................................................................... 49 
9.6 
Number of Blood Collections and the Volume of Blood Collected ............................................. 51 
10 MANAGEMENT OF SUBJECTS .................................................................................... 53 
10.1 
Notification to Other Departments and Hospitals ........................................................................ 53 
10.2 
Subject Compliance Instruction and Investigation of Compliance Status .................................... 53 
10.3 
Instructions to Subjects ................................................................................................................ 53 
10.3.1 
Visits to the Hospital ................................................................................................................ 53 
10.3.2 
Medication Diary ...................................................................................................................... 53 
10.3.3 
Contraception ........................................................................................................................... 53 
10.3.4 
Measures Taken in the Event of Pregnancy ............................................................................. 54 
11 ADVERSE EVENT REPORTING ................................................................................... 55 
11.1 
Adverse Events for Mandatory Reporting .................................................................................... 55 
11.1.1 
Definition of Serious Adverse Events ...................................................................................... 55 
11.1.2 
Treatment and Follow-Up of Adverse Events .......................................................................... 55 
11.1.2.1 
Treatment of the Subject ...................................................................................................... 55 
11.1.2.2 
Reporting to the Parties Concerned ...................................................................................... 55 
11.1.2.3 
Follow-Up of Adverse Events .............................................................................................. 56 
12 CRITERIA FOR SUBJECT WITHDRAWAL AND DISCONTINUATION OF THE 
STUDY, AND PROCEDURES THEREFOR .................................................................. 56 
12.1 
Withdrawal of a Subject from the Study ...................................................................................... 56 
12.1.1 
Subject Withdrawal Criteria ..................................................................................................... 56 
12.1.2 
Procedure for Withdrawing Subjects ........................................................................................ 56 


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12.2 
Site-Specific Study Discontinuation or Interruption .................................................................... 56 
12.3 
Discontinuation or Suspension of the Entire Study ...................................................................... 57 
13 STATISTICAL ANALYSIS ............................................................................................. 58 
13.1 
Statistical Analysis Methods ........................................................................................................ 58 
13.1.1 
Efficacy Evaluation .................................................................................................................. 58 
13.1.1.1 
Primary Evaluation ............................................................................................................... 58 
13.1.1.2 
Secondary Evaluations ......................................................................................................... 58 
13.1.2 
Safety Evaluation ..................................................................................................................... 58 
13.1.3 
Pharmacokinetic Evaluation ..................................................................................................... 58 
13.1.4 
Other Evaluation ....................................................................................................................... 59 
13.2 
Target Number of Subjects ........................................................................................................... 59 
13.3 
Significance Level Used ............................................................................................................... 59 
13.4 
Criteria for Discontinuation of the Study ..................................................................................... 59 
13.5 
Procedures for Handling Missing, Rejected, and Abnormal Data ................................................ 59 
13.6 
Procedures for Preparing the Analysis Plan and Reporting Deviations from the Original Plan
 ...................................................................................................................................................... 59 
13.7 
Selection of Subjects for Analysis ................................................................................................ 59 
13.7.1 
FAS........................................................................................................................................... 59 
13.7.2 
Safety Analysis Set ................................................................................................................... 59 
13.7.3 
Pharmacokinetic Analysis Set .................................................................................................. 60 
14 ETHICAL CONSIDERATIONS ...................................................................................... 61 
14.1 
IRB ............................................................................................................................................... 61 
14.1.1 
Review of the Appropriateness of Study Conduct ................................................................... 61 
14.1.2 
Continued Review .................................................................................................................... 61 
14.2 
Selection of Subjects and Safety Assurance ................................................................................. 61 
14.3 
Protection of Subjects’ Personal Information and Privacy ........................................................... 61 
14.4 
Time and Method of Obtaining Consent ...................................................................................... 61 
14.4.1 
Informed Consent ..................................................................................................................... 61 
14.4.1.1 
Informed Consent of Subjects .............................................................................................. 61 
14.4.2 
Storage of the Consent Form .................................................................................................... 62 
14.5 
Contents of the Informed Consent Form ...................................................................................... 62 
14.6 
Providing Information to Subjects, Revising the Informed Consent Form, and Obtaining 
Re-Consent ................................................................................................................................... 63 
15 MONETARY PAYMENT AND COMPENSATION FOR HEALTH DAMAGE .......... 63 
15.1 
Costs Related to the Study ............................................................................................................ 63 
15.2 
Expenses for Reducing the Burden of Subjects’ Participation in the Study ................................. 63 
15.3 
Compensation for Health Damage ............................................................................................... 63 
16 PROTOCOL COMPLIANCE, DEVIATION, CHANGE, AND AMENDMENT .......... 65 
16.1 
Compliance with the Protocol ...................................................................................................... 65 
16.2 
Protocol Deviation or Change ...................................................................................................... 65 


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16.3 
Protocol Amendment .................................................................................................................... 65 
17 PRECAUTIONS FOR ELECTRONIC CASE REPORT FORM PREPARATION ........ 66 
17.1 
Preparation and Reporting of Electronic Case Report Forms ...................................................... 66 
17.2 
Modification or Correction of the eCRF ...................................................................................... 66 
17.3 
Items for Which the Entry in the eCRF Can Be Handled as the Source Document (Source 
Data) ............................................................................................................................................. 66 
18 DIRECT ACCESS TO SOURCE DOCUMENTS, ETC. ................................................. 68 
19 QUALITY CONTROL AND QUALITY ASSURANCE OF THE STUDY ................... 68 
20 PLANNED STUDY PERIOD .......................................................................................... 68 
21 COMPLETION OF THE STUDY .................................................................................... 68 
22 RETENTION OF RECORDS, ETC. ................................................................................ 68 
22.1 
Retention at the IRB ..................................................................................................................... 68 
22.2 
Retention at the Study Site ........................................................................................................... 69 
22.3 
Retention by the Investigator........................................................................................................ 69 
22.4 
Retention by the Sponsor ............................................................................................................. 69 
22.5 
Retention of Source Documents Concerning KHK7580 Concentration Measurements .............. 70 
22.6 
Retention of Source Documents Concerning Clinical Laboratory Tests, etc. .............................. 70 
22.7 
Retention of Biological Samples .................................................................................................. 70 
23 PUBLICATION OF STUDY RESULTS ......................................................................... 71 
24 RATIONALE FOR THE SETTINGS ............................................................................... 72 
24.1 
Rationale for the Study Design..................................................................................................... 72 
24.2 
Rationale for the Inclusion Criteria .............................................................................................. 72 
24.3 
Rationale for the Exclusion Criteria ............................................................................................. 72 
24.4 
Rationale for the Dose, Dosing Period, and Mode of Administration .......................................... 72 
24.4.1 
Rationale for the Dose .............................................................................................................. 72 
24.4.2 
Rationale for the Dosing Period ............................................................................................... 73 
24.4.3 
Rationale for the Dose Adjustment Criteria ............................................................................. 73 
24.5 
Rationale for the Prohibited Concomitant Medication ................................................................. 74 
24.6 
Rationale for Restricted Concomitant Medications ...................................................................... 74 
24.7 
Rationale for the Subject Withdrawal Criteria ............................................................................. 74 
24.8 
Rationale for the Efficacy Endpoints ........................................................................................... 75 
24.9 
Rationale for Plasma KHK7580 Concentration Measurement ..................................................... 75 
24.10 
Rationale for the Target Number of Subjects ............................................................................... 76 
25 STUDY ADMINISTRATIVE STRUCTURE .................................................................. 77 
26 PRIMARY RESPONSIBILITIES OF THE INVESTIGATOR ....................................... 77 
27 REFERENCES .................................................................................................................. 78 


Protocol No.: 7580-101 
  
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1 HISTORY AND BACKGROUND OF THE STUDY 
1.1 
Background 


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1.2 
KHK7580 
1.3 
Non-Clinical Study Results 


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1.4 
Clinical Study Results 


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1.5 
Background to This Study 
2 COMPLIANCE WITH GCP, ETC. 
In keeping with the spirit of the Declaration of Helsinki, this study will be conducted in compliance with 
the Pharmaceuticals and Medical Devices Act, the Ministerial Ordinance on Good Clinical Practice for 
Drugs (Ordinance of the Ministry of Health and Welfare No. 28 of March 27, 1997), and partial 
amendments to the Ministerial Ordinance. 


Protocol No.: 7580-101 
  
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3 STUDY OBJECTIVES AND ENDPOINTS 
3.1 
Study Objectives 
3.1.1 
Primary Objective 
To evaluate the efficacy of KHK7580 orally administered for up to 24 weeks to patients with 
hypercalcemia in parathyroid carcinoma or PHPT who are unable to undergo PTx or relapse after PTx 
3.1.2 
Secondary Objective 
To evaluate the long-term safety and efficacy of KHK7580 orally administered to patients with 
hypercalcemia in parathyroid carcinoma or PHPT who are unable to undergo PTx or relapse after PTx 
3.2 
Endpoints 
3.2.1 
Efficacy Evaluation 
3.2.1.1 
Primary Endpoint 
• Number and percentage of subjects whose corrected serum Ca level was maintained at ≤ 10.3 mg/dL
for 2 weeks in the evaluation period
3.2.1.2 
Secondary Endpoints 
• Number and percentage of subjects whose corrected serum Ca level was decreased by ≥ 1.0 mg/dL
from baseline and remained decreased for 2 weeks in the evaluation period
• Corrected serum Ca level at each time point
• Intact PTH level at each time point
• Whole PTH level at each time point
3.2.2 
Safety Evaluation 
• Presence or absence of adverse events and adverse drug reactions, and the details thereof
• Laboratory values
• Vital sign
3.2.3 
Pharmacokinetic Evaluation 
• Plasma KHK7580 concentration
• Pharmacokinetic parameters (tmax and Cmax)
3.2.4 
Other Evaluation 
• QOL assessment (EQ-5D-5L)


Protocol No.: 7580-101 
  
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4 STUDY DESIGN 
4.1 
Study Design 
The design of this study is outlined in Table 4.1-1. 
This study is a multicenter, intra-subject dose adjustment study. It consists of the screening period (from 
the time of consent to the start of study drug administration), the evaluation period (up to 24 weeks from 
the start of study drug administration), and the extended administration period (until Week 52 after the 
evaluation period). 
The investigator or subinvestigator will conduct the screening after obtaining the written consent. 
Subsequently, eligible subjects will be enrolled before the start of study drug administration. 
Table 4.1-1.  Outline of the study design 
After enrollment, the date of the start of study treatment (Day 1) will be defined as Week 0, and the 
subjects will start to receive study drug at the starting dose of 2 mg once daily (daily dose: 2 mg). However, 
the starting dose may be 2 mg twice daily (daily dose: 4 mg) for subjects with a corrected serum Ca level of 
> 12.5 mg/dL at screening. Subsequently, the dose level will be adjusted for each subject in accordance 
with Section 7.1.1 “Dose, Mode of Administration, and Dosing Period” so that corrected serum Ca level 
can be controlled at ≤ 10.3 mg/dL, and the study drug will be orally administered at each dose level 1 to 4 
times daily. 
Subjects whose corrected serum Ca level have been maintained at ≤ 10.3 mg/dL for 2 weeks will be 
transferred to the extended administration period at the time even before Week 24. Other subjects will be 
transferred to the extended administration period at Week 24 if the investigator or subinvestigator has 
confirmed that there are no problems with their transfer to the extended administration period. See Table 
9.1-1 “Schedule of observation, investigation, and examination (evaluation period)” and Table 9.1-2 
“Schedule of observation, investigation, and examination (extended administration period)” for visit 
schedules for subjects transitioning to the extended administration period before Week 24. The study 
treatment period will be 52 weeks consisting of the evaluation period and the extended administration 
period. The time of transition to the extended administration period (starting week of prolongation) will be 
recorded in the electronic case report form (eCRF). Subjects will be withdrawn from the study at the end of 
the evaluation period if, at the discretion of the investigator or subinvestigator, they will not be transferred 


Protocol No.: 7580-101 
  
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to the extended administration period. If a subject did not enter the extended administration period, the 
reason will be recorded in the eCRF. 
Subjects will visit the hospital once every 2 weeks during the evaluation period. In the extended 
administration period following the evaluation period, subjects should visit the hospital to undergo 
scheduled tests at Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52. If the dose is increased or 
administration is resumed after an interruption, the date 2 weeks after the dose increase or resumption will 
be designated as the date of post-dose-increase (or post-resumption) visit, on which the subject should visit 
the hospital to undergo scheduled tests. 
4.2 
Type of Study 
Phase 3 clinical study (multicenter, intra-subject, dose adjustment study) 
5 STUDY DRUG 
5.1 
Investigational Drug (Investigational Therapy or Treatment) 
Identification code: KHK7580 
Generic name: Evocalcet (JAN), evocalcet (INN) 
Chemical nomenclature: 
2-{4-[(3S)-3-{[(1R)-1-(Naphthalen-1-yl)ethyl]amino}pyrrolidin-1-yl]phenyl}acetic acid 
Molecular formula: C24H26N2O2 
Molecular mass: 374.48 
5.2 
Contained Amount and Formulation 
Light yellow, film-coated tablets each containing 2 mg of KHK7580 
5.3 
Packaging 
Each box contains three PTP sheets, each of which contains 10 tablets of KHK7580 (2 mg). The PTP 
sheets are packaged in aluminum pillows (with desiccant). 
5.4 
Labeling 
The outer box will be labeled with a statement to the effect that the product is for investigational use, and 
with the sponsor's name and address, identification code, content, lot number, and storage method. 
5.5 
Storage Method 
Storage at room temperature (1 to 30°C). 
5.6 
Procedures for Delivery, Storage, Management, and Recovery of Study Drugs 
After conclusion of a clinical study agreement, the sponsor will deliver the study drug to the study site 
via a courier company contracted by                      . The sponsor will also prepare and deliver to the 
study site written procedures for the management of the study drug. 
The study drug administrator at the study site will appropriately store and manage the study drug in 
accordance with the written procedures, and will keep records of inventory, use status, returns, disposal, 
etc. The study drug administrator will check the number of unused study drugs and used study drugs 
(including PTP sheets and empty boxes), disposal records, etc. as appropriate, and reconcile them with the 


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study drug accountability record. In principle, PTP sheets and empty boxes should be discarded at the 
study site after completion of the study, but they may be returned to the sponsor. 
When returning or disposing of the study drug, the study drug administrator will provide the sponsor 
with a copy of the study drug accountability record. 
Leftover drugs of subjects who have completed or have been withdrawn from this study will not be 
reused for any reason whatsoever. 


Protocol No.: 7580-101 
  
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6 CRITERIA FOR SUBJECT ENROLLMENT 
6.1 
Target Disease (Diagnosis Group) 
Patients with hypercalcemia in parathyroid carcinoma or PHPT who are unable to undergo PTx or 
relapse after PTx 
6.2 
Inclusion Criteria 
Subjects enrolled in this study should satisfy all of the following criteria. 
1） 
Personally submitted written voluntary informed consent to participate in the study 
2） 
Aged ≥ 20 years at the time of consent 
3） 
A diagnosis of parathyroid carcinoma or PHPT who are unable to undergo PTx or relapse after 
PTx 
4） 
Corrected serum Ca level > 11.3 mg/dL at screening 
6.3 
Exclusion Criteria 
Any individuals falling under any of the following criteria should not be enrolled in this study. 
1） 
Treatment with cinacalcet hydrochloride (e.g., Regpara®) within 2 weeks before screening 
2） 
Start of treatment with denosumab (e.g., Ranmark® and Pralia®), bisphosphonates* and 
calcitonins for the treatment of hypercalcemia, and zoledronic acid hydrate (e.g., Reclast®) for the 
treatment of osteoporosis; change in dose or dosing regimen of such drugs; or change in type of 
such drugs within 12 weeks before screening 
*: Alendronate sodium hydrate (e.g., Teiroc®), zoledronic acid hydrate (e.g., Zometa® and 
zoledronic acid), and pamidronate disodium hydrate (e.g., Aredia®) 
3） 
Start of treatment with an active vitamin D preparation or its derivative, Ca preparation, 
bisphosphonates* for the treatment of osteoporosis, or calcitonins for purposes other than the 
treatment of hypercalcemia; change in dose or dosing regimen of such drugs; or change in type of 
such drugs within 2 weeks before screening 
*: Alendronate sodium hydrate (e.g., Fosamac®), ibandronate sodium hydrate (e.g., Bonviva®), 
etidronate disodium (e.g., Didronel®), minodronic acid hydrate (e.g., Recalbon®), and sodium 
risedronate hydrate (e.g., Benet®) 
4） 
Current or history of serious drug allergy. Drug dependence or alcohol dependence and/or their 
past history 
5） 
Severe heart disease (e.g., Class ≥ III per New York Heart Association classification; see 
Attachment 5 of the protocol [supplementary volume]) 
6） 
Severe hepatic impairment (e.g., treatment with antiviral therapy) 
7） 
Uncontrolled hypertension or diabetes 
8） 
History of diagnosis and treatment of malignant tumor within 5 years before screening (excluding 
parathyroid carcinoma, basal cell carcinoma, or surgically resected intraepithelial carcinoma of 
uterine cervix) 
9） 
Treatment with another investigational product (drug or unapproved medical device) in a clinical 
study or any study equivalent to clinical study within 12 weeks before screening 


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10） Pregnant, lactating, possibly pregnant female subject (subjects who have been amenorrheic for at 
least 12 months after the last menstrual period without an alternative medical cause are to be 
considered to have no childbearing potential) with positive pregnancy test at screening or with 
negative pregnancy test at screening who is unwilling to use adequate contraception according to 
the physician’s instructions or wishes to become pregnant during participation in the study 
11） Diagnosis of hypercalcemia induced by malignant tumor other than parathyroid carcinoma 
12） History of participating in a study of KHK7580 and prior exposure to KHK7580 
13） Other subjects unfit for participation in this study in the judgment of the investigator or 
subinvestigator 


Protocol No.: 7580-101 
  
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7 REGIMEN AND CONCOMITANT THERAPY 
7.1 
Dose, Mode of Administration, and Dosing Period 
7.1.1 
Dose and Mode of Administration 
7.1.1.1 
Dosage and Administration (Dose per Administration and Dosing 
Frequency) 
Study treatment will start with once-daily administration of KHK7580 2 mg (daily dose: 2 mg). 
However, the starting dose may be KHK7580 2 mg twice daily (daily dose: 4 mg) for subjects with a 
corrected serum Ca level of > 12.5 mg/dL at screening. Thereafter, the dosage will be adjusted in 
accordance with Section 7.1.1.2 “Dose Adjustment Criteria” until completion or discontinuation of the 
study. KHK7580 will be administered orally every day at any dosage and administration specified in (1) to 
(6), and administration at any other dosage and administration will not be allowed. 
(1) 2 mg once daily (daily dose: 2 mg) 
(2) 2 mg twice daily (daily dose: 4 mg) 
(3) 4 mg twice daily (daily dose: 8 mg) 
(4) 6 mg twice daily (daily dose: 12 mg) 
(5) 6 mg three time daily (daily dose: 18 mg) 
(6) 6 mg four times daily (daily dose: 24 mg) 
7.1.1.2 
Dose Adjustment Criteria 
7.1.1.2.1 
Criteria for Dose Increase 
In principle, dose increase will be performed on the day of scheduled visit. If all of the following criteria 
are met, the dose will be increased on a step-by-step basis in accordance with the dose and mode of 
administration specified in (1) to (6), Section 7.1.1.1. 
• Corrected serum Ca level > 10.3 mg/dL at the time of hospital visit.
• The current dose has been administered for at least 2 weeks.
• There are no safety problems with dose increase in the subject in the judgment of the investigator or
subinvestigator.
7.1.1.2.2 
Dose Reduction 
The dose will be reduced if the investigator or subinvestigator determines that the dose should be 
reduced due to the occurrence of an adverse event, etc. In principle, the dose of the study drug will be 
reduced on a step-by-step basis; however, if the investigator or subinvestigator deems it necessary, the 
dose may be reduced by two or more levels at a time. In that case, the lowest possible dose is 2 mg once 
daily (daily dose: 2 mg). If it is judged that the dose should be reduced further while once-daily 
administration at a dose of 2 mg is performed (daily dose: 2 mg), study treatment will be interrupted. 


Protocol No.: 7580-101 
  
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7.1.1.2.3 
Dose Increase After Dose Reduction 
In principle, the first dose increase after dose reduction will be performed on the day of scheduled visit. 
Dose increase may be performed when the investigator or subinvestigator determines that the dose can be 
increased. In principle, dose increase will be performed on a step-by-step basis; however, if the 
investigator or subinvestigator deems it necessary, the dose may be increased by two or more levels at a 
time, provided that the post-increase dose matches the dosage and administration immediately before dose 
reduction. 
7.1.1.2.4 
Criteria for Treatment Interruption 
Study drug administration will be interrupted if any of the following criteria is met. 
• Corrected serum Ca level ≤ 7.5 mg/dL.
• The investigator or subinvestigator has determined that study drug administration should be
interrupted due to the occurrence of an adverse event, etc.
• The investigator or subinvestigator has determined that the dose should be reduced while the study
drug is administered at a dose of 2 mg once daily (daily dose: 2 mg).
7.1.1.2.5 
Resumption of Study Drug Administration After Interruption 
In principle, study drug administration will be resumed on the day of scheduled visit. Administration 
will be resumed after the corrected serum Ca level has reached or exceeded 8.4 mg/dL AND the 
investigator or subinvestigator has judged that administration can be resumed in consideration of the safety 
of the subject. The dosage and administration at the time of resumption of administration will be the same 
as those immediately before interruption or the dosage and administration at a lower level. 
The duration of an interruption should not exceed 8 consecutive weeks; if the investigator or 
subinvestigator has judged that it is impossible to resume administration, the subject will be withdrawn 
from the study. 
7.1.2 
Dosing Period (Study Length) 
52 weeks (the evaluation period [up to 24 weeks] and the extended administration period combined) 
7.2 
Concomitant Drugs and Therapies (Concomitant Medications) 
If a drug or therapy other than the study drug was used between Week 0 and the completion or 
discontinuation of the study, the following information will be entered into the eCRF. However, 
concomitant therapy will be entered only if it is used as a treatment for the underlying disease. 
• Name of drug/therapy (reported name of drug, med, or therapy)
• Route of administration
• Duration of treatment (start date of medication / end date of medication)
• Reason for use (indication)
With regard to the restricted concomitant medications (Section 7.2.2), however, information about 
“dosing frequency per interval” and “total daily dose,” in addition to the items listed above, will be entered 
into the eCRF for the following drugs: active vitamin D preparations and their derivatives, Ca 
preparations, calcitonins not intended for the treatment of hypercalcemia, and bisphosphonates for the 
treatment of osteoporosis used from 2 weeks before screening until the completion or discontinuation of 


Protocol No.: 7580-101 
  
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the study; zoledronic acid hydrate (e.g., Reclast®) for the treatment of osteoporosis and denosumab 
(Pralia®) used from 12 weeks before screening until the completion or discontinuation of the study. No 
entries are necessary for fluid replacement with physiological saline or dissolution media for 
non-therapeutic purposes, local anesthetics for pain relief at the time of indwelling needle puncture, or 
contrast media for diagnostic imaging. 
7.2.1 
Prohibited Concomitant Medication 
Cinacalcet hydrochloride (e.g., Regpara®) may not be concomitantly used during the study participation 
period. This drug should not be used from 2 weeks before screening until the completion or 
discontinuation of the study. 
7.2.2 
Restricted Concomitant Medications 
If the following restricted concomitant medications are used, changes in the type or dosage and 
administration thereof will be prohibited from 2 weeks before screening until the completion or 
discontinuation of the study for 1) to 4), and from 12 weeks before screening until the completion or 
discontinuation of the study for 5) to 8). Also, in subjects who are not using any of these restricted 
concomitant medications, administration of a restricted concomitant medication may not be newly started 
during these time frames. 
1） 
Active vitamin D preparations and their derivatives 
2） 
Ca preparations 
3） 
Calcitonins not intended for the treatment of hypercalcemia 
4） 
Bisphosphonates for the treatment of osteoporosis (including those not listed below) 
− 
Alendronate sodium hydrate (e.g., Fosamac®) 
− 
Ibandronate sodium hydrate (e.g., Bonviva®) 
− 
Etidronate disodium (e.g., Didronel®) 
− 
Minodronic acid hydrate (e.g., Recalbon®) 
− 
Sodium risedronate hydrate (e.g., Benet®) 
5） 
Zoledronic acid hydrate for the treatment of osteoporosis. (e.g., Reclast®) 
6） 
Denosumab (e.g., Ranmark® and Pralia®) 
7） 
Calcitonins for the treatment of hypercalcemia 
8） 
Bisphosphonates for the treatment of hypercalcemia (including those not listed below) 
− 
Alendronate sodium hydrate (e.g., Teiroc®) 
− 
Zoledronic acid hydrate (e.g., Zometa® and zoledronic acid) 
− 
Pamidronate disodium hydrate (e.g., Aredia®) 


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8 REGISTRATION IN THE STUDY 
8.1  Method of Subject Registration 
The investigator or subinvestigator will provide a thorough explanation about this study to prospective 
subjects and obtain written informed consent for participation in the study if they are deemed to satisfy the 
inclusion criteria and not to fall under any of the exclusion criteria. After obtaining written informed 
consent, the investigator or subinvestigator will send a fax to the contact address indicated in Section 8.4 
by means of the Case Registration Form for the KHK7580 Phase 3 Clinical Study (see Attachment 3 of the 
protocol [supplementary volume]) for subjects whose eligibility has been confirmed through screening. 
Registration will be carried out in accordance with the provisions of Section 8.2. 
8.1.1 
Assignment of Subject Identifiers 
The investigator or subinvestigator will assign subject identifiers to all subjects who have given their 
consent at the study site in accordance with the following rules. The same subject identifier will be used for 
a subject throughout the study participation period. The last four digits of the subject identifier (XX-YY) 
will be used as the subject number. 
Subject identifier: 7580-101-XX-YY 
XX: Site number (see Attachment 1 of the protocol [supplementary volume]) 
YY: Serial number of the subject who has given his/her consent at the study site 
For example, the subject identifier of a subject who was the first to give his/her consent at a study site 
(site number: 01) would be 7580-101-01-01. 
When assigning a subject identifier to a subject, the investigator or subinvestigator will record the 
subject identifier in the screening log. 
8.2 
Registration Procedure 
Subject registration will be carried out in accordance with the following procedures. 
1） 
After obtaining informed consent, the investigator or subinvestigator will perform screening. 
2） 
The investigator or subinvestigator will check subjects against all inclusion and exclusion criteria, 
prepare the Case Registration Form for the KHK7580 Phase 3 Clinical Study (see Attachment 3 
of the protocol [supplementary volume]) for all subjects who have given their consent, whether or 
not the criteria are met, and notify the Study Registration Center described in Section 8.4 by fax. 
Registration will be done during the period from the date on which checking results for all 
inclusion and exclusion criteria are obtained (after screening results are known) until the start of 
study drug administration. However, if a subject withdraws consent or is found to be ineligible 
after consent has been obtained, the Case Registration Form for the KHK7580 Phase 3 Clinical 
Study (see Attachment 3 of the protocol [supplementary volume]) should be prepared promptly 
and faxed to the Study Registration Center described in Section 8.4. 
3） 
The 7580-101 Study Registration Center will verify the eligibility of subjects. The 7580-101 
Study Registration Center may inquire with the investigator or subinvestigator before the 
scheduled date of study drug administration if any questions arise about the information provided 
at the time of registration. For subjects who do not satisfy the inclusion criteria and/or fall under 


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any of the exclusion criteria, the investigator or subinvestigator will enter the reason for 
ineligibility, subject identifier, date of obtaining written informed consent, and sex in the eCRF. 
4） 
The investigator or subinvestigator will record and maintain a screening log of registered 
subjects. 
8.3 
Re-registration 
Subjects who were found to be ineligible may be re-registered at the discretion of the investigator or 
subinvestigator, provided that consent is obtained anew and the subjects undergo screening once again. 
When a subject who was once found to be ineligible is re-registered, a new subject identifier will be 
assigned. 
8.4 
Contact for Registration 
7580-101 Study Registration Center 
Fax:  
Reception hours: 9:00 to 18:00 (except Saturdays, Sundays, national holidays, and the 
period from December 29 through January 3) 


Protocol No.: 7580-101 
 
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9 OBSERVATION, INVESTIGATION, AND EXAMINATION ITEMS AND 
SCHEDULE 
9.1 
Schedule 
Screening will be performed in subjects who have given their written informed consent. Afterwards, the 
study drug will be administered to subjects whose eligibility has been confirmed and for whom registration 
has been completed, and observation, investigation, and examination will be performed according to the 
schedule described in Table 9.1-1 and Table 9.1-2. Details are given in Section 9.3 “Observation and 
Investigation Items and the Timing Thereof” and Section 9.4 “Examination Items and the Timing 
Thereof.” Visits and examinations will be carried out on the scheduled visit dates with an allowable 
window of ± 4 days during the period between Week 2 and Week 24, and on the scheduled visit dates with 
an allowable window of ± 7 days thereafter. If a decision is made to discontinue study drug administration 
on a day of scheduled visit, the results of the examination on that scheduled visit date may be handled as 
the results of withdrawal examination. 


Protocol No.: 7580-101 
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Table 9.1-1. Observation, investigation, and examination schedule (evaluation period) 
Obtaining 
informed consent 
Screening 
Registration 
Evaluation period 
  l 
At 
discontinuation 
Time after administration of the study drug (Weeks) 
0 
2 
4e 
6e 
8f 
10f 
12g 
14g 
16h 
18h 
20i 
22i 
24j 
Time after administration (h) 
Before 
administration 0.5 
1 
2 
3 
Obtaining informed consent 
X 
Study drug administration 
Subject demographics 
Xa 
Registration 
X 
Height 
Xa 
Body weight 
X 
X 
X 
QOL assessment 
X 
X 
X 
Vital sign 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood biochemistry 1 
Xb 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood biochemistry 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma drug concentrationc 
X 
X 
X 
X 
X 
X 
Xk 
Xk 
Xk 
Xk 
Xk 
Xk 
Pregnancy testd 
X 
X 
Electrocardiogram (12-lead) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
Confirmation of the use status 
of concomitant medications  
Investigation of administration 
status 
The allowable window period is ± 4 days of the scheduled visit dates (except for Week 0). 
a) Performed after informed consent is obtained and before the start of study drug administration (Week 0).
b) Corrected serum Ca, Ca, and Alb levels will be measured. In the event that the test result does not meet inclusion criteria 4), re-testing may be performed. If performed in Week 0, it will be handled as a test result in Week 
0. 
c) From Week 2 onwards, if a subject is not taking the study drug as of the day before his/her visit to the hospital, it is permissible not to perform blood collection on the day of hospital visit. It is also permissible not to 
perform post-dose blood collection in a subject for whom a decision to interrupt study drug administration has been made on the day of hospital visit. 
d) Female subjects only. However, no pregnancy test is required if at least 12 months have passed since the last menstrual period without any other medical reason. 
e) Subjects whose corrected serum Ca level has been maintained at ≤ 10.3 mg/dL for 2 weeks will immediately transition to the extended administration period, with the next visit being Week 8.
f) Subjects whose corrected serum Ca level has been maintained at ≤ 10.3 mg/dL for 2 weeks will immediately transition to the extended administration period, with the next visit being Week 12.
g) Subjects whose corrected serum Ca level has been maintained at ≤ 10.3 mg/dL for 2 weeks will immediately transition to the extended administration period, with the next visit being Week 16.
h) Subjects whose corrected serum Ca level has been maintained at ≤ 10.3 mg/dL for 2 weeks will immediately transition to the extended administration period, with the next visit being Week 20.


Protocol No.: 7580-101 
  
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i) Subjects whose corrected serum Ca level has been maintained at ≤ 10.3 mg/dL for 2 weeks will immediately transition to the extended administration period, with the next visit being Week 24. 
j) Subjects whose corrected serum Ca level has been maintained at ≤ 10.3 mg/dL for 2 weeks will immediately transition to the extended administration period, with the next visit being Week 28.
k) If the subject transitions to the extended administration period, plasma drug concentrations may be measured at the end of the evaluation period (0.5, 1, 2, and 3 hours) (see Table 9.1-2 “Observation, investigation, and 
examination schedule (extended administration period)”). 
l) If a decision is made to discontinue study drug administration on a day of scheduled visit, the results of the examination on that scheduled visit date may be handled as the results of withdrawal examination.
Table 9.1-2. Observation, investigation, and examination schedule (extended administration period) 
Extended administration period 
  l 
At 
discontinuation 
Time after the start of study drug administration (Weeks) 
  h 
At the 
first visit 
following 
dose 
increase or 
resumption 
after 
interruption
8a 
12b 
16c 
20d 
24e 
After the end of the evaluation 
periodj 
28f 
32 
36 
40 
44 
48 
52 
Time after administration (h) 
0.5 
1 
2 
3 
Study drug administration (h) 
X 
Body weight 
X 
X 
X 
QOL assessment 
X 
X 
X 
Vital sign 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood biochemistry 1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood biochemistry 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Plasma drug concentrationg 
Xi 
Xi 
Xi 
Xi 
Xi 
X 
X 
X 
X 
Pregnancy testk 
X 
X 
Electrocardiogram (12-lead) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
Confirmation of the use status of 
concomitant medications 
Investigation of administration 
status 
The allowable window for the scheduled visit dates is ± 4 days until Week 24 and ± 7 days thereafter. 
a) For subjects who completed the evaluation period in Week 4 or 6, hospital visits in the extended administration period will start in Week 8. 
b) For subjects who completed the evaluation period in Week 8 or 10, hospital visits in the extended administration period will start in Week 12.
c) For subjects who completed the evaluation period in Week 12 or 14, hospital visits in the extended administration period will start in Week 16. 
d) For subjects who completed the evaluation period in Week 16 or 18, hospital visits in the extended administration period will start in Week 20. 


Protocol No.: 7580-101 
  
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e) For subjects who completed the evaluation period in Week 20 or 22, hospital visits in the extended administration period will start in Week 24.
f) For subjects who completed the evaluation period in Week 24, hospital visits in the extended administration period will start in Week 28. 
g) If a subject is not receiving the study drug as of the day before his/her visit to the hospital, it is permissible not to perform blood collection on the day of hospital visit. It is also permissible not to perform post-dose blood
collection in a subject for whom a decision to interrupt study drug administration has been made on the day of hospital visit.
h) If the dose of the study drug is increased (with or without prior dose reduction) or administration is resumed after an interruption on a scheduled visit date, the date 2 weeks after the dose increase or resumption will be 
designated as the date of post-dose-increase (or post-resumption) visit, and scheduled tests will be performed on that date.
i) If measurement of plasma drug concentrations was not performed after the end of the evaluation period (0.5, 1, 2, and 3 hours), it should be performed by Week 24. 
j) On this date, subjects should not take the study drug before hospital visit.
k) Female subjects only. However, no pregnancy test is required if at least 12 months have passed since the last menstrual period without any other medical reason.
l) If a decision is made to discontinue study drug administration on a day of scheduled visit, the results of the examination on that scheduled visit date may be handled as the results of withdrawal examination.


Protocol No.: 7580-101 
  
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9.2 
Subject Demographics 
The following items will be investigated and entered into the eCRF. 
• Date of informed consent
• Sex
• Date of birth
• Medical history – Complication
• Medical history – Past medical history
• Medical history – Primary disease
• Date of diagnosis for primary disease
• Occurrence of pharmacotherapy for primary disease/PTx/parathyroid intervention therapy and start
date of procedure
• Use status of cinacalcet hydrochloride (cinacalcet hydrochloride before screening)
– Total daily dose
– Dosage (dosing frequency per interval)
– Dosing period (start date of medication and end date of medication)
– Reason of medication stopped
– UGI tract disturbance due to cinacalcet hydrochloride
• Other items related to the inclusion and exclusion criteria
Visit [allowable window]: At the time of screening [from the time of obtaining consent until before the 
start of study drug administration (Week 0)] 
9.3 
Observation and Investigation Items and the Timing Thereof 
9.3.1 
Exposure 
The following items will be entered into the eCRF for each scheduled visit date. 
• Start date of treatment
• End date of treatment
• Dosage and administration*1 (planned dosing frequency and dose)
• Status of study drug administration (number of tablets taken [actual dose] and compliance*2)
• Date and time when the study drug was taken*3
*1: If the dose was reduced or study drug administration was interrupted, the reason will be investigated
and entered into the eCRF. For dose reduction or interruption due to an adverse event, the details of 
the adverse event will be entered into the eCRF. 
*2: Only for 1 week prior to plasma drug concentration measurement. The date on which the subject
took the study drug in accordance with the dosage and administration specified by his/her doctor 
will be designated as the study drug compliance date, and the status of study drug compliance for 1 
week prior to plasma drug concentration measurement will be recorded in the eCRF on a daily 
basis. 
*3: Only on the scheduled visit dates on which the plasma drug concentration is measured. The date and
time of study drug administration immediately before plasma drug concentration measurement 
(latest date/time of administration before specimen collection), and, for Week 0 and the date of 


Protocol No.: 7580-101 
  
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plasma drug concentration measurement after the end of the evaluation period, the time of study 
drug administration on that day (latest time of administration before specimen collection of 
0.5h/1h/2h/3h on the specimen collection day) will be entered into the eCRF. 
Visit: [Evaluation period] Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, and at the time of 
discontinuation 
[Extended administration period] Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, at the 
first visit following dose increase or resumption after interruption, and at 
the time of discontinuation 
Allowable window: Within 4 days before and after the scheduled visit dates during the period from 
Week 2 to Week 24, and within 7 days before and after the scheduled visit dates thereafter 
9.3.2 
QOL Assessment (EQ-5D-5L) 
A five-item questionnaire survey on health condition will be conducted, and the results will be entered 
into the eCRF. In the questionnaire, the answer best representing the health condition on the day of the 
survey will be selected from among five options. 
The health condition on the day of the survey will also be assessed using a visual analogue scale, and the 
results will be entered into the eCRF. 
Visit: Weeks 0, 24, and 52, and at the time of discontinuation 
Allowable window: Within 4 days before and after the scheduled visit date in Week 24, and within 7 
days before and after the scheduled visit date in Week 52 
9.4 
Examination Items and the Timing Thereof 
9.4.1 
Laboratory Tests 
In order to determine whether there are any changes in laboratory values after study drug administration, 
tests will be performed according to the prespecified testing schedule, and the date of testing (date of 
sample collection) and test results (except for screening tests) will be entered into the eCRF. The tests in 
Week 0 will be performed before the first administration of the study drug. All laboratory tests, except for 
intact PTH and whole PTH levels, will be performed at the study site. Intact PTH and whole PTH levels 
will be measured at a central laboratory, and the results will be reported to the study site and sponsor. The 
allowable window for the timing of measurement of test items will be within 4 days before and after the 
scheduled visit dates during the period from Week 2 to Week 24, and within 7 days before and after the 
scheduled visit dates thereafter. 
9.4.1.1 
Hematology 
Test items: WBC, WBC fraction (Baso, Eosino, Neutro, Mono, and Lymph), RBC, Ht level, Hb 
concentration, and PLT 
Visit: [Evaluation period] Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, and at the time of 
discontinuation 


Protocol No.: 7580-101 
  
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[Extended administration period] Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, at the 
first visit following dose increase or resumption after interruption, and at 
the time of discontinuation 
9.4.1.2 
Blood Biochemistry 1 
Test items (in-hospital measurement): T-Cho, TG, TP, BUN, UA, Cr, T-Bil, AST, ALT, γ-GTP, LDH, 
ALP, CK, Na, K, Cl, Mg, corrected serum Ca*1, Ca, Alb, and P 
Visit: At the time of screening*2 
[Evaluation period] Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, and at the time of 
discontinuation 
[Extended administration period] Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, at the 
first visit following dose increase or resumption after interruption, and at the 
time of discontinuation 
*1: If the serum Alb value is less than 4.0 g/dL, the serum Ca level will be corrected according to the
following formula. If the serum Alb level is 4.0 g/dL or higher, the actual serum Ca level will be 
handled as the corrected serum Ca level. 
Corrected serum Ca level (mg/dL) = actual serum Ca level (mg/dL) + 4 - serum Alb value (g/dL) 
*2: Ca, corrected serum Ca level, and Alb will be measured. In the event that the test result does not
meet inclusion criteria 4), re-testing may be performed. If performed in Week 0, it will be handled 
as a test result in Week 0. 
9.4.1.3 
Blood Biochemistry 2 
Test items (central measurement): Intact PTH and whole PTH levels 
Visit: [Evaluation period] Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, and at the time of 
discontinuation 
[Extended administration period] Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, at the 
first visit following dose increase or resumption after interruption, and at 
the time of discontinuation 
9.4.1.4 
Urinalysis 
Test items: Specific gravity, pH, and qualitative measurements (glucose, protein, urobilinogen, and 
occult blood) 
Visit: [Evaluation period] Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, and at the time of 
discontinuation 
[Extended administration period] Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, at the 
first visit following dose increase or resumption after interruption, and at 
the time of discontinuation 
9.4.2 
Vital Signs and Other Tests 
The following tests will be performed, and the date of measurement and test results will be entered into 
the eCRF. The tests in Week 0 will be performed before the first administration of the study drug. The 


Protocol No.: 7580-101 
  
-46- 
allowable window for the timing of measurement of test items will be within 4 days before and after the 
scheduled visit dates during the period from Week 2 to Week 24, and within 7 days before and after the 
scheduled visit dates thereafter. 
9.4.2.1 
Height 
Test item: Height 
Visit [allowable window]: At the time of screening [from the time of obtaining consent until before the 
start of study drug administration (Week 0)] 
9.4.2.2 
Weight 
Test item: Weight 
Visit: Weeks 0, 24, and 52, and at the time of discontinuation 
9.4.2.3 
Vital Signs 
Test items: Blood pressure, pulse rate, and body temperature (axillary) 
Visit: [Evaluation period] Weeks 0, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, and at the time of 
discontinuation 
[Extended administration period] Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, at the 
first visit following dose increase or resumption after interruption, and at 
the time of discontinuation 
9.4.3 
Standard 12-Lead Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed and the following items will be entered into the eCRF. 
• Date of ECG
• Result or finding of ECG
If there are any findings, it will be determined whether or not the findings are clinically problematic
(interpretation: normal or abnormal, not clinically significant/abnormal, clinically significant), and will 
be entered into the eCRF.  
Test items: Basic waveform, QT interval, and QTc 
However, if the above items are not measurable due to atrial fibrillation or the like, such a 
measurement failure will not be handled as a deviation. 
Visit: [Evaluation period] Weeks 0*, 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, and 24, and at the time of 
discontinuation 
[Extended administration period] Weeks 8, 12, 16, 20, 24, 28, 32, 36, 40, 44, 48, and 52, at the 
first visit following dose increase or resumption after interruption, and at 
the time of discontinuation 
*: Performed before the first administration of the study drug. 
Allowable window: Within 4 days before and after the scheduled visit dates during the period from 
Week 2 to Week 24, and within 7 days before and after the scheduled visit dates thereafter 
9.4.4 
Pregnancy Test 
Test item: Pregnancy status* 


Protocol No.: 7580-101 
  
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Visit: At the time of screening, Week 52, and at the time of discontinuation 
*: Female subjects only. However, no pregnancy test is required if at least 12 months have passed 
since the last menstrual period without any other medical reason. 
9.4.5 
Drug Concentration Measurement 
9.4.5.1 
Plasma KHK7580 Concentrations 
Plasma KHK7580 concentrations will be measured. Residual samples after measurement of plasma 
drug concentrations may be used for the analysis of KHK7580 metabolites that is not planned in this study. 
Drug concentration data from this study may also be combined with data from other studies for population 
pharmacokinetic analysis. 
9.4.5.2 
Blood Collection Method and Sample Processing Method 
Venous blood (2 mL) will be collected in a vacuum blood collection tube containing EDTA-2K, and 
mixed promptly by inverting the tube. The plasma obtained by centrifugation will be divided into two 
equal portions and dispensed into two sample tubes. The plasma samples will be frozen immediately after 
dispensing, and cryopreserved at -20°C or below until the start of measurement. 
The date and time of blood collection (date/time of specimen collection) and the date and time when the 
study drug was taken (see Section 9.3.1) will be entered into the eCRF. 
9.4.5.3 
Blood Collection Time Points 
Visit of blood collection [allowable window]: 
Weeks 0 (before the first administration of the study drug, and 0.5 hours [± 10 minutes], 1 hour [± 10 
minutes], 2 hours [± 15 minutes], and 3 hours [± 15 minutes] after the first administration of the study 
drug), 2, 4, 8, 12, 16, 20, and 24, after the end of the evaluation period* (0.5 hours [± 10 minutes], 1 hour 
[± 10 minutes], 2 hours [± 15 minutes], and 3 hours [± 15 minutes] after administration of the study 
drug) 
*: If a subject transitions to the extended administration period before Week 24, blood collection will be 
performed in any one of Week 4, 8, 12, 16, 20, or 24. Subjects should come to the hospital without 
taking the study drug on the day when plasma drug concentration measurement after the end of the 
evaluation period is performed. 
Blood collection may be omitted if a subject was not taking the study drug as of the day before the day 
of blood collection. It is also permissible not to perform post-dose blood collection in a subject for 
whom a decision to interrupt study drug administration has been made on the day of blood collection. 
9.4.5.4 
Measurement Method and Test Plan 
Plasma drug concentration measurement will be performed at the Technical Solution Headquarters, 
using its own established LC/MS/MS method. Prior to the 
measurement, the study director at the company’s headquarters will prepare a test plan for 
concentration measurement. 


Protocol No.: 7580-101 
  
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9.4.5.5 
Method for Transportation of Plasma Samples 
 will take charge of collecting 
samples taken at study sites for drug concentration measurement. The company will forward frozen 
samples to                                                                                           . 
Study sites,                                                   , and 
 will store records 
of sample transfer and related information. 
9.4.5.6 
Reporting of Measurement Results 
The final report on measured plasma drug concentrations will be prepared by 
 and submitted to the sponsor. 


Protocol No.: 7580-101 
  
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9.5 
Adverse Events 
9.5.1 
Definition of Adverse Events 
An adverse event is defined as any undesirable medical incident that occurs in a subject receiving the 
study drug. This refers to any unwanted or unintended signs (including abnormal changes in clinical 
laboratory values), symptoms, or diseases that occur when the study drug is administered, whether or not 
they are causally related to the study drug. Adverse drug reactions are defined as adverse events that are 
judged to be either “related” or “possibly related” in terms of their causal relationship to the study drug. In 
patients with parathyroid carcinoma, exacerbation of the primary disease and accessory symptoms are not 
considered adverse events. 
For laboratory test items (hematology and blood biochemistry), the presence or absence of deviation 
(abnormal value) will be checked based on the reference values at each study site; if an abnormal value is 
observed, it will be judged whether the change is clinically problematic (abnormal change) as compared 
with the value before the start of study drug administration. However, changes in intact PTH levels, Ca 
levels, and corrected serum Ca levels will be handled as abnormal changes if such changes cannot be 
explained from the pharmacological perspective as judged by the investigator or subinvestigator in view of 
the pharmacological action of KHK7580. 
For signs, symptoms, and abnormal changes in clinical laboratory values associated with a specific 
disease (diagnostic name), the diagnostic name will be adopted as the adverse event term. However, in 
cases where signs or symptoms that are atypical for a specific disease, or extremely severe signs and 
symptoms develop, each of these signs and symptoms, as well as the diagnostic name, will be handled as 
adverse events. 
9.5.2 
Definition of Serious Adverse Events 
“Serious adverse event” refers to an adverse event that falls under any of the following conditions. 
However, hospitalization for examination and hospitalization planned in advance are exceptions. 
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/incapacity (in the opinion of the reporter) 
5） 
Is a congenital anomaly 
6） 
Other medically significant conditions 
9.5.3 
Definition of Other Significant Adverse Events 
“Other significant adverse events” are defined as all events, except serious adverse events, that result in 
discontinuation or interruption of study drug administration or in dose reduction. 
9.5.4 
Items to Be Investigated 
Information from the start of study drug administration to Week 52 (or at the time of discontinuation) 
will be entered into the eCRF for the following items. 


Protocol No.: 7580-101 
  
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Adverse events will be followed until they have been reversed to their state before study drug 
administration, or until the investigator or subinvestigator determines that follow-up is no longer necessary 
based on the subject’s condition, including symptoms, findings, and laboratory values. 
1） 
Reported term for the adverse event 
2） 
Start date of adverse event 
3） 
Severity/intensity 
• Mild: Signs or symptoms are present but do not interfere with daily activities.
• Moderate: Discomfort interferes with daily activities or there is an impact on the clinical
condition
• Severe: Daily activities are impossible or there is a significant impact on the clinical condition
4） 
Seriousness (serious event) 
• Serious (Yes): Events that correspond to the definition in Section 9.5.2
• Non-serious (No): Events that do not correspond to the definition in Section 9.5.2
5） 
Action taken with study treatment 
• Dose not changed
• Dose reduced
• Drug interrupted
• Drug withdrawn
• Not applicable
6） 
Other actions: Action other than that taken with study treatment (other action taken) 
• None
• Other drugs
• Other
7） 
Outcome of adverse event 
• Recovered/resolved
• Recovering/resolving
• Not recovered/not resolved
• Recovered/resolved with sequelae
• Fatal
• Unknown
8） 
End date of adverse event 
9） 
Causal relationship with the study drug (causality) 
The causal relationship with the study drug will be classified into the following three categories. 
For “not related,” the reason for the judgment will be entered into the eCRF. 
• Not related
• Possibly related
• Related


Protocol No.: 7580-101 
 
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9.6 
Number of Blood Collections and the Volume of Blood Collected 
Total number of blood collections: 29 times 
Total volume of blood collected: 234 mL 
As a guide, the prespecified number of blood collections and the volume of blood collected during the 
study participation period are shown in Table 9.6-1 and Table 9.6-2. The total number of blood collections 
and the total volume of blood collected have been calculated on the assumption that subjects will complete 
the evaluation period in Week 24 and go through the extended administration period until Week 52. 
However, the total number of blood collections and the total volume of blood collected may increase in 
cases where screening is carried out more than once and where a post-dose-increase (or post-resumption) 
visit occurs during the extended administration period. The total number of blood collections and the total 
volume of blood collected may also increase if additional/follow-up examination is performed in 
consideration of the safety of a subject. 


Protocol No.: 7580-101 
 
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Table 9.6-1.  Breakdown of the volume of blood collected (informed consent - evaluation period) 
Screening 
Time after the start of administration (Weeks) 
At the time of 
discontinuation 
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
22 
24 
Time after administration (h) 
Before 
administration 
0.5 
1 
2 
3 
Hematology 
- 
2 
- 
- 
- 
- 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Blood biochemistry 1 
2 
4 
- 
- 
- 
- 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
Blood biochemistry 2 
- 
4 
- 
- 
- 
- 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
4 
Plasma drug concentration 
- 
2 
2 
2 
2 
2 
2 
2 
- 
2 
- 
2 
- 
2 
- 
2 
- 
2 
- 
Total volume of blood collected 
2 
12 
2 
2 
2 
2 
12 
12 
10 
12 
10 
12 
10 
12 
10 
12 
10 
12 
10 
Table 9.6-2.  Breakdown of the volume of blood collected (extended administration period) 
Time after the start of administration (Weeks) 
At the first 
visit 
following 
dose 
increase or 
resumption 
after 
interruption 
At 
discontinuation 
8 
12 
16 
20 
24 
After the end of the 
evaluation period 
28 
32 
36 
40 
44 
48 
52 
Time after administration (h) 
0.5 
1 
2 
3 
Hematology 
2 
2 
2 
2 
2 
- 
- 
- 
- 
2 
2 
2 
2 
2 
2 
2 
2 
2 
Blood biochemistry 1 
4 
4 
4 
4 
4 
- 
- 
- 
- 
4 
4 
4 
4 
4 
4 
4 
4 
4 
Blood biochemistry 2 
4 
4 
4 
4 
4 
- 
- 
- 
- 
4 
4 
4 
4 
4 
4 
4 
4 
4 
Plasma drug concentration 
2 
2 
2 
2 
2 
2 
2 
2 
2 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Total volume of blood collected 
12 
12 
12 
12 
12 
2 
2 
2 
2 
10 
10 
10 
10 
10 
10 
10 
10 
10 


Protocol No.: 7580-101 
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10 MANAGEMENT OF SUBJECTS 
10.1 Notification to Other Departments and Hospitals 
Prior to the start of study drug administration, the investigator or subinvestigator will check whether the 
subject is visiting other departments or hospitals. If the subject has been visiting another department or 
hospital, the investigator or subinvestigator will inform the attending physician of the subject’s 
participation in the study. If subjects used a drug other than those prescribed by the investigator or 
subinvestigator, the name and use status of the drug will be investigated. 
The investigator or subinvestigator will take a similar action if a subject has newly visited another 
department or hospital during the study period. 
10.2 Subject Compliance Instruction and Investigation of Compliance Status 
The investigator or subinvestigator will prescribe the study drug to the subject at each visit. When 
prescribing the study drug, each subject will be explained and instructed on the dosage and administration 
and how to take the drug. As a guide, subjects will be instructed to take the drug once daily at 24-hour 
intervals, twice daily at 12-hour intervals, three times daily at 8-hour intervals, or four times daily at 6-hour 
intervals. Subjects will be instructed to bring at the next visit the study drugs that were not taken and empty 
PTP sheets for study drugs that were taken. If non-compliance with the study drug is noted, thorough 
instructions will be given once again. In particular, if an overdose is observed, the investigator or 
subinvestigator will take adequate measures while giving due consideration to the safety of the subject and 
determine whether or not the subject may continue the study. 
10.3 Instructions to Subjects 
The investigator, subinvestigator, or clinical study collaborator will instruct subjects on the following. 
10.3.1 Visits to the Hospital 
After giving their written informed consent, subjects will undergo screening. Afterwards, subjects will 
visit the hospital in accordance with Section 9.1 “Schedule.” Subjects who have been withdrawn from the 
study will undergo withdrawal examination as soon as possible. 
10.3.2 Medication Diary 
The investigator or subinvestigator will explain and instruct subjects to describe in the medication diary 
the status of study drug compliance on a daily basis and the time when the study drug was last taken before 
the scheduled visit, after the start of study drug administration. Subjects will also be instructed to bring 
their medication diary with them on scheduled visit dates. The medication diary will be checked on each 
scheduled visit date as to whether the medication diary is kept as specified in Section 10.2 “Subject 
Compliance Instruction and Investigation of Compliance Status.” If any inappropriate description is found, 
instructions will be given once again. 
10.3.3 Contraception 
The investigator or subinvestigator will instruct the subject to use appropriate contraceptive methods 
from the date of informed consent until 12 weeks after the end of the study drug administration in females 


Protocol No.: 7580-101 
 
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of childbearing potential or from the date of the start of the study drug administration until 12 weeks after 
the end of the study drug administration in men of reproductive potential. The appropriate contraceptive 
methods are either a combination of two types from among condoms, oral contraceptives, intrauterine 
contraceptive devices, and diaphragms, or abstinence. The investigator or subinvestigator will adequately 
inform subjects about the risk of pregnancy and the appropriate contraceptive methods. 
10.3.4 Measures Taken in the Event of Pregnancy 
Female subjects will be instructed to promptly report to the investigator or subinvestigator if it is found 
that they are pregnant after informed consent, and male subjects will also be instructed to promptly report 
to the investigator or subinvestigator if their partner becomes pregnant after the start of study drug 
administration. In the event that a female subject becomes pregnant, the investigator or subinvestigator 
will take appropriate measures for safety assurance, such as immediately withdrawing the subject from the 
study, and will follow up the subject until follow-up is deemed no longer necessary. In the event that a 
partner of a male subject becomes pregnant, the necessary follow-up and other measures will be performed 
after obtaining voluntary written consent of the partner. 


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11 ADVERSE EVENT REPORTING 
11.1 Adverse Events for Mandatory Reporting 
11.1.1 Definition of Serious Adverse Events 
See Section 9.5.2 “Definition of Serious Adverse Events.” 
11.1.2 Treatment and Follow-Up of Adverse Events 
11.1.2.1 Treatment of the Subject 
If an adverse event occurs, the investigator or subinvestigator will take appropriate measures to ensure 
the safety of the subject, such as providing appropriate medical care or withdrawing the subject from the 
study as necessary. 
11.1.2.2 Reporting to the Parties Concerned 
11.1.2.2.1 Reporting of Serious Adverse Events 
1） 
If a serious adverse event occurs, the investigator or subinvestigator will immediately (within 24 
hours of learning of the event’s occurrence) report the event to the Emergency Safety Information 
Reception Center or the sponsor, either orally, by telephone, email, or fax (using Attachment 4 
“Serious Adverse Event Report (First Report)” of the protocol (supplementary volume) or in the 
form specified by the study site), regardless of whether the event is causally related to the 
administration of the study drug. 
2） 
Afterwards, the investigator will also submit a Serious Adverse Event Report (Detailed Report) to 
the sponsor and the head of the study site within 7 days after he/she becomes aware the event’s 
occurrence. In doing so, the investigator will report to the head of the study site by identifying any 
serious unexpected adverse drug reaction. 
3） 
The investigator will also provide additional information as requested by the sponsor, the head of 
the study site, and the IRB. 
4） 
The head of the study site will consult the IRB as to whether the study may be continued at the 
study site. 
Emergency contact 
Emergency Safety Information Reception Center 
Tel.: 
 (pronounced as “shikyu fukusayo” in Japanese, meaning 
urgency and adverse drug reaction); fax:  
Reception hours: 24 hours (seven days a week) 
11.1.2.2.2 Reporting of Non-Serious Adverse Events 
If any adverse event of special concern occurs, the investigator or subinvestigator will promptly report 
to the sponsor about the event and the measures taken. Any other adverse events will also be reported to the 
sponsor as appropriate. 


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11.1.2.3 Follow-Up of Adverse Events 
Adverse events will be followed until they have been reversed to their state before study drug 
administration, or until the investigator or subinvestigator determines that follow-up is no longer necessary 
based on the subject’s condition, including symptoms, findings, and laboratory values. The eCRF should 
include information from study drug administration to the end of the study. 
12 CRITERIA FOR SUBJECT WITHDRAWAL AND DISCONTINUATION 
OF THE STUDY, AND PROCEDURES THEREFOR 
12.1 Withdrawal of a Subject from the Study 
12.1.1 Subject Withdrawal Criteria 
A subject will be withdrawn from the study if any of the following conditions apply. 
1） 
The subject is found to be ineligible for participation in this study after the start of the study. 
2） 
The subject wishes to withdraw the consent for the study. 
3） 
It is found not feasible to conduct the necessary observations and examinations due to the 
subject’s private reasons. 
4） 
The subject experiences an adverse event, and the investigator or subinvestigator determines that 
the subject should be withdrawn from the study. 
5） 
The subject applied PTx or parathyroid intervention therapy. 
6） 
The subject has not taken investigational therapy over 8 weeks. 
7） 
The investigator or subinvestigator determines that the subject should be withdrawn from the 
study. 
12.1.2 Procedure for Withdrawing Subjects 
The investigator or subinvestigator will take appropriate measures for a subject who has been withdrawn 
from the study due to a safety problem such as the occurrence of an adverse event. All subjects who have 
been withdrawn from the study will undergo withdrawal examination as soon as possible after safety is 
confirmed. 
For subjects who stopped visiting the hospital after study drug administration, follow-up and 
prespecified assessments will be carried out as much as possible while taking into account the human 
rights of the subject. 
The investigator or subinvestigator will investigate the date of withdrawn and the reason for withdrawal, 
and enter this information into the eCRF. 
12.2 Site-Specific Study Discontinuation or Interruption 
In the event of discontinuation or interruption of the study at a given study site due to reasons such as 
doubts about the safety of the study drug, the investigator must promptly notify the head of the study site in 
writing and provide a detailed written explanation of the discontinuation or interruption. The head of the 
study site will promptly report to the sponsor and IRB in writing to that effect and the reasons therefor. 
This study will also be discontinued at the study site if any of the following conditions apply. In that 
case, appropriate measures will be taken in the same manner as above. 


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1） 
The head of the study site proposes the revision of the protocol based on the opinions from the 
IRB that the head of the study site consulted, but the sponsor cannot accept the proposal. 
2） 
The IRB consulted by the head of the study site states that the study should not be continued, and 
the head of the study site directs that the study be discontinued. 
3） 
The study site has committed a serious or continuing violation of GCP, this protocol, or the 
clinical study agreement. 
12.3 Discontinuation or Suspension of the Entire Study 
In the event of discontinuation or suspension of the entire study during the course of the study, the 
sponsor will promptly notify the head of all study sites and the regulatory authorities, providing them with 
the details of the reasons for the discontinuation or suspension. Upon receiving the notification, the head of 
the study site will promptly notify the investigator and the IRB of the discontinuation or suspension and the 
reasons therefor in writing. If the entire study is discontinued or suspended, the investigator will promptly 
notify subjects of the discontinuation or suspension, provide appropriate medical care, and take other 
necessary measures. 


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13 STATISTICAL ANALYSIS 
13.1 Statistical Analysis Methods 
The main analytical items for evaluation of efficacy, safety, and pharmacokinetics, as well as the 
analytical methods, are as follows. 
Unless otherwise noted, categorical data will be summarized by frequency and percentage, and 
continuous data by summary statistics. The summary statistics will involve calculation of the number of 
subjects, mean, standard deviation, minimum, median, and maximum. 
13.1.1 Efficacy Evaluation 
13.1.1.1 Primary Evaluation 
• The number and percentage of subjects whose corrected serum Ca level was maintained at ≤10.3
mg/dL for 2 weeks in the evaluation period will be calculated, along with the exact 95% confidence
interval. Whether or not the lower limit of the exact 95% confidence interval exceeds the threshold
ratio of 11% will be used as a criterion for judging the efficacy.
13.1.1.2 Secondary Evaluations 
• The number and percentage of subjects whose corrected serum Ca level was decreased by ≥ 1.0
mg/dL from baseline and remained decreased for 2 weeks in the evaluation period will be calculated,
along with the accurate two-sided 95% confidence interval.
• The summary statistics of the actual measured values of corrected serum Ca level and changes from
baseline will be calculated for each measurement time point.
• The summary statistics of the actual measured values of intact PTH level and changes from baseline
will be calculated for each measurement time point.
• The summary statistics of the actual measured values of whole PTH level and changes from baseline
will be calculated for each measurement time point.
13.1.2 Safety Evaluation 
The incidence of each adverse event and adverse drug reaction that occurred or worsened after the start 
of study drug administration will be calculated. Calculation of the incidence of each adverse event and 
adverse drug reaction will be performed based on the MedDRA PT and SOC. 
With regard to laboratory parameters and vital sign values, summary statistics will be calculated for 
each evaluation time point. 
13.1.3 Pharmacokinetic Evaluation 
With regard to plasma KHK7580 concentrations, descriptive statistics will be shown for each blood 
collection time point. Pharmacokinetic parameters (tmax and Cmax) will also be calculated for each subject 
and descriptive statistics will be provided. In this study, Cmax is defined as the maximum plasma 
concentrations at 0.5, 1, 2, and 3 hours after administration, and tmax is defined as the time to reach the 
maximum plasma concentration. 


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13.1.4 Other Evaluation 
The results of the EQ-5D-5L will be tabulated. 
13.2 Target Number of Subjects 
At least 10 subjects receiving study treatment 
For the rationale, see Section 24.10 “Rationale for the Target Number of Subjects.” 
13.3 Significance Level Used 
A two-sided p-value of 5% will be used as a guide when a test is performed on an exploratory. 
13.4 Criteria for Discontinuation of the Study 
No study discontinuation criteria based on statistical evidence are provided. 
13.5 Procedures for Handling Missing, Rejected, and Abnormal Data 
For the analyses specified in Section 13.1, failure to obtain evaluable data for two consecutive weeks 
regarding the binary response variables for the percentage of subjects in the primary and secondary 
endpoints will be handled as an “unachieved” subject. Any missing value in continuous data will be 
handled as missing data, and no special complementary processing by a statistical method will be 
performed. If any specific handling of the data becomes necessary due to unforeseen events that were not 
expected at the start of the study, the handling method will be determined before database lock and 
described in the analysis plan. 
13.6 Procedures for Preparing the Analysis Plan and Reporting Deviations from the 
Original Plan 
The details of the final analysis plan, including the analyses shown in Section 13.1, will be finalized as 
the analysis plan by the time of database lock. Major changes to the analysis plan will be described in the 
clinical study report. 
13.7 Selection of Subjects for Analysis 
The following populations will be subject to analysis. Whether or not to include individual subjects in 
each of the analysis populations will be determined prior to database lock if necessary. 
13.7.1 FAS 
The FAS is defined as the population of the eligible subjects enrolled, excluding those falling under 
either or both of the following conditions. The FAS will be subject to efficacy evaluation. 
•
Subjects who have not received any study drug
•
Subjects from whom no data of corrected serum Ca levels after the start of study drug administration
have been obtained
13.7.2 Safety Analysis Set 
The safety analysis set is defined as the population of the eligible subjects enrolled, excluding those 
falling under the following condition. 


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• Subjects who have not received any study drug
13.7.3 Pharmacokinetic Analysis Set 
The pharmacokinetic analysis set is defined as the population of the eligible subjects enrolled, excluding 
those falling under either or both of the following conditions. 
• Subjects who have not received the study drug as prescribed
• Subjects in whom no blood collection for pharmacokinetic analysis has been performed after study
drug administration


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14 ETHICAL CONSIDERATIONS 
14.1 IRB 
14.1.1 Review of the Appropriateness of Study Conduct 
Prior to the conduct of the study, the protocol, the content of the informed consent form for subjects, and 
the appropriateness of study conduct will be reviewed from the perspective of ethical, scientific, and 
medical appropriateness, and approved by the IRB consulted by the head of the study site. 
14.1.2 Continued Review 
The investigator will submit a written summary of the current status of the study to the head of the study 
site at least one a year or upon request by the IRB for continued review by the IRB. 
14.2 Selection of Subjects and Safety Assurance 
In selecting subjects, the investigator or subinvestigator will carefully examine the appropriateness of 
study participation from the viewpoint of protecting human rights, by, for example, excluding those who 
may suffer undue disadvantage from not participating in the study (socially vulnerable persons). 
The investigator or subinvestigator will determine the eligibility of subjects for registration based on the 
enrollment criteria and thereby avoid registration of subjects whose safety cannot be ensured. 
During the study participation period, the investigator and subinvestigator will constantly monitor the 
health condition of subjects, such as by securing methods for emergency contact with the subjects, and 
collect and communicate safety information that may be relevant to the study drug. In the event of an 
adverse event, the investigator and subinvestigator will provide appropriate medical care, etc. to the 
subject, and, if necessary, discontinue study drug administration to ensure the safety of the subject. 
14.3 Protection of Subjects’ Personal Information and Privacy 
In preparing eCRF, the investigator or subinvestigator will use subject identifiers to identify individual 
subjects, and protect subjects’ personal information. 
Persons belonging to the sponsor’s organization involved in clinical studies should not divulge any 
subject secret learned in the course of duties in connection with the study without justifiable reason. 
14.4 Time and Method of Obtaining Consent 
14.4.1 Informed Consent 
14.4.1.1 Informed Consent of Subjects 
The investigator or subinvestigator will fully explain the details of this study to persons deemed 
appropriate as study subjects based on the informed consent form prescribed separately, prior to their 
participation in the study. In this process, a clinical study collaborator may also provide a supplementary 
explanation about the study. After giving the subject sufficient time to think about whether or not to 
participate in the study, the investigator or subinvestigator will obtain the subject’s voluntary consent to 
participate in the study in writing (consent document defined separately) before screening. 


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The investigator or subinvestigator who provided the explanation and the subject will affix their names 
and seals or signatures onto the consent form, and the consent form will be dated by each person. If a 
clinical study collaborator has provided a supplementary explanation, he/she will also affix his/her name 
and seal or signature onto the consent form, and date it. 
14.4.2 Storage of the Consent Form 
The consent form will be made in triplicate unless otherwise stipulated by the study site. The 
investigator or subinvestigator will provide the subject with a copy of the consent form for storage and a 
written explanation. The investigator or subinvestigator will submit the consent form for storage at the 
study site to the department designated by the study site, such as the study administration office of each 
study site, and also store the consent form for storage by the investigator together with the medical records, 
etc. 
14.5 Contents of the Informed Consent Form 
The following items must be included in the informed consent form. 
1） 
Experimental nature of the study 
2） 
Study objectives 
3） 
Name, title, and contact information of the investigator 
4） 
Method of the study 
5） 
Potential advantages to the subject’s mental and physical health as a result of the use of the study 
drug (or, if no such advantages are expected, a statement to that effect), and potential 
disadvantages to the subject 
6） 
Matters related to other treatment methods 
7） 
Duration of participation in the study 
8） 
That the subject may withdraw from the study at any point in time 
9） 
That the subject will not be treated disadvantageously by not participating in or withdrawing from 
the study 
10） That the source documents may be viewed by clinical research associates, auditors, IRB, etc. on 
condition that the subject’s confidentiality is protected 
11） That the confidentiality of the subject will be protected 
12） Contact information of the study site in the event of health damage 
13） That necessary treatment will be provided in the event of health damage 
14） Matters related to compensation for health damage 
15） The type of IRB that will investigate and deliberate on the appropriateness of the study, matters to 
be investigated and deliberated at each IRB, and other IRB-related matters pertaining to this study 
16） Matters related to costs to be borne by the subject, if any 
17） Necessary matters related to the study 
The following items should not be included in the informed consent form. 
1） 
A statement to the effect that a prospective subject should waive his/her rights, or any matter that 
makes him/her suspect such waiver 


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2） 
A statement to the effect that the sponsor, the study site, the investigator, or the subinvestigator is 
exempt from liability or their liability is reduced, or any matter that implies such exemption or 
reduction 
14.6 Providing Information to Subjects, Revising the Informed Consent Form, and 
Obtaining Re-Consent 
If the investigator or subinvestigator obtains new information that may influence the subject’s intention 
to continue participating in the study, the investigator or subinvestigator will promptly explain the contents 
of the new information to subjects during the study, and confirm whether or not the subject intends to 
continue participating in the study. Then, the investigator or subinvestigator will record in the medical 
record the contents of the explanation, the date of the explanation, the person with whom the intention was 
confirmed, and the intention. 
If the investigator deems it necessary to revise the informed consent form based on the explanation 
provided, he/she will promptly revise the informed consent form and obtain IRB approval. Then, the 
investigator or subinvestigator will provide an explanation once again by using the revised informed 
consent form, and obtain the subject’s written re-consent to continue participating in the study in the same 
manner as when obtaining the initial consent. 
15 MONETARY PAYMENT AND COMPENSATION FOR HEALTH 
DAMAGE 
15.1 Costs Related to the Study 
The cost of all tests performed during the period of KHK7580 administration should be borne by the 
sponsor under the system for healthcare services provided combining insurance-covered and non-covered 
services pertaining to the clinical study. 
15.2 Expenses for Reducing the Burden of Subjects’ Participation in the Study 
In order to reduce the burden of costs associated with subjects’ participation in study subjects, the 
sponsor should pay expenses for reducing the burden to the subjects through the study site concerned in 
accordance with the provisions of the study site. 
15.3 Compensation for Health Damage 
1） 
In the event of health damage to a subject as a result of this study, the investigator and 
subinvestigator should take necessary measures, such as providing medical treatment, and the 
sponsor should, in accordance with the subject’s request, bear the subject’s own medical expenses 
incurred for treatment, excluding benefits from health insurance, etc. 
2） 
If any health damage occurs to a subject as a result of this study and a dispute occurs or is likely to 
occur later with the subject, etc., the study site should immediately report to the sponsor, and the 
study site and the sponsor should cooperate to resolve the dispute. 
3） 
If any health damage occurs to a subject as a result of this study and liability for compensation 
arises afterwards, the compensation paid by the study site and the costs incurred for resolution 
should be borne by the sponsor, except where the damage is attributable to the study site. 


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4） 
If any health damage occurs to a subject as a result of this study and liability for compensation 
arises afterwards, the sponsor should accept the liability and bear the cost of compensation. 
5） 
The payment of expenses based on the liability for compensation set forth in the preceding 
paragraph should be made in accordance with the compensation rules established by the sponsor. 


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16 PROTOCOL COMPLIANCE, DEVIATION, CHANGE, AND 
AMENDMENT 
16.1 Compliance with the Protocol 
The investigator and the subinvestigator will comply with the protocol agreed to by the investigator and 
the sponsor and approved in writing by the IRB consulted by the head of the study site. 
16.2 Protocol Deviation or Change 
The investigator or subinvestigator should not deviate from or make a change to the protocol unless the 
investigator reaches a prior written agreement with the sponsor and obtains written approval from the IRB 
based on the IRB’s prior review. In the event of a deviation from or change to the protocol, the investigator 
or subinvestigator should document all of the deviation, regardless of the reason. 
The investigator or subinvestigator may deviate from or make a change to the protocol without prior 
written agreement with the sponsor and prior approval of the IRB if it is medically unavoidable, such as to 
eliminate an immediate hazard to the subject. In this case, the investigator should prepare a document 
describing the deviation or change and the reasons therefor and promptly submit it to the sponsor and the 
head of the study site. The investigator should also submit the document to the IRB via the head of the 
study site for approval, and should obtain approval from the head of the study site and the sponsor’s 
agreement in writing. 
If a protocol amendment is deemed appropriate in light of the nature of the deviation or change and the 
reasons therefor, the investigator should submit a protocol amendment draft to the sponsor, the head of the 
study site, and the IRB via the head of the study site for approval as soon as possible, and should obtain 
approval from the head of the study site and the sponsor’s agreement in writing. 
16.3 Protocol Amendment 
If the sponsor amends the protocol, the sponsor should provide the investigator with sufficient 
explanation along with the protocol amendment or a written document describing the amendment, and 
obtain agreement on the amendment. The investigator should conduct the study in accordance with the 
amended protocol after obtaining written approval based on the IRB’s prior review. However, this should 
not apply if the change is only related to administrative matters of the study (change of affiliation, job title, 
address, telephone number, etc.). 


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17 PRECAUTIONS FOR ELECTRONIC CASE REPORT FORM 
PREPARATION 
For subjects who completed examination and evaluation up to Week 24 (including those who withdrew 
from the study earlier), the evaluation up to Week 24 (or withdrawal) will be summarized as cut-off data. 
17.1 Preparation and Reporting of Electronic Case Report Forms 
In this study, an electronic data capture (EDC) system will be employed for data collection. The EDC 
system provides the study site with the function to enter data into the eCRF, to check the data entered, to 
respond to queries from the sponsor about input data, and to use electronic signatures. The data entered 
will be transmitted in encrypted form to the EDC server over the Internet. The sponsor has confirmed in 
advance that the EDC system complies with the requirements set forth in the Ministerial Ordinance on 
Good Clinical Practice for Drugs (Ordinance of the Ministry of Health and Welfare No. 28 of March 27, 
1997), partial amendments to the Ministerial Ordinance, and the “Use of Electromagnetic Records and 
Electronic Signatures in Applications for Approvals and Licenses of Pharmaceuticals, etc.” (PFSB 
Notification No. 0401022, dated April 1, 2005). 
The investigator will create an eCRF for each subject, verify that all data are accurate and complete, and 
then provide an electronic signature in the EDC system. If an eCRF was prepared by a subinvestigator or a 
clinical study collaborator, the investigator will inspect the eCRF to ensure that there are no problems prior 
to providing his/her electronic signature. The preparation of eCRFs should be in accordance with the 
“Guidelines on Modification or Correction of the eCRF” provided by the sponsor. 
In this study, subject data stored on the EDC server will be handled as the original eCRF. However, if 
the eCRF is moved from the EDC server to a non-rewritable medium (DVD, etc.), the eCRF in the medium 
will be handled as the original, and if the eCRF is moved to the electronic document management system, 
the eCRF in the electronic document management system will be handled as the original. When the eCRF 
is moved to the electronic document management system, the prespecified written procedures will be 
followed. 
The sponsor will provide a copy of the eCRF and the history of modifications or corrections to the study 
site. 
17.2 Modification or Correction of the eCRF 
The investigator, subinvestigator, or clinical study collaborator will follow the “Guidelines on 
Modification or Correction of the eCRF” provided by the sponsor when modifying or correcting the entry 
in the eCRF. The history of modifications or corrections of the eCRF will be automatically captured by the 
EDC system. 
17.3 Items for Which the Entry in the eCRF Can Be Handled as the Source Document 
(Source Data) 
The following items will be entered directly into the eCRF, and the entry in the eCRF may be handled as 
the source document (source data). If a similar entry is present in the medical record, it should be handled 
as the source document (source data). 
1） 
Adverse event name, severity, seriousness, action taken, outcome date, causal relationship with 
the study drug, and comments 


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2） 
Reasons for the use of concomitant drugs and concomitant therapies 
3） 
Date of discontinuation, reason for discontinuation, action taken, and subsequent course 
4） 
Other special remarks and comments from the investigator or subinvestigator 


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18 DIRECT ACCESS TO SOURCE DOCUMENTS, ETC. 
The investigator, subinvestigator, and the study site conducting this study should make all study-related 
records such as source documents available for direct access during monitoring and audits by the sponsor 
and inspection by the IRB and regulatory authorities. 
19 QUALITY CONTROL AND QUALITY ASSURANCE OF THE STUDY 
The sponsor will confirm through monitoring and auditing whether the study is conducted and the 
preparation, recording, and reporting of data are carried out in compliance with the protocol and the 
Ministerial Ordinance on Good Clinical Practice for Drugs (“GCP Ordinance”; Ordinance of the Ministry 
of Health and Welfare No. 28 of March 27, 1997). 
Data management and assurance will be performed in accordance with the sponsor’s standard operating 
procedures for the conduct of clinical studies and auditing procedures. 
Clinical research associates will ensure that the study is conducted in compliance with the GCP 
Ordinance, this protocol, and the written procedures for management of the study drug, and that eCRF 
entries are consistent with the source documents. Details of specific procedures will be provided in a 
separate monitoring plan or alternative written procedures. 
20 PLANNED STUDY PERIOD 
August 2017 - October 2019 
21 COMPLETION OF THE STUDY 
Upon completion of the administration and observation of all subjects at the study site as stipulated in 
the protocol, the investigator will report in writing to the head of the study site the fact that the study has 
been completed and a summary of the study results. 
The head of the study site will promptly notify the IRB and the sponsor of the completion of the study in 
writing, and report the summary of the study results based on the report submitted by the investigator. 
22 RETENTION OF RECORDS, ETC. 
22.1 Retention at the IRB 
1) Materials to be retained
The founder of the IRB will retain the standard operating procedures, a list of the board members 
(including the qualifications of each board member), a list of the occupations (job titles) and affiliations of 
the board members, documents submitted, records of meetings and summaries thereof, and other records 
such as letters. 
2) Retention period
The founder of the IRB will retain study-related documents and records until the later of the following 
dates. However, if the sponsor requires the retention of records for a longer period of time, the founder of 


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the IRB will discuss the retention period and method with the sponsor. If retention becomes no longer 
necessary, the sponsor will notify the founder of the IRB via the head of the study site. 
• The day of marketing approval for the study drug (or, if the development is discontinued, the day on
which three years have elapsed from the day on which the notification of discontinuation of
development was received.)
• The day on which three years have elapsed since discontinuation or completion of the study.
22.2 Retention at the Study Site 
1) Materials to be retained
The head of the study site will retain the study-related documents or records to be retained at the study 
site by appointing a person responsible for the retention of each record. 
2) Retention period
The head of the study site will retain study-related documents and records until the later of the following 
dates. However, if the sponsor requires the retention of records for a longer period of time, the head of the 
study site will discuss the retention period and method with the sponsor. If retention becomes no longer 
necessary, the sponsor will notify the head of the study site. 
• The day of marketing approval for the study drug (or, if the development is discontinued, the day on
which three years have elapsed from the day on which the notification of discontinuation of
development was received)
• The day on which three years have elapsed since discontinuation or completion of the study
22.3 Retention by the Investigator 
The investigator will retain study-related documents or records in accordance with the guidance of the 
head of the study site. 
22.4 Retention by the Sponsor 
1) Materials to be retained
The sponsor will retain the study-related documents or records to be retained. 
2) Retention period
The sponsor will retain study-related documents and records until the later of the following dates. 
• The day on which five years have elapsed from the day of marketing approval for the study drug (or,
if the development is discontinued, the day on which three years have elapsed from the day on which
the decision to discontinue development was made); or, the day on which reexamination is completed
if the drug must undergo reexamination after approval pursuant to the provisions of the
Pharmaceuticals and Medical Devices Act and the period until completion of reexamination is more
than five years
• The day on which three years have elapsed since discontinuation or completion of the study


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22.5 Retention of Source Documents Concerning KHK7580 Concentration 
Measurements 
Source documents concerning measurement of plasma KHK7580 concentrations will be retained at the 
laboratory where the measurement is performed. The retention period will be until the later of the 
following dates. Handling of source documents after the retention period will be discussed separately 
between the investigator and the sponsor. 
• The day on which five years have elapsed from the day of marketing approval for the study drug (or,
if the development is discontinued, the day on which three years have elapsed from the day on which
the notification was received that a decision to discontinue development had been made); or, the day
on which reexamination is completed if the drug must undergo reexamination after approval pursuant
to the provisions of the Pharmaceuticals and Medical Devices Act and the period until completion of
reexamination is more than five years
• The day on which three years have elapsed since discontinuation or completion of the study
22.6 Retention of Source Documents Concerning Clinical Laboratory Tests, etc. 
Source documents concerning clinical laboratory tests, etc. will be retained at the study site or the 
laboratory undertaking measurements. The retention period will be until the later of the following dates. 
Handling of source documents after the retention period will be discussed separately between the 
investigator and the sponsor. 
• The day on which five years have elapsed from the day of marketing approval for the study drug (or,
if the development is discontinued, the day on which three years have elapsed from the day on which
the notification was received that a decision to discontinue development had been made); or, the day
on which reexamination is completed if the drug must undergo reexamination after approval pursuant
to the provisions of the Pharmaceuticals and Medical Devices Act and the period until completion of
reexamination is more than five years
• The day on which three years have elapsed since discontinuation or completion of the study
22.7 Retention of Biological Samples 
1） 
Samples collected for hematological examination will be retained and discarded in accordance 
with the standard operating procedures of                                                after completion of 
measurements. Samples collected for blood biochemistry and for diagnosis of diseases will be 
retained in accordance with the standard operating procedures of                                                , 
and kept for one year thereafter. 
2） 
Blood plasma for pharmacokinetic analysis will be retained at  
 until the final report is completed. 
After the retention period specified above, the sponsor will retain the samples on its own responsibility 
for up to 15 years after completion of the study, and will use them for future research related to KHK7580 
(research that does not involve acquisition of genetic information). 


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23 PUBLICATION OF STUDY RESULTS 
The investigator and subinvestigator should obtain prior approval from the sponsor if they publish the 
results of this study in academic conferences, journals, and the like. 


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24 RATIONALE FOR THE SETTINGS 


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25 STUDY ADMINISTRATIVE STRUCTURE 
See Attachment 1 of the protocol (supplementary volume). 
26 PRIMARY RESPONSIBILITIES OF THE INVESTIGATOR 
See Attachment 2 of the protocol (supplementary volume). 


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27 REFERENCES 


Signature Page for
Signature Page for
Approval