Clinical trial NCT04225923
Conditions: Cytomegalovirus Disease
Sponsor: Nobelpharma
Start date: 2020-06-01; Completion date: 2023-02-08
Enrollment: 87 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective is to assess the efficacy and safety of NPC-21 when administered prophylactically to cytomegalovirus (CMV) seronegative patients receiving a first kidney transplant from a CMV seropositive donor.

Detailed description:
This is a Phase 2, randomized, double-blind, placebo-controlled study of NPC-21 for kidney transplant recipients at high risk of CMV infection in the United States and Japan. Approximately 108 eligible patients will be randomized prior to first study drug administration to receive low-dose NPC 21, high-dose NPC-21, or placebo. Randomization will be stratified by region (United States or Japan)

Arms: arm 1: NPC-21 (6mg/kg) will be administered arm 2: NPC-21 (12mg/kg) will be administered arm 3: Placebo (normal saline) will be administered
Interventions: intervention 1: NPC-21 Low dose intervention 2: NPC-21 High dose intervention 3: NPC-21 Placebo
Intervention descriptions: intervention 1: NPC-21 will be administered via an approximately 60-minute intravenous infusion on Day 1 and at Week 4, 8, 12 intervention 2: NPC-21 will be administered via an approximately 60-minute intravenous infusion on Day 1 and at Week 4, 8, 12 intervention 3: Placebo will be administered via an approximately 60-minute intravenous infusion on Day 1 and at Week 4, 8, 12

Protocol documents:
Prot_000.pdf: 
 
CLINICAL STUDY PROTOCOL 
 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of 
NPC-21 for Kidney Transplant Recipients at High-Risk of 
Cytomegalovirus Infection 
(LionHeart21) 
Investigational Product: NPC-21 
Protocol Number: NPC-21-2 
IND Number: 145353 
 
 
Sponsor: 
Nobelpharma Co., Ltd. 
NMF Kayabacho Bldg., 1-17-24, Shinkawa 
Chuo-ku, Tokyo 104-0033, Japan 
Telephone: +81-3-6670-3800 
Fax: +81-3-6670-3801 
 
 
Version Number: 5.0 
Original Protocol: 27 November 2019 
Amendment 1: 18 February 2020 
Amendment 2: 17 July 2020 
Amendment 3: 16 April 2021 
Amendment 4: 18 October 2021 
 
 
Confidentiality Statement 
The information in this document is confidential and is not to be disclosed without the written 
consent of Nobelpharma Co., Ltd. except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical study for Nobelpharma Co., Ltd. 
You are allowed to disclose the contents of this document only to your Institutional Review 
Board or Independent Ethics Committee and study personnel directly involved with conducting 
this protocol. Persons to whom the information is disclosed must be informed that the 
information is confidential and proprietary to Nobelpharma Co., Ltd. and that it may not be 
further disclosed to third parties. 




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INVESTIGATOR AGREEMENT 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design and 
specific provision of this protocol and will make a reasonable effort to complete the study within 
the time designated. I will provide copies of this protocol and access to all information furnished 
by Nobelpharma Co., Ltd. to study personnel under my supervision. I will discuss this material 
with them to ensure they are fully informed about the study product and study procedures. I will 
let them know that this information is confidential and proprietary to Nobelpharma Co., Ltd. and 
that it may not be further disclosed to third parties. I understand that the study may be terminated 
or enrollment suspended at any time by Nobelpharma Co., Ltd., with or without cause, or by me 
if it becomes necessary to protect the best interests of the study patients. 
I agree to conduct this study in full accordance with Food and Drug Administration Regulations, 
Institutional Review Board/Independent Ethics Committee Regulations, International Council for 
Harmonisation Guidelines for Good Clinical Practices, and the Japanese Ministerial Ordinance on 
Good Clinical Practice for Drugs, where applicable.  
 
 
 
 
 
 
______________________________________________  
____________________ 
Investigator’s Signature 
 
 
 
 
 
Date 
 
 
 
______________________________________________ 
Investigator’s Printed Name 
 


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SYNOPSIS 
TITLE: A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of NPC-21 for Kidney 
Transplant Recipients at High-Risk of Cytomegalovirus Infection (LionHeart21) 
PROTOCOL NUMBER: NPC-21-2 
INVESTIGATIONAL PRODUCT: NPC-21 
PHASE: 2 
OBJECTIVE: 
The primary objective is to assess the efficacy and safety of NPC-21 when administered 
prophylactically to cytomegalovirus (CMV) seronegative patients receiving a first kidney 
transplant from a CMV seropositive donor. 
POPULATION: 
Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Male or female patients 18 to ≤75 (<76) years of age in the United States or 20 to 
≤75 (<76) years of age in Japan at the time of obtaining informed consent. 
2. Patients must be CMV seronegative pre-transplant and scheduled to receive or have received 
(within 7 days prior to first study drug administration) a first kidney transplant from a CMV 
seropositive donor.  
3. Patients must be willing and able to give written informed consent for participation in the 
study.  
4. Patients must be eligible to undergo kidney transplantation from a living or deceased donor, 
as per institutional standards.  
5. Female patients of non-childbearing potential must be either surgically sterile (hysterectomy, 
bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before 
Screening) or postmenopausal, defined as spontaneous amenorrhea for at least 2 years, with 
follicle-stimulating hormone in the postmenopausal range at Screening, based on the 
laboratory’s reference range.  
6. Female patients of childbearing potential (ie, not postmenopausal or surgically sterilized) must 
have a negative urine or serum pregnancy test result at Screening. Participating female patients 
of childbearing potential must agree to use 1 of the following throughout the duration of the 
study and for 90 days following the last study drug administration: 
o One highly effective method of contraception and an acceptable barrier method (condom 
used by male partner plus spermicide).  
o Two highly effective methods of contraception. 


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Investigators will select the appropriate methods of contraception in accordance with local 
regulatory requirements. Highly effective methods of contraception that result in a low failure 
rate (ie, <1% per year) when used consistently and correctly include the following: 
o Combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only 
hormonal contraception associated with inhibition of ovulation (oral, injectable, or 
implantable), intrauterine device, or intrauterine hormone-releasing system for at least 
12 weeks before Screening. 
o Bilateral tubal occlusion or vasectomized partner at least 26 weeks before Screening. 
Note: A vasectomized partner is a highly effective method of contraception, provided 
that the male partner is the sole sexual partner of the study patient who is a female of 
childbearing potential and that the vasectomized partner has received medical assessment 
of surgical success. 
o Sexual abstinence. 
Note: True abstinence, when in line with the preferred and usual lifestyle of the patient, 
is considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug treatment. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable methods of contraception.  
7. Male patients must agree to abstain from sperm donation and use condoms with spermicide 
during sexual intercourse between Screening and at least 90 days after administration of the 
last dose of study drug. Male patients must ensure nonpregnant female partners of childbearing 
potential comply with the contraception requirements in Inclusion Criterion 6.  
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Patients who have received a previous solid organ transplantation or hematopoietic stem cell 
transplantation. 
2. Patients who receive a multi-organ transplant.  
3. Patients who have CMV disease (CMV syndrome or tissue-invasive CMV disease) or CMV 
viremia (polymerase chain reaction [PCR] analysis or antigenemia testing in local laboratory 
meets the local criteria for CMV viremia) at Screening.  
4. Patients who have a positive donor-specific antibody within 90 days prior to Randomization 
confirmed via medical records.  
5. Patients whose body weight is more than 120 kg at Screening.  
Note: In case of hemodialysis patients, body weight is defined immediately after dialysis or 
dry weight. In case of peritoneal dialysis patients, body weight is defined after removal of 
dialysate or dry weight.  
Note: Body weight measured within 7 days prior to pre-Randomization is permitted.  


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6. Patients who have received the following anti-CMV therapy within 7 days prior to 
Randomization and/or plan to receive the following anti-CMV therapy during the study: 
o Anti-CMV agents (eg, foscarnet, ganciclovir, valganciclovir, letermovir, high dose 
acyclovir [≥500 mg/m2 intravenously every 8 hours, 10 mg/kg intravenously every 
8 hours or 800 mg orally 4 times a day], high dose valacyclovir [1000 mg orally 3 times 
a day], high dose famciclovir [500 mg orally every 8 hours], or cidofovir). 
Note: The use of anti-CMV agents per local standard of care during the Rescue Phase of 
the study is permitted.  
Note: The use of anti-herpes simplex virus and anti-varicella zoster virus prophylaxis for 
at-risk patients is recommended (as long as the doses are below the one specified above). 
7. Patients who have received the following therapy within 28 days prior to Randomization 
and/or plan to receive the following anti-CMV therapy during the study: 
o CMV hyperimmune globulin (eg, CytoGam®). 
o Intravenous immunoglobulin.  
o Plasmapheresis (receipt prior to first study drug administration is acceptable). 
8. Patients with a history of a serious drug allergy to proteins, immunoglobulins, transfusions, or 
vaccines or any excipient of the NPC-21 formulation. 
9. Patients with severe hepatic insufficiency at Screening (eg, Child-Pugh Class C). 
10. Patients with active and untreated hepatitis B virus or hepatitis C virus, as documented as part 
of the pre-transplant testing. 
11. Patients with known human immunodeficiency virus infection, based on medical records 
serology.  
12. Patients with any uncontrolled infection at Randomization or a history of serious and 
uncontrolled infection within 6 months prior to Randomization.  
13. Patients who are pregnant or lactating. 
14. Patients with a history of malignancy within 5 years prior to Randomization other than 
curatively treated in situ cervical carcinoma, cutaneous basal cell carcinoma, or cutaneous 
squamous cell carcinoma.   
15. Patients with a history of alcohol or drug abuse or dependence within 1 year prior to 
Randomization that, in the opinion of the Investigator, would preclude study participation. 
16. Patients who have previously participated in this study or any other study involving NPC-21. 
17. Patients who have previously participated or are currently participating in any study involving 
the administration of a CMV vaccine or another CMV investigational agent. 


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18. Patients who have participated in another interventional clinical study and received another 
investigational product (ie, not approved by the Food and Drug Administration in the United 
States or the Ministry of Health, Labour and Welfare in Japan) within 90 days before 
Randomization. 
19. Patients who are unable or unwilling, in the opinion of the Investigator, to comply with the 
protocol.    
STUDY DESIGN AND DURATION: 
This is a Phase 2, randomized, double-blind, placebo-controlled study of NPC-21 for kidney 
transplant recipients at high risk of CMV infection at approximately 25 clinical sites in the United 
States and Japan. Approximately 108 eligible patients will be randomized in a 4:1:4 ratio prior to 
first study drug administration to receive 6 mg/kg NPC-21, 12 mg/kg NPC-21, or placebo. 
Randomization will be stratified by region (United States or Japan). 
A schematic representing the study’s design is shown below:  
Adult CMV seronegative patients receiving a first kidney transplant from CMV seropositive 
donors will be enrolled in the study. Participation in the study will consist of a Screening Period 
(up to 14 days prior to first study drug administration), a 16-week Treatment Period, and a 12-week 
Observation Period. The total duration of the study (including Screening, Treatment Period, and 
Observation Period) will be approximately 30 weeks. After first study drug administration, 
patients who develop detectable CMV disease (CMV syndrome or tissue-invasive CMV disease) 
or CMV viremia (defined as the detection of ≥250 IU/mL in plasma measured by PCR analysis in 
central laboratory or meets the local criteria for CMV viremia measured by PCR analysis or 
antigenemia testing) can enter the Rescue Phase of the study and be treated by anti-CMV agents 
per local standard of care until the patient is negative for CMV viremia, has recovered from CMV 


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disease, or up to Week 28, whichever comes first. When this rescue therapy is completed, the 
Rescue Phase is terminated at least 4 Study Weeks after the last study drug administration and all 
Week 28 procedures will be performed as per the Early Termination Visit and Withdrawal 
Procedures.  
The 16-week Treatment Period will include study drug administration on Day 1 and at Weeks 4, 
8, and 12. The 16-week Treatment Period will begin as soon as practical post-transplant but no 
later than 7 days post-transplant.  
Blood samples will be collected at Screening; prior to study drug administration on dosing days 
(Day 1 and at Weeks 4, 8, and 12); and at Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 
19, 20, 21, 22, 23, 24, 26, and 28 for CMV deoxyribonucleic acid (DNA) analysis utilizing PCR 
analysis or CMV antigenemia testing. The central laboratory will perform CMV PCR analysis, 
and the local laboratory will perform CMV PCR analysis or CMV antigenemia testing consistently 
throughout the study. Upon entering the Rescue Phase, a blood sample will be collected for CMV 
DNA analysis utilizing PCR analysis performed by the central laboratory. 
Blood samples for anti–NPC-21 antibody testing will be collected prior to study drug 
administration on dosing days (Day 1 and at Weeks 4, 8, and 12) and at Weeks 16 and 28.  
Blood samples that will be stored for screening for resistant strains analysis will be collected prior 
to study drug administration on Day 1 and at Weeks 16 and 28 and at the initiation of the Rescue 
Phase.  
Blood samples for serum NPC-21 concentration measurements will be collected within 2 hours 
prior to study drug administration and at 2 hours (±30 minutes) following the beginning of the 
infusion on dosing days (Day 1 and at Weeks 4, 8, and 12) and at Weeks 1, 2, 3, 6, 10, 14, 16, 20, 
24, and 28 (Note: Sample collection time points at each visit may be updated based on each 
administration data).   
The EuroQol 5 Dimensions 5 Levels questionnaire (EQ-5D-5L) will be performed prior to study 
drug administration on Day 1, at Weeks 16 and 28, and at the initiation of the Rescue Phase.  
The safety of NPC-21 in CMV seronegative patients will be evaluated through physical 
examination findings, 12-lead electrocardiograms (ECGs), vital signs, changes in clinical 
laboratory assessments (blood biochemistry [including liver function tests and enzymes], 
hematology [including complete blood count with differential], coagulation, and urinalysis), and 
adverse event monitoring. 
DOSAGE FORMS AND ROUTE OF ADMINISTRATION: 
NPC-21 (at a dose of 6 or 12 mg/kg of actual body weight [at Screening]) or placebo (normal 
saline) will be administered via an approximately 60-minute (5 mL/minute) intravenous infusion 
on Day 1 and at Weeks 4, 8, and 12. 
EFFICACY VARIABLES:  
The primary efficacy endpoint is the incidence of CMV disease (CMV syndrome or 
tissue-invasive CMV disease) or CMV viremia (defined as the detection of ≥250 IU/mL in plasma 
measured by PCR analysis in central laboratory or meets the local criteria for CMV viremia 
measured by PCR analysis or antigenemia testing) by Week 16.    


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The secondary efficacy endpoints include the following: 
• Incidence of CMV disease or CMV viremia by Week 28  
• Incidence of CMV disease 
• Incidence of CMV viremia 
• Time to detectable CMV disease or CMV viremia 
• Time to detectable CMV disease 
• Time to detectable CMV viremia 
• Amount of CMV DNA by PCR analyzed by the central laboratory 
• Incidence and duration of anti-CMV therapy during the Rescue Phase 
• Changes in EQ-5D-5L score from Baseline to Weeks 16 and 28 
IMMUNOGENICITY VARIABLES: 
The immunogenicity of NPC-21 in CMV seronegative patients will be evaluated by anti–NPC-21 
antibody testing. Blood samples will be collected prior to study drug administration on dosing 
days (Day 1 and at Weeks 4, 8, and 12) and at Weeks 16 and 28 for anti–NPC-21 antibody 
measurements. Samples may be collected by home healthcare services (United States only) at 
non-dosing day visits. 
VIROLOGY VARIABLES: 
Antiviral resistance in CMV seronegative patients will be evaluated by resistant strains genotypic 
analysis. Blood samples will be stored for screening for resistant strains analysis and will be 
collected prior to study drug administration on Day 1, at Weeks 16 and 28, and at the initiation of 
the Rescue Phase. Samples may be collected by home healthcare services (United States only) at 
non-dosing day visits. The resistant strains analysis of blood samples from patients with treatment 
failure will be conducted in this Phase 2 study based on analysis study protocol.  
SAFETY VARIABLES: 
The safety of NPC-21 in CMV seronegative patients will be evaluated through physical 
examination findings, 12-lead ECGs, vital signs, changes in clinical laboratory assessments (blood 
biochemistry [including liver function tests and enzymes], hematology [including complete blood 
count with differential], coagulation, and urinalysis), and adverse event monitoring. 
STATISTICAL ANALYSES: 
Summary statistics will be presented by treatment group. Unless otherwise stated, continuous 
variables will be summarized by using the number of non-missing observations, arithmetic mean, 
standard deviation, median, minimum, and maximum values as descriptive statistics. Categorical 
variables will be summarized by using the frequency count, the percentage of patients with 
95% confidence intervals in each category as descriptive statistics. Statistical tests will be 2-sided 
at the α=0.05 significance level. The procedures for handling missing, unused, or spurious data, 


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along with the detailed method for analysis of each variable will be presented in the Statistical 
Analysis Plan. 
Changes in study visit schedules, missed or delayed visits, or patient discontinuations and the 
relationship to Coronavirus Disease 2019 (COVID-19) will be captured in the electronic Case 
Report Forms. Protocol deviations in study procedures due to COVID-19 will be reported in the 
Clinical Study Report. 
Analysis Populations 
The Intent-to-Treat Population will include all randomized patients. 
The modified Intent-to-Treat (mITT) Population will include all patients who receive a kidney 
transplant from a living or deceased donor and receive at least 1 dose of study drug 
(6 mg/kg NPC-21, 12 mg/kg NPC-21, or placebo). The mITT Population will be used for all 
efficacy analyses.  
The Pharmacokinetic (PK) Population will include all patients who receive any amount of study 
drug (6 mg/kg NPC-21, 12 mg/kg NPC-21, or placebo) and have evaluable PK data. The 
PK Population will be used for the PK analyses and exposure-response analyses.  
The Safety Population will include all randomized patients who receive at least 1 dose of study 
drug (NPC-21 or placebo). The Safety Population will be used for safety analyses. 
Analysis of Efficacy 
The mITT Population will be used for all efficacy analyses.  
The primary efficacy endpoint will be the proportion of patients with the occurrence of CMV 
disease (CMV syndrome or tissue-invasive CMV disease) or CMV viremia (defined as the 
detection of ≥250 IU/mL in plasma measured by PCR analysis in central laboratory or meets the 
local criteria for CMV viremia measured by PCR analysis or antigenemia testing) by Week 16.  
The primary efficacy endpoint will be summarized by treatment group and compared across 
placebo and the 6 mg/kg NPC-21 treatment group using a logistic regression analysis with 
stratification factor of region (United States or Japan) as a covariate.  
Other efficacy endpoints will be summarized descriptively by treatment group using the 
mITT Population.  
Analysis of Pharmacokinetics 
Serum concentrations of NPC-21 will be summarized using descriptive statistics. In addition, 
analysis of the concentration data as part of population-PK modeling will be described in a 
separate PK Analysis Plan and reported separately.  
Analysis of Exposure-Response 
Exposure-response analyses will be performed to propose target concentrations using PK 
parameters estimated by population-PK, efficacy variables, and biomarkers.  
Analysis of Safety 
The Safety Population will be used for all safety analyses. Safety will be summarized descriptively 
by treatment group.  


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Descriptive summary statistics will be provided for all safety variables, including 12-lead ECGs, 
vital signs, clinical laboratory assessments, and adverse events reported during the study.  
The number and percentage of patients experiencing treatment-emergent adverse events will be 
summarized. Summaries will be produced for each body system, as well as for each preferred term 
using the Medical Dictionary for Regulatory Activities. The number and percentage of patients 
experiencing serious adverse events will also be summarized. 
SAMPLE SIZE DETERMINATION: 
A total sample size of approximately 108 patients is planned for the study, with a 
1:1 randomization ratio for 6 mg/kg NPC-21 versus placebo and another 12 patients for high-level 
dose of 12 mg/kg NPC-21 (4:1:4 randomization ratio for 6 mg/kg NPC-21, 12 mg/kg NPC-21, or 
placebo). The sample size calculation is based on the mITT Population from the first dose of 
NPC-21 through Week 16 for the occurrence of CMV disease (CMV syndrome or tissue-invasive 
CMV disease) or CMV viremia (defined as the detection of ≥250 IU/mL in plasma measured by 
PCR analysis in central laboratory or meets the local criteria for CMV viremia measured by PCR 
analysis or antigenemia testing) primary endpoint. Assuming an early discontinuation rate of 15%, 
approximately 48 patients each in the 6 mg/kg NPC-21 and placebo arms are needed with a 2-sided 
significance level of 0.05 and a power of 80% to detect a difference between NPC-21 at a predicted 
incidence rate of CMV disease (CMV syndrome or tissue-invasive CMV disease) or CMV viremia 
of 30% versus 60% for placebo. In addition, a sample size of 12 patients for the 12 mg/kg NPC-21 
arm is considered adequate for the planned exposure-response analysis.  
SITES: Approximately 25 clinical sites in the United States and Japan 
SPONSOR: 
Nobelpharma Co., Ltd. 
NMF Kayabacho Bldg., 1-17-24, Shinkawa 
Chuo-ku, Tokyo 104-0033, Japan  
Telephone: +81-3-6670-3800 
Fax: +81-3-6670-3801 


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TABLE OF CONTENTS 
Signature Page ................................................................................................................................ 2 
Investigator Agreement ................................................................................................................... 3 
Synopsis .......................................................................................................................................... 4 
Table of Contents .......................................................................................................................... 12 
List of Figures ............................................................................................................................... 16 
List of Abbreviations and Definition of Terms............................................................................. 17 
1 Introduction and Background Information ............................................................................. 19 
1.1 
Rationale ........................................................................................................................ 21 
1.2 
Risk/Benefit ................................................................................................................... 23 
2 Study Objective ....................................................................................................................... 24 
2.1 
Primary Objective ......................................................................................................... 24 
3 Study Description.................................................................................................................... 25 
3.1 
Summary of Study Design ............................................................................................ 25 
4 Selection and Withdrawal of Patients ..................................................................................... 27 
4.1 
Inclusion Criteria ........................................................................................................... 27 
4.2 
Exclusion Criteria .......................................................................................................... 28 
4.3 
Withdrawal Criteria ....................................................................................................... 29 
5 Study Treatments .................................................................................................................... 32 
5.1 
Treatment Groups .......................................................................................................... 32 
5.2 
Rationale for Dosing ..................................................................................................... 32 
5.3 
Randomization and Blinding ......................................................................................... 32 
5.4 
Breaking the Blind ........................................................................................................ 33 
5.5 
Drug Supplies ................................................................................................................ 33 
5.5.1 Formulation and Packaging ............................................................................... 33 
5.5.2 Study Drug Preparation and Dispensing ........................................................... 33 
5.5.3 Study Drug Administration ............................................................................... 34 
5.5.4 Treatment Compliance ...................................................................................... 34 
5.5.5 Storage and Accountability ............................................................................... 34 
5.6 
Prior and Concomitant Medications and/or Procedures ................................................ 35 
5.6.1 Excluded Medications and/or Procedures ......................................................... 35 


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5.6.2 Coronavirus Disease 2019 Vaccination, Treatment, and Care .......................... 35 
5.6.3 Documentation of Prior and Concomitant Medication Use .............................. 35 
6 Study Procedures .................................................................................................................... 36 
6.1 
Informed Consent .......................................................................................................... 36 
6.2 
Screening Visit (Day -14 to Day -1) ............................................................................. 36 
6.3 
Pre-Randomization and Randomization ........................................................................ 37 
6.3.1 Pre-Randomization ............................................................................................ 37 
6.3.2 Randomization .................................................................................................. 37 
6.4 
Treatment Period (Day 1 to Day 113) ........................................................................... 37 
6.4.1 Day 1 ................................................................................................................. 38 
6.4.2 Weeks 1, 2, and 3 (Days 8, 15, and 22) ............................................................. 39 
6.4.3 Week 4 (Day 29) ............................................................................................... 39 
6.4.4 Weeks 5, 6, and 7 (Days 36, 43, and 50) ........................................................... 40 
6.4.5 Week 8 (Day 57) ............................................................................................... 40 
6.4.6 Weeks 9, 10, and 11 (Days 64, 71, and 78) ....................................................... 41 
6.4.7 Week 12 (Day 85) ............................................................................................. 42 
6.4.8 Weeks 13, 14, and 15 (Days 92, 99, and 106) ................................................... 43 
6.4.9 Week 16 (Day 113) ........................................................................................... 43 
6.5 
Observation Period (Day 114 to Day 197) .................................................................... 44 
6.5.1 Weeks 17, 18, and 19 (Days 120, 127, and 134) ............................................... 44 
6.5.2 Week 20 (Day 141) ........................................................................................... 44 
6.5.3 Weeks 21, 22, and 23 (Days 148, 155, and 162) ............................................... 45 
6.5.4 Week 24 (Day 169) ........................................................................................... 45 
6.5.5 Week 26 (Day 183) ........................................................................................... 46 
6.5.6 Week 28 (Day 197) ........................................................................................... 46 
6.6 
Rescue Phase ................................................................................................................. 47 
6.7 
Early Termination Visit and Withdrawal Procedures ................................................... 48 
7 Efficacy Assessments.............................................................................................................. 49 
7.1 
Primary Efficacy Endpoint ............................................................................................ 49 
7.2 
Secondary Efficacy Endpoints ...................................................................................... 49 
7.3 
Cytomegalovirus Deoxyribonucleic Acid and Antigenemia Test ................................. 49 
7.4 
EuroQol 5 Dimensions 5 Levels Questionnaire ............................................................ 49 


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8 Immunogenicity and Virology Assessments .......................................................................... 50 
8.1 
Anti–NPC-21 Antibody ................................................................................................. 50 
8.2 
Screening for Resistant Strains Analysis ...................................................................... 50 
9 Safety Assessments ................................................................................................................. 51 
9.1 
Adverse Events .............................................................................................................. 51 
9.1.1 Adverse (Drug) Reaction .................................................................................. 52 
9.1.2 Unexpected Adverse Drug Reaction ................................................................. 52 
9.1.3 Assessment of Adverse Events by the Investigator .......................................... 52 
9.1.4 Adverse Events of Special Interest .................................................................... 53 
9.2 
Serious Adverse Events ................................................................................................. 54 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators ................................ 54 
9.4 
Pregnancy Reporting ..................................................................................................... 55 
9.5 
Expedited Reporting ...................................................................................................... 56 
9.6 
Special Situation Reports .............................................................................................. 56 
9.7 
Clinical Laboratory Evaluations .................................................................................... 57 
9.8 
Vital Signs ..................................................................................................................... 57 
9.9 
Electrocardiograms ........................................................................................................ 57 
9.10 Physical Examinations .................................................................................................. 57 
9.11 Cytomegalovirus Serology ............................................................................................ 58 
9.12 Serum NPC-21 Concentration Measurement ................................................................ 58 
10 Statistics .................................................................................................................................. 59 
10.1 Analysis Populations ..................................................................................................... 59 
10.2 Statistical Methods ........................................................................................................ 59 
10.2.1 Analysis of Efficacy .......................................................................................... 59 
10.2.2 Analysis of Pharmacokinetics ........................................................................... 60 
10.2.3 Analysis of Exposure-Response ........................................................................ 60 
10.2.4 Analysis of Safety ............................................................................................. 60 
10.2.5 Interim Analysis ................................................................................................ 60 
10.2.6 Data and Safety Monitoring Board ................................................................... 60 
10.2.7 Sample Size Determination ............................................................................... 60 
11 Data Management and Record Keeping ................................................................................. 62 
11.1 Data Management ......................................................................................................... 62 


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11.1.1 Data Handling ................................................................................................... 62 
11.1.2 Computer Systems ............................................................................................. 62 
11.1.3 Data Entry ......................................................................................................... 62 
11.1.4 Medical Information Coding ............................................................................. 62 
11.1.5 Data Validation ................................................................................................. 62 
11.2 Record Keeping ............................................................................................................. 62 
12 Investigator Requirements and Quality Control ..................................................................... 63 
12.1 Ethical Conduct of the Study ........................................................................................ 63 
12.2 Institutional Review Board/Independent Ethics Committee ......................................... 63 
12.3 Informed Consent .......................................................................................................... 63 
12.4 Subject Card .................................................................................................................. 63 
12.5 Study Monitoring Requirements ................................................................................... 64 
12.6 Disclosure of Data ......................................................................................................... 64 
12.7 Retention of Records ..................................................................................................... 64 
12.8 Publication Policy ......................................................................................................... 65 
12.9 Financial Disclosure ...................................................................................................... 65 
12.10 Insurance and Indemnity ............................................................................................... 65 
12.11 Legal Aspects ................................................................................................................ 65 
13 Study Administrative Information .......................................................................................... 66 
13.1 Protocol Amendments ................................................................................................... 66 
14 References ............................................................................................................................... 67 
Appendix A: Schedule of Procedures ........................................................................................... 70 
Appendix B: Clinical Laboratory Analytes .................................................................................. 74 
Appendix C: The Definition of Cytomegalovirus Syndrome ....................................................... 76 
Appendix D: The Definitions of Cytomegalovirus Disease ......................................................... 77 


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LIST OF FIGURES 
Figure 1. Study Schematic.......................................................................................................... 25 
Figure 2. Home Healthcare Services .......................................................................................... 36 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS  
Abbreviation 
Definition 
aa 
Amino acids 
AD 
Antigenic domain 
ADR 
Adverse drug reaction 
AESI 
Adverse event of special interest 
AUC 
Area under the concentration-time curve 
CFR 
Code of Federal Regulations 
CMV 
Cytomegalovirus 
COVID-19 
Coronavirus Disease 2019 
CRA 
Clinical research associate 
CTA 
Clinical trial authorization 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
EDC 
Electronic data capture 
EIU 
Exposure In Utero 
EQ-5D-5L 
EuroQol 5 Dimensions 5 Levels questionnaire 
FDA 
Food and Drug Administration 
FSH 
Follicle-stimulating hormone 
gB 
Glycoprotein B 
GCP 
Good Clinical Practice 
GCV 
Ganciclovir 
hCMV 
Human cytomegalovirus 
HSCT 
Hematopoietic stem cell transplantation 
HSV 
Herpes simplex virus 
IC50 
50% inhibitory concentration 
IC90 
90% inhibitory concentration 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IgG1 
Immunoglobulin G1 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IVIg 
Intravenous immunoglobulin 
mITT 
Modified Intent-to-Treat 


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Abbreviation 
Definition 
NIMP 
Non-investigational medicinal product  
(Note: Except for NPC-21 for this study) 
PCR 
Polymerase chain reaction 
PK 
Pharmacokinetic(s) 
SAE 
Serious adverse event 
SAR 
Serious adverse reaction 
SOT 
Solid organ transplant 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
t1/2 
Half-life 
VGCV 
Valganciclovir 
VZV 
Varicella zoster virus 
WHO 
World Health Organization 


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1 
INTRODUCTION AND BACKGROUND INFORMATION  
Human cytomegalovirus (hCMV) is a member of the Herpesviridae family double-stranded 
deoxyribonucleic acid (DNA) viruses that become latent in host cells after acute infection. 
Cytomegalovirus (CMV) infection is ubiquitous and high seroprevalence has been reported in 
worldwide populations. In the United States, CMV seroprevalence ranges from 40% to 80%.1,2,3 
Cytomegalovirus infection is usually harmless, except in the fetus and the immunocompromised 
host. In the immunocompromised host, primary infection, reinfection, or reactivation of latent 
virus can cause significant morbidity and mortality. Persons undergoing a solid organ transplant 
(SOT) are particularly susceptible to both primary infection and reactivation of CMV as a result 
of the pharmacologic immunosuppression used to prevent graft rejection. 
Cytomegalovirus entry into host cells requires the stepwise coordination of multiple virus-encoded 
envelope proteins. Following viral attachment, which is mediated by interactions between the 
CMV glycoprotein M/glycoprotein N complex and host heparin sulfate proteoglycans,4,5 the virus 
envelope fuses with cellular membranes through the combination of glycoprotein B (gB) and 
glycoprotein H/glycoprotein L complexes. Glycoprotein B is essential for the attachment, entry, 
fusion, and cell-to-cell spread of CMV.5 In addition, gB is the dominant antigen on the CMV 
envelope, and close to 100% of CMV infected individuals develop antibodies against this 
glycoprotein.6 Antibody preadsorption experiments with recombinant-derived gB have shown that 
in some human sera, a considerable fraction of the neutralizing response is directed against gB.6,7 
Three antigenic sites, antigenic domain (AD)-1, AD-2, and AD-3, have been identified in gB and 
consist of amino acids (aa) 552 to 635, aa 50 to 77, and aa 783 to 906, respectively.8,9,10 Antigenic 
domain 1 is highly conserved among clinical CMV strains and is an essential structural domain 
for gB function.11,12,13 The majority of gB-specific antibodies that develop during natural CMV 
infection are directed against AD-1,14 and antibodies that bind to AD-1 can have virus-neutralizing 
capacity. 15 , 16  Therefore, AD-1 of CMV gB is a potential candidate region in targeting a 
neutralizing prophylactic and therapeutic antibody against CMV infection. 
Human cytomegalovirus is usually transmitted as an inapparent infection during infancy and 
establishes a latent infection in T-lymphocytes, monocytes, macrophage cells, or salivary glands. 
When infected with hCMV for the first time during puberty or later, hCMV infection manifests as 
infectious mononucleosis-like symptoms, such as fever, swollen lymph nodes, and abnormal 
hepatic function. However, individuals with reduced immunity, such as those with acquired 
immunodeficiency, malignant tumors, SOT, and hematopoietic stem cell transplantation (HSCT), 
develop significant symptoms, such as pneumonia, retinitis, gastroenteritis, and encephalitis, 
resulting in a poor prognosis. 
The morbidity and mortality associated with CMV infection are secondary to both the direct and 
the indirect effects of CMV. Cytomegalovirus infection can result in CMV disease, both CMV 
syndrome and CMV tissue-invasive disease. The highest risk of CMV disease occurs in CMV 
seronegative recipients of an organ from a CMV seropositive donor. Nearly 40,000 SOTs occur in 
the United States each year.17 The most common organ transplanted is the kidney, followed by the 
liver. Because of the immunosuppression required to prevent rejection of the graft, the host is 
predisposed to infections. Like HSCT recipients, CMV is one of the most important viral infections 
occurring in SOT. Not only is infection a risk factor for CMV disease, including CMV viral 
syndrome and tissue-invasive disease, it is also an independent risk factor for secondary 
bacteremia, Epstein-Barr virus-mediated, post-transplant lymphoproliferative disorder and 


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allograft injury.18 Peak viral load, rate of increase of viral load, and a threshold level of viremia 
have all been associated with risk for CMV disease.19 Highest risk persons for CMV infection and 
disease are those that are seronegative recipients paired with a seropositive organ donor. However, 
seropositive recipients are also at risk for disease. 
In SOT recipients, hCMV is a causative virus for morbidity and mortality within 6 months of the 
transplant.20,21 In addition, hCMV has been reported to be involved in the risk of developing 
allograft injury or rejection22,23 and opportunistic infections.24 In addition, it has been reported that 
in transplant recipients not receiving prophylaxis or preemptive treatment, the overall incidence of 
symptomatic CMV infections reached 40% to 60%, with the incidence and severity being highest 
among hCMV seronegative recipients transplanted from hCMV seropositive donors.25 In HSCT 
recipients, CMV seropositive recipients are at the highest risk for the development of CMV 
infection regardless of the donor’s CMV serostatus. Without intervention, approximately 80% of 
CMV seropositive HSCT patients will experience CMV infection (viremia) and approximately 
30% of patients with CMV viremia will develop CMV disease.26 
Human cytomegalovirus infection causes organ damage (direct effect) after the stage of hCMV 
viremia, and affects chronic inflammation and the immune system, leading to acute rejection and 
the development of new infections (indirect effect). Prevention of hCMV infection is thus critically 
important for successful organ transplantation. The mainstay in clinical practice is prophylaxis or 
preemptive treatment with antiviral drugs given transplantation in SOT and HSCT recipients. The 
first-line antiviral drug used in the treatment is ganciclovir (GCV) or valganciclovir (VGCV). 
However, the use of GCV, VGCV, and other antiviral drugs raises concerns about serious adverse 
drug reactions (ADRs), such as bone marrow depression and renal disorder as well as the 
development of GCV-resistant strains.27 As an alternative approach, CMV antibodies have been 
used successfully to treat CMV-induced disease. For example, CMV hyperimmunoglobulin has 
demonstrated efficacy in certain SOT recipients,28 and a more recent study found that pooled 
human immunoglobulin G products from CMV-positive individuals are effective in protecting 
infants from congenital CMV infection. 29 Likewise, letermovir, a CMV agent intended for 
prophylaxis, became available recently for use in allogeneic HSCT patients, but its potential risks 
of drug interaction with immunosuppressive agents and antiviral resistance may limit treatment 
options. 30  Therefore, the development of a novel drug that provides an effective and safe 
alternative or addition to current CMV therapies is necessary. 
NPC-21 is a human monoclonal immunoglobulin G1 (IgG1) lambda against the AD-1 on hCMV 
gB. Antigenic domain 1, the dominant antigen of the hCMV envelope, is reported to exhibit little 
sequence variation in clinical isolates of hCMV.13 A cell clone that produces NPC-21 was selected 
from B-lymphocytes isolated from peripheral blood of a healthy individual with a history of CMV 
infection. NPC-21 is produced by recombinant DNA technology in Chinese hamster ovary cells. 
NPC-21 has been demonstrated in vitro to inhibit infection of a cultivated CMV strain in the 
pharmacology study using ARPE-19 cell (epidermal cell line). 
NPC-21 is a non-immunomodulatory human monoclonal antibody with a relatively safe 
toxicological profile, causing no deaths and producing only mild reversible changes in 
hematological parameters (ie, decreased erythrocyte count, hematocrit value, and hemoglobin 
concentration) following repeated dosing in monkeys. Additionally, no cross reactivity was seen 
in a study of cross reactivity in human and monkey tissue. Although these changes occurred at a 
dose with sufficient safety margins and after repeated doses, the hematology parameters will be 
carefully monitored in clinical studies. 


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A first-in-human study was conducted in 40 healthy Japanese and Caucasian male volunteers in 
which NPC-21 or placebo was infused over a duration of 60 minutes. This single ascending dose 
study confirmed tolerability of NPC-21 up to 20 mg/kg, with no serious adverse events (SAEs), 
ADRs, or withdrawals due to adverse events. Anti–NPC-21 antibodies were detected in some 
subjects, although all were found to be preexisting conditions. 
Taken together, nonclinical data and clinical data available to date support further clinical 
investigation of NPC-21 in the prevention of CMV disease.  
In March 2020, the Coronavirus Disease 2019 (COVID-19), caused by infection with severe acute 
respiratory syndrome coronavirus 2, was characterized as a pandemic by the World Health 
Organization (WHO). The COVID-19 pandemic impacted clinical studies worldwide due to 
quarantines, site closures, travel limitations, diversion of resources, and/or general interruptions in 
study-related procedures.  
This study protocol includes contingency measures to manage disruptions due to COVID-19; see 
Section 5.6.2 for information regarding acceptable COVID-19 vaccines and medications and 
Sections 6, 7.3, 7.4, 8.1, 8.2, 9.7, 9.8, 9.9, 9.10, and 9.12 and Appendix A for details on procedures 
that may be performed by home healthcare services (United States only) due to COVID-19 
restrictions or other concerns, such as the need to avoid risks of COVID-19 infection. The impacts 
of these implemented contingency measures on the outcomes of this study, including any protocol 
deviations that result from COVID-19 illness and/or COVID-19 control measures will be 
discussed in the Clinical Study Report. 
1.1 
Rationale 
NPC-21 is a fully human monoclonal antibody that targets the AD-1 on hCMV surface gB. Based 
on binding affinity to the AD-1 and potency of neutralization, a cell clone that expresses NPC-21 
was selected from B-lymphocytes isolated from the peripheral blood of a healthy individual with 
a history of hCMV infection. NPC-21 is composed of two heavy chains (454 amino acid residues) 
and two light chains (216 amino acid residues) connected by inter-chain disulfide bonds. Chinese 
hamster ovary cells are used for the production of NPC-21, and the antibody secreted into the 
growth medium is subsequently purified through a series of filtration and chromatographic steps. 
The isotype and subclass of NPC-21 were identified as IgG1 lambda. NPC-21 is being developed 
for the prevention of CMV-associated disease. 
Human cytomegalovirus gB is a surface glycoprotein that spans the viral lipid bilayer envelope 
and is the principle envelope antigen essential for viral attachment, entry, fusion, and cell-to-cell 
transmission.5 Close to 100% of individuals who are infected with hCMV develop antibodies 
against gB.6 In antibody preadsorption experiments using recombinant-derived gB, results have 
shown that a considerable fraction of the neutralizing response, in some human sera, was directed 
against gB.6,7 
Based on analysis of multiple hCMV clinical isolates, AD-1 is a highly conserved immunogenic, 
external domain and is an essential structural domain for gB function.11,12,13 According to Schoppel 
et al, the majority of gB-specific antibodies that are induced by natural hCMV infection are 
directed against AD-1,14 and the antibodies that bind to AD-1 are often neutralizing.15,16 
NPC-21 acts by binding to AD-1 on the hCMV gB and blocking the essential processes of 
attachment, entry, fusion, and cell-to-cell spread of hCMV. NPC-21 neutralizes not only the 
reference laboratory strains AD169,31 Towne,32 and Davis,33 but also the clinical isolate Merlin,34 


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when cultured in human fibroblasts. The 50% inhibitory concentration (IC50) range was 0.015 to 
0.032 μg/mL, and the 90% inhibitory concentration (IC90) range was 0.086 to 0.51 μg/mL. 
Additionally, NPC-21 exhibited 682 to 1977 times more potent neutralization activities when the 
IC90 values for individual strains were compared to those for anti-CMV hyperimmunoglobulin 
(CytoGam®). Epithelial cells are a principal target for hCMV primary infection, and these cells are 
highly permissive for replication.35 Therefore, a strictly cell-associated mode of hCMV infection 
more accurately reflects the in vivo situation.36 Given this observation, the ability of NPC-21 to 
inhibit cell-to-cell transmission of epithelial cell-tropic hCMV clinical isolates was examined in 
human retinal pigment epithelial cells, ie, ARPE-19 cells. NPC-21 inhibited the cell-to-cell 
transmission of hCMV clinical isolates with an IC50 range of 1.0 to 3.1 μg/mL and an IC90 range 
of 13 to 19 μg/mL. In addition, an in vitro combination study indicated that the inhibitory effect 
of NPC-21 on hCMV plaque formation was additive or synergistic with the currently approved 
viral DNA polymerase inhibitors GCV, cidofovir, foscarnet, and acyclovir, suggesting that 
NPC-21 does not interfere with DNA polymerase inhibitor antiviral activity and can be potentially 
used as part of a combination therapy.  
Toxicity of NPC-21 was evaluated in compliance with Good Laboratory Practice regulations. 
Once weekly intravenous administration of NPC-21 in male and female cynomolgus monkeys at 
doses up to 100 mg/kg for 4 weeks (total of 4 doses) was well-tolerated. There were no deaths, 
and no adverse clinical signs attributable to NPC-21 treatment were observed in any animal. 
Treatment with NPC-21 doses of up to 100 mg/kg did not noticeably affect electrocardiography, 
blood pressure, or respiration rates, suggesting an absence of effects on cardiovascular and 
respiratory functions. In addition, NPC-21 doses of up to 100 mg/kg had no effects on the central 
nervous system.  
At the 100 mg/kg dose, reversible hematologic changes were observed at the end of the 4-week 
dosing period (a decreased erythrocyte count, hematocrit value, and hemoglobin concentration in 
3 of 12 animals, with an increased reticulocyte ratio in 2 of these animals). The increased or normal 
reticulocyte ratio and unchanged leukocyte counts in these animals suggested there were minimal 
toxicological effects on hematopoiesis. The possibility that NPC-21 had some effects on peripheral 
erythrocytes cannot be excluded. Thus, the no observed adverse effect level was considered to be 
50 mg/kg in both male and female monkeys. 
A first-in-human Phase 1 study of NPC-21 was conducted in 40 healthy Japanese and Caucasian 
male adults, in which a single administration of NPC-21 or placebo was infused over a duration of 
60 minutes. This single ascending dose study confirmed tolerability of NPC-21 up to 20 mg/kg. 
All adverse events were mild in severity. There were no SAEs, deaths, significant adverse events, 
or adverse events that led to treatment discontinuation. Anti–NPC-21 antibodies were detected in 
6 out of 40 individuals, but in all cases, the antibodies were present prior to administration of 
NPC-21.  
In the Phase 1 study, the maximum serum concentration, area under the concentration-time curve 
(AUC) from time 0 to the last measurable concentration, and the AUC from time 0 to infinity 
increased dose-dependently as was demonstrated by a linear regression analysis and a power model 
analysis. For other pharmacokinetic parameters (time to maximum serum concentration, half-life 
[t1/2], clearance, volume of distribution, mean residence time, and elimination rate constant), no 
significant difference between dose levels was observed. The t1/2 was estimated to be 612.30 to 
790.41 hours, and the elimination pattern was considered biphasic.  


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Nobelpharma Co., Ltd. proposes to continue the NPC-21 development program with a Phase 2, 
randomized, double-blind, placebo-controlled study in CMV seronegative patients undergoing a 
first kidney transplant from a CMV seropositive donor. Eligible patients will be randomized 
following kidney transplantation and will enter a 16-week Treatment Period, in which they will be 
randomized to NPC-21 6 mg/kg, NPC-21 12 mg/kg, or placebo on Day 1 and at Weeks 4, 8, and 
12 for 16 weeks (total of 4 infusions). Safety will be closely monitored throughout the duration of 
the study. At any time during the study, patients who develop detectable CMV viremia or CMV 
disease can enter the Rescue Phase of the study and be treated by standard preemptive CMV 
therapy.  
1.2 
Risk/Benefit 
Cytomegalovirus disease causes significant morbidity and mortality in transplant recipients. 
Prevention or treatment with directed antivirals or immunoglobulins is associated with toxicity 
and high cost, and does not eliminate all of the associated morbidities. The expected advantage of 
NPC-21, a human monoclonal antibody against the AD-1 on CMV gB, is superior safety profiles. 
NPC-21 binds to AD-1 specific on CMV gB to inhibit the cell-to-cell transmission of hCMV. 
Phase 1 study data indicate NPC-21 has been generally safe and well tolerated, although the 
number of subjects studied to date is relatively small. A total of 40 subjects (32 Japanese, 
8 Caucasian) were enrolled in the Phase 1 study. The study incorporated a total of 5 steps, 
consisting of 4 dose groups of 1, 3, 10, and 20 mg/kg for Japanese subjects, and 1 dose group of 
10 mg/kg for Caucasian subjects. Overall, NPC-21 was safe and well tolerated. There were no 
deaths or SAEs. A total of 23 adverse events in 16 subjects were all mild in severity and not related 
to the study drug. In addition, there were no adverse events leading to discontinuation or other 
significant adverse events. No particular correlation was found between the dose level of the test 
drug and the incidence of adverse events. When Japanese and Caucasian subjects were compared 
at the same dose level (10 mg/kg), the nature and pattern of adverse events were comparable, 
showing no obvious difference between the 2 races. Laboratory related adverse events were also 
reported but all were mild in severity and judged not related to the study drug. Anti–NPC-21 
antibody was detected in 6 subjects, but 1 subject was from the placebo group and, in all cases, the 
antibodies were present prior to administration of NPC-21. There was no tendency toward increase 
in antibody concentration after the study treatment. 
In the Phase 1 single dose study, no conditions suggestive of anaphylaxis associated with NPC-21 
were observed. Serious hypersensitivity reactions, such as anaphylaxis, have been reported with 
the use of other antibody drugs. Therefore, the possibility of such reactions to NPC-21, an antibody 
drug, cannot be ruled out. 


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2 
STUDY OBJECTIVE 
2.1 
Primary Objective 
The primary objective is to assess the efficacy and safety of NPC-21 when administered 
prophylactically to CMV seronegative patients receiving a first kidney transplant from a CMV 
seropositive donor. 
 


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3 
STUDY DESCRIPTION 
3.1 
Summary of Study Design 
This is a Phase 2, randomized, double-blind, placebo-controlled study of NPC-21 for kidney 
transplant recipients at high risk of CMV infection at approximately 25 clinical sites in the 
United States and Japan. Approximately 108 eligible patients will be randomized in a 4:1:4 ratio 
prior to first study drug administration to receive 6 mg/kg NPC-21, 12 mg/kg NPC-21, or placebo. 
Randomization will be stratified by region (United States or Japan). 
Figure 1 displays a schematic of the study’s design. 
Figure 1. Study Schematic 
 
Adult CMV seronegative patients receiving a first kidney transplant from CMV seropositive 
donors will be enrolled in the study. Participation in the study will consist of a Screening Period 
(up to 14 days prior to first study drug administration), a 16-week Treatment Period, and a 12-week 
Observation Period. The total duration of the study (including Screening, Treatment Period, and 
Observation Period) will be approximately 30 weeks. After first study drug administration, 
patients who develop detectable CMV disease (CMV syndrome or tissue-invasive CMV disease) 
or CMV viremia (defined as the detection of ≥250 IU/mL in plasma measured by polymerase chain 
reaction [PCR] analysis in central laboratory or meets the local criteria for CMV viremia measured 
by PCR analysis or antigenemia testing) can enter the Rescue Phase of the study and be treated by 
anti-CMV agents per local standard of care until the patient is negative for CMV viremia, has 
recovered from CMV disease, or up to Week 28, whichever comes first. When this rescue therapy 
is completed, the Rescue Phase is terminated at least 4 Study Weeks after the last study drug 
administration and all Week 28 procedures will be performed as per Section 6.7 Early Termination 
Visit and Withdrawal Procedures. 


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The 16-week Treatment Period will include study drug administration on Day 1 and at Weeks 4, 
8, and 12. The 16-week Treatment Period will begin as soon as practical post-transplant but no 
later than 7 days post-transplant.  
Blood samples will be collected at Screening; prior to study drug administration on dosing days 
(Day 1 and at Weeks 4, 8, and 12); and at Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 
19, 20, 21, 22, 23, 24, 26, and 28 for CMV DNA analysis utilizing PCR analysis or CMV 
antigenemia testing. The central laboratory will perform CMV PCR analysis, and the local 
laboratory will perform CMV PCR analysis or CMV antigenemia testing consistently throughout 
the study. Upon entering the Rescue Phase, a blood sample will be collected for CMV DNA 
analysis utilizing PCR analysis performed by the central laboratory.  
Blood samples for anti–NPC-21 antibody testing will be collected prior to study drug 
administration on dosing days (Day 1 and at Weeks 4, 8, and 12) and at Weeks 16 and 28.  
Blood samples that will be stored for screening for resistant strains analysis will be collected prior 
to study drug administration on Day 1 and at Weeks 16 and 28 and at the initiation of the Rescue 
Phase.  
Blood samples for serum NPC-21 concentration measurements will be collected within 2 hours 
prior to study drug administration and at 2 hours (±30 minutes) following the beginning of the 
infusion on dosing days (Day 1 and at Weeks 4, 8, and 12) and at Weeks 1, 2, 3, 6, 10, 14, 16, 20, 
24, and 28 (Note: Sample collection time points at each visit may be updated based on each 
administration data).   
The EuroQol 5 Dimensions 5 Levels questionnaire (EQ-5D-5L) will be performed prior to study 
drug administration on Day 1, at Weeks 16 and 28, and at the initiation of the Rescue Phase.  
The safety of NPC-21 in CMV seronegative patients will be evaluated through physical 
examination findings, 12-lead electrocardiograms (ECGs), vital signs, changes in clinical 
laboratory assessments (blood biochemistry [including liver function tests and enzymes], 
hematology [including complete blood count with differential], coagulation, and urinalysis), and 
adverse event monitoring. 


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4 
SELECTION AND WITHDRAWAL OF PATIENTS  
4.1 
Inclusion Criteria 
Patients who meet all of the following criteria will be eligible to participate in the study: 
1. Male or female patients 18 to ≤75 (<76) years of age in the United States or 20 to 
≤75 (<76) years of age in Japan at the time of obtaining informed consent. 
2. Patients must be CMV seronegative pre-transplant and scheduled to receive or have received 
(within 7 days prior to first study drug administration) a first kidney transplant from a CMV 
seropositive donor.  
3. Patients must be willing and able to give written informed consent for participation in the study.  
4. Patients must be eligible to undergo kidney transplantation from a living or deceased donor, as 
per institutional standards.  
5. Female patients of non-childbearing potential must be either surgically sterile (hysterectomy, 
bilateral tubal ligation, salpingectomy, and/or bilateral oophorectomy at least 26 weeks before 
Screening) or postmenopausal, defined as spontaneous amenorrhea for at least 2 years, with 
follicle-stimulating hormone (FSH) in the postmenopausal range at Screening, based on the 
laboratory’s reference range.  
6. Female patients of childbearing potential (ie, not postmenopausal or surgically sterilized) must 
have a negative urine or serum pregnancy test result at Screening. Participating female patients 
of childbearing potential must agree to use 1 of the following throughout the duration of the 
study and for 90 days following the last study drug administration: 
o One highly effective method of contraception and an acceptable barrier method (condom 
used by male partner plus spermicide). 
o Two highly effective methods of contraception.  
Investigators will select the appropriate methods of contraception in accordance with local 
regulatory requirements. Highly effective methods of contraception that result in a low failure 
rate (ie, <1% per year) when used consistently and correctly include the following: 
o Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation (oral, intravaginal, or transdermal), progestogen-only hormonal 
contraception associated with inhibition of ovulation (oral, injectable, or implantable), 
intrauterine device, or intrauterine hormone-releasing system for at least 12 weeks before 
Screening. 
o Bilateral tubal occlusion or vasectomized partner at least 26 weeks before Screening. 
Note: A vasectomized partner is a highly effective method of contraception, provided that 
the male partner is the sole sexual partner of the study patient who is a female of 
childbearing potential and that the vasectomized partner has received medical assessment 
of surgical success. 


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o Sexual abstinence. 
Note: True abstinence, when in line with the preferred and usual lifestyle of the patient, is 
considered a highly effective method only if defined as refraining from heterosexual 
intercourse during the entire period of risk associated with the study drug treatment. 
Periodic abstinence (eg, calendar, ovulation, symptothermal, postovulation methods) and 
withdrawal are not acceptable methods of contraception.  
7. Male patients must agree to abstain from sperm donation and use condoms with spermicide 
during sexual intercourse between Screening and at least 90 days after administration of the 
last dose of study drug. Male patients must ensure nonpregnant female partners of childbearing 
potential comply with the contraception requirements in Inclusion Criterion 6.  
4.2 
Exclusion Criteria 
Patients who meet any of the following criteria will be excluded from participation in the study: 
1. Patients who have received a previous solid organ transplantation or HSCT. 
2. Patients who receive a multi-organ transplant.  
3. Patients who have CMV disease (CMV syndrome or tissue-invasive CMV disease) or CMV 
viremia (PCR analysis or antigenemia testing in local laboratory meets the local criteria for 
CMV viremia) at Screening.  
4. Patients who have a positive donor-specific antibody within 90 days prior to Randomization 
confirmed via medical records.  
5. Patients whose body weight is more than 120 kg at Screening.  
Note: In case of hemodialysis patients, body weight is defined immediately after dialysis or 
dry weight. In case of peritoneal dialysis patients, body weight is defined after removal of 
dialysate or dry weight.  
Note: Body weight measured within 7 days prior to pre-Randomization is permitted.  
6. Patients who have received the following anti-CMV therapy within 7 days prior to 
Randomization and/or plan to receive the following anti-CMV therapy during the study: 
o Anti-CMV agents (eg, foscarnet, GCV, VGCV, letermovir, high dose acyclovir 
[≥500 mg/m2 intravenously every 8 hours, 10 mg/kg intravenously every 8 hours or 
800 mg orally 4 times a day], high dose valacyclovir [1000 mg orally 3 times a day], high 
dose famciclovir [500 mg orally every 8 hours], or cidofovir). 
Note: The use of anti-CMV agents per local standard of care during the Rescue Phase of 
the study is permitted.   
Note: The use of anti-herpes simplex virus (HSV) and anti-varicella zoster virus (VZV) 
prophylaxis for at-risk patients is recommended (as long as the doses are below the one 
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7. Patients who have received the following therapy within 28 days prior to Randomization and/or 
plan to receive the following anti-CMV therapy during the study: 
o CMV hyperimmune globulin (eg, CytoGam®). 
o Intravenous immunoglobulin (IVIg).  
o Plasmapheresis (receipt prior to first study drug administration is acceptable). 
8. Patients with a history of a serious drug allergy to proteins, immunoglobulins, transfusions, or 
vaccines or any excipient of the NPC-21 formulation. 
9. Patients with severe hepatic insufficiency at Screening (eg, Child-Pugh Class C). 
10. Patients with active and untreated hepatitis B virus or hepatitis C virus, as documented as part 
of the pre-transplant testing. 
11. Patients with known human immunodeficiency virus infection, based on medical records 
serology.  
12. Patients with any uncontrolled infection at Randomization or a history of serious and 
uncontrolled infection within 6 months prior to Randomization.  
13. Patients who are pregnant or lactating. 
14. Patients with a history of malignancy within 5 years prior to Randomization other than 
curatively treated in situ cervical carcinoma, cutaneous basal cell carcinoma, or cutaneous 
squamous cell carcinoma.  
15. Patients with a history of alcohol or drug abuse or dependence within 1 year prior to 
Randomization that, in the opinion of the Investigator, would preclude study participation. 
16. Patients who have previously participated in this study or any other study involving NPC-21. 
17. Patients who have previously participated or are currently participating in any study involving 
the administration of a CMV vaccine or another CMV investigational agent. 
18. Patients who have participated in another interventional clinical study and received another 
investigational product (ie, not approved by the Food and Drug Administration [FDA] in the 
United States or the Ministry of Health, Labour and Welfare in Japan) within 90 days before 
Randomization. 
19. Patients who are unable or unwilling, in the opinion of the Investigator, to comply with the 
protocol.    
4.3 
Withdrawal Criteria 
Patients may be discontinued from study drug for any of the following reasons:  
• The patient no longer meets all inclusion criteria or meets any exclusion criteria and is found 
to be ineligible for participation through procedures (eg, medical examinations) performed 
after Randomization.  
• Occurrence of any medical condition or circumstance that exposes the patient to substantial 
risk and/or does not allow the patient to adhere to the requirements of the protocol. 


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• Any SAE, clinically significant adverse event, severe laboratory abnormality, intercurrent 
illness, or other medical condition that indicates to the Investigator that continued 
participation is not in the best interest of the patient. 
• Pregnancy. 
• Requirement of the following therapy: 
o CMV hyperimmune globulin (eg, CytoGam®). 
o IVIg. 
o Plasmapheresis.  
• Patient failure to comply with protocol requirements or study-related procedures and the 
Investigator considers it inappropriate to administer the study drug. 
• Initiation of Rescue Phase. 
Patients who discontinue study drug for any reason should be followed per the study schedule of 
events until the end of study participation.  
Participation of a patient in this clinical study may be discontinued for any of the following 
reasons: 
• The patient withdraws consent or requests discontinuation from the study for any reason. 
• Termination of the study by the Sponsor or the regulatory authority. 
• If a patient develops COVID-19 and is unable to continue with study visits and observations, 
the patient should be discontinued from the study and standard of care CMV treatment 
should be initiated, if necessary. If COVID-19 treatment will be provided to the patient, the 
Investigator should notify the Medical Monitor prior to study discontinuation, if possible. All 
patients should be followed for safety and resolution of COVID-19 infection. Patients who 
are able to complete study-related visits as an outpatient or via home healthcare services 
(United States only) or are inpatient and can receive study treatment will be allowed to 
continue to participate in the study if they do not receive any experimental treatments for 
COVID-19. 
In the case of patients lost to follow-up, attempts to contact the patient must be made and 
documented in the patient’s medical records. 
If a patient withdraws prematurely from the study due to the above criteria or any other reason, 
study staff should make every effort to complete the full panel of assessments scheduled for the 
End of Treatment visit (Week 28). The reason for patient withdrawal must be documented in the 
electronic Case Report Form (eCRF). 
Withdrawn patients will not be replaced.  
The Sponsor may consider immediately stopping or terminating the study for any of the following 
reasons:  
• Data and Safety Monitoring Board (DSMB) recommendation.  
• Grade 3 or higher infusion reactions are observed in >3 patients.  


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• Decision from a competent authority. 
• Lack of study drug supply.  


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5 
STUDY TREATMENTS 
5.1 
Treatment Groups 
Eligible patients will be randomized in a 4:1:4 ratio prior to first study drug administration to 1 of 
the following treatment groups:  
• NPC-21 (at a dose of 6 mg/kg of actual body weight [at Screening]) administered via an 
approximately 60-minute (5 mL/minute) intravenous infusion   
• NPC-21 (at a dose of 12 mg/kg of actual body weight [at Screening]) administered via an 
approximately 60-minute (5 mL/minute) intravenous infusion 
• Placebo (normal saline) administered via an approximately 60-minute (5 mL/minute) 
intravenous infusion 
5.2 
Rationale for Dosing 
NPC-21 at a dose of 6 or 12 mg/kg of actual body weight (at Screening) will be administered via 
an approximately 60-minute (5 mL/minute) intravenous infusion. These doses were determined 
based on the pharmacokinetic (PK) and safety and tolerability data up to 20 mg/kg from the 
Phase 1 single dose clinical study.  
From the inhibitory effect of NPC-21 on the cell-to-cell transmission of 8 hCMV clinical isolates, 
NPC-21 inhibited cell-to-cell transmission of all clinical hCMV isolates tested with IC90 range of 
13 to 19 µg/mL. The Sponsor concludes that NPC-21 is effective in the prevention of CMV 
infection when the trough concentration of NPC-21 is over 19 µg/mL. Based on simulations using 
the PK data from the Phase 1 study, it is assumed that 6 mg/kg once every 4 weeks will keep 
19 µg/mL at the lower limit of the 95% confidence interval at the trough of Day 29. A small cohort 
of 12 mg/kg NPC-21 has been added for exposure-response analysis.  
5.3 
Randomization and Blinding 
At Screening, a unique patient identification number will be established for each patient who has 
provided written informed consent. This patient identification number will be used for patient 
identification throughout the study and in all study-related documentation. This will be a 5 digit 
hyphenated number of the following format: XYY-ZZ, where X is the country number (1 [US] or 
2 [Japan]), YY is the sequential unique site identification number, and ZZ is a sequential unique 
number assigned to the patient at that site. Each patient number will be assigned only once and 
will not be reassigned to another patient if a patient fails during Screening. Interactive Response 
Technology (IRT) will not allow repeat of numbers. This unique identifier will be used in all study 
documentation for that patient from first to last contact.   
After informed consent and body weight are obtained, pre-Randomization will take place via the 
IRT system to 1 of 3 treatment groups (6 mg/kg NPC-21, 12 mg/kg NPC-21, or placebo) in a 
4:1:4 ratio. Randomization will be stratified by region (United States or Japan). Randomization 
will take place prior to first study drug administration after confirming all criteria. Randomization 
procedures may occur on Day -1 or Day 1 prior to first study drug administration.  
The Sponsor designee (eg, IRT vendor) will have a designated randomization administrator who 
will maintain the randomization codes in accordance with standard operating procedures to ensure 
the blind integrity is properly maintained. Care should be exercised to ensure that only study staff 




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Additional details regarding study drug preparation and dispensing are provided in the Pharmacy 
Manual.  
5.5.3 
Study Drug Administration 
Patients randomized to NPC-21 will be administered a dose of 6 or 12 mg/kg of actual body weight 
(at Screening) via an approximately 60-minute (5 mL/minute) intravenous infusion on Day 1 and 
at Weeks 4, 8, and 12.  
Patients randomized to placebo will be administered approximately 300 mL of normal saline via 
an approximately 60-minute (5 mL/minute) intravenous infusion on Day 1 and at Weeks 4, 8, 
and 12.  
Patients will be asked to remain at rest in the supine position, in principle, during study drug 
administration and should remain resting, in principle, from the end of study drug administration 
until the tests scheduled within 1 hour after study drug administration. 
If an adverse event, especially an infusion reaction, occurs during study drug administration and 
the Investigator deems it necessary, deceleration, suspension, or resumption of study drug 
administration is allowed. In case of a Grade 2 infusion reaction, study drug administration will be 
suspended and study drug administration will be resumed (flow rate will be 2.5 mL/minute) after 
recovery from the symptoms by treatments. In the case of a Grade 3 or higher infusion reaction, 
study drug administration will be terminated. Details will be entered in the eCRF. Refer to the 
Pharmacy Manual for more information.    
The day of administration as well as the administration start and end time will be entered in the 
eCRF.  
5.5.4 
Treatment Compliance 
Study drug will be administered intravenously by site staff. Dosing compliance will be recorded 
by the Investigator or designee at the site. The date and time of study drug administration will be 
recorded.  
5.5.5 
Storage and Accountability 
Records will be maintained indicating the receipt and dispensation of all study drug supplies. At 
the conclusion of the study, the clinical research associate (CRA) will conduct an unblinded review 
of study drug inventory, and the results will be recorded in the Drug Accountability Log. Any 
unused drug will be returned to the depot. If no study drug remains, this will be indicated in the 
Drug Accountability Log.  
Study drug will be stored at 
 in a secured area with access limited to authorized 
personnel. The unblinded site pharmacist will perform an ongoing inventory of study drug 
products on behalf of the Sponsor and must keep an accurate inventory of study drug shipments 
received and amount of study drug used per patient.  


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5.6 
Prior and Concomitant Medications and/or Procedures 
5.6.1 
Excluded Medications and/or Procedures 
The following anti-CMV therapies will be prohibited within 7 days prior to Randomization 
through the end of the study:  
• Anti-CMV agents (eg, foscarnet, GCV, VGCV, letermovir, high dose acyclovir [≥500 mg/m2 
intravenously every 8 hours, 10 mg/kg intravenously every 8 hours or 800 mg orally 4 times 
a day], high dose valacyclovir [1000 mg orally 3 times a day], high dose famciclovir [500 mg 
orally every 8 hours], or cidofovir). 
Note: The use of anti-CMV agents per local standard of care during the Rescue Phase of the 
study is permitted. 
Note: The use of anti-HSV and anti-VZV prophylaxis for at-risk patients is recommended (as 
long as the doses are below the one specified above).  
The following therapies will be prohibited within 28 days prior to Randomization through the end 
of the study: 
• CMV hyperimmune globulin (eg, CytoGam®) 
• IVIg 
• Plasmapheresis (receipt prior to first study drug administration is acceptable) 
5.6.2 
Coronavirus Disease 2019 Vaccination, Treatment, and Care 
The following COVID-19 vaccines and medications are acceptable: 
• It is acceptable for patients to receive COVID-19 vaccinations where emergency use 
authorization is given. COVID-19 vaccinations given to prevent COVID-19 infections must 
not be administered within 72 hours of the study drug administration. 
• Medications that are approved by regulatory authorities for other indications 
(eg, dexamethasone) may be given for COVID-19 infections while the patient is in the study. 
Experimental medications for COVID-19 infections will be excluded (eg, mesenchymal stem 
cells). 
5.6.3 
Documentation of Prior and Concomitant Medication Use 
All medications (including COVID-19 vaccinations) taken by the patient within 14 days prior to 
study drug administration on Day 1 will be recorded (COVID-19 vaccinations administered prior 
to informed consent will also be recorded). During the study, any medications (including 
COVID-19 vaccinations or medications) administered in addition to study drug, whether allowed 
per the protocol or not, must be documented in the eCRF. The drug name, start and end date(s), 
and indication will be recorded for all medications. Dosing information will also be recorded for 
immunosuppression therapy, induction therapy, and anti-CMV agents.  


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6 
STUDY PROCEDURES 
Adult CMV seronegative patients must be scheduled to receive or have received (within 7 days 
prior to first study drug administration) a first kidney transplant from a CMV seropositive donor. 
The 16-week Treatment Period will begin as soon as practical post-transplant but no later than 
7 days post-transplant. 
During the Treatment Period, visits on dosing days (Day 1 and at Weeks 4, 8, and 12) should be 
conducted in person.  
Home healthcare services (United States only) may be utilized for non-dosing day visits of the 
Treatment Period and Observation Period, as shown in Figure 2, and at Rescue Phase visits due to 
COVID-19 restrictions or other concerns, such as the need to avoid risks of COVID-19 infection.  
Home healthcare services may perform the following procedures at non-dosing day visits: record 
concomitant medications, obtain body weight, perform physical examination, record vital signs, 
collect samples for analysis by the central laboratory, perform 12-lead ECG, perform EQ-5D-5L, 
and record adverse events. See the study reference manual for details.  
Figure 2. Home Healthcare Services 
ET = Early Termination; HH = home healthcare. 
6.1 
Informed Consent 
Written informed consent for the study will be obtained from all patients before any study-specific 
procedures are performed. See Section 12.3 for details on informed consent.  
6.2 
Screening Visit (Day -14 to Day -1) 
The following procedures will be performed at the Screening Visit: 
• Obtain informed consent. 
• Perform pre-Randomization (see Section 6.3 for details).  
• Obtain demographics.  
• Obtain medical/surgical history and present illness. 
• Record prior and concomitant medications.  
• Obtain height.  
• Obtain body weight (prior to pre-Randomization). 
Note: In case of hemodialysis patients, body weight is defined immediately after dialysis or 
dry weight. In case of peritoneal dialysis patients, body weight is defined after removal of 
dialysate or dry weight.  


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Note: Body weight measured within 7 days prior to pre-Randomization is permitted. 
• Perform complete physical examination.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature).  
• Perform urine or serum pregnancy test for females of childbearing potential only.  
• Perform FSH test for females of non-childbearing potential only (if necessary).   
• Collect blood sample for CMV serology for analysis by the local laboratory (within 90 days 
of Randomization).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory.  
• Collect urine sample for urinalysis by the local laboratory (if possible).  
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory.  
• Perform 12-lead ECG.  
• Confirm patient meets all inclusion criteria and no exclusion criteria (until Randomization).  
• Perform Randomization if Randomization will occur on Day -1 (see Section 6.3 for details).  
• Record adverse events.  
6.3 
Pre-Randomization and Randomization 
6.3.1 
Pre-Randomization  
After informed consent and body weight are obtained, pre-Randomization will take place via the 
IRT system to 1 of 3 treatment groups (6 mg/kg NPC-21, 12 mg/kg NPC-21, or placebo) in a 
4:1:4 ratio. Randomization will be stratified by region (United States or Japan).  
6.3.2 
Randomization 
Randomization will take place prior to the first study drug administration after confirming all 
criteria. Randomization procedures may occur on Day -1 or Day 1 prior to first study drug 
administration. If the patient is found to be ineligible during Screening, the dropout procedures 
will be carried out promptly.  
6.4 
Treatment Period (Day 1 to Day 113) 
The 16-week Treatment Period will begin as soon as practical post-transplant but no later than 
7 days post-transplant. During the Treatment Period (excluding Day 1), visits and procedures will 
occur within ±3 days of the scheduled time. After first study drug administration, patients who 
develop detectable CMV disease (CMV syndrome [see Appendix C for definition of CMV 
syndrome] or tissue-invasive CMV disease [see Appendix D for definitions of CMV disease]) or 
CMV viremia (defined as the detection of ≥250 IU/mL in plasma measured by PCR analysis in 
central laboratory or meets the local criteria for CMV viremia measured by PCR analysis or 
antigenemia testing) can enter the Rescue Phase of the study and be treated by anti-CMV agents 
per local standard of care until the patient is negative for CMV viremia, has recovered from CMV 


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disease, or up to Week 28, whichever comes first. When this rescue therapy is completed, the 
Rescue Phase is terminated at least 4 Study Weeks after the last study drug administration and all 
Week 28 procedures will be performed as per Section 6.7 Early Termination Visit and Withdrawal 
Procedures. See Section 6.6 for a list of procedures to be performed upon entering the Rescue 
Phase.  
Note: During the Treatment Period, visits on dosing days (Day 1 and at Weeks 4, 8, and 12) should 
be conducted in person. Visits on non-dosing days of the Treatment Period (Weeks 1, 2, 3, 5, 6, 7, 
9, 10, 11, 13, 14, 15, and 16) may be conducted by home healthcare services (United States only).  
6.4.1 
Day 1 
The following procedures will be performed at Day 1: 
• Record prior and concomitant medications.  
• Obtain body weight (prior to study drug administration).  
• Perform complete physical examination (prior to study drug administration and within 1 hour 
of the end of the infusion).  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature) 
(prior to study drug administration and within 1 hour of the end of the infusion).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites) (prior to study drug 
administration).  
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (prior to study drug administration) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory (prior to study drug 
administration).  
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory (prior to study drug administration).  
• Collect blood samples that will be stored for screening for resistant strains analysis (prior to 
study drug administration).  
• Collect blood sample for serum NPC-21 concentration measurement (within 2 hours prior to 
study drug administration and at 2 hours [±30 minutes] following the beginning of the 
infusion).  
• Collect blood sample for anti–NPC-21 antibody measurement (prior to study drug 
administration).  
• Perform EQ-5D-5L (prior to study drug administration).  
• Perform Randomization (prior to study drug administration) if Randomization will occur on 
Day 1 (see Section 6.3 for details).  
• Administer NPC-21 (at a dose of 6 or 12 mg/kg of actual body weight [at Screening]) or 
placebo via an approximately 60-minute intravenous infusion at a constant rate of 
5 mL/minute.  


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Note: Patients will be asked to remain at rest in the supine position, in principle, during study 
drug administration and should remain resting, in principle, from the end of study drug 
administration until the tests scheduled within 1 hour after study drug administration. 
Note: If an adverse event occurs during study drug administration and the Investigator deems 
it necessary, deceleration, suspension, or resumption of study drug administration is allowed 
(see Section 5.5.3 for details).  
• Record adverse events.  
6.4.2 
Weeks 1, 2, and 3 (Days 8, 15, and 22) 
The following procedures will be performed at Weeks 1, 2, and 3 (Days 8, 15, and 22): 
• Record concomitant medications.  
• Perform complete physical examination.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites) (Weeks 1 and 2 only). 
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (Weeks 1 and 2 only) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory.  
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory.  
• Collect blood sample for serum NPC-21 concentration measurement. 
• Record adverse events. 
6.4.3 
Week 4 (Day 29) 
The following procedures will be performed at Week 4 (Day 29):  
• Record concomitant medications.  
• Obtain body weight (prior to study drug administration).  
• Perform complete physical examination (prior to study drug administration).  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature) 
(prior to study drug administration).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites) (prior to study drug 
administration).  
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (prior to study drug administration) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory (prior to study drug 
administration). 


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• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory (prior to study drug administration).  
• Collect blood sample for serum NPC-21 concentration measurement (within 2 hours prior to 
study drug administration and at 2 hours [±30 minutes] following the beginning of the 
infusion).  
• Collect blood sample for anti–NPC-21 antibody measurement (prior to study drug 
administration).  
• Perform 12-lead ECG (prior to study drug administration).  
• Administer NPC-21 (at a dose of 6 or 12 mg/kg of actual body weight [at Screening]) or 
placebo via an approximately 60-minute intravenous infusion at a constant rate of 
5 mL/minute.  
Note: Patients will be asked to remain at rest in the supine position, in principle, during study 
drug administration and should remain resting, in principle, from the end of study drug 
administration until the tests scheduled within 1 hour after study drug administration. 
Note: If an adverse event occurs during study drug administration and the Investigator deems 
it necessary, deceleration, suspension, or resumption of study drug administration is allowed 
(see Section 5.5.3 for details). 
• Record adverse events. 
6.4.4 
Weeks 5, 6, and 7 (Days 36, 43, and 50) 
The following procedures will be performed at Weeks 5, 6, and 7 (Days 36, 43, and 50): 
• Record concomitant medications.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites) (Week 6 only).  
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (Week 6 only) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory. 
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory.  
• Collect blood sample for serum NPC-21 concentration measurement (Week 6 only). 
• Record adverse events. 
6.4.5 
Week 8 (Day 57) 
The following procedures will be performed at Week 8 (Day 57):  
• Record concomitant medications.  
• Obtain body weight (prior to study drug administration).  


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• Perform complete physical examination (prior to study drug administration).  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature) 
(prior to study drug administration).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites) (prior to study drug 
administration).  
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (prior to study drug administration) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory (prior to study drug 
administration).  
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory (prior to study drug administration).  
• Collect blood sample for serum NPC-21 concentration measurement (within 2 hours prior to 
study drug administration and at 2 hours [±30 minutes] following the beginning of the 
infusion).  
• Collect blood sample for anti–NPC-21 antibody measurement (prior to study drug 
administration).  
• Perform 12-lead ECG (prior to study drug administration).  
• Administer NPC-21 (at a dose of 6 or 12 mg/kg of actual body weight [at Screening]) or 
placebo via an approximately 60-minute intravenous infusion at a constant rate of 
5 mL/minute.  
Note: Patients will be asked to remain at rest in the supine position, in principle, during study 
drug administration and should remain resting, in principle, from the end of study drug 
administration until the tests scheduled within 1 hour after study drug administration. 
Note: If an adverse event occurs during study drug administration and the Investigator deems 
it necessary, deceleration, suspension, or resumption of study drug administration is allowed 
(see Section 5.5.3 for details). 
• Record adverse events. 
6.4.6 
Weeks 9, 10, and 11 (Days 64, 71, and 78) 
The following procedures will be performed at Weeks 9, 10, and 11 (Days 64, 71, and 78): 
• Record concomitant medications.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites) (Week 10 only).  
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (Week 10 only) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory.  


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• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory.  
• Collect blood sample for serum NPC-21 concentration measurement (Week 10 only). 
• Record adverse events. 
6.4.7 
Week 12 (Day 85) 
The following procedures will be performed at Week 12 (Day 85):  
• Record concomitant medications.  
• Obtain body weight (prior to study drug administration).  
• Perform complete physical examination (prior to study drug administration).  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature) 
(prior to study drug administration).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites) (prior to study drug 
administration).  
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (prior to study drug administration) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory (prior to study drug 
administration).  
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory (prior to study drug administration).  
• Collect blood sample for serum NPC-21 concentration measurement (within 2 hours prior to 
study drug administration and at 2 hours [±30 minutes] following the beginning of the 
infusion).  
• Collect blood sample for anti–NPC-21 antibody measurement (prior to study drug 
administration).  
• Perform 12-lead ECG (prior to study drug administration).  
• Administer NPC-21 (at a dose of 6 or 12 mg/kg of actual body weight [at Screening]) or 
placebo via an approximately 60-minute intravenous infusion at a constant rate of 
5 mL/minute.  
Note: Patients will be asked to remain at rest in the supine position, in principle, during study 
drug administration and should remain resting, in principle, from the end of study drug 
administration until the tests scheduled within 1 hour after study drug administration. 
Note: If an adverse event occurs during study drug administration and the Investigator deems 
it necessary, deceleration, suspension, or resumption of study drug administration is allowed 
(see Section 5.5.3 for details). 
• Record adverse events. 


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6.4.8 
Weeks 13, 14, and 15 (Days 92, 99, and 106) 
The following procedures will be performed at Weeks 13, 14, and 15 (Days 92, 99, and 106): 
• Record concomitant medications.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites) (Week 14 only). 
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (Week 14 only) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory.  
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory.  
• Collect blood sample for serum NPC-21 concentration measurement (Week 14 only). 
• Record adverse events. 
6.4.9 
Week 16 (Day 113) 
The following procedures will be performed at Week 16 (Day 113):  
• Record concomitant medications.  
• Obtain body weight.  
• Perform complete physical examination.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites).  
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory. 
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory.  
• Collect blood sample for serum NPC-21 concentration measurement.  
• Collect blood sample for anti–NPC-21 antibody measurement.  
• Collect blood samples that will be stored for screening for resistant strains analysis.   
• Perform 12-lead ECG.  
• Perform EQ-5D-5L.  
• Record adverse events. 


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6.5 
Observation Period (Day 114 to Day 197) 
During the 12-week Observation Period, visits and procedures will occur within ±3 days of the 
scheduled time. After first study drug administration, patients who develop detectable CMV 
disease (CMV syndrome [see Appendix C for definition of CMV syndrome] or tissue-invasive 
CMV disease [see Appendix D for definitions of CMV disease]) or CMV viremia (defined as the 
detection of ≥250 IU/mL in plasma measured by PCR analysis in central laboratory or meets the 
local criteria for CMV viremia measured by PCR analysis or antigenemia testing) can enter the 
Rescue Phase of the study and be treated by anti-CMV agents per local standard of care until the 
patient is negative for CMV viremia, has recovered from CMV disease, or up to Week 28, 
whichever comes first. When this rescue therapy is completed, the Rescue Phase is terminated at 
least 4 Study Weeks after the last study drug administration and all Week 28 procedures will be 
performed as per Section 6.7 Early Termination Visit and Withdrawal Procedures. See Section 6.6 
for a list of procedures to be performed upon entering the Rescue Phase.  
Note: Home healthcare services (United States only) may be utilized at Weeks 17, 18, 19, 20, 21, 
22, 23, 24, 26, and 28.  
Note: During the 12-week Observation Period, visits at Weeks 17, 19, 21, and 23 may be missed 
due to unavoidable circumstances (eg, holidays, natural disasters). However, every attempt should 
be made to ensure a visit occurs. In this case, study staff will make contact with the patient to 
evaluate their condition, eg, review concomitant medications, any new adverse events since the 
last visit.   
6.5.1 
Weeks 17, 18, and 19 (Days 120, 127, and 134) 
The following procedures will be performed at Weeks 17, 18, and 19 (Days 120, 127, and 134): 
Note: During the 12-week Observation Period, visits at Weeks 17 and 19 may be missed due to 
unavoidable circumstances (eg, holidays, natural disasters). However, every attempt should be 
made to ensure a visit occurs. In this case, study staff will make contact with the patient to evaluate 
their condition, eg, review concomitant medications, any new adverse events since the last visit.   
• Record concomitant medications.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature).  
• Collect blood sample for CMV DNA analysis by the central laboratory.  
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory.  
Note: It is not necessary to collect blood samples for the local laboratory in the case home 
healthcare services (United States only) are utilized.  
• Record adverse events. 
6.5.2 
Week 20 (Day 141) 
The following procedures will be performed at Week 20 (Day 141): 
• Record concomitant medications.  
• Obtain body weight.  


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• Perform complete physical examination.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites).  
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory.  
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory.  
• Collect blood sample for serum NPC-21 concentration measurement.  
• Perform 12-lead ECG.  
• Record adverse events. 
6.5.3 
Weeks 21, 22, and 23 (Days 148, 155, and 162) 
The following procedures will be performed at Weeks 21, 22, and 23 (Days 148, 155, and 162): 
Note: During the 12-week Observation Period, visits at Weeks 21 and 23 may be missed due to 
unavoidable circumstances (eg, holidays, natural disasters). However, every attempt should be 
made to ensure a visit occurs. In this case, study staff will make contact with the patient to evaluate 
their condition, eg, review concomitant medications, any new adverse events since the last visit.   
• Record concomitant medications.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature).  
• Collect blood sample for CMV DNA analysis by the central laboratory.  
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory.  
Note: It is not necessary to collect blood samples for the local laboratory in the case home 
healthcare services (United States only) are utilized. 
• Record adverse events. 
6.5.4 
Week 24 (Day 169) 
The following procedures will be performed at Week 24 (Day 169): 
• Record concomitant medications.  
• Obtain body weight.  
• Perform complete physical examination.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature).  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites).  


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• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory.  
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory.  
• Collect blood sample for serum NPC-21 concentration measurement.  
• Perform 12-lead ECG.  
• Record adverse events. 
6.5.5 
Week 26 (Day 183) 
The following procedures will be performed at Week 26 (Day 183): 
• Record concomitant medications. 
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature). 
• Collect blood sample for CMV DNA analysis by the central laboratory. 
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory. 
Note: It is not necessary to collect blood samples for the local laboratory in the case home 
healthcare services (United States only) are utilized.  
• Record adverse events. 
6.5.6 
Week 28 (Day 197) 
The following procedures will be performed at Week 28 (Day 197): 
• Record concomitant medications. 
• Obtain body weight. 
• Perform complete physical examination.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature). 
• Perform urine or serum pregnancy test for females of childbearing potential only.  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites). 
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (if possible). 
• Collect blood sample for CMV DNA analysis by the central laboratory. 
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory. 
• Collect blood sample for serum NPC-21 concentration measurement. 


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• Collect blood sample for anti–NPC-21 antibody measurement. 
• Collect blood samples that will be stored for screening for resistant strains analysis. 
• Perform 12-lead ECG. 
• Perform EQ-5D-5L. 
• Record adverse events. 
6.6 
Rescue Phase 
After first study drug administration, patients who develop detectable CMV disease (CMV 
syndrome [see Appendix C for definition of CMV syndrome] or tissue-invasive CMV disease 
[see Appendix D for definitions of CMV disease]) or CMV viremia (defined as the detection of 
≥250 IU/mL in plasma measured by PCR analysis in central laboratory or meets the local criteria 
for CMV viremia measured by PCR analysis or antigenemia testing) can enter the Rescue Phase 
of the study and be treated by anti-CMV agents per local standard of care until the patient is 
negative for CMV viremia, has recovered from CMV disease, or up to Week 28, whichever comes 
first. When this rescue therapy is completed, the Rescue Phase is terminated at least 4 Study Weeks 
after the last study drug administration and all Week 28 procedures will be performed as per 
Section 6.7 Early Termination Visit and Withdrawal Procedures.  
Note: Collection of blood samples for serum NPC-21 concentration measurement at Weeks 4, 8, 
and 12 during the Rescue Phase will be handled in the same manner as visits without study drug 
administration. 
Note: If the patient is negative for CMV viremia or has recovered from CMV disease before 
4 Study Weeks have passed following last study drug administration, weekly scheduled visits are 
not required. The Rescue Phase visits may be conducted by home healthcare services (United 
States only). The Rescue Phase procedures may be performed at the next scheduled visit after 
detecting CMV viremia or CMV disease with or without anti-CMV agents per local standard of 
care. Some Investigators may prescribe anti-CMV agents (eg, VGCV) in advance and instruct the 
patient to start taking the drug as soon as possible for safety if the disease or viremia develops. If 
this is the case, the Rescue Phase procedures may be performed at the next scheduled visit.  
The following procedures will be performed upon entering the Rescue Phase:  
• Record the rescue in IRT. 
• Record concomitant medications. 
• Record the date and reason for entering the Rescue Phase. 
• Perform complete physical examination.  
• Collect blood sample for CMV DNA analysis by the central laboratory.  
• Collect blood samples that will be stored for screening for resistant strains analysis.  
• Perform EQ-5D-5L.  
• Record adverse events.    


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6.7 
Early Termination Visit and Withdrawal Procedures 
The end of treatment for patients completing the study is Week 28. For patients who are withdrawn 
from the study prior to completion, all Week 28 procedures will be performed at an Early 
Termination visit. The Early Termination visit may be conducted by home healthcare services 
(United States only). These procedures include the following:  
• Record concomitant medications.  
• Obtain body weight.  
• Perform complete physical examination.  
• Record vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature).  
• Perform urine or serum pregnancy test for females of childbearing potential only.  
• Collect blood samples for blood biochemistry, hematology, and coagulation for analysis by 
the local laboratory (Japan sites) and central laboratory (US sites).  
• Collect urine sample for urinalysis by the local laboratory (Japan sites) and central laboratory 
(US sites) (if possible).  
• Collect blood sample for CMV DNA analysis by the central laboratory.  
• Collect blood samples for CMV DNA analysis or CMV antigenemia testing for analysis by 
the local laboratory.  
• Collect blood sample for serum NPC-21 concentration measurement.  
• Collect blood sample for anti–NPC-21 antibody measurement.  
• Collect blood samples that will be stored for screening for resistant strains analysis.   
• Perform 12-lead ECG.  
• Perform EQ-5D-5L.  
• Record adverse events. 


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7 
EFFICACY ASSESSMENTS 
7.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the incidence of CMV disease (CMV syndrome [see Appendix C 
for definition of CMV syndrome] or tissue-invasive CMV disease [see Appendix D for definitions 
of CMV disease]) or CMV viremia (defined as the detection of ≥250 IU/mL in plasma measured 
by PCR analysis in central laboratory or meets the local criteria for CMV viremia measured by 
PCR analysis or antigenemia testing) by Week 16.  
7.2 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints include the following: 
• Incidence of CMV disease or CMV viremia by Week 28  
• Incidence of CMV disease 
• Incidence of CMV viremia 
• Time to detectable CMV disease or CMV viremia 
• Time to detectable CMV disease 
• Time to detectable CMV viremia 
• Amount of CMV DNA by PCR analyzed by the central laboratory 
• Incidence and duration of anti-CMV therapy during the Rescue Phase 
• Changes in EQ-5D-5L score from Baseline to Weeks 16 and 28 
7.3 
Cytomegalovirus Deoxyribonucleic Acid and Antigenemia Test 
Blood samples will be collected at Screening; prior to study drug administration on dosing days 
(Day 1 and at Weeks 4, 8, and 12); and at Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 
19, 20, 21, 22, 23, 24, 26, and 28 for CMV DNA analysis utilizing PCR analysis or CMV 
antigenemia testing. The central laboratory will perform CMV PCR analysis, and the local 
laboratory will perform CMV PCR analysis or CMV antigenemia testing consistently throughout 
the study. Upon entering the Rescue Phase, a blood sample will be collected for CMV DNA 
analysis utilizing PCR analysis performed by the central laboratory. Samples for evaluation by the 
central laboratory may be collected by home healthcare services (United States only) at non-dosing 
day visits.  
Home healthcare services (United States only) may be utilized for CMV PCR analysis at the 
central laboratory. In the case home healthcare services (United States only) are utilized, it is not 
necessary to collect blood samples for CMV DNA analysis or CMV antigenemia testing for 
analysis by the local laboratory. See the study reference manual for details.  
7.4 
EuroQol 5 Dimensions 5 Levels Questionnaire 
The EQ-5D-5L (paper version) will be performed prior to study drug administration on Day 1, at 
Weeks 16 and 28, and at the initiation of the Rescue Phase. The EQ-5D-5L may be performed by 
home healthcare services (United States only) at non-dosing day visits.  


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8 
IMMUNOGENICITY AND VIROLOGY ASSESSMENTS 
8.1 
Anti–NPC-21 Antibody 
The immunogenicity of NPC-21 in CMV seronegative patients will be evaluated by anti–NPC-21 
antibody testing. Blood will be drawn prior to study drug administration on dosing days (Day 1 
and at Weeks 4, 8, and 12) and at Weeks 16 and 28 for anti–NPC-21 antibody measurements. 
Samples may be collected by home healthcare services (United States only) at non-dosing day 
visits. 
8.2 
Screening for Resistant Strains Analysis 
Antiviral resistance in CMV seronegative patients will be evaluated by resistant strains genotypic 
analysis. Blood samples will be stored for screening for resistant strains analysis and will be 
collected prior to study drug administration on Day 1, at Weeks 16 and 28, and at the initiation of 
the Rescue Phase. Samples may be collected by home healthcare services (United States only) at 
non-dosing day visits. The resistant strains analysis of blood samples from patients with treatment 
failure will be conducted in this Phase 2 study based on analysis study protocol.  
 


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9 
SAFETY ASSESSMENTS 
9.1 
Adverse Events 
An adverse event is defined as any untoward medical occurrence in a clinical investigation patient 
administered a pharmaceutical product, which does not necessarily have a causal relationship with 
this treatment. An adverse event can therefore be any unfavorable and/or unintended sign 
(including an abnormal laboratory finding), symptom, or disease temporally associated with the 
use of an investigational medicinal product, whether or not related to the investigational medicinal 
product. All adverse events, including observed or volunteered problems, complaints, or symptoms, 
are to be recorded on the appropriate eCRF. 
Adverse events, which include clinical laboratory test variables, will be monitored and 
documented from the time informed consent is obtained until Week 28. Should the patient 
terminate the study early, SAEs should be reported up until the Early Termination visit or 90 days 
after the last administration of study drug, whichever is later. Patients should be instructed to report 
any adverse event that they experience to the Investigator, whether or not they think the event is 
due to study drug. Beginning at the time informed consent is obtained, Investigators should make 
an assessment for adverse events at each visit and record the event on the appropriate adverse event 
eCRF. 
Wherever possible, a specific disease or syndrome rather than individual associated signs and 
symptoms should be identified by the Investigator and recorded on the eCRF. However, if an 
observed or reported sign or symptom is not considered a component of a specific disease or 
syndrome by the Investigator, it should be recorded as a separate adverse event on the eCRF. 
Additionally, the condition that led to a medical or surgical procedure (eg, surgery, endoscopy, 
tooth extraction, or transfusion) should be recorded as an adverse event, not the procedure itself.  
Any medical condition already present at the time of signing informed consent should be recorded 
as medical history and not be reported as an adverse event unless the medical condition or signs 
or symptoms present at Baseline changes in severity, frequency, or seriousness at any time during 
the study. In this case, it should be reported as an adverse event. 
Laboratory Abnormalities 
Clinically significant abnormal laboratory or other examination (eg, ECG, CMV testing) findings 
that are detected during the study or are present at the time informed consent is obtained and 
significantly worsen during the study should be reported as adverse events, as described below. 
The Investigator will exercise his or her medical and scientific judgment in deciding whether an 
abnormal laboratory finding or other abnormal assessment is clinically significant. Clinically 
significant abnormal laboratory values occurring during the clinical study will be followed until 
repeat tests return to normal, stabilize, or are no longer clinically significant. Abnormal test results 
that are determined to be an error should not be reported as an adverse event. Laboratory 
abnormalities or other abnormal clinical findings (eg, ECG abnormalities) should be reported as 
an adverse event if any of the following are applicable: 
• If an intervention is required as a result of the abnormality 
• If action taken with study drug is required as a result of the abnormality 
• Based on the clinical judgment of the Investigator 


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Where possible, the specific disease or syndrome that caused the abnormal laboratory result should 
be recorded as the adverse event term. 
9.1.1 
Adverse (Drug) Reaction 
All noxious and unintended responses to a medicinal product related to any dose should be 
considered an ADR. “Responses” to a medicinal product means that a causal relationship between 
a medicinal product and an adverse event is at least a reasonable possibility, ie, the relationship 
cannot be ruled out. 
9.1.2 
Unexpected Adverse Drug Reaction 
An Unexpected Adverse Drug Reaction is defined as an adverse reaction, the nature or severity of 
which is not consistent with the applicable product information. For NPC-21 the reference safety 
information is included in the Investigator’s Brochure currently in force. The reference safety 
information will be reviewed yearly and the periodicity of the review will be harmonized with the 
reporting period of the Development Safety Update Report. Any adverse event that is both 
unexpected (not consistent with the applicable product information) and also meets the definition 
of an SAE/serious adverse reaction (SAR) would be considered a Suspected Unexpected Serious 
Adverse Reaction (SUSAR).  
9.1.3 
Assessment of Adverse Events by the Investigator 
The Investigator will assess the severity (intensity) of each adverse event as mild, moderate, severe, 
life-threatening, or death and will also categorize each adverse event as to its potential relationship 
to study drug using the categories of related or not related. 
Assessment of Severity 
The severity of all adverse events should be graded according to the Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0. For those adverse event terms not listed in the 
CTCAE, the following grading system should be used: 
• CTCAE Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated 
• CTCAE Grade 2: Moderate; minimal local or noninvasive intervention indicated; limiting 
age-appropriate instrumental activities of daily living 
• CTCAE Grade 3: Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care 
activities of daily living 
• CTCAE Grade 4: Life-threatening consequences; urgent intervention indicated 
• CTCAE Grade 5: Death related to the adverse event 
Causality Assessment 
The relationship of an adverse event to the administration of study drug is to be assessed according 
to the following definitions: 
Not related (unrelated, not related, unlikely to be related) – The time course between the 
administration of study drug and the occurrence or worsening of the adverse event rules out a 


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causal relationship and another cause (concomitant drugs, therapies, complications, etc) is 
suspected. 
Related (possibly, probably, or definitely related) – The time course between the administration of 
study drug and the occurrence or worsening of the adverse event is consistent with a causal 
relationship and no other cause (concomitant drugs, therapies, complications, etc) can be identified. 
The definition implies a reasonable possibility of a causal relationship between the event and study 
drug. This means that there are facts (evidence) or arguments to suggest a causal relationship. 
The following factors should also be considered: 
• The temporal sequence from study drug administration- 
The event should occur after study drug is given. The length of time from study drug exposure 
to the event should be evaluated in the clinical context of the event. 
• Underlying, concomitant, intercurrent diseases- 
Each report should be evaluated in the context of the natural history and course of the disease 
being treated and any other disease the patient may have. 
• Concomitant medication- 
The other drugs the patient is taking or the treatment the patient receives should be examined 
to determine whether any of them might be recognized to cause the event in question. 
• The known response pattern for this class of study drug- 
Clinical and/or preclinical data may indicate whether a particular response is likely to be a 
class effect. 
• Exposure to physical and/or mental stresses- 
The exposure to stress might induce adverse changes in the recipient and provide a logical and 
better explanation for the event. 
• The pharmacology of study drug- 
The known pharmacologic properties (absorption, distribution, metabolism, and excretion) of 
study drug should be considered. 
9.1.4 
Adverse Events of Special Interest 
The Investigator will monitor each patient for clinical and laboratory evidence for predefined 
adverse events of special interest (AESIs) throughout the patient’s participation in this study.  
The Investigator will assess and record any additional information on the AESI in detail on an 
adverse event form, which must be submitted within 24 hours of awareness of the event. 
Events of serious hypersensitivity that are Grade 3 or higher or lead to treatment discontinuation 
will be monitored as AESIs during this study.  
During the course of the study, additional AESIs may be identified by the Sponsor. 
Adverse events of special interest must be recorded in the eCRF. 


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9.2 
Serious Adverse Events 
An adverse event or adverse reaction is considered serious if, in the view of either the Investigator 
or Sponsor, it results in any of the following outcomes: 
• Death. 
• A life-threatening adverse event. 
Note: The term “life-threatening” in the definition of “serious” refers to an event in which the 
patient was at risk of death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe.  
• Requires hospitalization or prolongation of existing hospitalizations. 
Note: Any hospitalization requiring admission for at least 1 day or an overnight stay will be 
considered an inpatient hospitalization. An emergency room or urgent care visit without 
hospital admission will not be recorded as an SAE under this criterion, nor will hospitalization 
for a procedure scheduled or planned before signing of informed consent, or elective treatment 
of a preexisting condition that did not worsen from Baseline. However, unexpected 
complications and/or prolongation of hospitalization that occur during elective surgery should 
be recorded as adverse events and assessed for seriousness. Admission to the hospital for social 
or situational reasons (ie, no place to stay, live too far away to come for hospital visits, respite 
care) will not be considered inpatient hospitalizations.  
• A persistent or significant disability/incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
• An important medical event. 
Note: Important medical events that do not meet any of the above criteria may be considered 
an SAE when, based upon appropriate medical judgment, they may jeopardize the patient and 
may require medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not result in 
inpatient hospitalizations, or the development of drug dependency. 
9.3 
Serious Adverse Event Reporting − Procedures for Investigators 
Initial Reports 
All SAEs occurring from the time informed consent is obtained until Week 28 must be reported to 
 within 24 hours of the knowledge of the occurrence. Should the patient 
terminate the study early, SAEs should be reported up until the Early Termination visit or 90 days 
after the last administration of study drug, whichever is later. After the reporting window, any SAE 
that the Investigator becomes aware of and is considered related to study drug should be reported 
to 
 or the Sponsor/designee. 
To report the SAE, complete the SAE form electronically in the electronic data capture (EDC) 
system for the study. When the form is completed, 
 will be notified 
electronically by the EDC system and will retrieve the form. If the event meets serious criteria and 
it is not possible to access the EDC system, send an email to 
 at 




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classification as an SAE (ie, postpartum complication, spontaneous abortion, stillbirth, neonatal 
death, or congenital anomaly), the Investigator should follow the procedures for reporting an SAE. 
9.5 
Expedited Reporting 
The Sponsor/designee will report all relevant information about SUSARs that are fatal or 
life-threatening as soon as possible to the relevant authorities in all the countries concerned, and 
in any case no later than 7 days after knowledge by the Sponsor/designee of such a case.  
All other SUSARs (except fatal/life-threatening) will be reported to the relevant authorities as soon 
as possible but within a maximum of 15 days of first knowledge by the Sponsor/designee.  
When an event is considered to be a SUSAR, the blind will be broken by 
 
for that specific patient. The blind will be maintained for persons responsible for the ongoing 
conduct of the study.  
The Sponsor/designee will also report any additional expedited safety reports required in 
accordance with the timelines outlined in country-specific legislation.  
The Sponsor/designee will also inform all investigators as required per local regulation. 
The requirements above refer to the requirements relating to the investigational medicinal product. 
Expedited reporting of SUSARs related to non-investigational medical products (NIMPs) is not 
required. All SARs, regardless of expectedness, will be reported to the manufacturer of the 
marketed product. Line listings of cases related to NIMPs will be included in the Development 
Safety Update Report. 
9.6 
Special Situation Reports 
Special situation reports include reports of overdose, misuse, abuse, medication error, and reports 
of adverse reactions associated with product complaints. 
• Overdose: Refers to the administration of a quantity of a medicinal product given per 
administration or cumulatively (accidentally or intentionally), which is above the maximum 
recommended dose according to the protocol. Clinical judgment should always be applied. In 
cases of a discrepancy in the drug accountability, an overdose will be established only when 
it is clear that the patient has taken additional dose(s) or the Investigator has reason to suspect 
that the patient has taken additional dose(s).  
• Misuse: Refers to situations where the medicinal product is intentionally and inappropriately 
used in a way that is not in accordance with the protocol instructions or local prescribing 
information and may be accompanied by harmful physical and/or psychological effects.  
• Abuse: Is defined as persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
• Medication error: Is any unintentional error in the prescribing, dispensing, or administration 
of a medicinal product by a healthcare professional, patient, or consumer, respectively. The 
administration or consumption of the unassigned treatment and administration of an expired 
product are always reportable as medication errors, cases of patients missing doses of the 
investigational product are not considered reportable as medication error. 




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9.11 
Cytomegalovirus Serology 
Cytomegalovirus serology will be tested using an enzyme immunoassay to detect CMV antibodies 
(immunoglobulin G) at Screening. Cytomegalovirus serology will be tested at the local laboratory 
within 90 days of Randomization to determine eligibility for the study.  
9.12 
Serum NPC-21 Concentration Measurement 
Blood will be drawn on Day 1 and at Weeks 1, 2, 3, 4, 6, 8, 10, 12, 14, 16, 20, 24, and 28 for serum 
NPC-21 concentration measurement. On dosing days (Day 1 and at Weeks 4, 8, and 12), blood 
samples will be collected within 2 hours prior to study drug administration and at 2 hours 
(±30 minutes) following the beginning of the infusion (Note: Sample collection time points at each 
visit may be updated based on each administration data). Samples may be collected by home 
healthcare services (United States only) at non-dosing day visits. 


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10 
STATISTICS 
Summary statistics will be presented by treatment group. Unless otherwise stated, continuous 
variables will be summarized by using the number of non-missing observations, arithmetic mean, 
standard deviation, median, minimum, and maximum values as descriptive statistics. Categorical 
variables will be summarized by using the frequency count, the percentage of patients with 
95% confidence intervals in each category as descriptive statistics. Statistical tests will be 2-sided 
at the α=0.05 significance level. The procedures for handling missing, unused, or spurious data, 
along with the detailed method for analysis of each variable will be presented in the Statistical 
Analysis Plan.  
Changes in study visit schedules, missed or delayed visits, or patient discontinuations and the 
relationship to COVID-19 will be captured in the eCRFs. Protocol deviations in study procedures 
due to COVID-19 will be reported in the Clinical Study Report. 
10.1 
Analysis Populations 
The Intent-to-Treat Population will include all randomized patients. 
The modified Intent-to-Treat (mITT) Population will include all patients who receive a kidney 
transplant from a living or deceased donor and receive at least 1 dose of study drug 
(6 mg/kg NPC-21, 12 mg/kg NPC-21, or placebo). The mITT Population will be used for all 
efficacy analyses.  
The PK Population will include all patients who receive any amount of study drug 
(6 mg/kg NPC-21, 12 mg/kg NPC-21, or placebo) and have evaluable PK data. The PK Population 
will be used for the PK analyses and exposure-response analyses.  
The Safety Population will include all randomized patients who receive at least 1 dose of study 
drug (NPC-21 or placebo). The Safety Population will be used for safety analyses. 
10.2 
Statistical Methods 
10.2.1 
Analysis of Efficacy 
The mITT Population will be used for all efficacy analyses.  
The primary efficacy endpoint will be the proportion of patients with the occurrence of CMV 
disease (CMV syndrome [see Appendix C for definition of CMV syndrome] or tissue-invasive 
CMV disease [see Appendix D for definitions of CMV disease]) or CMV viremia (defined as the 
detection of ≥250 IU/mL in plasma measured by PCR analysis in central laboratory or meets the 
local criteria for CMV viremia measured by PCR analysis or antigenemia testing) by Week 16. 
Non-responders will include all patients who develop CMV disease or CMV viremia. In principle, 
patients who discontinue from the study prior to Week 16 in the absence of CMV disease or CMV 
viremia will be considered as non-responders. If warranted under special circumstances, a patient 
who discontinues from the study prior to Week 16 may be discussed with the medical expert to 
determine status as a responder or non-responder. If this occurs, the rationale for considering the 
patient as a responder will be finalized before database lock and documented in the Statistical 
Analysis Plan. Sensitivity analysis may be performed to assess the impact of these patients on 
analysis results.   


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The primary efficacy endpoint will be summarized by treatment group and compared across 
placebo and the 6 mg/kg NPC-21 treatment group using a logistic regression analysis with 
stratification factor of region (United States or Japan) as a covariate.  
Other efficacy endpoints will be summarized descriptively by treatment group using the 
mITT Population.  
10.2.2 
Analysis of Pharmacokinetics 
Serum concentrations of NPC-21 will be summarized using descriptive statistics. In addition, 
analysis of the concentration data as part of population-PK modeling will be described in a separate 
PK Analysis Plan and reported separately.  
10.2.3 
Analysis of Exposure-Response 
Exposure-response analyses will be performed to propose target concentrations using PK 
parameters estimated by population-PK, efficacy variables, and biomarkers. 
10.2.4 
Analysis of Safety 
The Safety Population will be used for all safety analyses. Safety will be summarized descriptively 
by treatment group.  
Descriptive summary statistics will be provided for all safety variables, including 12-lead ECGs, 
vital signs, clinical laboratory assessments, and adverse events reported during the study.  
The number and percentage of patients experiencing treatment-emergent adverse events will be 
summarized. Summaries will be produced for each body system, as well as for each preferred term 
using the Medical Dictionary for Regulatory Activities. The number and percentage of patients 
experiencing SAEs will also be summarized. 
10.2.5 
Interim Analysis 
No interim analysis is planned.  
10.2.6 
Data and Safety Monitoring Board 
The safekeeping and monitoring of data collection will be performed by an independent third party 
DSMB. The DSMB will be independent of the Sponsor, contract research organization, study 
Investigators, and anyone involved in the care or evaluation of study patients. Members of the 
DSMB will not have scientific, financial, or other conflicts of interest related to the Sponsor or 
Investigators.  
The DSMB will meet to review unblinded aggregate and individual patient data related to safety, 
data integrity, and overall conduct of the study and will provide recommendations to continue, 
temporarily halt, modify, or terminate the study based on data analysis. The committee may 
communicate other recommendations or concerns as deemed appropriate. Additional information 
will be provided in the DSMB charter as approved by the members.   
10.2.7 
Sample Size Determination 
A total sample size of approximately 108 patients is planned for the study, with a 
1:1 randomization ratio for 6 mg/kg NPC-21 versus placebo and another 12 patients for high-level 


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dose of 12 mg/kg NPC-21 (4:1:4 randomization ratio for 6 mg/kg NPC-21, 12 mg/kg NPC-21, or 
placebo). The sample size calculation is based on the mITT Population from the first dose of 
NPC-21 through Week 16 for the occurrence of CMV disease (CMV syndrome or tissue-invasive 
CMV disease) or CMV viremia (defined as the detection of ≥250 IU/mL in plasma measured by 
PCR analysis in central laboratory or meets the local criteria for CMV viremia measured by PCR 
analysis or antigenemia testing) primary endpoint. Assuming an early discontinuation rate of 15%, 
approximately 48 patients each in the 6 mg/kg NPC-21 and placebo arms are needed with a 2-sided 
significance level of 0.05 and a power of 80% to detect a difference between NPC-21 at a predicted 
incidence rate of CMV disease (CMV syndrome or tissue-invasive CMV disease) or CMV viremia 
of 30% versus 60% for placebo. In addition, a sample size of 12 patients for the 12 mg/kg NPC-21 
arm is considered adequate for the planned exposure-response analysis.  


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11 
DATA MANAGEMENT AND RECORD KEEPING 
11.1 
Data Management 
11.1.1 
Data Handling 
Data will be recorded at the site on eCRFs and reviewed by the CRA during monitoring visits. The 
CRAs will verify data recorded in the EDC system with source documents. All corrections or 
changes made to any study data must be appropriately tracked in an audit trail in the EDC system. 
An eCRF will be considered complete when all missing, incorrect, and/or inconsistent data have 
been accounted for. 
11.1.2 
Computer Systems 
Data will be processed using a validated computer system conforming to regulatory requirements. 
11.1.3 
Data Entry 
Data must be recorded using the EDC system as the study is in progress. All site personnel must 
log into the system using their secure user name and password in order to enter, review, or correct 
study data. These procedures must comply with Title 21 of the Code of Federal Regulations 
(21 CFR Part 11) and other appropriate international regulations. All passwords will be strictly 
confidential. 
11.1.4 
Medical Information Coding 
For medical information, the following thesauri will be used: 
• Medical Dictionary for Regulatory Activities (latest) for medical history and adverse events 
• WHO Drug Dictionary for prior and concomitant medications 
11.1.5 
Data Validation 
Validation checks programmed within the EDC system, as well as supplemental validation 
performed via review of the downloaded data, will be applied to the data in order to ensure accurate, 
consistent, and reliable data. Data identified as erroneous, or data that are missing, will be referred 
to the investigative site for resolution through data queries. 
The eCRFs must be reviewed and electronically signed by the Investigator. 
11.2 
Record Keeping 
Records of patients, source documents, monitoring visit logs, eCRFs, inventory of study product, 
regulatory documents, and other Sponsor correspondence pertaining to the study must be kept in 
the appropriate study files at the site. Source data is defined as all information in original records 
and certified copies of original records of clinical findings, observations, or other activities in a 
clinical study necessary for the evaluation and reconstruction of the clinical study. Source data are 
contained in source documents (original records or certified copies). These records will be retained 
in a secure file for the period as set forth in the Clinical Study Agreement. Prior to transfer or 
destruction of these records, the Sponsor must be notified in writing and be given the opportunity 
to further store such records.  


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12 
INVESTIGATOR REQUIREMENTS AND QUALITY CONTROL  
12.1 
Ethical Conduct of the Study 
Good Clinical Practice is an international ethical and scientific quality standard for designing, 
conducting, recording, and reporting studies that involve human subjects. Compliance with this 
standard provides public assurance that the rights, safety, and well-being of study patients are 
protected, consistent with the principles that have their origin in the Declaration of Helsinki, and 
that the clinical study data are credible. 
12.2 
Institutional Review Board/Independent Ethics Committee 
The IRB/IEC will review all appropriate study documentation in order to safeguard the rights, 
safety, and well-being of patients. The study will only be conducted at sites where IRB/IEC 
approval has been obtained. The protocol, Investigator’s Brochure, informed consent form (ICF), 
advertisements (if applicable), written information given to the patients, safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB/IEC by the 
Investigator. 
Federal regulations and International Council for Harmonisation (ICH) Guidelines require that 
approval be obtained from an IRB/IEC prior to participation of patients in research studies. Prior 
to study onset, the protocol, any protocol amendments, ICFs, advertisements to be used for patient 
recruitment, and any other written information regarding this study to be provided to a patient must 
be approved by the IRB/IEC. 
No drug will be released to the site for dosing until written IRB/IEC authorization has been 
received by the Sponsor. For Japanese sites, no drug will be released to the site for dosing until 
execution of contract with the study site.  
12.3 
Informed Consent 
The ICF and any changes to the ICF made during the course of the study must be agreed to by the 
Sponsor or designee and the IRB/IEC prior to its use and must be in compliance with all ICH GCP, 
local regulatory requirements, and legal requirements.   
The Investigator must ensure that each study patient is fully informed about the nature and 
objectives of the study and possible risks associated with participation and must ensure that the 
patient has been informed of his/her rights to privacy. The Investigator will obtain written informed 
consent from each patient before any study-specific activity is performed and should document in 
the source documentation that consent was obtained prior to enrollment in the study. The original 
signed copy of the ICF must be maintained by the Investigator and is subject to inspection by a 
representative of the Sponsor, their representatives, auditors, the IRB/IEC and/or regulatory 
agencies. A copy of the signed ICF will be given to the patient. 
12.4 
Subject Card  
On enrollment in the study, the patient will receive a subject card to be carried at all times. The 
subject card will state that the patient is participating in a clinical research study, type of treatment, 
number of intravenous infusions received, and contact details in case of an SAE. 


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12.5 
Study Monitoring Requirements 
It is the responsibility of the Investigator to ensure that the study is conducted in accordance with 
the protocol, ICH GCP, the Japanese Ministerial Ordinance on GCP for Drugs, 
Directive 2001/20/EC, and the Declaration of Helsinki, where applicable, and that valid data are 
entered into the eCRFs. 
To achieve this objective, the monitor’s duties are to aid the Investigator and, at the same time, the 
Sponsor in the maintenance of complete, legible, well organized and easily retrievable data. Before 
the enrollment of any patient in this study, the Sponsor or their designee will review with the 
Investigator and site personnel the following documents: protocol, Investigator’s Brochure, eCRFs 
and procedures for their completion, informed consent process, and the procedure for reporting 
SAEs. 
The Investigator will permit the Sponsor or their designee to monitor the study as frequently as 
deemed necessary to determine that data recording and protocol adherence are satisfactory. During 
the monitoring visits, information recorded on the eCRFs will be verified against source 
documents, and requests for clarification or correction may be made. After the eCRF data are 
entered by the site, the CRA will review the data for safety information, completeness, accuracy, 
and logical consistency. Computer programs that identify data inconsistencies may be used to help 
monitor the clinical study. If necessary, requests for clarification or correction will be sent to 
investigators. The Investigator and his/her staff will be expected to cooperate with the monitor and 
provide any missing information, whenever possible. 
All monitoring activities will be reported and archived. In addition, monitoring visits will be 
documented at the investigational site by signature and date on the study-specific monitoring log. 
12.6 
Disclosure of Data 
Data generated by this study must be available for inspection by the FDA, Japanese health 
authorities, namely Pharmaceuticals and Medical Devices Agency, the Sponsor or their designee, 
other applicable foreign health authorities, and the IRB/IEC as appropriate. Patients may request 
their medical information be given to their personal physician or other appropriate medical 
personnel responsible for their welfare. 
Patient medical information obtained during the study is confidential and disclosure to third parties 
other than those noted above is prohibited. 
12.7 
Retention of Records 
To enable evaluations and/or audits from regulatory authorities or the Sponsor, the Investigator 
will keep records, including the identity of all participating patients (sufficient information to link 
records, eg, eCRFs and hospital records), all original signed ICFs, copies of all eCRFs, SAE forms, 
source documents, and detailed records of treatment disposition. The records should be retained 
by the Investigator according to specifications in the ICH guidelines, local regulations, or as 
specified in the Clinical Study Agreement, whichever is longer. The Investigator must obtain 
written permission from the Sponsor before disposing of any records, even if retention 
requirements have been met. 


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If the Investigator relocates, retires, or for any reason withdraws from the study, the Sponsor should 
be prospectively notified. The study records must be transferred to an acceptable designee, such 
as another Investigator, another institution, or the Sponsor.   
12.8 
Publication Policy 
Following completion of the study, the data may be considered for publication in a scientific 
journal or for reporting at a scientific meeting. Each Investigator is obligated to keep data 
pertaining to the study confidential. The Investigator must consult with the Sponsor before any 
study data are submitted for publication. The Sponsor reserves the right to deny publication rights 
until mutual agreement on the content, format, interpretation of data in the manuscript, and journal 
selected for publication are achieved. 
12.9 
Financial Disclosure 
Investigators are required to provide financial disclosure information to the Sponsor to permit the 
Sponsor to fulfill its obligations under 21 CFR Part 54. In addition, investigators must commit to 
promptly updating this information if any relevant changes occur during the study and for a period 
of 1 year after the completion of the study. 
12.10 
Insurance and Indemnity 
In accordance with the relevant national regulations, the Sponsor has obtained patient liability 
insurance for all patients who have given their consent to the clinical study. This coverage is 
designed for the event that a fatality, physical injury, or damage to health occurs during the clinical 
study’s execution. The clinical trial compensation guidelines established by the Sponsor is applied. 
12.11 
Legal Aspects 
The clinical study is submitted to the relevant national competent authorities in all participating 
countries to achieve a clinical trial authorization (CTA). 
The study will commence (ie, initiation of study centers) when the CTA and favorable Ethics 
opinions have been received.  


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13 
STUDY ADMINISTRATIVE INFORMATION 
13.1 
Protocol Amendments 
Any amendments to the study protocol will be communicated to the Investigators by 
 or 
the Sponsor. All protocol amendments will undergo the same review and approval process as the 
original protocol. A protocol amendment may be implemented after it has been approved by the 
IRB/IEC, unless immediate implementation of the change is necessary for patient safety. In this 
case, the situation must be documented and reported to the IRB/IEC within 5 working days. 


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14 
REFERENCES 
 
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3. 
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6. 
Marshall GS, Rabalais GP, Stout GG, et al. Antibodies to recombinant-derived 
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Britt WJ, Vugler L, Butfiloski EJ, et al. Cell surface expression of human 
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8. 
Kniess N, Mach M, Fay J, et al. Distribution of linear antigenic sites on glycoprotein 
gp55 of human cytomegalovirus. J Virol. 1991;65(1):138-146.  
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Meyer H, Sundqvist VA, Pereira L, et al. Glycoprotein gp116 of human cytomegalovirus 
contains epitopes for strain-common and strain-specific antibodies. J Gen Virol. 
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10. 
Wagner B, Kropff B, Kalbacher H, et al. A continuous sequence of more than 70 amino 
acids is essential for antibody binding to the dominant antigenic site of glycoprotein gp58 
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11. 
Lehner R, Stamminger T, Mach M. Comparative sequence analysis of human 
cytomegalovirus strains. J Clin Microbiol. 1991;29(11):2494-2502.  
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Qadri I, Navarro D, Paz P, et al. Assembly of conformation-dependent neutralizing 
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1992;73(Pt 11):2913-2921.  
13. 
Britt WJ, Jarvis MA, Drummond DD, et al. Antigenic domain 1 is required for 
oligomerization of human cytomegalovirus glycoprotein B. J Virol. 
2005;79(7):4066-4079. 
14. 
Schoppel K, Kropff B, Schmidt C, et al. The humoral immune response against human 
cytomegalovirus is characterized by a delayed synthesis of glycoprotein-specific 
antibodies. J Infect Dis. 1997;175(3):533-544. 
15. 
Aulitzky WE, Schulz TF, Tilg H, et al. Human monoclonal antibodies neutralizing 
cytomegalovirus (CMV) for prophylaxis of CMV disease: report of a phase I trial in bone 
marrow transplant recipients. J Infect Dis. 1991;163(6):1344-1347. 
 


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16. 
Ohlin M, Sundqvist VA, Mach M, et al. Fine specificity of the human immune response 
to the major neutralization epitopes expressed on cytomegalovirus gp58/116 (gB), as 
determined with human monoclonal antibodies. J Virol. 1993;67(2):703-710. 
17. 
IRODaT Database, International Registry on Organ Donation and Transplantation. 
18. 
Humar A, Snydman D, AST Infectious Diseases Community of Practice. 
Cytomegalovirus in solid organ transplant recipients. Am J Transplant. 
2009;9(Suppl 4):S78-S86. 
19. 
Emery VC, Sabin CA, Cope AV, et al. Application of viral-load kinetics to identify 
patients who develop cytomegalovirus disease after transplantation. Lancet. 
2000;355(9220):2032-2036. 
20. 
Fishman JA, Emery V, Freeman R, et al. Cytomegalovirus in 
transplantation – challenging the status quo. Clin Transplant. 2007;21(2):149-158. 
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Fishman JA, Rubin RH. Infection in organ-transplant recipients. N Engl J Med. 
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22. 
Grattan MT, Moreno-Cabral CE, Starnes VA, et al. Cytomegalovirus infection is 
associated with cardiac allograft rejection and atherosclerosis. JAMA. 
1989;261(24):3561-3566. 
23. 
Valantine HA. Role of CMV in transplant coronary artery disease and survival after heart 
transplantation. Transpl Infect Dis. 1999;1 Suppl 1:25-30. 
24. 
van den Berg AP, Klompmaker IJ, Haagsma EB, et al. Evidence for an increased rate of 
bacterial infections in liver transplant patients with cytomegalovirus infection. 
Clin Transplant. 1996;10(2):224-231. 
25. 
Sia IG, Patel R. New strategies for prevention and therapy of cytomegalovirus infection 
and disease in solid-organ transplant recipients. Clin Microbiol Rev. 2000;13(1):83-121. 
26. 
Ljungman P, Hakki M, Boeckh M. Cytomegalovirus in hematopoietic stem cell 
transplant recipients. Infect Dis Clin North Am. 2010;24(2):319-337. 
27. 
Japanese Society for Clinical Renal Transplantation Guideline Committee, ed. The 
Clinical Guideline for Cytomegalovirus Disease after Kidney Transplantation 2011. 
Tokyo: Nihon Igakukan; 2011. 
28. 
Snydman DR. Cytomegalovirus immunoglobulins in the prevention and treatment of 
cytomegalovirus disease. Rev Infect Dis. 1990;12 Suppl 7:S839-S848. 
29. 
Nigro G, Adler SP, La Torre R, et al. Passive immunization during pregnancy for 
congenital cytomegalovirus infection. N Engl J Med. 2005;353(13):1350-1362. 
30. 
Melendez DP, Razonable RR. Letermovir and inhibitors of the terminase complex: a 
promising new class of investigational antiviral drugs against human cytomegalovirus. 
Infect Drug Resist. 2015;8:269-277. 
31. 
Rowe WP, Hartley JW, Waterman S, et al. Cytopathogenic agent resembling human 
salivary gland virus recovered from tissue cultures of human adenoids. Proc Soc Exp Biol 
Med. 1956;92(2):418-424. 
32. 
Plotkin SA, Furukawa T, Zygraich N, et al. Candidate cytomegalovirus strain for human 
vaccination. Infect Immun. 1975;12(3):521-527. 
33. 
Weller TH, MacAuley JC, Craig JM, et al. Isolation of intranuclear inclusion producing 
agents from infants with illnesses resembling cytomegalic inclusion disease. Proc Soc 
Exp Biol Med. 1957;94(1):4-12. 
 


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34. 
Dolan A, Cunningham C, Hector RD, et al. Genetic content of wild-type human 
cytomegalovirus. J Gen Virol. 2004;85(Pt 5):1301-1312. 
35. 
Sinzger C, Digel M, Jahn G. Cytomegalovirus cell tropism. Curr Top Microbiol 
Immunol. 2008;325:63-83. 
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Sinzger C, Mangin M, Weinstock C, et al. Effect of serum and CTL on focal growth of 
human cytomegalovirus. J Clin Virol. 2007;38(2):112-119. 


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APPENDIX A: SCHEDULE OF PROCEDURES 
 
Scra 
Treatment Periodb,c,d 
Observation Periodd,e 
Study Week 
-2  
to 0 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
26 
28/ 
ETf 
Study Day 
-14 
to -1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
183 
197 
Visit Window 
 
 
±3 days 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-Randomizationg 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomizationh 
Xi 
Xi 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CMV serologyj 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Transplantation 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/surgical 
history and present 
illness 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/concomitant 
medicationsk  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weightk,l 
Xm 
Xn 
 
 
 
Xn 
 
 
 
Xn 
 
 
 
Xn 
 
 
 
X 
 
X 
 
X 
 
X 
Physical 
examinationk 
X 
Xn,o 
X 
X 
X 
Xn 
 
 
 
Xn 
 
 
 
Xn 
 
 
 
X 
 
X 
 
X 
 
X 
Vital signsk,p 
X 
Xn,o 
X 
X 
X 
Xn 
X 
X 
X 
Xn 
X 
X 
X 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood 
biochemistry, 
hematology, 
coagulation, and 
urinalysisk,q 
X 
Xn 
X 
X 
 
Xn 
 
X 
 
Xn 
 
X 
 
Xn 
 
X 
 
X 
 
X 
 
X 
 
X 


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Scra 
Treatment Periodb,c,d 
Observation Periodd,e 
Study Week 
-2  
to 0 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
21 
22 
23 
24 
26 
28/ 
ETf 
Study Day 
-14 
to -1 
1 
8 
15 
22 
29 
36 
43 
50 
57 
64 
71 
78 
85 
92 
99 
106 
113 
120 
127 
134 
141 
148 
155 
162 
169 
183 
197 
Visit Window 
 
 
±3 days 
Assessment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FSH, pregnancy 
testr 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
CMV DNA (central 
laboratory)k,s 
 
Xn 
X 
X 
X 
Xn 
X 
X 
X 
Xn 
X 
X 
X 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CMV DNA or 
antigenemia tests 
(local laboratory)t,u 
X 
Xn 
X 
X 
X 
Xn 
X 
X 
X 
Xn 
X 
X 
X 
Xn 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead ECGk,v 
X 
 
 
 
 
Xn 
 
 
 
Xn 
 
 
 
Xn 
 
 
 
X 
 
X 
 
X 
 
X 
Adverse event 
assessmentk 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study drug 
administrationw 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Serum NPC-21 
concentration 
measurementk,x 
 
Xy 
X 
X 
X 
Xy 
 
X 
 
Xy 
 
X 
 
Xy 
 
X 
 
X 
 
X 
 
X 
 
X 
Anti–NPC-21 
antibody 
measurementk,z 
 
Xn 
 
 
 
Xn 
 
 
 
Xn 
 
 
 
Xn 
 
 
 
X 
 
 
 
 
 
X 
Screening for 
resistant strains 
analysisk,aa 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
EQ-5D-5Lk 
 
Xn 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
a. 
Screening procedures will take place up to 14 days prior to first study drug administration.  
b. 
The Treatment Period will begin as soon as practical post-transplant but no later than 7 days post-transplant.  
c. 
During the Treatment Period, visits on dosing days (Day 1 and at Weeks 4, 8, and 12) should be conducted in person. Visits on non-dosing days of the Treatment Period 
(Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, and 16) may be conducted by home healthcare services (United States only). Home healthcare services may perform the 
following procedures at non-dosing day visits: record concomitant medications, obtain body weight, perform physical examination, record vital signs, collect samples for 
analysis by the central laboratory, perform 12-lead ECG, perform EQ-5D-5L, and record adverse events. 
d. 
After first study drug administration, patients who develop detectable CMV disease (CMV syndrome or tissue-invasive CMV disease) or CMV viremia (defined as the 
detection of ≥250 IU/mL in plasma measured by PCR analysis in central laboratory or meets the local criteria for CMV viremia measured by PCR analysis or antigenemia 


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testing) can enter the Rescue Phase of the study and be treated by anti-CMV agents per local standard of care until the patient is negative for CMV viremia, has recovered 
from CMV disease, or up to Week 28, whichever comes first. When this rescue therapy is completed, the Rescue Phase is terminated at least 4 Study Weeks after the last 
study drug administration and all Week 28 procedures will be performed as per the Early Termination Visit and Withdrawal Procedures. Note: Collection of blood samples for 
serum NPC-21 concentration measurement at Weeks 4, 8, and 12 during the Rescue Phase will be handled in the same manner as visits without study drug administration. 
Note: If the patient is negative for CMV viremia or has recovered from CMV disease before 4 StudyWeeks have passed following last study drug administration, weekly 
scheduled visits are not required. The Rescue Phase visits may be conducted by home healthcare services (United States only). Home healthcare services may perform the 
following procedures at non-dosing day visits: record concomitant medications, obtain body weight, perform physical examination, record vital signs, collect samples for 
analysis by the central laboratory, perform 12-lead ECG, perform EQ-5D-5L, and record adverse events. The Rescue Phase procedures may be performed at the next 
scheduled visit after detecting CMV viremia or CMV disease with or without anti-CMV agents per local standard of care. Some Investigators may prescribe anti-CMV agents 
(eg, VGCV) in advance and instruct the patient to start taking the drug as soon as possible for safety if the disease or viremia develops. If this is the case, the Rescue Phase 
procedures may be performed at the next scheduled visit. The following procedures will be performed upon entering the Rescue Phase: record the rescue in IRT, record 
concomitant medications, record the date and reason for entering the Rescue Phase, perform complete physical examination, collect blood sample for CMV DNA analysis by 
the central laboratory, collect blood samples that will be stored for screening for resistant strains analysis, perform EQ-5D-5L, and record adverse events.  
Note: During the 12-week Observation Period, visits at Weeks 17, 19, 21, and 23 may be missed due to unavoidable circumstances (eg, holidays, natural disasters). However, 
every attempt should be made to ensure a visit occurs. In this case, study staff will make contact with the patient to evaluate their condition, eg, review concomitant 
medications, any new adverse events since the last visit.   
e. 
During the Observation Period, home healthcare services (United States only) may be utilized at Weeks 17, 18, 19, 20, 21, 22, 23, 24, 26, and 28. Home healthcare services 
may perform the following procedures at non-dosing day visits: record concomitant medications, obtain body weight, perform physical examination, record vital signs, collect 
samples for analysis by the central laboratory, perform 12-lead ECG, perform EQ-5D-5L, and record adverse events. 
f. 
For patients who are withdrawn from the study prior to completion, all Week 28 procedures will be performed at an ET visit.  
g. 
After informed consent and body weight are obtained, pre-Randomization will take place via the IRT system to 1 of 3 treatment groups (6 mg/kg NPC-21, 12 mg/kg NPC-21, 
or placebo) in a 4:1:4 ratio. Randomization will be stratified by region (United States or Japan). 
h. 
Randomization will take place prior to first study drug administration after confirming all criteria. Randomization procedures may occur on Day -1 or Day 1 prior to first 
study drug administration. If the patient is found to be ineligible during Screening, the dropout procedures will be carried out promptly.  
i. 
Perform Randomization on Day -1 or Day 1 prior to first study drug administration.  
j. 
CMV serology will be tested using an enzyme immunoassay to detect CMV antibodies (IgG). CMV serology will be tested at the local laboratory within 90 days of 
Randomization to determine eligibility for the study.  
k. 
May be performed by home healthcare services (United States only) at Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, and 28, the Early 
Termination visit, and at Rescue Phase visits.  
l. 
In case of hemodialysis patients, body weight is defined immediately after dialysis or dry weight. In case of peritoneal dialysis patients, body weight is defined after removal 
of dialysate or dry weight.  
m. Body weight measured within 7 days prior to pre-Randomization is permitted. 
n. 
Perform prior to study drug administration.  
o. 
Perform within 1 hour of the end of the infusion.  
p. 
Vital signs will include systolic and diastolic blood pressure, pulse rate, and body temperature.  
q. 
Blood biochemistry includes liver function tests and enzymes. Hematology includes complete blood count with differential. Urine samples will be collected if possible. Blood 
biochemistry, hematology, coagulation, and urinalysis will be evaluated at the local laboratory at Screening and at the local laboratory (Japan sites) and central laboratory (US 
sites) prior to study drug administration on dosing days (Day 1 and at Weeks 4, 8, and 12) and at Weeks 1, 2, 6, 10, 14, 16, 20, 24, and 28. Samples for evaluation by the 
central laboratory may be collected by home healthcare services (United States only) at non-dosing day visits. 
r. 
A urine or serum pregnancy test will be performed at Screening and at Week 28 for all females of childbearing potential, and they must have a negative test result. An FSH 
test will be performed for females of non-childbearing potential (if necessary) at Screening. If a female patient of childbearing potential discontinues the study early, a urine or 
serum pregnancy test will be performed at the ET visit.   
s. 
Collect blood samples for CMV DNA analysis utilizing PCR analysis. The central laboratory will perform CMV PCR analysis. Samples for evaluation by the central 
laboratory may be collected by home healthcare services (United States only) at non-dosing day visits.   


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t. 
Collect blood samples for CMV DNA or antigenemia testing. The local laboratory will perform CMV PCR analysis or CMV antigenemia testing consistently throughout the 
study.  
u. 
In the case home healthcare services (United States only) are utilized, it is not necessary to collect blood samples for CMV DNA analysis or CMV antigenemia testing for 
analysis by the local laboratory.  
v. 
Additional follow-up ECGs may be performed if clinically indicated.  
w. Administer NPC-21 (at a dose of 6 or 12 mg/kg of actual body weight [at Screening]) or placebo via an approximately 60-minute intravenous infusion at a constant rate of 
5 mL/minute (Note: If an adverse event occurs during study drug administration and the Investigator deems it necessary, deceleration, suspension, or resumption of study drug 
administration is allowed).  
x. 
Collect blood sample for serum NPC-21 concentration measurements. Samples may be collected by home healthcare services (United States only) at non-dosing day visits. 
y. 
Blood samples for serum NPC-21 concentration measurements will be collected within 2 hours prior to study drug administration and at 2 hours (±30 minutes) following the 
beginning of the infusion (Note: Sample collection time points at each visit may be updated based on each administration data).  
z. 
Collect blood samples for anti–NPC-21 antibody measurements. Samples may be collected by home healthcare services (United States only) at non-dosing day visits. 
aa. Collect blood samples that will be stored for screening for resistant strains analysis. Samples may be collected by home healthcare services (United States only) at non-dosing 
day visits. 
CMV = cytomegalovirus; DNA = deoxyribonucleic acid; ECG = electrocardiogram; EQ-5D-5L = EuroQol 5 Dimensions 5 Levels questionnaire; ET = Early Termination; 
FSH = follicle-stimulating hormone; IgG = immunoglobulin G; IRT = Interactive Response Technology; PCR = polymerase chain reaction; Scr = Screening; US = United States; 
VGCV = valganciclovir.


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APPENDIX B: CLINICAL LABORATORY ANALYTES 
Standard Safety Chemistry Panel 
Alanine aminotransferase 
Albumin 
Alkaline phosphatase 
Amylase 
Aspartate aminotransferase 
Blood urea nitrogen 
Calcium 
Chloride 
C-reactive protein 
Creatine kinase 
Creatinine 
Direct bilirubin 
Estimated glomerular filtration rate 
Gamma-glutamyl transferase 
Glucose 
Indirect bilirubin 
Inorganic phosphorus 
Lactate dehydrogenase 
Lipase 
Potassium 
Sodium 
Total bilirubin 
Total cholesterol 
Total protein 
Triglycerides 
Uric acid 
 
Hematology 
Hematocrit 
Hemoglobin 
Platelets 
Red blood cell count 
Reticulocyte 
White blood cell count and differential [1] 
1. Neutrophils, eosinophils, basophils, lymphocytes, and monocytes. 
 
Coagulation 
Activated partial thromboplastin time 
International normalized ratio 
Prothrombin time 
 
 
Urinalysis 
Bilirubin 
Blood 
Glucose 
Ketones 
Leukocyte esterase 
Microscopy [2] 
Nitrite 
pH 
Protein 
Specific gravity 
Urobilinogen 
 
2. Microscopy is performed only as needed based on positive dipstick test results. 
 
Pregnancy Tests (Female Patients of Childbearing Potential Only) 
Urine or serum  
 


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Endocrinology (Postmenopausal Female Patients Only) 
Follicle-stimulating hormone [3]  
 
3. Follicle-stimulating hormone in postmenopausal female patients, with spontaneous 
amenorrhea for at least 2 years, to confirm their postmenopausal status. 
 
 


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APPENDIX C: THE DEFINITION OF CYTOMEGALOVIRUS 
SYNDROME 
Cytomegalovirus Syndrome  
Cytomegalovirus (CMV) syndrome is a disease deﬁnition that should only be used in solid organ 
transplant recipients. Because it is impossible to exclude all other causes of the clinical 
symptomatology described as CMV syndrome, a “proven” category cannot be deﬁned. The 
deﬁnition of probable CMV syndrome requires detection of CMV in blood by viral isolation, rapid 
culture, antigenemia, or nucleic acid testing together with at least 2 of the following: 
1. Fever ≥38°C for at least 2 days. 
2. New or increased malaise (toxicity Grade 2) or new or increased fatigue (toxicity Grade 3) 
(National Cancer Institute: Common Terminology Criteria for Adverse Events, version 4.0). 
3. Leukopenia or neutropenia on 2 separate measurements at least 24 hours apart, deﬁned as a 
white blood cell (WBC) count of <3500 cells/µL, if the WBC count prior to the development 
of clinical symptoms was ≥4000 cells/µL, or a WBC decrease of >20%, if the WBC count 
prior to the development of clinical symptoms was <4000 cells/µL. The corresponding 
neutrophil counts are <1500 cells/µL or a decrease of >20% if the neutrophil count before the 
onset of symptoms was <1500 cells/µL. 
4. Greater than or equal to 5% atypical lymphocytes. 
5. Thrombocytopenia deﬁned as a platelet count of <100,000 cells/µL if the platelet count prior 
to the development of clinical symptoms was ≥115,000 cells/µL or a decrease of >20% if the 
platelet count prior to the development of clinical symptoms was <115,000 cells/µL. 
6. Elevation 
of 
hepatic 
aminotransferases 
(alanine 
aminotransferase 
or 
aspartate 
aminotransferase) to 2 times the upper limit of normal (applicable to non-liver transplant 
recipients).1 
Sources:  
1. Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of cytomegalovirus infection and disease 
in transplant patients for use in clinical trials. Clin Infect Dis. 2017;64(1):87-91. 


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APPENDIX D: THE DEFINITIONS OF CYTOMEGALOVIRUS DISEASE 
Cytomegalovirus Disease Definitions 
The definitions of cytomegalovirus disease are provided in Ljungman et al.1   
Sources:  
1. Ljungman P, Boeckh M, Hirsch HH, et al. Definitions of cytomegalovirus infection and disease 
in transplant patients for use in clinical trials. Clin Infect Dis. 2017;64(1):87-91. 

SAP_001.pdf: 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Protocol Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study of NPC-21 for Kidney Transplant Recipients at High-
Risk of Cytomegalovirus Infection (LionHeart21) 
 
Protocol Number: 
NPC-21-2 
Protocol Version/Date: 
Version 5.0/18 October 2021 
Investigational Product: 
NPC-21 
 
 
Sponsor: 
Nobelpharma Co., Ltd. 
NMF Kayabacho Bldg., 1-17-24, Shinkawa 
Chuo-ku, Tokyo 104-0033, Japan 
 
Telephone: +81-3-6670-3800 
Fax: +81-3-6670-3801 
 
SAP Version/Date: 
Version 1.0/29 March 2023 
 
CONFIDENTIAL 
The information in this document is confidential and is not to be disclosed without the written 
consent of Nobelpharma Co., Ltd. except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical study for Nobelpharma Co., Ltd. 
You are allowed to disclose the contents of this document only to your Institutional Review Board 
or Independent Ethics Committee and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Nobelpharma Co., Ltd. and that it may not be further disclosed to 
third parties. 
 
 




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VERSION HISTORY 
Version 
Version Date 
Description 
1.0 
29 March 2023 
Original signed version 
 
 


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TABLE OF CONTENTS 
1 
Introduction .......................................................................................................................... 7 
2 
Study Overview .................................................................................................................... 7 
2.1 
Study Objectives ............................................................................................................ 7 
2.1.1 
Primary Objective ................................................................................................... 7 
2.2 
Study Design ................................................................................................................. 7 
2.2.1 
Overview ............................................................................................................... 7 
2.2.2 
Randomization ........................................................................................................ 8 
2.2.3 
Study Drug ............................................................................................................. 9 
2.2.4 
Sample Size Determination....................................................................................... 9 
2.3 
Study Endpoints ............................................................................................................. 9 
2.3.1 
Primary Efficacy Endpoint ....................................................................................... 9 
2.3.2 
Secondary Efficacy Endpoints .................................................................................. 9 
2.3.3 
EuroQol 5 Dimensions 5 Levels Questionnaire ..........................................................10 
2.3.4 
Safety Endpoints ....................................................................................................10 
3 
Statistical Methodology.........................................................................................................10 
3.1 
General Considerations ..................................................................................................10 
3.1.1 
Analysis Day .........................................................................................................10 
3.1.2 
Analysis Visits .......................................................................................................10 
3.1.3 
Definition of Baseline .............................................................................................11 
3.1.4 
Summary Statistics .................................................................................................11 
3.1.5 
Handling of Dropouts and Missing Data ....................................................................12 
3.2 
Analysis Populations .....................................................................................................12 
3.2.1 
Intent-to-Treat Population .......................................................................................12 
3.2.2 
Modified Intent-to-Treat Population .........................................................................12 
3.2.3 
Per Protocol Population ...........................................................................................12 
3.2.4 
Pharmacokinetic Population ....................................................................................13 
3.2.5 
Safety Population ...................................................................................................13 
3.3 
Patient Data and Study Conduct ......................................................................................13 
3.3.1 
Patient Disposition .................................................................................................13 
3.3.2 
Protocol Deviations ................................................................................................13 
3.3.3 
Analysis Populations ..............................................................................................13 
3.3.4 
Demographic and Baseline Characteristics ................................................................13 
3.3.5 
Medical History .....................................................................................................14 
3.3.6 
Prior and Concomitant Medications ..........................................................................14 
3.3.7 
Study Drug Exposure ..............................................................................................15 
3.4 
Efficacy Assessment ......................................................................................................15 
3.4.1 
Primary Efficacy Analysis .......................................................................................15 
3.4.2 
Secondary Efficacy Analysis ...................................................................................16 
3.4.3 
Exploratory Analysis ..............................................................................................17 


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3.4.4 
Subgroup Analysis .................................................................................................17 
3.5 
Analysis of Pharmacokinetic ...........................................................................................17 
3.6 
Analysis of Exposure-Response ......................................................................................18 
3.7 
Safety Assessment .........................................................................................................18 
3.7.1 
Adverse Events ......................................................................................................18 
3.7.2 
Clinical Laboratory Evaluations ...............................................................................19 
3.7.3 
Vital Signs.............................................................................................................19 
3.7.4 
Electrocardiograms .................................................................................................20 
3.7.5 
Physical Examinations ............................................................................................20 
3.7.6 
Data Safety Monitoring Board .................................................................................20 
3.8 
Interim Analysis ............................................................................................................20 
4 
Changes from Protocol-Specified Statistical Analyses...............................................................20 
5 
Programming Specifications ..................................................................................................20 
 
 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
Adverse Event 
AESIs 
Adverse Events of Special Interest 
ATC 
Anatomical Therapeutic Chemical 
BLQ 
Below the Lower Limit of Quantification 
CMV 
Cytomegalovirus 
COVID-19 
Coronavirus Disease 2019 
eCRF 
Electronic Case Report Form 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DNA 
Deoxyribonucleic Acid 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiograms 
EDC 
Electronic Data Capture 
EQ-5D-5L 
EuroQol 5 Dimensions 5 Levels Questionnaire 
IRT 
Interactive Response Technology 
ITT 
Intent-to-Treat  
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-to-Treat 
NCI 
National Cancer Institute 
PCR 
Polymerase Chain Reaction 
PK 
Pharmacokinetics 
PP 
Per Protocol 
PT 
Preferred Term 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
TEAE 
Treatment-emergent Adverse Event 
TESAE 
Treatment-emergent Serious Adverse Event 
WHO 
World Health Organization 
 
 


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1 INTRODUCTION 
The purpose of this Statistical Analysis Plan (SAP) is to provide a description of the statistical methods to 
be implemented for the analysis of data for Nobelpharma Co., Ltd. protocol NPC-21-2 (Version 5.0; 18 
October 2021). The SAP will be finalized prior to database lock. Any deviations from the SAP after 
database lock will be documented in the final Clinical Study Report (CSR). 
2 STUDY OVERVIEW 
2.1 Study Objectives 
2.1.1 Primary Objective 
The primary objective is to assess the efficacy and safety of NPC-21 when administered prophylactically 
to cytomegalovirus (CMV) seronegative patients receiving a first kidney transplant from a CMV 
seropositive donor. 
2.2 Study Design 
2.2.1 Overview 
This is a Phase 2, randomized, double-blind, placebo-controlled study of NPC-21 for kidney transplant 
recipients at high risk of CMV infection at approximately 25 clinical sites in the United States and Japan. 
Approximately 108 eligible patients will be randomized in a 4:1:4 ratio prior to first study drug 
administration to receive 6 mg/kg NPC-21, 12 mg/kg NPC-21, or placebo. Randomization will be stratified 
by region (United States or Japan).  
Figure 1 displays a schematic of the study’s design. 
Figure 1. Study Schematic 
 


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Adult CMV seronegative patients receiving a first kidney transplant from CMV seropositive donors will be 
enrolled in the study. Participation in the study will consist of a Screening Period (up to 14 days prior to 
first study drug administration), a 16-week Treatment Period, and a 12-week Observation Period. The total 
duration of the study (including Screening, Treatment Period, and Observation Period) will be 
approximately 30 weeks. After first study drug administration, patients who develop detectable CMV 
disease (CMV syndrome or tissue-invasive CMV disease) or CMV viremia (defined as the detection of 
≥250 IU/mL in plasma measured by polymerase chain reaction [PCR] analysis in central laboratory or 
meets the local criteria for CMV viremia measured by PCR analysis or antigenemia testing) can enter the 
Rescue Phase of the study and be treated by anti-CMV agents per local standard of care until the patient is 
negative for CMV viremia, has recovered from CMV disease, or up to Week 28, whichever comes first. 
When this rescue therapy is completed, the Rescue Phase is terminated at least 4 Study Weeks after the last 
study drug administration and all Week 28 procedures will be performed as per Section 6.7 the Early 
Termination Visit and Withdrawal Procedures of the protocol.  
The 16-week Treatment Period will include study drug administration on Day 1 and at Weeks 4, 8, and 12. 
The 16-week Treatment Period will begin as soon as practical post-transplant but no later than 7 days post-
transplant.  
Blood samples will be collected at Screening; prior to study drug administration on dosing days (Day 1 and 
at Weeks 4, 8, and 12); and at Weeks 1, 2, 3, 5, 6, 7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 
26, and 28 for CMV deoxyribonucleic acid (DNA) analysis utilizing PCR analysis or CMV antigenemia 
testing. The central laboratory will perform CMV PCR analysis, and the local laboratory will perform CMV 
PCR analysis or CMV antigenemia testing consistently throughout the study. Upon entering the Rescue 
Phase, a blood sample will be collected for CMV DNA analysis utilizing PCR analysis performed by the 
central laboratory.  
Blood samples for anti–NPC-21 antibody testing will be collected prior to study drug administration on 
dosing days (Day 1 and at Weeks 4, 8, and 12) and at Weeks 16 and 28.  
Blood samples that will be stored for screening for resistant strains analysis will be collected prior to study 
drug administration on Day 1 and at Weeks 16 and 28 and at the initiation of the Rescue Phase.  
Blood samples for serum NPC-21 concentration measurements will be collected within 2 hours prior to 
study drug administration and at 2 hours (±30 minutes) following the beginning of the infusion on dosing 
days (Day 1 and at Weeks 4, 8, and 12) and at Weeks 1, 2, 3, 6, 10, 14, 16, 20, 24, and 28 (Note: Sample 
collection time points at each visit may be updated based on each administration data).  
The EuroQol 5 Dimensions 5 Levels questionnaire (EQ-5D-5L) will be performed prior to study drug 
administration on Day 1, at Weeks 16 and 28, and at the initiation of the Rescue Phase.  
The safety of NPC-21 in CMV seronegative patients will be evaluated through physical examination 
findings, 12-lead electrocardiograms (ECGs), vital signs, changes in clinical laboratory assessments (blood 
biochemistry [including liver function tests and enzymes], hematology [including complete blood count 
with differential], coagulation, and urinalysis), and adverse event (AE) monitoring. 
2.2.2 Randomization  
At Screening, a unique patient identification number will be established for each patient who has provided 
written informed consent. This patient identification number will be used for patient identification 
throughout the study and in all study-related documentation. This will be a 5 digit hyphenated number of 
the following format: XYY-ZZ, where X is the country number (1 [US] or 2 [Japan]), YY is the sequential 
unique site identification number, and ZZ is a sequential unique number assigned to the patient at that site. 


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Each patient number will be assigned only once and will not be reassigned to another patient if a patient 
fails during Screening. Interactive Response Technology (IRT) will not allow repeat of numbers. This 
unique identifier will be used in all study documentation for that patient from first to last contact.  
After informed consent and body weight are obtained, pre-Randomization will take place via the IRT 
system to 1 of 3 treatment groups (6 mg/kg NPC-21, 12 mg/kg NPC-21, or placebo) in a 4:1:4 ratio. 
Randomization will be stratified by region (United States or Japan). Randomization will take place prior to 
first study drug administration after confirming all criteria. Randomization procedures may occur on Day -
1 or Day 1 prior to first study drug administration.  
2.2.3 Study Drug 
 
 
 
 
 
 
 Normal saline supplied by 
 will be used as the placebo. 
2.2.4 Sample Size Determination 
A total sample size of approximately 108 patients is planned for the study, with a 1:1 randomization ratio 
for 6 mg/kg NPC-21 versus placebo and another 12 patients for high-level dose of 12 mg/kg NPC-21 (4:1:4 
randomization ratio for 6 mg/kg NPC-21, 12 mg/kg NPC-21, or placebo). The sample size calculation is 
based on the modified Intent-to-Treat (mITT) Population from the first dose of NPC-21 through Week 16 
for the occurrence of CMV disease (CMV syndrome or tissue-invasive CMV disease) or CMV viremia 
(defined as the detection of ≥ 250 IU/mL in plasma measured by PCR analysis in central laboratory or 
meets the local criteria for CMV viremia measured by PCR analysis or antigenemia testing) primary 
endpoint. Assuming an early discontinuation rate of 15%, approximately 48 patients each in the 6 mg/kg 
NPC-21 and placebo arms are needed with a 2-sided significance level of 0.05 and a power of 80% to detect 
a difference between NPC-21 at a predicted incidence rate of CMV disease (CMV syndrome or tissue-
invasive CMV disease) or CMV viremia of 30% versus 60% for placebo. In addition, a sample size of 12 
patients for the 12 mg/kg NPC-21 arm is considered adequate for the planned exposure-response analysis.  
2.3 Study Endpoints 
2.3.1 Primary Efficacy Endpoint 
The primary efficacy endpoint is the incidence of CMV disease (CMV syndrome [see Appendix C of 
protocol for definition of CMV syndrome] or tissue-invasive CMV disease [see Appendix D of protocol 
for definitions of CMV disease]) or CMV viremia (defined as the detection of  ≥ 250 IU/mL in plasma 
measured by PCR analysis in central laboratory or meets the local criteria for CMV viremia measured by 
PCR analysis or antigenemia testing) by Week 16. 
2.3.2 Secondary Efficacy Endpoints 
The secondary efficacy endpoints include the following:  
• 
Incidence of CMV disease or CMV viremia by Week 28  
• 
Incidence of CMV disease  
• 
Incidence of CMV viremia  


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• 
Time to detectable CMV disease or CMV viremia  
• 
Time to detectable CMV disease 
• 
Time to detectable CMV viremia  
• 
Amount of CMV DNA by PCR analyzed by the central laboratory  
• 
Incidence and duration of anti-CMV therapy during the Rescue Phase  
• 
Changes in EQ-5D-5L score from Baseline to Weeks 16 and 28 
2.3.3 EuroQol 5 Dimensions 5 Levels Questionnaire 
EQ-5D-5L is developed by EuroQol Research Foundation and is a measure of health-related quality of life. 
It consists of two elements, 5-item questionnaire and EQ-Visual Analogue Scale. EQ-5D-5L is a version 
that further improves sensitivity of EQ-5D-3L and that provides respondents with a wider range of options 
to describe their health, which has five response levels.   
• 
5-Item Questionnaire: The questionnaire provides a simple descriptive profile of health state. The 
questionnaire comprises 5 dimensions (mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression) and each dimension has 5 response levels (1-no problems, 2-slight problems, 
3-moderate problems, 4-severe problems, 5-unable to/extreme problems).  
2.3.4 Safety Endpoints 
The safety of NPC-21 in CMV seronegative patients will be evaluated through physical examination 
findings, 12-lead ECGs, vital signs, changes in clinical laboratory assessments (blood biochemistry 
[including liver function tests and enzymes], hematology [including complete blood count with differential], 
coagulation, and urinalysis), and AE monitoring. 
Events of serious hypersensitivity that are Grade 3 or higher or lead to treatment discontinuation will be 
monitored as AEs of special interest (AESIs) during this study. During the course of the study, vacuolization 
associated with immunoglobulin will be added as AESIs, and additional AESIs may be identified by the 
Sponsor. 
3 STATISTICAL METHODOLOGY 
3.1 General Considerations 
3.1.1 Analysis Day 
Analysis day will be calculated from the date of first dose of study drug.  The day of the first dose of 
study drug will be Day 1, and the day immediately before Day 1 will be Day -1. There will be no Day 0. 
3.1.2 Analysis Visits 
The low analysis day of the analysis window will be calculated as the midpoint between the scheduled 
assessment and previously scheduled assessment for that parameter. The high analysis day of the analysis 
window will be calculated as the midpoint between the scheduled assessment and the next scheduled 
assessment for that parameter. Within each analysis visit, scheduled visits will be assigned to the analysis 
visit. If a scheduled visit is not available, unscheduled and early termination visits will be assigned to 
analysis visits using analysis visit windows based on the actual date the assessment took place.  
Where multiple measurements for a particular parameter appear within an analysis window, the scheduled 
visit will be used. If no scheduled visit appears in the analysis window, the result closest to the target day 
will be used. If equidistant and both are unscheduled and/or early termination visits, the later result will be 
used for the summary measure.  Specially, if patients do not receive the study drug at scheduled visit (e.g., 


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Day 29) but receive the study drug within this visit window and record as “Unscheduled”, the results close 
to this unscheduled visit will be used if there are both results for scheduled visit and unscheduled visit. The 
analysis visit table below is applicable for both safety and efficacy analysis.  
Analysis Visit 
Target Day 
Low Analysis Day 
High Analysis Day 
Baseline 
1 
Null 
1 
Day 8 
8 
2 
11 
Day 15 
15 
12 
18 
Day 22 
22 
19 
25 
Day 29 
29 
26 
32 
Day 36 
36 
33 
39 
Day 43 
43 
40 
46 
Day 50 
50 
47 
53 
Day 57 
57 
54 
60 
Day 64 
64 
61 
67 
Day 71 
71 
68 
74 
Day 78 
78 
75 
81 
Day 85 
85 
82 
88 
Day 92 
92 
89 
95 
Day 99 
99 
96 
102 
Day 106 
106 
103 
109 
Day 113 
113 
110 
116 
Day 120 
120 
117 
123 
Day 127 
127 
124 
130 
Day 134 
134 
131 
137 
Day 141 
141 
138 
144 
Day 148 
148 
145 
151 
Day 155 
155 
152 
158 
Day 162 
162 
159 
165 
Day 169 
169 
166 
176 
Day 183 
183 
177 
189 
Day 197/ET    
197 
190 
200 
 
3.1.3 Definition of Baseline 
Baseline is defined as the last non-missing measurement prior to the first dose of study drug. Both date 
and time will be considered in baseline derivation. Measurement from Day 1 prior to study drug 
administration will be used. If not available, the last non-missing measurement prior to Day 1 will be 
used.   
3.1.4 Summary Statistics 
Summary statistics will be presented by treatment group. Unless otherwise stated, continuous variables will 
be summarized by using the number of non-missing observations, arithmetic mean, standard deviation, 
median, minimum, and maximum values as descriptive statistics. Categorical variables will be summarized 
by using the frequency count and the percentage of patients in each category as descriptive statistics. 95% 
confidence intervals will be provided for categorical efficacy endpoints.  
For time-to-event variables, the Kaplan-Meier method will be used to estimate the median time (weeks) 
and its 95% confidence interval. 


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3.1.5 Handling of Dropouts and Missing Data 
In general, data will be analyzed and presented as observed and will not be imputed for the analysis of 
efficacy. 
In case the start and end dates for AEs and concomitant medications/procedures are missing or incomplete, 
the missing component(s) will be assumed as the most conservative value possible. For example, AEs with 
missing start dates, but with stop dates either overlapping into the treatment period or missing, will be 
counted as treatment-emergent, taking the worst-case approach. When partial dates are present in the data, 
both a partial start date and/or a partial stop date will be evaluated to determine whether it can be 
conclusively established that the AE started prior to the start of study treatment or ended prior to the start 
of study treatment. If the above cannot be conclusively established based on the partial and/or present dates, 
then the AE will be considered as treatment-emergent. Actual data values as they appear in the original 
electronic case report forms (eCRFs) will be presented in the data listings. 
All central CMV DNA PCR values will be used for the efficacy analyses and the local laboratory values 
will be listed. For the calculation of descriptive statistics of central CMV DNA results, below the lower 
limit of quantification (BLQ) values will be set to zero if result is reported as “< 102” with unit “IU/mL”. 
Missing data reported as “quality not sufficient” will not be imputed. 
Changes in study visit schedules, missed or delayed visits, or patient discontinuations and the relationship 
to COVID-19 will be captured in the eCRFs.  
3.2 Analysis Populations 
3.2.1 Intent-to-Treat Population 
The Intent-to-Treat (ITT) Population will include all randomized patients. 
3.2.2 Modified Intent-to-Treat Population  
The modified Intent-to-Treat (mITT) Population will include all patients who receive a kidney transplant 
from a living or deceased donor and receive at least 1 dose of study drug (6 mg/kg NPC-21, 12 mg/kg NPC-
21, or placebo). The mITT Population will be used for all efficacy analyses. 
3.2.3 Per Protocol Population  
The Per Protocol (PP) Population will include all patients in the mITT Population who have no major 
protocol deviations. PP Population will be used for primary endpoint analyses. Major protocol deviations 
that may impact the primary efficacy assessment may include but are not limited to: 
• 
Failed to meet eligibility criteria at randomization 
• 
The first dose of study drug was not administered within 7 days of the kidney transplant 
• 
The study treatment was administered out of the protocol allowed window 
• 
Failed to receive the study treatment at scheduled visit 
• 
Failed to complete the infusion and underdosed 
• 
Took the wrong study drug (i.e., did not take the randomized study drug) 
• 
Used a restricted concomitant medication not permitted per protocol 
• 
Any other major protocol deviations 
A list of subjects with major protocol deviations leading to exclusion from the PP Population will be 
finalized prior to unblinding the randomized treatment assignments. 


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3.2.4 Pharmacokinetic Population  
The Pharmacokinetic (PK) Population will include all patients who receive any amount of study drug (6 
mg/kg NPC-21, 12 mg/kg NPC-21, or placebo) and have evaluable PK data. The PK Population will be 
used for the PK analyses and exposure-response analyses. 
3.2.5 Safety Population  
The Safety Population will include all randomized patients who receive at least 1 dose of study drug (6 
mg/kg NPC-21, 12 mg/kg NPC-21,  or placebo). The Safety Population will be used for safety analyses. 
3.3 Patient Data and Study Conduct 
3.3.1 Patient Disposition 
The following patient disposition categories will be summarized via counts and percentages by treatment 
group and in total for all screened patients: 
• 
Patients who were screened 
• 
Patients who were randomized 
• 
Patients who were treated 
• 
Patients who end study treatment and continued in the study for assessments 
• 
Patients who end study treatment but discontinued in the study for assessments 
o Primary reason for discontinuation 
• 
Patients who completed the study 
• 
Patients who withdrew early from the study 
o Withdrew early from the study before Week 16  
o Withdrew early from the study after Week 16 
o Primary reason for early withdrawal 
• 
Patients who entered rescue phase  
o Reason for entering rescue phase 
All patient disposition data will be listed by-patient. 
3.3.2 Protocol Deviations 
Counts and percentages of patients with protocol deviations by CSR reportable deviation category will be 
summarized by treatment group and in total based on the ITT Population. Descriptions and categories of 
CSR reportable events are found in the Protocol Deviation Plan. 
Protocol deviations in study procedures due to COVID-19 will be reported in the CSR. All protocol 
deviations data will be listed by-patient. 
3.3.3 Analysis Populations 
Counts and percentages of patients in each analysis population will be summarized by treatment group and 
in total based on all randomized patients.  
All analysis population data will be listed by-patient. 
3.3.4 Demographic and Baseline Characteristics 
The following demographic and baseline characteristics will be summarized: 
• 
Country (United States, Japan) 


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• 
Age (Years)  
• 
Age group ( < 65, ≥ 65) 
• 
Sex (Male, Female) 
o Childbearing potential 
• 
Ethnicity (Hispanic or Latino, Not Hispanic or Latino, Not Reported, Unknown) 
• 
Race (American Indian or Alaska Native, Asian, Black or African American, Native Hawaiian or 
Other Pacific Islander, White, Other: Specify) 
• 
Height (cm) 
• 
Weight at pre-randomization (kg) 
• 
Weight group (< 100 kg, ≥ 100 kg) 
• 
Body mass index (kg/m2)  
• 
Time from transplantation to first dose date(days) 
o Day = First dose date of study drug – date of kidney transplant + 1. 
• 
Primary disease (Diabetic Kidney Disease, Glomerulonephritis, Polycystic Kidney Disease, 
Other, Not Specified, Unknown) 
• 
Donor status (Deceased, Living) 
• 
ABO compatibility (Compatible, Incompatible) 
• 
Dialysis introduction (Yes, No) 
o Dialysis specify (Hemodialysis, Peritoneal Dialysis) 
• 
Central CMV DNA level (IU/mL) at baseline  
• 
Induction therapy (Yes, No), if yes, summarize by the below categories:  
o Alemtuzumab 
o ATG (Thymoglobulin®) 
o Rituximab 
o Basiliximab 
o Bortezomib 
o Eculizumab 
• 
Immunosuppressive agents at randomization (Azathioprine, Belatacept, Cyclosporine, 
Everolimus, Gusperimus, MMF, Sirolimus, Steroids, Tacrolimus) 
Demographic and baseline characteristics will be summarized with descriptive statistics or counts and 
percentages of patients as appropriate by treatment group and in total for all defined analysis populations. 
3.3.5 Medical History 
Counts and percentages of patients who experienced any past and/or concomitant diseases, and counts and 
percentages of patients who experienced any past surgeries will be summarized by treatment group and in 
total.  
Medical history will be coded to system organ class (SOC) and preferred term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA) v24.0. Counts and percentages of patients with medical 
history by SOC and PT will be summarized by treatment group and in total based on Safety Population. 
All medical/surgical history data will be listed by-patient. 
3.3.6 Prior and Concomitant Medications 
Concomitant medications will be coded to anatomical therapeutic chemical (ATC) class and PT using the 
WHODrug Global B3, March 2021. Medications will be considered as prior medications if they stopped 
prior to the first dose of study drug and concomitant medications if they were taken at any time after the 


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first dose of study drug (i.e., started prior to the first dose of study drug and were ongoing, or started after 
the first dose of study drug). 
If a medication has incomplete start or stop dates, dates will be imputed to determine whether a medication 
should be considered prior or concomitant. If a medication start date is incomplete, the first day of the 
month will be imputed for missing day and January will be imputed for missing month. If a medication stop 
date is incomplete, the last day of the month will be imputed for missing day and December will be imputed 
for missing month. Incomplete start and stop dates will be listed as collected without imputation. 
Counts and percentages of patients taking prior and concomitant medications by ATC class and PT will be 
summarized by treatment group and in total based on the Safety Population, separately. Patients will be 
counted only once by medication class or name. 
All prior and concomitant medications will be listed by-patient. 
3.3.7 Study Drug Exposure  
The duration of study drug will be calculated as: 
• 
Duration of study drug (days) = last dose date of study drug + 28 – first dose date of study drug  
Total volume administered (mL): 
• 
Total volume administered (mL) = cumulative volume of study drug administered up to last dose 
Total study drug administered (mg): 
• 
Total study drug administered (mg) = 10 × Total volume administered (mL) 
Duration of study drug, total study drug administered (mg), and the count and percentages of number of 
infusions administered (e.g., 1, 2, 3, 4) will be summarized by treatment group.  
In addition, for each scheduled visit (e.g., Day 1, Day 29, Day 57, and Day 85), the proportion of patients 
who receive the treatment among patients who are expected to receive the treatment will be summarized. 
For each visit, the patients who withdraw from the treatment or enter the rescue phase by this visit will be 
excluded from the analysis. 
All study drug exposure data will be listed by-patient. 
3.4 Efficacy Assessment 
The mITT Population will be used for efficacy analyses. The primary efficacy endpoint will also be 
analyzed on the PP Population. 
3.4.1 Primary Efficacy Analysis 
The proportion of patients with the occurrence of CMV disease (CMV syndrome [see Appendix C of the 
protocol for definition of CMV syndrome] or tissue-invasive CMV disease [see Appendix D of the protocol 
for definitions of CMV disease]) or CMV viremia (defined as the detection of ≥ 250 IU/mL in plasma 
measured by PCR analysis in central laboratory or meets the local criteria for CMV viremia measured by 
PCR analysis or antigenemia testing) by Week 16 will be summarized by treatment group.  
The 2-sided 95% exact Clopper-Pearson confidence intervals of the proportions will be provided. For any 
two treatment groups, the proportion difference and 95% unstratified Miettinen-Nurminen (score) 
confidence limits will be presented.  


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Comparisons across placebo and 6 mg/kg NPC-21 treatment group will use logistic regression analysis with 
stratification factor of region (United States or Japan) as a covariate  
Non-responders will include all patients who develop CMV disease or CMV viremia. In principle, patients 
who discontinue from the study prior to Week 16 in the absence of CMV disease or CMV viremia will be 
considered as non-responders. If warranted under special circumstances, a patient who discontinues from 
the study prior to Week 16 may be discussed with the medical expert to determine status as a responder or 
non-responder. If this occurs, the rationale for considering the patient as a responder will be finalized before 
database lock and documented in this SAP. Sensitivity analysis may be performed to assess the impact of 
these patients on analysis results. 
3.4.2 Secondary Efficacy Analysis 
3.4.2.1 
Categorical Endpoints 
The categorical endpoints as below will be analyzed using the same analysis method as primary analysis:  
• 
Incidence of CMV disease or CMV viremia by Week 28  
• 
Incidence of CMV disease by Week 16 
• 
Incidence of CMV disease by Week 28 
• 
Incidence of CMV viremia by Week 16 
• 
Incidence of CMV viremia by Week 28 
• 
Incidence of anti-CMV therapy during the Rescue Phase 
3.4.2.2 
Continuous Endpoints 
Descriptive statistics will be presented by treatment group for the continuous endpoints as below:  
• 
Amount of CMV DNA by PCR analyzed by the central laboratory  
o Descriptive statistics will be provided for amount of CMV DNA (IU/mL) at each 
scheduled visit and changes from baseline will be presented as well.  
• 
Duration of anti-CMV therapy during the Rescue Phase  
• 
Duration of the detection of CMV DNA ≥ 250 IU/mL in plasma measured by PCR analysis in 
central laboratory 
• 
Changes in EQ-5D-5L score from Baseline to Weeks 16 and 28 
o Counts and percentages of patients with each of five response levels in each domain will 
be presented by treatment and visit.  
o Changes from baseline for total health status will be presented as well.  
3.4.2.3 
Time-to-Event Endpoints 
The time-to-event endpoints include:  
• 
Time to detectable CMV disease or CMV viremia by Week 28 
• 
Time to detectable CMV disease by Week 28 
• 
Time to detectable CMV viremia by Week 28 
For each time-to-event endpoint, the count and proportion of patients experiencing event and censored will 
be summarized by treatment group. The Kaplan-Meier estimate of median time and Brookmeyer-Crowley 
95% confidence intervals will be presented. Log-rank test will be used to test whether there is significant 
difference among groups. 
The endpoints will be calculated as:  


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• 
Time to detectable CMV disease or CMV viremia by Week 28 (Weeks) = (Date of CMV disease 
or CMV viremia – first dose date of study drug + 1)/7. 
• 
Time to detectable CMV disease by Week 28 (Weeks) = (Date of CMV disease – first dose date of 
study drug + 1)/7. 
• 
Time to detectable CMV viremia by Week 28 (Weeks) = (Date of CMV viremia – first dose date 
of study drug + 1)/7. 
If patients experience CMV disease or CMV viremia, the dates of entering Rescue Phase will be used to 
determine the date of CMV disease or CMV viremia and the patients will not be censored. Patients who do 
not experience CMV disease or CMV viremia will be censored at the latest CMV viremia assessments. 
3.4.3 Exploratory Analysis 
As the exploratory analysis, incidence of CMV disease or CMV viremia by Week 16 assessed by Endpoint 
data reviewers will be analyzed using the method described in Section 3.4.1. In addition, the below 
endpoints will also be analyzed. 
• 
Incidence of CMV disease or CMV viremia by Week 28  
• 
Incidence of CMV disease by Week 28  
• 
Incidence of CMV viremia by Week 28 
In addition, the Endpoint data reviewer findings will be listed by-patient. 
As the supportive analysis, only criteria using the detection of ≥ 250 IU/mL in plasma measured by PCR 
analysis in central laboratory will be considered for the analysis of primary efficacy endpoint in Section 
3.4.1. Non-responders will include all patients who have central CMV DNA assessments ≥ 250 IU/mL by 
Week 16. Patients who discontinue from the study prior to Week 16 in the absence of central CMV DNA 
assessments ≥ 250 IU/mL will be considered as non-responders. 
3.4.4 Subgroup Analysis 
Subgroup analysis will be performed to explore the consistency of the treatment effect for subgroups. 
Statistical analysis of the primary efficacy endpoint and selected secondary efficacy endpoints will be 
provided within each category of the following variables if the data allows: 
• 
Country (United States, Japan) 
• 
Weight group (< 100 kg, ≥ 100 kg) 
• 
ABO compatibility (Compatible, Incompatible) 
• 
Induction therapy (Yes, No) 
• 
Donor status (Deceased, Living) 
3.5 Analysis of Pharmacokinetic  
Serum concentrations of NPC-21 will be summarized using descriptive statistics. Geometric mean and 
geometric coefficient of variation will also be provided. For the calculation of descriptive statistics, BLQ 
values will be set to zero and missing data will not be imputed. 2-hour post-dose samples collected outside 
the sampling window of 2 hours +/- 30 minutes after infusion start may be excluded from the calculation 
of descriptive statistics. Plots of mean concentrations of plasma NPC-21 versus time will be generated for 
each dose group and scheduled visit.  


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In addition, analysis of the concentration data as part of population-PK modeling will be described in a 
separate PK Analysis Plan and reported separately.  
The PK listing will be provided. 
3.6 Analysis of Exposure-Response 
Exposure-response analyses will be performed to propose target concentrations using PK parameters 
estimated by population-PK, efficacy variables, and biomarker, which will be described in a separate 
analysis plan. 
3.7 Safety Assessment 
The Safety Population will be used for all safety analyses. Safety will be summarized descriptively by 
treatment group. 
Descriptive summary statistics will be provided for all safety variables, including 12-lead ECGs, vital signs, 
clinical laboratory assessments, and AEs reported during the study. 
3.7.1 Adverse Events 
AEs will be monitored and documented from the time informed consent is obtained until Week 28. All AEs 
will be coded using MedDRA v24.0.   
Treatment-emergent AEs (TEAEs) are defined as AEs that start on or after the first dose of study drug.  
Events of serious hypersensitivity that are Grade 3 or higher or lead to treatment study drug discontinuation 
and vacuolization associated with immunoglobulin will be monitored as AESIs. 
An overview of AEs will be provided including counts and percentages of patients (and event counts) with 
the following: 
• 
Any TEAEs  
• 
Any Grade 3 or higher TEAEs 
• 
Any study drug related TEAEs 
• 
Any study drug related Grade 3 or higher TEAEs 
• 
Any AEs related to anti-CMV rescue medication 
• 
Any AESIs 
• 
Any Grade 3 or higher AESIs 
• 
Any SAEs 
• 
Any treatment-emergent serious AEs (TESAEs) 
• 
Any TEAEs leading to discontinuation of study drug 
• 
Any TEAEs leading to discontinuation of study 
• 
Any AEs leading to death 
• 
Any AEs related to COVID-19 
Numbers and percentages of patients will also be presented by SOC and PT for each category in the 
summary tables. 
Listings will be presented for AEs, Grade 3 or higher AEs,  SAEs and TEAEs leading to discontinuation 
of study drug. 


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3.7.2 Clinical Laboratory Evaluations  
Standard clinical laboratory profiles for blood biochemistry, hematology, coagulation, and urinalysis will 
be evaluated at the local laboratory at Screening and at the local laboratory (Japan sites) and central 
laboratory (US sites) prior to study drug administration on dosing days (Day 1 and at Weeks 4, 8, and 12) 
and at Weeks 1, 2, 6, 10, 14, 16, 20, 24, and 28. Samples for evaluation by the central laboratory may be 
collected by home healthcare services at non-dosing day visits. See Appendix B of the protocol for a 
complete list of laboratory analytes. 
Clinical laboratory evaluations will be summarized using descriptive statistics if sufficient data is available 
for selected laboratory parameters including absolute measurements and changes from baseline by 
scheduled time of evaluation. Changes from baseline by scheduled time of evaluation will include last 
analysis visit, maximum post-treatment value, and minimum post-treatment value. Both scheduled and 
unscheduled post-treatment visits will be considered for the summaries of the maximum and minimum 
post-treatment values. 
Abnormal laboratory results will be graded according to NCI CTCAE v5.0. A shift table, presenting the 2-
way frequency tabulation for baseline and the worst post-baseline grade according to NCI CTCAE grades, 
will be provided for selected clinical laboratory tests. For select parameters (e.g. glucose), separate shift 
tables indicating hyper–and hypo-directionality of change may be produced. The worst post-baseline grade 
will be derived from all post-baseline visits including scheduled and unscheduled. 
The shift table for all parameters will be provided based on the categories Low, Normal and High based on 
normal ranges. Hyper–and hypo-directionality of change may be produced.  
Clinical laboratory evaluations will be listed by-patient. Abnormal values will be flagged.    
3.7.3 Vital Signs 
Vital signs (systolic and diastolic blood pressure, pulse rate, and body temperature) will be taken in the 
supine or sitting position after resting at Screening; prior to study drug administration on dosing days (Day 
1 and at Weeks 4, 8, and 12); within 1 hour of the end of the infusion on Day 1; and at Weeks 1, 2, 3, 5, 6, 
7, 9, 10, 11, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 26, and 28. Vital signs may be taken by home 
healthcare services at non-dosing day visits. 
Descriptive statistics will be provided for vital signs assessments. Changes from baseline by scheduled 
evaluation, and maximum and minimum post-treatment values may be presented. Both scheduled and 
unscheduled post-treatment values will be considered for summaries of the minimum and maximum. 
The counts and percentages of patients with the following potentially abnormal vital signs at any post-
baseline visits will be summarized: 
• 
Pulse rate < 50 bmp and decrease ≥ 15 bpm from baseline   
• 
Pulse rate > 100 bpm and increase ≥ 15 bpm from baseline 
• 
Systolic blood pressure ≤ 90 mmHg and decrease ≥ 20 mmHg from baseline 
• 
Systolic blood pressure ≥ 140 mmHg and increase ≥ 20 mmHg from baseline 
• 
Diastolic blood pressure ≤ 50 mmHg and decrease ≥ 10 mmHg from baseline 
• 
Diastolic blood pressure ≥ 90 mmHg and increase ≥ 10 mmHg from baseline 
Vital signs assessments will be listed by-patient.   


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3.7.4 Electrocardiograms 
A 12-lead ECG will be performed in a supine position after resting at Screening; prior to study drug 
administration at Weeks 4, 8, and 12; and at Weeks 16, 20, 24, and 28. Additional follow-up ECGs may be 
performed if clinically indicated. A 12-lead ECG may be performed by home healthcare services at non-
dosing day visits. 
Overall evaluation of ECG is collected at each visit in terms of  
• 
Normal  
• 
Abnormal, not clinically significant  
• 
Abnormal, clinically significant 
The counts and percentages of patients within each category will be summarized by treatment group and 
visit.  
ECG assessments will be presented in a by-patient listing. 
3.7.5 Physical Examinations 
A complete physical examination will be performed at Screening; prior to study drug administration on 
dosing days (Day 1 and at Weeks 4, 8, and 12); within 1 hour of the end of the infusion on Day 1; at Weeks 
1, 2, 3, 16, 20, 24, and 28; and at the initiation of the Rescue Phase. A physical examination may be 
performed by home healthcare services at non-dosing day visits. 
The physical examination will be presented in a by-patient listing.  
3.7.6 Data Safety Monitoring Board 
The Data Safety Monitoring Board (DSMB) will meet to review unblinded aggregate and individual patient 
data related to safety, data integrity, and overall conduct of the study and will provide recommendations to 
continue, temporarily halt, modify, or terminate the study based on data analysis. The committee may 
communicate other recommendations or concerns as deemed appropriate. Additional information will be 
provided in the DSMB charter as approved by the members. 
3.8 Interim Analysis 
No interim analysis is planned. 
4 CHANGES FROM PROTOCOL-SPECIFIED STATISTICAL 
ANALYSES 
In Section 3.4.2.2 for secondary efficacy analysis, the below secondary analysis was added compared to 
protocol:  
• 
Duration of the detection of CMV DNA ≥ 250 IU/mL in plasma measured by PCR analysis in 
central laboratory. 
The section 3.4.3 was added as the exploratory analysis to the endpoints.  
5 PROGRAMMING SPECIFICATIONS 
Analyses will be performed using SAS® version 9.3 or higher.  All available data will be presented in 
patient data listings which will be sorted by patient and visit date as applicable. Detailed Programming 
Specifications will be provided in a separate document. 


 
 
 
 
 
STATISTICAL ANALYSIS PLAN ADDENDUM 
 
Protocol Title: 
A Phase 2, Randomized, Double-Blind, Placebo-Controlled 
Study of NPC-21 for Kidney Transplant Recipients at High-
Risk of Cytomegalovirus Infection (LionHeart21) 
 
Protocol Number: 
NPC-21-2 
Protocol Version/Date: 
Version 5.0/18 October 2021 
Investigational Product: 
NPC-21 
 
 
Sponsor: 
Nobelpharma Co., Ltd. 
NMF Kayabacho Bldg., 1-17-24, Shinkawa 
Chuo-ku, Tokyo 104-0033, Japan 
 
Telephone: +81-3-6670-3800 
Fax: +81-3-6670-3801 
 
SAP Version/Date: 
Version 1.0/29 March 2023 
SAP Addendum 
Version/Date: 
Version 1.0/15 May 2023 
 
CONFIDENTIAL 
The information in this document is confidential and is not to be disclosed without the written 
consent of Nobelpharma Co., Ltd. except to the extent that disclosure would be required by law 
and for the purpose of evaluating and/or conducting a clinical study for Nobelpharma Co., Ltd. 
You are allowed to disclose the contents of this document only to your Institutional Review Board 
or Independent Ethics Committee and study personnel directly involved with conducting this 
protocol. Persons to whom the information is disclosed must be informed that the information is 
confidential and proprietary to Nobelpharma Co., Ltd. and that it may not be further disclosed to 
third parties. 
 
 




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TABLE OF CONTENTS 
1 
INTRODUCTION ................................................................................................................. 4 
2 
DATA ANALYSIS CHANGES .............................................................................................. 4 
2.1 
Categorical Endpoints ..................................................................................................... 4 
2.2 
Exploratory Analysis ...................................................................................................... 4 
 
 
 


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1 INTRODUCTION 
The statistical analysis plan (SAP), version 1.0, for the study with protocol number NPC-21-2 was finalized 
on 29 March 2023.  
The final database lock for this study was on 30 March 2023 with last signature data lock approval on 03 
April 2023. Further updates to the planned analysis are documented in this addendum.  
Summary of changes: 
• 
Updated the analysis methods of some secondary and exploratory endpoints 
2 DATA ANALYSIS CHANGES 
2.1 Categorical Endpoints 
In SAP version 1.0, section 3.4.2.1 describes that the categorical endpoints are analyzed using the same 
analysis method as the primary endpoint.  
However, for the analysis of primary endpoint, the non-responders include all patients who develop CMV 
disease or CMV viremia and patients who discontinue from the study prior to Week 16 in the absence of 
CMV disease or CMV viremia. 
This SAP addendum further clarifies that for the endpoints below, patients who discontinued from the 
study prior to Week 16 in the absence of CMV disease would not be considered as non-responders: 
• 
Incidence of CMV disease by Week 16  
• 
Incidence of CMV disease by Week 28 
For the endpoints below, patients who discontinued from the study prior to Week 16 in the absence of 
CMV viremia would not be considered as non-responders:  
• 
Incidence of CMV viremia by Week 16 
• 
Incidence of CMV viremia by Week 28 
For the secondary endpoint “Incidence of CMV disease or CMV viremia by Week 28”, the same analysis 
method as the primary endpoint is used by still including patients who discontinued from the study prior 
to Week 16 in the absence of CMV disease or CMV viremia as non-responders.  
2.2 Exploratory Analysis 
In SAP version 1.0, the first paragraph of section 3.4.3 describes that the endpoints below are analyzed 
using the same method as the primary endpoint: 
• 
Incidence of CMV disease or CMV viremia by Week 16 
• 
Incidence of CMV disease or CMV viremia by Week 28 
• 
Incidence of CMV disease by Week 28  
• 
Incidence of CMV viremia by Week 28 
 


Nobelpharma Co., Ltd. 
CONFIDENTIAL 
Statistical Analysis Plan Addendum 
NPC-21-2 
 
Version 1.0, 12 May 2023 
Page 5 of 5 
 
 
This SAP addendum further clarifies that for the endpoint “Incidence of CMV disease by Week 28”, 
patients who discontinued from the study prior to Week 16 in the absence of CMV disease would not be 
considered as non-responders.  
For the endpoints “Incidence of CMV viremia by Week 28”, patients who discontinued from the study prior 
to Week 16 in the absence of CMV viremia would not be considered as non-responders. 
For the endpoints “Incidence of CMV disease or CMV viremia by Week 16” and “Incidence of CMV 
disease or CMV viremia by Week 28”, the same analysis method as the primary endpoint is used by still 
including patients who discontinued from the study prior to Week 16 in the absence of CMV disease or 
CMV viremia as non-responders.