A Phase II/III Study of Sargramostim in Patients With Coronavirus Disease-2019 (COVID-19)
Phase: PHASE2
Conditions: COVID-19
Sponsor: Nobelpharma

 
 
 
 
 
 
 
 
Clinical Study Protocol 
 
 
A Phase II/III Study of Sargramostim in Patients with Coronavirus 
Disease-2019 (COVID-19)  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nobel Pharma Co. Ltd.  
 
 
 
 
Protocol No. 
NPC-26-1 
Date of issue  
April 22, 2021 
Version number 
5.0 

 
 
Handling Instruction of the Clinical Study Protocol 
The information described in this protocol is to be provided only to those involved in the clinical 
study (head of the medical institution, principal investigator, subinvestigator, study collaborator, 
investigational product manager, members of the Institutional Review Board, and others appropriately 
designated). No information described in the protocol can be disclosed to a third party without written 
permission from Nobel Pharma Co. Ltd., unless necessary for the conduct of the clinical study, such as 
disclosing the necessary information to obtain informed consent from subjects who wish to participate in 
the clinical study. 
All or a part of the protocol must not be duplicated, copied, or transcribed, regardless of its method 
(including photocopy, magnetic, or optical media input). In addition, prior written approval by Nobel 
Pharma Co. Ltd.shall be obtained when the information described in the protocol is to be published or 
disclosed to a third party. 
 

 
 
List of Abbreviations 
Abbreviation 
Description 
A-aDO2 
Alveolar–arterial oxygen gradient 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ARDS 
Acute Respiratory Distress 
Syndrome 
AST 
Aspartate aminotransferase 
BUN 
Blood urea nitrogen 
Ca 
Calcium 
CCL 
CC chemokine ligand 
CK 
Creatine kinase 
CI 
Confidence interval 
Cl 
Chlorine 
COVID-19 
Coronavirus disease-2019 
CPK 
Creatine phosphokinase 
CRO 
Contract research organization 
CRP 
C-reactive protein 
CT 
Computed tomography 
CXCL 
C-X-C motif chemokine ligand 
ECG 
Electrocardiography 
ECMO 
Extracorporeal membrane 
oxygenation 
eCRF 
Electronic case report form 
EDC 
Electronic Data Capture 
FAS 
Full Analysis Set 
FiO2 
Fraction of inspiratory oxygen 
GCP 
Good Clincal Practice 
GM-CSF 
Granulocyte–macrophage colony 
stimulating factor 
GOT 
Glutamic oxaloacetic transaminase 
GPT 
Glutamic pyruvic transaminase 
hCG 
Human chorionic gonadotropin 
HDL 
High-density lipoprotein 
HRCT 
High-resolution computed 
tomography 
IRB 
Institutional Review Board 
IL 
Interleukin 
IQR 
Interquartile range 
IWRS 
Interactive web response system 
K 
Potassium 
LDH 
Lactate dehydrogenase 
LDL 
Low-density lipoprotein 
MedDRA 
Medical Dictionary for Regulatory 
Activities 
MMP 
Matrix metalloproteinase 
Na 
Sodium 
P 
Inorganic phosphorus 
PaCO2 
Partial pressure of carbon dioxide 
PaO2 
Partial pressure of oxygen 
PB 
Barometric pressure 

 
 
Abbreviation 
Description 
PCR 
Polymerase chain reaction 
pH 
potential of Hydrogen 
PH2O 
Partial pressure of water vapor in 
inspired air 
PT 
Preferred terms 
R 
Respiratory quotient 
rhGM-CSF 
Recombinant human granulocyte-
macrophage colony 
stimulating factor 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SARS-CoV-2 
Severe acute respiratory syndrome 
coronavirus 2 
SaO2 
Arterial oxygen saturation 
SOC 
System organ class 
SOP 
Standard operating procedures 
SP 
Safety Population 
SpO2 
Percutaneous oxygen saturation 
TG 
Triglyceride 
TNF 
Tumor necrosis factor 
γ-GTP 
γ-Glutamyl transpeptidase 
 
 
 
 
Definition of Term 
Term 
Definition 
Investigators 
Principal investigator or sub-investigator 
 
 

i 
 
Table of Contents 
1 Synopsis ......................................................................... 1 
2 Observation and Examination Schedule ................................................. 6 
3 Study Administrative Structure ........................................................ 8 
4 Background Information ............................................................. 8 
4.1 Introduction ..................................................................... 8 
4.2 Nonclinical studies ................................................................ 9 
4.3 Clinical studies ................................................................... 9 
4.4 Known or unknown adverse drug reactions ............................................ 10 
5 Objective, Endpoints, and Parameters .................................................. 10 
5.1 Objective ...................................................................... 10 
5.2 Endpoints ...................................................................... 11 
5.2.1 Efficacy endpoints .............................................................. 11 
5.2.1.1 Number of days to achieve at least 2-rank improvement on a 7-point ordinal scale .......... 12 
5.2.1.2 Changes in alveolar -arterial oxygen gradient (A-aDO2) ............................... 12 
5.2.1.3 Number of days until discharge .................................................. 12 
5.2.1.4 Proportion of subjects whose category has shifted to Category 1 or 2 on a 7-point ordinal scale 12 
5.2.1.5 Changes in pulmonary inflammatory findings ....................................... 13 
5.2.1.6 Changes in arterial blood gas parameters (PaO2, PaCO2) .............................. 13 
5.2.1.7 Changes in inflammatory markers and cytokines .................................... 13 
5.2.1.8 Distribution and proportion of each category on a 7-point ordinal scale ................... 13 
5.2.1.9 Distribution and proportion of each category of oxygen requirement ..................... 13 
5.2.2 Safety endpoints ............................................................... 13 
5.2.2.1 Incidence of AEs and SAEs ..................................................... 14 
5.3 Parameters ..................................................................... 14 
5.3.1 Efficacy parameters ............................................................. 14 
5.3.2 Safety parameters .............................................................. 14 
6 Study Design ..................................................................... 14 
6.1 Overview of study design .......................................................... 14 
6.2 Rationale for study design ......................................................... 15 
6.3 Rationale for dosage and administration .............................................. 15 
7 Subjects ......................................................................... 16 
7.1 Inclusion criteria ................................................................ 16 
7.2 Exclusion criteria ................................................................ 17 
8 Subject Information, Informed Consent, and Subject Authorization .......................... 19 
8.1 Informed consent form ............................................................ 19 
8.2 Timing and procedures for obtaining informed consent................................... 20 
8.2.1 Explanation of the clinical study and obtaining informed consent ......................... 20 
8.2.2 Delivery of informed consent form ................................................. 21 
8.3 Obtaining new information and revision of informed consent form ......................... 21 
8.4 Others ......................................................................... 21 

 
ii 
 
9 Study Drug ...................................................................... 22 
9.1 Test drug ....................................................................... 22 
9.2 Packaging and labeling of test drug .................................................. 22 
9.3 Physiological saline for dissolution of the test drug and for the control group ................. 22 
9.4 Management of test drug .......................................................... 22 
10 Study Procedures ................................................................. 23 
10.1 Enrollment of subject ............................................................ 23 
10.2 Randomization ................................................................. 23 
10.3 Administration of study drug ...................................................... 24 
10.4 Disclosure of allocation code in an emergency ........................................ 24 
10.5 Unblinding after completion of clinical study ......................................... 25 
11 Concomitant Medication/Therapy .................................................... 25 
12 Management of Subject ............................................................ 25 
13 Measurement of Parameters ........................................................ 26 
13.1 Subject characteristics ........................................................... 26 
13.2 Physical examination ............................................................ 26 
13.3 7-point ordinal scale ............................................................. 27 
13.4 Vital signs .................................................................... 27 
13.5 12-lead Electrocardiography ...................................................... 27 
13.6 Laboratory tests (blood chemistry, hematology, urinalysis, and pregnancy test) .............. 27 
13.7 Percutaneous oxygen saturation (SpO2) .............................................. 28 
13.8 Inflammatory marker ............................................................ 28 
13.9 Cytokines ..................................................................... 28 
13.10 Arterial blood gas analysis (PaO2, PaCO2, A-aDO2, others) ............................. 28 
13.11 Chest HRCT or plain chest CT or chest X-ray ........................................ 29 
13.12 Oxygen requirement ............................................................ 29 
13.13 Confirmation of AEs ........................................................... 30 
13.14 Confirmation of concomitant medication/therapy ..................................... 30 
14 AEs and adverse drug reactions (ADRs) ............................................... 30 
14.1 Definition of AE ................................................................ 30 
14.2 Definition of ADR .............................................................. 30 
14.3 Severity of AEs ................................................................ 31 
14.4 SAEs......................................................................... 31 
14.5 Significant AEs ................................................................ 32 
14.6 Causality...................................................................... 32 
14.7 Predictability of AEs ............................................................ 32 
14.8 Observation of AEs ............................................................. 32 
14.9 Pregnancy ..................................................................... 33 
14.10 Reporting of SAEs ............................................................. 33 
14.10.1 Principal investigator ......................................................... 33 
14.10.2 Sponsor .................................................................... 34 

 
iii 
 
15 Criteria for Discontinuation of Study, Subject and Study Drug ............................. 34 
15.1 Study drug discontinuation ....................................................... 34 
15.2 Withdrawal of a subject from the study .............................................. 35 
15.3 Premature termination of entire or a part of the study ................................... 36 
16 Protocol Compliance and Amendment ................................................ 36 
16.1 Protocol compliance and deviation ................................................. 36 
16.2 Protocol amendment............................................................. 36 
17 Statistical Analysis ............................................................... 37 
17.1 Analysis sets ................................................................... 37 
17.1.1 Efficacy analysis set ........................................................... 37 
17.1.2 Safety population ............................................................. 37 
17.2 Statistical analysis items and analytical method ....................................... 37 
17.2.1 Subject characteristics .......................................................... 37 
17.2.2 Efficacy evaluation ............................................................ 37 
17.2.3 Safety evaluation .............................................................. 38 
17.3 Exploratory analysis ............................................................. 38 
17.4 Handling procedures for missing, non-adopted and abnormal data ......................... 38 
17.5 Significance Level .............................................................. 38 
17.6 Changes of analysis plan ......................................................... 39 
18 Target Number of Subjects ......................................................... 39 
19 Study Period .................................................................... 39 
20 eCRF and Others ................................................................. 40 
20.1 Data entry in eCRF and reporting .................................................. 40 
20.2 Confirmation of eCRF by the principal investigator .................................... 40 
20.3 Data lock and unlock of eCRF ..................................................... 40 
21 Source Documents ............................................................... 41 
21.1 Direct access to source data and documents .......................................... 41 
21.2 Data to be handled as source document in the eCRF .................................... 41 
22 Quality Control and Quality Assurance ............................................... 41 
22.1 Quality control ................................................................. 42 
22.2 Quality assurance ............................................................... 42 
23 Ethics .......................................................................... 42 
23.1 Compliance of GCP and others .................................................... 42 
23.2 Review by IRB ................................................................. 43 
23.3 Subject confidentiality ........................................................... 43 
23.4 Compensation for health damages .................................................. 43 
23.5 Payment policy ................................................................. 43 
24 Retention of Record .............................................................. 43 
24.1 Retention of records and others .................................................... 43 
24.1.1 Sponsor ..................................................................... 43 

 
iv 
 
24.1.2 Medical institution ............................................................ 43 
24.2 Retention period ................................................................ 44 
24.2.1 Sponsor ..................................................................... 44 
24.2.2 Medical institution ............................................................ 44 
24.2.3 Founder of IRB ............................................................... 44 
25 Publication Policy ................................................................ 45 
26 List of Attachments ............................................................... 45 
27 Reference ...................................................................... 45 
 

 
1 
 
1 Synopsis 
Study title 
A phase II/III study of sargramostim in patients with coronavirus disease-2019 (COVID-
19)  
Protocol number 
NPC-26-1 
Study objective 
To evaluate the efficacy and safety of inhalation administration of sargramostim for 5 
days, in principle (up to 10 days) as Add-on treatment to the standard treatment in 
COVID-19 patients.  
Study design 
A randomized, placebo-controlled, double-blind, group comparison, multicenter study 
Study subjects 
Moderate stage II1 COVID-19 patients with clinically diagnosed pneumonia 
Inclusion criteria 
Japanese male or female subjects who have been confirmed to meet all the following 
criteria. 
(1) Hospitalized patients under treatment who were severe acute respiratory syndrome 
coronavirus 2 [SARS-CoV-2] positive by polymerase chain reaction (PCR) test. 
(2) Patients with clinically diagnosed pneumonia and a percutaneous oxygen 
saturation [SpO2] of 93% or less on breathing of room air at bed rest. 
(3) Patients for whom written informed consent has been obtained from those 
themselves or the legally acceptable representatives. 
(4) Patients aged 20 years or older and younger than 85 years at the time of obtaining 
informed consent.  
Exclusion 
criteria 
 
Subjects who meet any of the following criteria will be excluded. Unless otherwise 
stated, the following criteria refer to those at the time of screening. 
(1) Patients who have allergic reactions or hypersensitivity to the active ingredient of 
the test drug (sargramostim) or its additives (mannitol, sucrose and tromethamine) 
or yeast-derived products or others. 
(2) Patients who have been participating in other intervention studies, such as studies 
on unapproved pharmacotherapy, within 90 days prior to screening. 
(3) Patients who have experienced off-label use of approved drugs (including those for 
COVID-19 treatment other than steroids and favipiravir as standard treatment) 
within 7 days prior to screening.  
(4) Patients who are not expected to survive longer than 24 hours after commencement 
of study drug administration. 
(5) Patients who are using invasive ventilator or extracorporeal membrane 
oxygenation (ECMO). 
(6) Patients who have a chronic respiratory disease requiring continuous home oxygen 
therapy or ventilator use. 
(7) Patients with an underlying condition that is considered very unlikely to withdraw 
ventilator (e.g., motor neuron disease, Duchenne muscular dystrophy, rapidly 
progressive interstitial pulmonary fibrosis). 
(8) Patients who have a disease including bronchial asthma, lower respiratory tract 
infections, and interstitial lung diseases that may affect the assessment of the 
clinical study, since before the symptom onset of COVID-19. 

 
2 
 
(9) Patients who have a disease including leukemia and leukocytosis that causes 
leukocytosis. 
(10) Patients who have a chronic kidney disease requiring dialysis. 
(11) Patients who have severe liver failure (Child Pugh grade C). 
(12) Patients who are pregnant or breastfeeding or who are positive on pregnancy test. 
(13) Patients aged 80 years or older who have cardiac disease, cerebrovascular disorder, 
BMI 30 or higher, dyslipidemia, hypertension or diabetes 
(14) Other patients considered inappropriate by the investigators for inclusion in the 
study  
Test drug 
Sargramostim 
(A lyophilized preparation containing 250 μg of sargramostim in 1 vial) 
Dosage and 
administration 
Active treatment group: 250 μg/vial of sargramostim will be dissolved in 4 mL of 
physiological saline and 125 μg of which will be administered using inhaler twice 
daily in approximately 10-15 minutes. 
Control group: 2 mL of physiological saline will be administered using inhaler twice 
daily in approximately 10-15 minutes. 
Treatment period 
5 days, in principle (up to 10 days) 
Prohibited 
concomitant 
medications/ther
apies 
【Prohibited concomitant medication】 
Concomitant use of any unapproved drugs (including off-label use of approved drugs 
and use at unapproved dosage and administration, excluding steroids as standard 
treatment at each institution) will be prohibited throughout the study period. In addition, 
the combination of sargramostim with chemotherapy and radiotherapy is 
contraindicated. Except treatment/therapy mentioned above, there are no specific 
prohibited concomitant medications in this study. And steroids used as standard 
treatment at each institution, approved antiviral agents, or others can be used 
concomitantly as a part of standard treatment.  
【Prohibited concomitant therapy】 
If a subject has started to use invasive ventilation or ECMO, the study drug 
administration will be terminated after initiation of use of such devices (see "15.1 Study 
drug discontinuation "). The necessity to use these devices as part of the standard 
treatment for COVID-19 will be judged based on the subject’s condition and medical 
necessity during the study period. 
Study procedures 
COVID-19 patients will be randomly assigned to either of the following two groups in a 
2:1 ratio: 
Sargramostim (125 μg) or physiological saline will be administered by inhalation twice 
daily for 5 days, in principle (up to 10 days) as Add-on treatment to the standard 
treatment. 
(1) Active treatment group (standard treatment plus sargramostim) 
(2) Control group (standard treatment plus physiological saline) 

 
3 
 
Stratified allocation with standard treatment as the allocation factor will be performed 
for randomization. 
Observation 
period  
Period until Day 28 (including the case after discharge) 
Endpoints 
【Efficacy endpoints】 
Primary endpoint 
Number of days to achieve at least 2-rank improvement on a 7-point ordinal scale from 
baseline until Day 28. 
Secondary endpoints 
(1) Changes in alveolar-arterial oxygen partial pressure gradient (A-aDO2) on Day 5 
and at the end of administration from baseline. 
(2) Number of days until discharge from baseline (days of shifting to Category 7 on a 
7-point ordinal scale). 
(3) Proportion of subjects whose category has shifted to Category 1 or 2 on a 7-point 
ordinal scale from baseline until Day 28. 
(4) Changes in pulmonary inflammatory findings on Day 5 and at the end of 
administration from baseline. 
(5) Changes in arterial blood-gas parameters (partial pressure of oxygen [PaO2] and 
partial pressure of carbon dioxide [PaCO2]) on Day 5 and at the end of 
administration from baseline. 
(6) Changes in inflammatory markers and cytokines at the end of administration from 
baseline. 
(7) Distribution and proportion of each category on a 7-point ordinal scale on Day 14 
and Day 28. 
(8) Distribution and proportion of each category of oxygen requirement until Day 14. 
(9) Other exploratory items (details will be specified separately in the statistical 
analysis plan). 
【Safety endpoints】 
Incidence of adverse events and serious adverse event. 

 
4 
 
Efficacy 
parameters  
 
(1) 7-point ordinal scale 
Category 
Ordinal scale  
1 
Have died 
2 
Use an invasive ventilator or ECMO  
3 
Use a noninvasive ventilator or high-flow oxygen supply device 
4 
Require oxygen supply 
5 
Do not require oxygen supply but require continuous therapy (related to 
COVID-19 or others) 
6 
Do not require both oxygen supply and continuous therapy  
7 
Have been discharged from hospital  
(2) Arterial blood gas analysis Arterial blood gas analysis (PaO2, PaCO2, A-aDO2, 
others). 
(3) Chest high-resolution computed tomography (HRCT) or plain chest CT or chest X-
ray  
(4) Inflammatory marker (C-reactive protein [CRP]) 
(5) Cytokines (IL-6, IL-1β, TNF-α, IL-10, CCL17, CXCL9, MMP-12). 
(6) Oxygen requirement 
Category 
Ordinal scale 
1 
Require oxygen supply of 4 L/min or more using oxygen mask 
2 
Require oxygen supply of 2 L/min or more using nasal cannulas 
3 
Require oxygen supply of less than 2 L/min using nasal cannulas 
4 
Do not require oxygen supply but feel shortness of breath during 
walking or moving  
5 
Do not require oxygen supply and do not feel shortness of breath during 
walking or moving. 
Safety 
parameters 
Physical examinationVital signs12-lead Laboratory tests (blood chemistry, hematology, 
urinalysis, and pregnancy test)Confirmation of AEs. 
Target number of 
subjects  
60 subjects (2:1 for active treatment group: control group) 
Statistical 
analysis 
【Efficacy】  
Regarding the number of days to achieve at least 2-rank improvement on a 7-point 
ordinal scale from baseline until Day 28, the primary efficacy endpoint, estimation of 
the proportion of improvement by treatment group using the Kaplan-Meier method, and 
the comparison between groups using the log-rank test at a significance level of 5% will 
be performed as primary analysis. In addition, evaluation using Cox's proportional 
hazards model with the allocation factor as a covariate will be performed. 
For other efficacy endpoints, distribution or summary statistics by treatment group will 
be provided, and differences between groups will be estimated and tested statistically. 
【Safety】 
A 95% confidence interval is calculated for the incidence of adverse events by treatment 
group. 
Medical experts 
 
 
 

 
5 
 
Coordinating 
investigator  
 
Study Period  
October 2020 to October 2021 
 

6 
 
2 Observation and Examination Schedule 
Item 
Screening 
 
Date of 
allocation 
Observation period 5) 
Discontinuation/ 
Exit Test 6) 
Day 0 
Day 1 Day 2 Day 3 Day 4 Day 5 Day 6 Day 7 Day 8 Day 9 
Day 
10 
Day 11
～14 
Day 15
～28 
 
Acceptable window 
 To Day 0 
-2 days 7) 
－ 
－ 
－ 
－ 
+1 
day 7) 
－ 
－ 
－ 
－ 
－ 
－ 
－ 
+1 day 
Informed consent 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history/current medical conditions  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Subject characteristics 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Height and weight 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion criteria  
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Percutaneous oxygen saturation (SpO2) 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Allocation  
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug administration 1) 
 
 
● 
● 
● 
● 
● 
○ 
○ 
○ 
○ 
○ 
 
 
 
7-point ordinal scale 2) 
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
Oxygen requirement  
 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
● 
 
 
Arterial blood gas analysis (PaO2、PaCO2、A-aDO2, 
others) 
 
 
●3) 
 
 
 
● 
 
 
 
 
 
 
 
● 
Inflammatory markers, cytokines  
 
 
●3) 
 
● 
 
● 
 
 
 
 
 
 
 
● 
Chest HRCT or plain chest CT or 
Chest X-ray 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
 
● 
Physical examination 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
 
● 
Vital sign 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
 
● 
12-lead ECG  
 
● 
 
 
 
 
● 
 
 
 
 
 
 
 
● 
Laboratory tests (blood chemistry, 
hematology and urinalysis) 
 
● 
 
 
 
 
● 
 
 
 
 
 
 
 
● 
Pregnancy test (urine or blood sample)  
 
● 
 
 
 
 
 
 
 
 
 
 
 
 
 
adverse events4) 
 
 
● 
 
 
 
 
 
 
 
 
 
 
● 
 
Concomitant medication/therapy 
● 
 
 
 
 
 
 
 
 
 
 
 
● 
 
 
●：Will be performed in all the subjects  ○：Will be performed only in the subjects who continue to receive the study drug after Day 5. 
1) 
Inhalation administration will be started on the morning of Day 1 and performed twice daily (morning, evening) for 5 days, in principle (up to 10 days).  
2) 
Will be evaluated every day during the period between Day 1 and Day 28. Use or no use of a ventilator will be included in this evaluation. 
3) 
Will be performed prior to study drug administration. 
4) 
Only the adverse events that have occurred until Day 14 after the start of study drug administration. may be collected and entered in the electronic case report form. Serious adverse events related to the study 
drug administration will be collected until Day 28. 

 
7 
 
5) 
Assessment of efficacy on the 7-point ordinal scale and oxygen requirement will be performed after completion of the second dose (inhalation) of the day.  
6) 
Will be performed on the day of discontinuation if study drug administration has been prematurely discontinued before Day 5, or on the day of the last dose in the case that the last day is not Day 5. 
7) 
Except 7-point ordinal scale and oxygen requirement. 

8 
 
3 Study Administrative Structure 
Refer to Attachment 1 for the study administrative structure. 
4 Background Information 
Refer to the latest Investigator's Brochure2 for more background information on sargramostim. 
4.1 Introduction 
As of September 7, 2020, approximately 27 million people have been affected with COVID-19 
worldwide and more than 70,000 people in Japan, and the number of deaths is also continuously 
increasing to reach 900,000 worldwide3,4. While many affected individuals end with subclinical 
infection, those who become critically ill are complicated by pneumonia or acute respiratory symptoms, 
leading to use of intubation or mechanical ventilation, and may come to use ECMO, and death may 
occur in some cases. It is considered that acute respiratory distress syndrome (ARDS) is rapidly 
progressing in patients who are going to die5. Therapeutic agents for COVID-19 patients are currently 
being developed in different countries. In Japan, remdesivir (Veklury ®) was approved in May in 2020. 
And dexamethasone, a steroid drug, was added to the "Drugs Approved in Japan” 1 for treatment of 
COVID-19 patients in July1. However, these drugs can be used only for patients requiring oxygen 
inhalation or patients with more severe disease conditions as a rule, thus, it is difficult to say that 
adequate treatment options are available.   
Granulocyte-monocyte colony-stimulating factor (GM-CSF) is a type of cytokines, and its action to 
promote the differentiation and increase of pluripotent hematopoietic stem cells into neutrophils, 
monocytes/macrophages, and dendritic cells has been known. Moreover, the therapeutic effects of GM-
CSF on lung diseases infected by virus are expected as shown by various researches in recent years. For 
example, the following research has been published6; when GM-CSF conditional knock-out mouse were 
infected with influenza virus, ARDS developed and death occurred in untreated individuals, however, 
when GM-CSF has been highly expressed in those mouse after infection, shifts from M1 macrophages to 
M2 occurred and cytokine storm activated by M1 macrophages was inhibited, leading to prevention of 
ARDS development to improve survival.  
Sargramostim is a recombinant human GM-CSF (rhGM-CSF) produced by yeasts. After obtaining 
approval in 1991 in the United States, sargramostim has been marketed by Partner Therapeutics as a 
trade name of Leukine ® (injectable) and has been used in several indications, including shortening time 
to neutrophil recovery and reducing the incidence of severe and life-threatening infections and infections 
resulting in death following induction chemotherapy in patients with acute myeloid leukemia. Although 
sargramostim has not been approved in Japan, a placebo-controlled phase III study7 (investigator-
initiated study) of inhalation administration of sargramostim has been conducted in patients with 
autoimmune pulmonary alveolar proteinosis by Professor Nakata and colleagues at Niigata University. 
In this study, alveolar-to-arterial oxygen uptake, using the alveolar air-arterial oxygen partial pressure 

 
9 
 
gradient (A-aDO2) as an efficacy endpoint, was improved, and the efficacy and safety of inhalation 
administration of sargramostim has been confirmed.  
Various basic studies have been reported that sargramostim is also efficacious in relieving symptoms 
of COVID-19. Its main pharmacological actions include:1. sargramostim promotes differentiation and 
increase of granulocytes and macrophages from pluripotent hematopoietic stem cells; 2.sargramostim 
promotes survival and activation of mature myeloid cells; 3.sargramostim shifts M1 macrophages of 
alveolar macrophages to M2 macrophages after viral infection; 4.sargramostim activates innate and 
acquired immunity by activation and proliferative stimulation of dendritic cells and T cells; 
5.sargramostim accelerates viral clearance; 6.sargramostim promotes proliferation and barrier repair of 
respiratory epithelial cells; and 7.sargramostim ameliorates immunosuppression (immunoparalysis) 
caused by overproduction of anti-inflammatory cytokines.  
At present, most of the drugs for treatment of COVID-19 including those approved in Japan 
(remdesivir) or under development (e.g., favipiravir) are antiviral drugs targeting RNA-polymerase for 
viral proliferation. On the other hand, sargramostim is an agent differently targeting to suppress 
inflammation of virally infected lungs, and not a steroid drug. In the future, intensification therapy of 
sargramostim combined with other drugs may also be expected. 
This study will evaluate the efficacy and safety of inhalation administration of sargramostim in 
COVID-19 patients in collaboration with Japanese medical institutions, and aim to submit application of 
the drug for early market introduction.  
 
4.2  Nonclinical studies 
The nonclinical toxicity studies required to initiate clinical studies of sargramostim have been 
evaluated in repeated-dose toxicity studies in monkeys including a 14 days intravenous administration 
study, a 6 weeks subcutaneous administration study, and a 26 weeks inhalation administration 
(intermittent administration) study, and no specific safety concerns have been observed. 
In the 26-week intermittent inhalation administration study, 3 cynomolgus monkeys/sex/group were 
treated with 0 (vehicle), 5, 100, or 500 μg/kg/day of sargramostim for 1 week followed by a 1-week 
washout cycle for 26 weeks. No deaths were reported during the observation period in either group. 
There were no apparent toxicities associated with sargramostim administration throughout the study, and 
the no-observed-adverse-effect-level under the study conditions was considered to be 500 μg/kg/day for 
both sexes. 
 
4.3 Clinical studies 
Inhalation administration of sargramostim has been experienced in humans in the Phase I studies in 
healthy adults and patients with autoimmune pulmonary alveolar proteinosis8, a Phase II study9 in 
patients with autoimmune pulmonary alveolar proteinosis (6 cycles of 125 μg inhaled twice daily for 8 
days plus a 6-day washout followed by 6 cycles of 125 μg inhaled once daily for 4 days plus a 10-day 

 
10 
 
washout), and a placebo-controlled Phase III study7 in patients with autoimmune pulmonary alveolar 
proteinosis (125 μg inhaled twice daily for 7 days every other week for 24 weeks). No safety concerns 
have been observed in these studies. Regarding the safety of high dose of inhalation administration of 
sargramostim, it has also been reported10 that the maximum tolerated dose was not reached in a study in 
which 40 patients with lung metastases from malignant melanoma received inhalation administration of 
500-2000 μg of sargramostim twice daily for 7 days repeatedly every other week (unless there was 
worsening of symptoms or serious adverse events).  
In addition, an investigator-initiated study11 in 80 of COVID-19 patients is ongoing in Belgium. An 
interim analysis based on 20 patients suggested the efficacy of sargramostim for A-aDO2 (p=0.053), and 
further data supporting the efficacy and safety of sargramostim for COVID-19 will be expected by 
accumulating the cases in the future.  
In the sargramostim development in Japan, considering the results of basic studies on sargramostim or 
GM-CSF as well as the tendency of COVID-19 Japanese patients becoming more severe, the efficacy 
and safety of inhalation administration of sargramostim will be evaluated in moderate stage II1 COVID-
19 Japanese patients with clinically diagnosed pneumonia. 
 
4.4 Known or unknown adverse drug reactions 
The most recent Investigator's Brochure2 shall be referred to for potential risks of sargramostim 
administration. 
When sargramostim is administered by inhalation in COVID-19 patients, no other adverse events 
(AEs) will be anticipated than those related to COVID-19.  
COVID-19 is the most recent syndrome, and available data on this disease are limited. Usual 
symptoms that are considered the expected events and the symptoms observed during the natural course 
of the disease include dyspnea, cough, sputum production, expectoration, discomfort, myalgia, malaise, 
fever, anorexia, vomiting, diarrhea, headache, sore throat, chest tightness, chest pain, chest discomfort, 
laboratory test abnormalities [white blood cells count decreased, lymphocytes count decreased, platelets 
count decreased, C-reactive protein (CRP) increased], decreased oxygen saturation, progression of 
respiratory failure, progression to ARDS, hypotension, and progression to multiple organ failure. 12, 13, 14, 
15.  
 
5 Objective, Endpoints, and Parameters 
5.1 Objective 
To evaluate the efficacy and safety of inhalation administration of sargramostim for 5 days, in 
principle (up to 10 days) as Add-on treatment to standard treatment in COVID-19 patients.  
 

 
11 
 
5.2 Endpoints 
5.2.1 Efficacy endpoints  
Primary efficacy endpoint 
Number of days to achieve at least 2-rank improvement on a 7-point ordinal scale from baseline until 
Day 28. 
[Rationale] 
A 7-point ordinal scale is one of the commonly used scales for assessment of drugs used in the clinical 
studies of COVID-19 and was set as an index to numerically assess the improvement effect of 
sargramostim administration on the disease condition. Taking the study drug administration period (5 
days, in principle [up to 10 days]) in this study, the usual period for treatment and hospital stay of 
COVID-19 patients in Japan, and the results of other clinical studies into account, the required number 
of days to achieve at least 2-rank improvement on a 7-point ordinal scale from baseline until Day 28 was 
set as the primary efficacy endpoint. 
Secondary endpoints 
(1) Changes in alveolar-arterial oxygen partial pressure gradient (A-aDO2) from baseline to Day 5 and 
the end of administration. 
(2) Number of days until discharge from baseline (days for shifting to Category 7 on a 7-point ordinal 
scale). 
(3) Proportion of subjects whose category has shifted to Category 1 or 2 on a 7-point ordinal scale 
from baseline until Day 28. 
(4) Changes in pulmonary inflammatory findings from baseline to Day 5 and the end of administration. 
(5) Changes in arterial blood-gas parameters (partial pressure of oxygen [PaO2] and partial pressure of 
carbon dioxide [PaCO2]) from baseline to Day 5 and the end of administration. 
(6) Changes in inflammatory markers and cytokines from baseline to the end of administration. 
(7) Distribution and proportion of each category on 7-point ordinal scale on Day 14 and Day 28. 
(8) Distribution and proportion of each category of oxygen requirement until Day 14. 
(9) Other exploratory items (details will be specified separately in the statistical analysis plan). 
 
[Rationale] 
(1) An interim analysis of the clinical study 11 being conducted in Belgium in COVID-19 patients (20/ 
target sample size of 80) suggested the efficacy of sargramostim for A-aDO2, an index of arterial 
oxygen uptake (see 6.3 Rationale for dosage and administration). Therefore, changes in A-aDO2 
was set as a secondary endpoint in this study. Since the duration of the study drug administration in 
this study is set to be "5 days, in principle (up to 10 days) ", both the periods of "Day 5 from 
baseline" and "End of administration from baseline" were set for assessment.   
(2) As an evaluation of the drug for COVID-19 from clinical standpoint, "number of days until 
discharge from hospital" considered to be equally important with " number of days to achieve at 
least 2-rank improvement on a 7-point ordinal scale" was set.  
(3) In order to visualize the inhibitory effects of sargramostim on the shifting of disease condition to 
more severe condition from a simple pneumonic condition, proportion of subjects whose category 

 
12 
 
has shifted to Category 1 or 2 (worsening to use of invasive ventilator or worse) on a 7-point 
ordinal scale until Day 28 was set as an index.  
(4) This endpoint was set in order to evaluate the effect of sargramostim on pneumonia. 
(5) This endpoint was set in order to evaluate the effect of sargramostim on pulmonary function.  
(6) This endpoint was set in order to evaluate the effect of sargramostim on the inflammatory changes.  
(7) Data derived from the same measurement parameter as those for the primary endpoint were to be 
assessed secondarily from different point of view. In addition, since the disease condition requiring 
treatment may likely be persistent in a COVID-19 patient requiring hospitalization, the assessment 
time was set not only on Day 14 but also on Day 28.   
(8) Oxygen supply is considered to be one of the clinical indicators to assess respiratory failure and 
thus was set as a categorized ordinal scale. 
(9) Since the data on inhalation administration of sargramostim to Japanese population as well as 
the data on the pathology of COVID-19 over time in Japanese population will be valuable, an 
exploratory endpoint will be added as needed. 
5.2.1.1 Number of days to achieve at least 2-rank improvement on a 7-point ordinal scale 
The clinical condition of a subject will be comprehensively measured at the timing specified in "2 
Observation and Examination Schedule" and will be evaluated according to "13.3 7-point ordinal scale" 
by the investigators.  
Assessment on Day 0 will be used as a baseline value, and the number days to achieve at least 2-rank 
improvement (see Table 13.3-1) from baseline will be assessed.  
 
5.2.1.2 Changes in alveolar -arterial oxygen gradient (A-aDO2) 
A-aDO2 will be measured and calculated according to "13.10 Arterial blood-gas analysis (PaO2, 
PaCO2, A-aDO2, others) " at the timing specified in "2 Observation and Examination Schedule." 
Measurement values obtained prior to study drug administration on Day 1 will be used as baseline 
values, and changes of A-aDO2 values from baseline will be assessed. 
 
5.2.1.3 Number of days until discharge 
The category of the disease condition on Day 0 of a subject is supposed to fall into one of Category 3 
to 5 on a 7-point ordinal scale (see Table 13.3-1). The number of days required to have been shifted from 
the category on Day 0 to Category 7 will be evaluated.  
 
5.2.1.4 Proportion of subjects whose category has shifted to Category 1 or 2 on a 7-point 
ordinal scale  
The category of the disease condition on Day 0 of a subject is supposed to fall into one of Category 3 
to 5 on a 7-point ordinal scale (see Table 13.3-1). The proportion of subjects whose category has shifted 
from the category on Day 0 to Category 1 or 2 at the time of evaluation will be calculated.  
 

 
13 
 
5.2.1.5 Changes in pulmonary inflammatory findings 
Inflammatory findings in the lungs will be examined according to “13.11 Chest HRCT or plain chest 
CT or chest X-ray” at the timing specified in "2 Observation and Examination Schedule", and the results 
will be judged by the investigators. 
Quantitative changes will be assessed using densitometry for chest HRCT. The judgement on Day 0 
will be used as the baseline value, and changes in inflammatory changes from baseline will be assessed 
according to the separately defined criteria. 
 
5.2.1.6  Changes in arterial blood gas parameters (PaO2, PaCO2)  
PaO2 and PaCO2 will be measured according to "13.10 Arterial blood gas analysis(PaO2, PaCO2, A-
aDO2, others)" at the timing specified in "2 Observation and Examination Schedule". 
Measurement values prior to study drug administration on Day 1 will be used as the baseline values, 
and the changes from baseline will be assessed. 
 
5.2.1.7 Changes in inflammatory markers and cytokines 
Inflammatory markers and cytokines will be measured according to "13.8 Inflammatory marker" and 
"13.9 Cytokines" at the timing specified in "2 Observation and Examination Schedule". 
Measurement values prior to study drug administration on Day 1 is used as baseline values, and 
changes from baseline will be assessed.  
 
5.2.1.8 Distribution and proportion of each category on a 7-point ordinal scale 
Distribution of category (Category 1-7) on a 7-point ordinal scale (see Table 13.3-1) and the 
proportion of each category will be evaluated. Details of the categories will be defined in the statistical 
analysis plan separately.  
 
5.2.1.9 Distribution and proportion of each category of oxygen requirement  
Oxygen requirement will be classified into 5 categories (see Table 13.12-1) and the distribution and 
proportion of each category will be evaluated. Details of the categories will be defined in the statistical 
analysis plan separately.  
 
5.2.2 Safety endpoints 
Incidence of adverse events (AEs) and serious adverse events (SAEs) 
 

 
14 
 
[Rationale] 
An event reported as an AE is not only the subjective symptoms reported by the subject, but also 
reflects the medical judgment of the investigators based on the results of the safety assessment. The 
incidence of AEs (or SAEs) is the most appropriate and widely accepted measure for safety evaluation in 
clinical studies, thus was set. 
5.2.2.1 Incidence of AEs and SAEs 
Information on AEs occurring from the start of study drug administration until Day 14 will be 
collected in this study. For SAEs related to the study drug, those occurring until Day 28 will be 
collected. The number of subjects with AEs and the incidence of AEs will be calculated by seriousness, 
system organ class (SOC) and/or preferred term (PT), and severity by treatment group. 
 
5.3 Parameters 
5.3.1 Efficacy parameters 
7-point Ordinal scale, arterial blood gas analysis (PaO2, PaCO2, A-aDO2, others), HRCT or chest 
simple CT or chest X-ray, inflammatory markers, cytokines, oxygen requirement. 
 
5.3.2 Safety parameters 
Physical examination, vital signs, 12-lead ECG, laboratory tests (blood chemistry, hematology, 
urinalysis, and pregnancy test), AEs. 
 
6 Study Design  
6.1 Overview of study design  
This is a randomized, placebo-controlled, double-blind, group-comparison, multicenter study. 
The efficacy and safety will be evaluated when sargramostim or physiological saline is administered 
by inhalation for 5 days, in principle (up to 10 days) as Add-on treatment to standard treatment in 
COVID-19 patients. 
Enrolled subjects will be randomized in a 2:1 ratio to receive either standard treatment plus 
sargramostim (active treatment group) or standard treatment plus physiological saline (control group). 
The study design is shown in Figure 6.1-1 
 
 

 
16 
 
19 patients [p=0.053, compared with standard treatment (without sargramostim)] for A-aDO2, the 
primary endpoint, in the interim analysis (20/ target number of 80 subjects) of the clinical study being 
conducted in Belgium 11.  
Inhalation administration for 5 consecutive days was set based on the fact that inhalation 
administration for 7 consecutive days has been confirmed safe in the placebo-controlled phase III study 
in patients with autoimmune pulmonary alveolar proteinosis (investigator-initiated study) conducted in 
Japan7.  
In the clinical study 11 in COVID-19 patients being conducted in Belgium and the U.S., 5 days was set 
for inhalation administration of sargramostim. If the investigator determined it necessary to administer 
sargramostim after the sixth day, sargramostim was to be administered intravenously (approved route of 
administration in the U.S.) for further five days. Based on this, the administration period in this study 
was set as "5 days, in principle (up to 10 days) " by the inhalation administration route. 
Final observations are to be performed until Day 28 (including the case after discharge from hospital), 
so that not only the observations during treatment period but also the follow-up observations can be 
performed to observe prognosis after the end of administration.  
Because it is difficult to obtain the placebo preparation of the test drug, an unblinded pharmacist is to 
prepare the physiological saline for the control group and the control drug is to be administered by 
inhalation in the same manner as in the active treatment group. 
7 Subjects 
Patients with moderate-II coronavirus disease-2019 (COVID-19) who were clinically diagnosed 
pneumonia. 
 
[Rationale] 
Considering the mechanism of action of sargramostim, patients with clinically diagnosed pneumonia 
whose respiratory function is suggestively decreased are to be included in the study. In addition, patient 
population without use of invasive ventilator yet (the category of a patient that falls into one of Category 
3 to 5 on a 7-point ordinal scale (see Table 13.3-1)) is to be chosen in order that an accurate dose of 
study drug can be administered by inhalation. 
 
7.1 Inclusion criteria  
Japanese male or female subjects who have been confirmed to meet all the following criteria. 
(1) Hospitalized patients under treatment who were severe acute respiratory syndrome coronavirus 2 
[SARS-CoV-2] positive by polymerase chain reaction (PCR) test. 
(2) Patients with clinically diagnosed pneumonia and a percutaneous oxygen saturation [SpO2] of 93% 
or less on breathing of room air at bed rest. 
(3) Patients for whom written informed consent has been obtained from those themselves or the legally 
acceptable representatives. 

 
17 
 
(4) Patients aged 20 years or older and younger than 85 years at the time of obtaining informed 
consent. 
 
[Rationale] 
- Although overseas clinical studies have already preceded, Japanese patients were considered unlikely 
to be included in these studies. Japanese patients are to be enrolled in this study in order to evaluate 
the efficacy and safety in Japanese patients. 
- Sargramostim was approved in the United States in 1991 and its clinical experience has been 
established in the market. Moreover, since no difference in safety profile between sexes has been 
observed in the clinical experience in patients with autoimmune pulmonary alveolar proteinosis in 
Japan, both sexes are to be included in the study. 
(1) It was set in order to confirm that the patient is a COVID-19 patient.  
(2) Considering the mechanism of action of sargramostim, the severity classification of the disease was 
set in reference to the current " Guide to new coronavirus infections (COVID-19) practice " 1 . 
(3) It was set based on the Declaration of Helsinki and the GCP. 
(4) The lower limit (20 years) was set for adults under the Japanese law. 
Considering that the fatality due to COVID-19 becomes higher for patients who are elderly and 
also have underlying disease, patients aged 80 years and older with an underlying disease are 
excluded and the upper limit was set as < 85 years in order to enroll the patient population that is as 
close to actual clinical situation of COVID-19 as possible. 
 
7.2 Exclusion criteria 
Subjects who meet any of the following criteria will be excluded. Unless otherwise stated, the 
following criteria refer to those at the time of screening. 
(1) Patients who have allergic reactions or hypersensitivity to the active ingredient of the test drug 
(sargramostim) or its additives (mannitol, sucrose and tromethamine) or yeast-derived products or 
other. 
(2) Patients who have been participating in other intervention studies, such as a study on unapproved 
pharmacotherapy, within 90 days prior to screening. 
(3) Patients who have experienced off-label use of approved drugs (including those for COVID-19 
treatment other than steroids and favipiravir as standard treatment) within 7 days prior to screening. 
(4) Patients who are not expected to survive longer than 24 hours after commencement of study drug 
administration 
(5) Patients who are using invasive ventilator or extracorporeal membrane oxygenation (ECMO). 
(6) Patients who have a chronic respiratory disease requiring continuous home oxygen therapy or 
ventilator use. 
(7) Patients with an underlying condition that is considered very unlikely to withdraw ventilator (e.g., 
motor neuron disease, Duchenne muscular dystrophy, rapidly progressive interstitial pulmonary 
fibrosis). 
(8) Patients who have a disease including bronchial asthma, lower respiratory tract infections, or 
interstitial lung diseases that may affect the assessment of the clinical study, since before the 
symptom onset of COVID-19. 

 
18 
 
(9) Patients who have a disease including leukemia or leukocytosis that causes leukocytosis. 
(10) Patients who have a chronic kidney disease requiring dialysis. 
(11) Patients who have severe liver failure (Child Pugh grade C). 
(12) Patients who are pregnant or breastfeeding or who are positive on pregnancy test. 
(13) Patients aged 80 years or older who have/are cardiac disease, cerebrovascular disorder, obese 
patient (BMI 30 or higher), dyslipidemia, hypertension or diabetes 
(14) Other patients considered inappropriate by the investigators for inclusion in the study 
 
[Rationale] 
- In order to minimize the burden of the medical front for the treatment of COVID-19 patients, the 
assessment results at screening are to be applied as much as possible, as far as the results are 
considered reasonable. 
(1) It was set to ensure the safety of subjects. 
(2) It was set as a general item to ensure the safety of the subjects and to evaluate the study ethically 
and appropriately. 
(3) The objective of this study is to evaluate the Add-on effect of sargramostim on the standard 
treatment. It was set in order to eliminate effects by other treatments that have not been recognized 
or established as "standard treatment". 
(4) It was set because participation of patients who require emergency care with the highest priority is 
not considered appropriate. 
(5) Subjects who entered a stage to use invasive ventilator or ECMO are to be excluded from the study 
because inhalation administration of the sargramostim is difficult for these subjects and this disease 
condition of the subject has been included in the criteria for the study drug discontinuation. 
(6) Patients with underlying disease who meet this criterion are to be excluded from the study because 
it is difficult to accurately assess whether use of ventilator is due to COVID-19 infection or not.  
(7) Patients with these diseases are to be excluded from the study because they are likely to develop 
more severe pneumonia resulting in death. 
(8) It was set in order to exclude patients who have been having diseases which may affect the 
assessment of arterial blood gas analysis or others, a measurement parameter of the study, since 
before the onset of COVID-19.  
(9) It was set in order to exclude patients with increased risk of safety concerns due to administration 
of the study drug. 
(10) It was set in consideration that patients with chronic kidney disease requiring hemodialysis are at 
increased risk to become severe COVID-19 and that sargramostim is removed by hemodialysis.  
(11) Patients who meet this criterion are likely to be seriously ill at the onset of infection and their 
mortality become higher when intubated due to respiratory failure, thus are to be excluded from the 
study. 
(12) It was set because the safety of administration of sargramostim during pregnancy or lactation has 
not been established. Women of childbearing potential are to be excluded from the study if they are 
positive on pregnancy test.  
(13) Elderly patients with an underlying disorder are excluded because they are at increased risk of 
becoming severe and death. 

 
19 
 
(14) Other than the predetermined criteria, it was set as a general exclusion criterion so that inclusion 
validity can be assessed at the discretion of the investigators.  
 
8 Subject Information, Informed Consent, and Subject Authorization 
8.1 Informed consent form 
Prior to the implementation of the study, the principal investigator will collaborate with the sponsor, 
prepare an informed consent form, submit it to the head of the medical institution for approval by the 
Institutional Review Board (IRB), and submit the approved informed consent form to the sponsor. The 
informed consent form shall include the following information as stipulated in the GCP. 
① The clinical study involves research. 
② Objectives of the clinical study. 
③ Study procedures (including those aspects of the study that are experimental, patient 
inclusion/exclusion criteria) 
④ Expected duration of the patient’s participation in the study. 
⑤ Approximate number of patients involved in the study. 
⑥ Anticipated clinical benefits and risks or inconveniences to the patient.  
⑦ Other treatment that may be available to the patient, and their important potential benefits and risks. 
⑧ Compensation and/or treatment available to the patient in the event of study-related injury. 
⑨ The patient’s participation in the clinical study is voluntary, and the patient or the patient's legally 
acceptable representative may refuse to participate or withdraw from the study, at any time, without 
penalty or loss of benefit to which the patient is otherwise entitled. 
⑩ The patient or the patient's legally acceptable representative should promptly be informed if 
information becomes available that may be relevant to the patient’s willingness to continue 
participation in the clinical study. 
⑪ Foreseeable circumstances and/or reasons under which the patient’s participation in the clinical 
study may be terminated. 
⑫ Monitors, auditors, IRB, and regulatory authorities are given direct access to the patient’s original 
medical records. In such cases, the confidentiality of the patient should be protected, and by signing 
and dating the informed consent form, the patient or the patient's legally acceptable representative is 
authorizing such access. 
⑬ If the results of the clinical study are published, the patient’s identity should remain confidential. 
⑭ Anticipated expenses, if any, to the patient for participating in the clinical study. 
⑮ Anticipated prorated payment, if any, to the patient for participating in the clinical study 
(arrangements for prorated payment). 
⑯ Name, title, and address of contact of the principal investigator or subinvestigator. 
⑰ Persons to contact for further information regarding the clinical study and the rights of patients, or 
the medical institution to refer to and contact in the event of the study-related injury, when the 
patient or patient’s legally acceptable representative requested such information.  
⑱ The patient’s responsibilities. 

 
20 
 
⑲ Types of the IRB that review and discuss the appropriateness of this clinical study, items that are 
investigated and discussed by the IRB, and other matters related to the IRB related to this clinical 
study.  
⑳ That the IRB's procedures, etc. may be checked. Provide public access to the IRB's procedures on 
the website of the medical institution, etc., by keeping the website addressed, if not publicly 
available, and the IRB's procedures, etc., in the office, etc. Description of “If you wish to check the 
IRB's procedures, please offer it”.  
 
8.2 Timing and procedures for obtaining informed consent 
8.2.1 Explanation of the clinical study and obtaining informed consent 
After the clinical study agreement between the medical institution and the sponsor has been signed, 
the investigators shall explain the details of the clinical study, etc., using the explanation materials for 
informed consent form to the candidate patient, shall provide the patient with the opportunity to ask 
questions and sufficient time to decide whether or not to participate in the clinical study, and shall obtain 
voluntarily written informed consent from the patient before conducting any procedures for 
examinations and observations described in the protocol. 
If the investigators judge that the candidate patient does not have adequate ability to provide consent 
due to mental retardation, etc., the investigators shall provide the legally acceptable representative 
(person with parental authority, guardian or similar, or person who acts in the patient's best interest) with 
adequate information using explanation materials for informed consent, shall give the opportunity to ask 
questions and shall give sufficient time to decide whether or not the candidate patient to participate in 
the clinical study, and shall obtain voluntarily written informed consent from the legally acceptable 
representative. At obtaining informed consent, a document where the relationship between the legally 
acceptable representative and the candidate patient has been recorded will be retained. In this case, the 
investigators shall explain to the candidate patient about the clinical study using the explanation 
materials for informed consent depending on his/her comprehensibility, and shall obtain voluntarily 
written confirmation for participation in the clinical study from the candidate patient, if possible. 
However, if the candidate patient himself/herself refuses to participate in the clinical study, the 
investigators are not allowed to involve the candidate patient in the clinical study even though the 
written consent has been obtained from the legally acceptable representative. 
If it is difficult to explain to the candidate patient about the clinical study due to his/her disease 
condition or age, and it is not possible to obtain signed consent, the fact and the reason for not having 
obtained signed consent shall be recorded in the informed consent form signed by the legally acceptable 
representative or in the medical record.  
 

 
21 
 
8.2.2 Delivery of informed consent form 
The investigators shall provide the candidate patient or the legally acceptable representative with a 
copy of the informed consent form signed and sealed or signed by the investigators and the candidate 
patient as well as the explanation materials. The investigators shall provide the candidate patient and the 
legally acceptable representative with sufficient time to ask questions and to decide whether to 
participate in the clinical study before obtaining informed consent. The investigators shall answer all the 
questions so that the candidate patient and the legally acceptable representative are satisfied with the 
answers.  
 
8.3 Obtaining new information and revision of informed consent form 
If new information has been obtained that may affect the willingness of the subject and the legally 
acceptable representative to continue participating in the clinical study, the investigators shall revise the 
informed consent form based on the new information and obtain approval from the IRB. 
In addition, the investigators shall promptly inform the subject and the legally acceptable 
representative of the relevant information, shall confirm again the willingness of the subject and the 
legally acceptable representative whether to continue participating in the clinical study, and shall record 
the result in the medical record, etc. Moreover, the investigators shall explain the details of the revised 
informed consent form approved by the IRB to the subject and the legally acceptable representative, and 
again shall obtain a written informed consent form as specified in "8.2 Timing and procedures for 
obtaining informed consent."  
 
8.4 Others  
The investigators shall comply with the following items when obtaining informed consent from the 
candidate patient and the legally acceptable representative. 
① The investigators shall not give unjustified effect such that they force to participate or continue 
participation in a clinical study to the candidate patient and the legally acceptable representative.  
② The informed consent form, the explanation materials and the information provided verbally shall 
not contain any phrases that cause or suspect to waive the right of the candidate patient and the 
legally acceptable representative, or that cause or suspect to exempt the investigators, the medical 
institution, or the sponsor from their legal responsibility.  
③ The informed consent form and the information provided verbally shall be understandable by the 
candidate patient and the legally acceptable representative and shall be available in non-
professional language as far as possible.  
④ Regardless of the reason, the clinical study shall not be initiated based on the only informed consent 
obtained orally.  
 

 
22 
 
9 Study Drug 
9.1 Test drug  
Non-proprietary name：sargramostim (Code name: NPC-26)  
Dosage form/Strength：A lyophilized preparation containing 250 μg of sargramostim in 1 vial  
Storage conditions：4℃ (2 to 8℃) 
 
9.2 Packaging and labeling of test drug 
The vials will be placed in individual packaging boxes. The label and package will contain the 
following information. Expiration date will be specified in a separate written procedure. 
- A statement that the test drug is for clinical study use. 
- Name and address of the sponsor. 
- Identification number. 
- Manufacturing number. 
- Storage condition. 
 
9.3 Physiological saline for dissolution of the test drug and for the control group 
In the active treatment group in the study, the test drug will be dissolved in physiological saline and 
administered by inhalation. In the control group, the physiological saline itself will be administered by 
inhalation (see "10.3 Administration of study drug"). The physiological saline used in the study will not 
be supplied by the sponsor, but purchased by the medical institution.  
Therefore, the records of storage, management, and delivery of physiological saline will not be 
applicable to "9.4 Management of test drug" in the next section.  
 
9.4 Management of test drug  
(1) The sponsor will deliver the test drug and the " Investigational product handling procedures" to the 
Investigational product manager after a contractual agreement with the medical institution has been 
signed.  
(2) The Investigational product manager will store and manage the test drug in accordance with the " 
Investigational product handling procedures", and record the prescription at the medical institution, 
usage in each subject, disposition, and return of the test drug to the sponsor onto the Investigational 
product management sheet. 
(3) The Investigational product manager will store the used test drug, unused test drugs, and package, 
outer box at the appropriate time in accordance with the " Investigational product handling 
procedures " based on the rule of the medical institution until they are retrieved by the sponsor. 
Moreover, a copy of the Investigational product management sheet will be provided to the sponsor 
appropriately. 

 
23 
 
10 Study Procedures 
This is a randomized, placebo-controlled, double-blind, group-comparison, multicenter study. Refer to 
Figure 6.1-1 for the study design.  
 
10.1 Enrollment of subject  
The investigators will assign a subject identification code to subjects in the order of giving informed 
consent, and enter the information of the eligible randomized subjects in the electronic case report form 
(eCRF). The subject identification code will be composed of a two-digit number assigned to each 
medical institution and a three-digit number assigned to each subject in ascending order from 001 within 
the medical institution connecting with a hyphen (ex. the subject identification code of the first subject in 
medical institution 01 is "01-001"). Moreover, a duplicable "Screening list" will be prepared. The 
following information will be included in the Screening list. 
［First sheet］ 
Date of informed consent, subject’s name, medical record number, subject identification code, date of 
screening test, and screening test results (by eligibility) will be recorded and stored at the medical 
institution.  
［Second sheet］ 
Information other than the subject’s name and the medical record number on the first sheet will copied 
on the second sheet. After the clinical study has been terminated, the principal investigator will 
confirm the contents, sign and seal, or sign, and submit it to the sponsor.  
 
The investigators will conduct observations/examinations on the day of allocation (Day 0) for eligible 
subjects based on the screening test results, ensure that the inclusion criteria are met, and enter the 
required information in the eCRF. This electronic entry will be regarded as enrollment of the subject, 
then the investigators will instruct the unblinded pharmacist to randomize the subject.  
 
10.2 Randomization 
Randomization will be performed by the unblinded pharmacist using the web-automated 
responsiveness system (IWRS) of the eCRF. The unblinded pharmacist shall be specifically in charge of 
allocation, preparation and arrangement of the study drug and must not perform any other study-related 
duties other than those assigned. The unblinded pharmacist must not disclose any information on 
allocation to others except the unblinded monitor. When the allocation code is recorded or duplicated for 
the purpose of preparation and arrangement of the study drug, the unblinded pharmacist shall strictly 
control these documents so that they are not seen by others. The unblinded pharmacist shall discard these 
documents in an appropriate manner as soon as possible after use. 

 
24 
 
Stratified allocation using standard treatment as the allocation factor will be performed at the 
randomization. Enrolled subjects will be randomized in a 2:1 ratio to either the active treatment group or 
the control group.  
The investigators and the study collaborator other than the unblinded pharmacist should not be present 
at the operations for preparation and dispensing of the study drug performed by the unblinded 
pharmacist.  
 
10.3 Administration of study drug 
Administration of study drug will start in the morning of Day 1 (twice daily, in the morning and 
evening between Day 1 and Day 5).  
In the active treatment group, 250 μg/vial of sargramostim will be dissolved in 4 mL of physiological 
saline, and 2 mL of which will be administered twice daily (in the morning and evening) using an inhaler 
for 5 days, in principle (up to 10 days). In the control group, 2 mL of physiological saline will be 
administered twice daily (in the morning and evening) using an inhaler for 5 days, in principle (up to 10 
days). 
Approximately 10-15 minutes will be taken for one inhalation administration which shall be continue 
until the prepared solution has been depleted. During the inhalation administration, air cleaner or similar 
will be available for prevention against infection for healthcare workers and other patients. 
The start date and time of the study drug administration should be recorded in the eCRF. Details of the 
preparation and dispensing of the study drug should be in accordance with the procedures specified 
separately. 
 
All subjects may continue to receive inhalation administration of the study drug at the discretion of the 
investigators for up to Day 10 from Day 6 onward. After Day 6, the dosage and administration should be 
the same as that in the first 5 days.  
Occurrence of serious allergic or anaphylactic reactions after administration of sargramostim has been 
reported. If a serious allergic or anaphylactic reaction occurs, administration should be discontinued and 
appropriate therapy should be initiated. The investigators shall follow up at least 1 hour after inhalation 
administration to ensure that no clinical symptoms such as acute hypersensitivity reactions (e.g., facial or 
extremity swelling, cough, urticaria, decreased consciousness, respiratory distress) are observed.  
 
10.4 Disclosure of allocation code in an emergency  
When disclosure of allocation code in an emergency is requested by the investigators through the 
sponsor in the event of a serious adverse event, the unblinded pharmacist will disclose the allocation 
code of the subject in accordance with the procedures provided by the sponsor separately.  
 

 
25 
 
10.5 Unblinding after completion of clinical study 
The allocation code for this study will be stored in the EDC system, but only the unblinded pharmacist 
and the unblinded monitors will be allowed to review the code during the study period. After completion 
of the clinical study, the data will be locked in the blinded condition according to the predetermined 
procedures,then the allocation code will be outputted from the EDC system and unblinded. 
 
11 Concomitant Medication/Therapy 
A standard treatment for each subject against COVID-19 will be chosen and performed appropriately 
based on medical judgment, with reference to current knowledge and guideline1, 16, 17.  
 
Concomitant use of any unapproved drugs (including off-label use of approved drug and use at 
unapproved dosage and administration, excluding steroids as standard treatment at each medical 
institution) will be prohibited throughout the study period (with an exception of concomitant 
medication/therapy given after study discontinuation when a subject meets any of the criteria for the 
study drug discontinuation and is removed from the study. See “15.1 Study drug discontinuation”). In 
addition, the combination of sargramostim with chemotherapy and radiotherapy is contraindicated. 
Except treatment/therapy mentioned above, there are no specific prohibited concomitant medications in 
this study. And steroids as standard treatment at each medical institution and approved antivirals, or 
others can be concomitantly used as part of standard treatment.  
If a subject initiates use of invasive ventilator or ECMO, administration of the study drug will be 
terminated after use of these devices has been initiated (see "15.1 Study drug discontinuation"). The 
necessity to use these devices during the study period will be judged as part of the standard treatment 
against COVID-19 according to the disease condition and medical necessity of the subject.  
 
The investigators will record and report the concomitant medications/therapies used during the study 
(see 13.14 Confirmation of concomitant medication/therapy). 
 
12 Management of Subject 
If a subject is discharged from the hospital during the study period, the subject shall be appropriately 
instructed to receive the observation/examination at the timing specified in the "2 Observation and 
Examination Schedule" and to avoid pregnancy or breastfeeding until the last observation for a female 
subject of childbearing potential. 
 

 
26 
 
13 Measurement of Parameters 
In accordance with “2 Observation and Examination Schedule”, observations/examinations and 
evaluations will be performed, and the date and the results of observations/examinations will be recorded 
in the source documents such as the medical record. In addition, the prespecified data will be entered in 
the eCRF. 
After obtaining written informed consent from the candidate patient and the legally acceptable 
representative in accordance with "8.2 Timing and procedures for obtaining informed consent”, the 
investigators will perform a screening test. The screening test results will be entered in the eCRF. The 
data at the screening test may be used if they have been collected within 7 days prior to informed 
consent. In addition, when the examinations scheduled on Day 0 have been collected prior to informed 
consent, the data may be used if they were collected within 2 days prior to Day 0. 
Additional observations/examinations may be performed at the discretion of the investigators 
depending on the results of the scheduled observations/examinations, even if those additional 
observations/examinations are not included in the scheduled observations/examinations. If the scheduled 
observations/examinations were not performed, the reason should be clarified. 
The study period will be from the day of informed consent to the day of the last observation (Day 28) 
(including the case of discharge from hospital). After completion of the final observations/examinations, 
completion of the study and the date of completion will be recorded in the eCRF.  
Refer to "15 Criteria for Discontinuation of Study, Subject and Study Drug " for premature 
termination of study participation of a subject or discontinuation of study drug. 
Follow-up examination will be conducted according to "14.8 Observation of AEs".  
 
13.1 Subject characteristics 
The date of informed consent, date of birth, sex, height, weight, alcohol consumption, smoking 
history, presence or absence of allergies (drugs, food, etc.), date of COVID-19 onset, date of collection 
of a sample where SARS-CoV-2 was detected positive by PCR test, past medical history/current medical 
condition, prior medication/therapy, concomitant medication/therapy. 
The date and the results of the observations/examinations will be entered in the eCRF. 
 
13.2 Physical examination 
The investigators will conduct physical examination (medical interview, inspection, palpation, and 
auscultation, etc.) according to the standard procedures of the medical institution, and the results will be 
recorded. Also, the date and the results of the examinations will be entered in the eCRF.  

 
27 
 
13.3 7-point ordinal scale 
The investigators will evaluate the category on a 7-point scale, referring to Table 13.3-1. The 
evaluation results will be recorded. Also, the date and the results of the evaluation will be entered in the 
eCRF. 
 
Table 13.3-1 7-Point Ordinal Scale 
Category 
Ordinal scale 
1 
Have died 
2 
Use an invasive ventilator or ECMO  
3 
Use a noninvasive ventilator or high-flow oxygen supply device 
4 
Require oxygen supply 
5 
Do not require oxygen supply but require continuous therapy (related to 
COVID-19 or others). 
6 
Do not require both oxygen supply and continuous therapy  
7 
Have been discharged from hospital  
 
13.4 Vital signs 
Blood pressure (systolic, diastolic), pulse rate, body temperature and respiratory rate will be measured 
and recorded. The date and the results of the measurements will be entered in the eCRF. 
Blood pressure and pulse rate will be measured after resting for about 5 minutes. The blood pressure 
may be measured in either supine or sitting position, but the posture for blood pressure measurement 
should remain constant throughout the study whenever possible. 
The site (forehead, ear, axilla, etc.) for body temperature measurement in the same subject should 
remain constant throughout the study whenever possible.  
 
13.5 12-lead Electrocardiography 
Twelve-lead electrocardiography (ECG) will be performed after resting for at least 5 minutes in 
accordance with the standard procedure of the medical institution.  
The investigators or the designated, will confirm and assess the electrocardiogram, and record. The 
date of assessment, heart rate, and assessment results will be entered in the eCRF.  
 
13.6 Laboratory tests (blood chemistry, hematology, urinalysis, and pregnancy test) 
The following items will be measured at the medical institution. If the measurement results deviate 
from the reference value, the investigators will assess whether the deviation is clinically significant. 
Pregnancy test will be performed only for women of childbearing potential. Pregnancy test will not 
necessarily be required for a female subject considered unable to become pregnant due to the following 
reasons: menopause (amenorrhea for at least 12 months without medical reasons), total hysterectomy, or 
that she does not get the first menstruation yet. The date of the sapmle collection and the test results will 
be entered in the eCRF. 

 
28 
 
Abnormal changes in laboratory test values that are judged by the investigators to be applicable to 
adverse events will be reported separately as adverse events (see "14.1 Definitions of AE"). 
 
Table 13.6-1 List of Laboratory Parameters 
Hematology  
Red blood cells count, white blood cells count, differential white leucocytes 
(neutrophils, lymphocytes, monocytes, eosinophils, basophils), platelets count, 
hemoglobin, hematocrit  
Blood chemistry  
Total protein, albumin, AST (GOT), ALT (GPT), γ-GTP, AlP, LDH, CK (CPK), 
total bilirubin, total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides 
(TG), BUN, creatinine, blood glucose, Ca, Na, K, P, Cl 
Urinalysis  
Occult blood, protein, glucose, urobilinogen 
Pregnancy test  
Urine hCG or serum hCG 
 
13.7 Percutaneous oxygen saturation (SpO2) 
Percutaneous oxygen saturation (SpO2) will be measured using a pulse oximeter on breathing of room 
air in bed rest. The date and the test results will be entered in the eCRF  
 
13.8 Inflammatory marker 
C-reactive protein (CRP) will be measured at the medical institution. The date of sample collection 
and the test results will be entered in the eCRF. 
 
13.9 Cytokines 
The following cytokines will be measured at the central laboratory. Measurement results will not be 
disclosed until the code breaking after the clinical study has been completed. The date of sample 
collection will be entered in the eCRF : IL-6, IL-1β, TNF-α, IL-10, CCL17, CXCL9, MMP-12. 
Sample collection and storage will be performed in accordance with the procedures specified 
separately. 
 
13.10 Arterial blood gas analysis (PaO2, PaCO2, A-aDO2, others) 
The subject will take a rest for at least 5 minutes under breathing of room air (when oxygen is being 
inhaled, the device will be temporarily removed) in a supine position on bed in a physicians room or in 
an examination room, then SpO2 will be confirmed to be stable on a pulse oximeter and the blood 
sample will be collected from the artery using a blood collection kit designated by the medical 
institution. After blood sample is collected, the sample will be mixed adequately, and blood gas will be 
measured within 30 minutes using a blood gas analyzer. If it takes more than 10 minutes from blood 
collection to measurement, the blood sample will be kept in ice water. Whether the examination is 
possible or not will be determined to secure the subject safety considering the following criteria: 

 
29 
 
(1) SpO2 94% or lower under the use of nasal high flow or mask 
(2) SpO2 93% or lower under oxygen supply of 4 L/min or more using nasal cannulas 
A-aDO2 will be automatically calculated using the following formula and automatically entered in the 
eCRF:  
A-aDO2 = (PB − PH2O) × FiO2 − PaCO2/R + {PaCO2 × FiO2 × (1-R)/R} − PaO2 
, where 
PB: barometric pressure (measured at each medical institution) 
PH2O: partial pressure of water vapor in inspired air (47 mmHg) 
R: respiratory quotient (0.80) 
FiO2: fraction of inspiratory oxygen (0.21) 
 
The date of sample collection and the measurement values of PBs and PaO2, PaCO2, pH, SaO2 will be 
entered in the eCRF 
 
13.11 Chest HRCT or plain chest CT or chest X-ray  
Chest high-resolution computed tomography (HRCT), plain chest CT, or chest X-ray will be 
performed in each subject (or at each medical institution) by choosing one of the above-mentioned 
examinations, and the same examination will be performed throughout the study period. 
Details of image capturing condition and CT values for performing chest HRCT will be described in 
the HRCT testing procedures, whereas other image capturing procedures will be performed according to 
the standard procedures of the medical institution. Quantitative assessment of findings such as ground-
glass opacity for the chest HRCT images will be performed using densitometry according to the 
procedures specified separately. The date of examination and the assessment results will be entered in 
the eCRF.  
Image capturing of plain chest CT and chest X-ray will be performed according to the standard 
procedures of the medical institution, and those images will be assessed by the radiologist or the 
investigators of the medical institution. The assessment results will be recorded. The date of examination 
and the assessment results will be entered in the eCRF.  
 
13.12 Oxygen requirement 
The investigators will evaluate the category of oxygen requirement of a subject classified in 5 
categories, referring to Table 13.12-1. The date of evaluation and the results will be entered in the eCRF.  
 

 
30 
 
Table 13.12-1 Oxygen Requirement 
Category 
Ordinal scale  
1 
Require oxygen supply of 4 L/min or more using oxygen mask 
2 
Require oxygen supply of 2 L/min or more using nasal cannulas 
3 
Require oxygen supply of less than 2 L/min using nasal cannulas 
4 
Do not require oxygen supply but feel shortness of breath during 
walking or moving  
5 
Do not require oxygen supply and do not feel shortness of breath during 
walking or moving. 
 
13.13 Confirmation of AEs 
If an AE is reported by a subject at any time during medical interview, or at voluntary visit, or on 
telephone contact, information on the name of the AE, date and time of onset, severity, seriousness, 
causality, treatment, outcome, and date of outcome will be obtained and recorded. In the case of an SAE, 
the SAE should be reported in accordance with "14.10 Reporting of SAEs".  
 
13.14 Confirmation of concomitant medication/therapy 
Regarding concomitant medication, information on the name of the concomitant medication, route of 
administration, treatment duration, and reason for use of the concomitant medication will be recorded 
and entered in the eCRF. Regarding concomitant therapy, information on the name of the therapy, start 
and end dates of implementation, and reason for implementation will be recorded and entered in the 
eCRF. 
 
14 AEs and adverse drug reactions (ADRs) 
14.1 Definition of AE 
An AE is any unfavorable or unintended sign (including abnormal laboratory changes), symptom, or 
disease occurring in an assigned subject from the start of study drug administration, whether or not 
related to the study drug. Events occurring before the start of study drug administration will be treated as 
a current medical condition in this study.  
AEs required to be entered in the eCRF will be those occurring from the start of study drug 
administration to Day 14 in this study. SAEs related to the study drug should be collected until Day 28. 
Moreover, the subject's current medical condition is not considered an AE unless the severity worsens 
or the incidence increases after study drug administration. If the investigators judge that the change in a 
laboratory test value is an unfavorable event for the subject, the event will be assessed as an AE.  
 
14.2 Definition of ADR 
ADR is at least reasonably likely to be related to the study drug and a causal relationship cannot be 
ruled out (see "14.6 Causality").  

 
31 
 
14.3 Severity of AEs 
The severity of an AE will be assessed by classifying the AE into three grades: mild, moderate, and 
severe, referring to the following criteria and Pharmaceutical Safety Notification No. 80 (June 29, 1992) 
"Criteria for Classification of Seriousness of Adverse Drug Reactions". Grades 1 ,2, and 3 defined in the 
above mentioned notification correspond approximately to mild, moderate, severe, respectively.  
 
■Criteria  
1) 
Mild：Symptoms are mild and easily tolerated by the subject. 
2) 
Moderate：The event causes the subject discomfort and interrupts the subject's usual activities 
and some treatment is required. 
3) 
Severe：The event makes daily activities severely. 
 
■Reference: Cited from Pharmaceutical Safety Notification No. 80 "Criteria for Classification of 
Seriousness of Adverse Drug Reactions" 
Grade 1 
The event considered to be a minor adverse drug reaction 
Grade 2 
The event considered to be neither a serious nor a minor adverse drug reaction 
Grade 3 
The event considered to be a serious adverse drug reaction. In other words, it may 
result in death or permanent dysfunction that interferes with daily life depending 
on the subject's nature and condition at the time of onset.  
 
14.4 SAEs 
The following AEs are defined as SAEs. Scheduled hospitalization for surgery or examination, 
educational hospitalization, hospitalization and prolongation of hospitalization due to the convenience of 
the home caregiver, hospitalization for disease control, and hospitalization for health care (medical 
examination) check will not be regarded as hospitalization and prolongation of the hospitalization.  
 
1) 
Results in death. 
2) 
Is life threatening.※1 
3) 
Hospitalized to hospital or clinic※2 or require prolongation of existing hospitalization for 
treatment. 
4) 
May result in disability/incapability. 
5) 
May likely result in disability/incapability. 
6) 
Is serious according to items 1) through 5)※3 above. 
7) 
Is a congenital anomaly/birth defect 
 
※1： 
The term “life threatening” refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event that hypothetically might 
have caused death if it was more severe.  

 
32 
 
※2： 
"Hospitalization" in this clinical study refers to staying at a medical institution for at 
least one night. And prolonged treatment in an outpatient setting, such as infusion, 
or staying at a medical institution intended for examination will not be regarded as 
hospitalization. If a patient has been treated for a long time on the emergency visit, 
the investigators will judge whether the case is a hospitalization case or not, taking 
the situation into account.  
※3： 
In case of a significant event that does not result in immediate life-threatening or 
death or hospitalization but may jeopardize the subject or require intervention to 
avoid the consequences described above, whether expedited reporting, as described 
below, is required or not should be judged based on the medical and scientific 
reasons, however, it should usually be considered serious. For example, blood 
disorders, renal and hepatic disorders, and central nervous system disorders which 
are considered medically important, bronchospasm requiring intensive care in the 
emergency room, or convulsions that do not result in hospitalization, drug 
dependency or substance abuse, etc. are included in this criterion.  
 
14.5 Significant AEs 
A significant AE is not an SAE, but is judged to be of special interest due to its clinical significance. 
A non-SAE leading to study drug discontinuation will be regarded as a significant AE. 
 
14.6 Causality 
The causal relationship between AE and study drug will be assessed as follows. If an AE is applicable 
to 2), the AE will be regarded as an ADR. 
 
1) 
Not related: The temporal sequence of the AE to the administration of the study drug is not 
reasonable, or there is another obvious cause including current disease at onset, other 
medicinal product, or environmental factors or others.  
2) 
Related: Events other than those "not related"  
 
14.7 Predictability of AEs  
Of AEs (including ADRs previously reported to the MHLW), those of which nature, severity, or 
frequency, etc. cannot be predicted according to the Investigator's Brochure 2will be regarded as 
“unknown” and those which can be predicted will be regarded as “known”.  
 
14.8 Observation of AEs 
The investigators shall observe the occurrence of AEs carefully through medical interview, medical 
examination, etc. from the start of study drug administration. If any AE is observed, appropriate 
measures should be taken, and the AE shall be followed up by the investigators until the AE disappears 

 
33 
 
or resolves as far as possible. However, if the investigators judge that further follow-up observation is 
not necessary and discontinue follow-up observation, or if the subject refuses it, the reason shall be 
entered in the eCRF. 
For any AEs that have occurred, information of the name of the event, date and time of onset (or date 
and time when the event was found), severity, seriousness (serious/non-serious), action taken with the 
study drug (if yes, its contents), treatment for the event (yes or no), outcome, date and time of outcome 
(when the event disappeared, the date and time of disappearance), and causality to the study drug should 
be entered in detail in the eCRF.  
 
14.9 Pregnancy 
When a female subject has been known or suspected to be pregnant during the study period, the 
investigators shall immediately discontinue the study drug administration and shall report the 
prespecified information (at least subject identification code, date of acknowledgment of pregnancy, 
dates of start and discontinuation of the study drug administration) to the sponsor. Pregnancy is not 
handled as AE, but the follow-up observation shall be conducted until the outcome (delivery, etc.) is 
confirmed. 
Data on sargramostim in pregnant and lactating women are limited, and there are no data on inhalation 
administration of sargramostim, thus the safety of sargramostim has not been established. Risks for 
spontaneous abortion and harm to the embryo and fetus have been reported in the rabbit studies.  
There is no information on sargramostim regarding its presence in human breast milk, its effects on 
breastfeeding children, or its effects on milk production. It has been reported that administration of 
sargramostim to rabbits during lactation resulted in decreased survival of offspring after birth.  
 
14.10 Reporting of SAEs 
14.10.1 Principal investigator 
If an SAE occurs during the period from the start of study drug administration to Day 14, the 
investigators will take the necessary measures with the highest priority given to the safety of the subject, 
regardless of whether it is related to the study drug or not. The principal investigator will report the event 
to the sponsor. However, if the event is an SAE and related to the study drug, the event that have 
occurred until Day 28 will be reported to the sponsor in the same manner even after completion of the 
above-mentioned period.  
The procedures are outlined below. 
 
(1) The sponsor should be informed of the occurrence of an SAE within 24 hours of acknowledgment 
of the occurrence (A form of “Report on serious adverse event (initial announcement)” shall be 
used, whenever possible). In addition, the SAE should be immediately reported to the head of the 
medical institution.  

 
34 
 
(2) A form of “Report on serious adverse event” shall be prepared and reported to the sponsor and the 
head of the medical institution at the earliest possible time within 7 days after the first 
announcement has been submitted to the sponsor, and a copy of the report will be retained.  
(3) The investigators shall make efforts to collect more detailed information, and report it to the 
sponsor and the head of the medical institution if new information becomes available.  
 
Emergency Contact (Sponsor)  
Nobel Pharma Co., Ltd. Research and Development Division 
17-24, Shinkawa 1-chome, Chuo-ku, Tokyo〒104-0033  
TEL：03-6670-3812、FAX：03-6670-5051 
Night and holiday： 
 
 
 
14.10.2 Sponsor 
The sponsor shall follow the following procedures when the occurrence of an SAE has been reported 
by the investigators.  
 
(1) “Report on serious adverse event” shall be obtained at the earliest possible time within 7 days after 
the first announcement has been received from the investigators. 
(2) The sponsor will check details of the “Report on serious adverse event”, and refer to the 
investigators as appropriate if any additional information is considered necessary.   
(3) If the report is judged to meet the requirements of Article 273 of the Enforcement Regulations of 
the Pharmaceuticals and Medical Devices Act, the sponsor should report the SAE to the regulatory 
authorities within the specified period. In addition, the sponsor will report the relevant SAE in 
writing to each principal investigator and the head of each medical institution.  
 
15 Criteria for Discontinuation of Study, Subject and Study Drug  
15.1 Study drug discontinuation 
If the subject meets any of the following criteria at any time before the second dose on Day 5, study 
drug administration for the subject shall be discontinued. 
(1) The subject has started to use invasive ventilator or ECMO.  
(2) The WBC count of the subject exceeds 25,000/μL. 
(3) An AE has occurred and the investigators judged it difficult to continue study drug administration.  
(4) The subject was found to be pregnant or suspected to be pregnant, or the subject wished to be 
pregnant or breastfeeding.  
(5) The subject was discharged from the hospital (including transfer to another hospital) and cannot 
continue to receive the study drug.  
 
[Rationale] 

 
35 
 
(1) It was set because accurate specified dose  of the study drug is thought difficult.  
(2) and (3) It was set in order to ensure the safety of the subject. 
(4) It was set because the safety of sargramostim administration during pregnancy or lactation has not 
been established. 
(5) The possibility of discontinuation due to inevitable accident was considered. 
 
Discontinuation of study drug administration does not necessarily preclude discontinuation of 
participation of the subject in the clinical study, and a policy was decided to follow-up and to collect the 
data on Japanese COVID-19 patients who participated in the clinical study whenever possible.  
 
If an event meets the criteria for study drug discontinuation, the investigators shall follow the 
following procedures. 
- The investigators shall immediately discontinue the study drug administration for the subject 
and perform observations/examinations at the time of discontinuation within 1 day of the 
discontinuation of study drug administration.  
- If the event does not meet the criteria of “15.2 Withdrawal of subject from the study” and the 
observations/examinations can be performed, the subject will continue to participate in the 
study and continue the scheduled study procedures other than the administration of the study 
drug. 
- The date and reason for discontinuation of study drug administration, as well as comments on 
discontinuation as appropriate, will be entered in the eCRF.  
 
15.2 Withdrawal of a subject from the study  
A subject who meets any of the following criteria shall be withdrawn from study participation. 
(1) The subject was found not to meet the inclusion criteria or to meet the exclusion criteria and to be 
ineligible for the clinical study according to the results of medical examinations, etc. performed 
after start of the clinical study.  
(2) The subject or the legally acceptable representative has requested to terminate the clinical study or 
to withdraw his/her consent.  
(3) The subject was dead. 
(4) The investigators judged that continuation of the clinical study is not desirable for the subject due 
to other reasons. 
 
[Rationale] 
(1) It was set as a general item to ensure safety of the subject and to properly evaluate the study. 
(2) It was set in accordance with the principles of the Declaration of Helsinki and the GCP.  
(3) Since continuous observation cannot be performed, it was set as a discontinuation criterion due to 
inevitable accident.  
(4) In addition to above mentioned criteria, it was set as a general item for discontinuation criteria so 
that the investigators can judge appropriateness to continue the clinical study.  
 

 
36 
 
If an event occurs to meet the criteria for withdrawal of subjects from the study, the investigators shall 
follow the following procedures.  
- The date of discontinuation (the date on which discontinuation was judged and the date of last 
dose, if possible) and the reason for discontinuation, as well as comments on discontinuation if 
necessary, will be entered in the eCRF. 
 
15.3 Premature termination of entire or a part of the study 
(1) If the sponsor decides to discontinue a part of or entire clinical study, the sponsor should promptly 
report the details of the discontinuation and the reasons to all the principal investigators, the heads 
of all the medical institution, and the regulatory authorities involved in the clinical study in writing. 
(2) When the head of the medical institution received a report to discontinue a part of or entire clinical 
study from the sponsor, he/she shall promptly inform the principal investigator and the IRB in 
writing and provide a detailed explanation.  
(3) When the clinical study is to be discontinued, the investigators shall promptly notify the subject of 
the discontinuation of the clinical study and provide appropriate medical care and take other 
necessary measures.  
 
16 Protocol Compliance and Amendment 
16.1 Protocol compliance and deviation 
(1) This study shall be conducted in compliance with the protocol in agreement between the principal 
investigator and the sponsor. 
(2) The investigators shall not deviate from or change the protocol without prior written agreement 
with the sponsor and prior approval by the IRB. However, this does not apply to cases where 
medical treatment is unavoidable (emergency deviation) such as avoiding the immediate hazard of 
the subject.  
(3) In case of emergency deviation, the principal investigator shall submit the emergency deviation 
report to the sponsor and the head of the medical institution, then approval/agreement by the IRB, 
the head of the medical institution, and the sponsor shall be obtained.  
(4) The investigators shall document any actions that deviate from the protocol.  
 
16.2 Protocol amendment 
(1) The sponsor must revise the protocol in consultation with the medical experts when applicable to 
the following items.  
- The sponsor has known information related to the quality, efficacy, and safety of the test drug 
or other information important for proper conduct of the clinical study.  
- a change in the protocol becomes necessary due to unavoidable medical reason. 
(2) The sponsor shall promptly inform the principal investigator of the finalized amendment in writing. 
(3) The principal investigator will fully review the ethical and scientific appropriateness to conduct the 
clinical study in accordance with the revised protocol.  

 
37 
 
(4) After discussing the revised protocol between the sponsor and the principal investigator, they shall 
sign, or sign and seal each other on the two copies of the revised protocol or equivalent as a proof 
of agreement. In addition, an approval shall be obtained from the IRB.  
(5) When the sponsor receives an instruction to make a change in the protocol from the IRB or the 
secretariat of the clinical study, the sponsor will discuss the change with the medical experts as 
appropriate and report the conclusion of discussion to the principal investigator.  
 
17 Statistical Analysis  
Statistical analysis will be performed in accordance with "Statistical Principles for Clinical 
Studies"(Notification No. 1047 of the Evaluation and Licensing Division, PMSB dated November 30, 
1998). The analysis items and technical details described in this section should be described separately in 
the statistical analysis plan.  
 
17.1 Analysis sets  
17.1.1 Efficacy analysis set  
The Full Analysis Set (FAS) is defined as any of the assigned subjects, excluding those who were not 
administered with the study drug or for whom no information on efficacyafter allocation was available. 
Analysis in FAS will be performed in this study. 
 
17.1.2 Safety population 
All subjects who received the assigned study drug will be included in the Safety Population (SP). 
 
17.2 Statistical analysis items and analytical method 
Details of the analysis items and analytical methods will be provided in the statistical analysis plan.  
 
17.2.1 Subject characteristics 
Regarding the background parameters of the subjects, the frequency distribution (number of 
subjects, %) for categorical data, summary statistics (mean, standard deviation, median, minimum, 
maximum, etc.) for continuous data, and the frequency distribution as necessary when data are 
categorized, will be determined by treatment group.  
 
17.2.2 Efficacy evaluation 
Regarding the number of days to achieve at least 2-rank improvement on a 7-point ordinal scale from 
baseline until Day 28, an efficacy endpoint, the improvement rate by treatment group will be estimated 
using Kaplan-Meier method, and an analysis for comparison between groups at a significance level of 

 
38 
 
5% using the log-rank test will be performed as the primary analysis. In addition, Cox's proportional 
hazards model using the allocation factor as a covariate will be used for evaluation.  
Regarding other efficacy endpoints, distribution or summary statistics by treatment group will be 
provided, and differences between groups will be estimated and statistically analyzed.  
 
17.2.3 Safety evaluation  
(1) AEs and ADRs 
Regarding all AEs and ADRs that occurred, the number of subjects and the number of events 
will be tabulated by event and by severity of the event by treatment group. In addition, a 95% 
confidence interval will be calculated for the incidence of AEs by treatment group.  
Moreover, the names of AEs entered in the eCRF will be tabulated by preferred term (PT) coded 
using MedDRA. SAEs and significant AEs will be listed for each subject, then the clinical course 
and causality will be narrated.  
 
(2) Laboratory test and vital signs 
Regarding data on laboratory test and vital signs, summary statistics will be calculated by 
treatment group and observation time for continuous data, and frequency distribution (number of 
subjects, %) will be calculated for categorical data. The changes over time in laboratory test values 
will be shown in graph as needed, and a list of laboratory test values exceeding the reference value 
of the medical institution will be prepared.   
 
17.3 Exploratory analysis  
Additionally, exploratory analysis will be conducted as needed. Moreover, graphs and/or tables will 
be prepared as necessary.  
 
17.4 Handling procedures for missing, non-adopted and abnormal data  
(1) If measurement error, other artificial error, etc. are scientifically proven in the laboratory 
measurement, re-measurement results will be adopted.  
(2) if the reason of occurrence of abnormal data is not clear, such data will be used for evaluation. 
(3) In the event of missing data not stipulated above, handling of such data will be discussed with the 
medical experts as necessary before fixing the data.  
 
17.5 Significance Level  
As a rule, the significance level will be set at two-sided 5% and the confidence coefficient (1-α) for 
interval estimation will be set at two-sided 95%.  
 

 
39 
 
17.6 Changes of analysis plan  
(1) When the analysis plan is to be changed, the person in charge for statistical analysis and the 
statistical analysis manager will prepare a revised statistical analysis plan after clarifying the timing 
of the change, its purpose, and the effect of the change on the interpretation of the study results.  
(2) The person in charge for statistical analysis and the statistical analysis manager will state the date 
and the reasons of the change of analysis plan in the statistical analysis report.  
(3) The sponsor will state the time and the reasons of the change of analysis plan as well as the 
discussion of impact of the additional analysis on the interpretation of the study results in the 
clinical study report.  
 
18 Target Number of Subjects 
60 subjects (randomized in a 2:1 ratio to either of the active treatment group or the control group)  
 
[Rationale] 
In a preliminary analysis of the ACTT study18 of remdesivir among other preceding studies in 
COVID-19 patients, no data on the number of days to achieve at least 2-rank improvement on a 7-point 
ordinal scale was reported, but the median time to remission (no treatment or discharge) of clinical 
symptoms was 11 days (95%CI:9-12 days) in the remdesivir group and 15 days (95%CI:13-19 days) in 
the placebo group. In an open-label study19 of mavrilimumab, a monoclonal antibody of GM-CSF 
receptor, the median recovery days was 8 days (IQR, 5-11 days) in the mavrilimumab group and 19 days 
(IQR, 11-28 days) in the standard therapy group. Given the above results and the small difference 
between the number of patients with at least 2-rank improvement and the number of recovered patients 
in any of the studies, and assuming that the median values of the active treatment group and the control 
group are 10 days and 14 days, respectively, and when a significance test for two groups is conducted 
using the log-rank test of the Kaplan-Meier estimates, the required number of patients with a 
significance level of 5% and a power of at least 80% was calculated to be 40 in the active treatment 
group and 20 in the control group (82.1% power from a simulation when 1000 times of random number 
is generated from normal distribution where the mean values are 10 in the active treatment group and 14 
in the control group and a common standard deviation is 4.5). 
 
19 Study Period 
October 2020 to October 2021  
 

 
40 
 
20 eCRF and Others 
20.1 Data entry in eCRF and reporting 
An eCRF will be applied for the case report form. Based on the source documents, data entry will be 
performed by the investigators or study collaborator using the Electronic Data Capture (EDC) system 
designated by the sponsor, thus the eCRF will be prepared. Data entry by the study collaborator is 
allowed only for the transcription of the data described in the source documents. Data entry, changes, 
and revision in the eCRF will be performed in accordance with the “Data entry manual for eCRF” 
provided separately by the sponsor. The subinvestigator or study collaborator who enters the eCRF must 
be a person registered in the "List of subinvestigators and study collaborators".   
 
20.2 Confirmation of eCRF by the principal investigator 
The details entered by the subinvestigator or study collaborator will be checked by the principal 
investigator at each time or before data fixation.  
The principal investigator will check the details entered in the EDC system, confirm that all the 
entered data (including audit trails and query responses) are accurate and complete, and will 
electronically make a sign. 
If there is any discrepancy between the source documents and the data entered in the EDC system, the 
principal investigator will prepare a record explaining the reason for the discrepancy and appropriately 
store the record. A copy of the record will be promptly submitted to the sponsor. 
Regardless of whether the principal investigator checks or not, if the sponsor and the person in charge 
of data management of the CRO or the monitor recognize that the entered data are inconsistent or 
suspected during data cleaning process or by direct access, they will issue a query and request to 
reconfirm, add, change, or amend the entered data as necessary.  
 
20.3 Data lock and unlock of eCRF 
After data cleaning of the eCRF has been completed by the sponsor and the CRO, then all the entered 
data in the eCRF will be confirmed and electronically signed by the principal investigator. After above 
mentioned procedures have been completed, the person in charge of data management will perform data 
lock operations according to the data management procedures. No additions, changes or corrections can 
be made after data lock. If correction, etc. is required after data lock, the person in charge of data 
management will unlock the data at the request of the sponsor. The sponsor will notify the principal 
investigator that the data has been unlocked. After unlocking, the task of adding, changing, or correcting 
will become possible.  
 

 
41 
 
21 Source Documents 
The source documents are the records including medical records, laboratory test records, and 
treatment records of the study drug, and others necessary for the reproducibility and evaluation of the 
factual process of the clinical study. Also, the source documents include the documents, data, and 
records using which the eCRF is prepared. In this clinical study, the following documents will be 
specifically defined as the source documents. In addition to these documents, each medical institution 
may include additional documents agreed in writing in the source documents. They will be stored 
together with other study related documents. 
 
- Medical records; laboratory test data; nursing records 
- Informed consent form 
- Screening list  
- Drug accountability logs 
- Electronic medium in which the image file is stored 
- Confirmation slip for checking calls, etc. 
 
21.1 Direct access to source data and documents 
The principal investigator and the medical institution will give direct access upon request from the 
sponsor and CRO monitors, auditors, IRB, and regulatory authorities so that they can investigate and 
confirm the documents including the source documents and the study related documents which have to 
be retained in accordance with the clinical study agreement, etc. 
 
21.2 Data to be handled as source document in the eCRF 
If the following data are not written in the source document, the information directly entered in the 
eCRF will be regarded as the source document.  
(1) Confirmation of inclusion and exclusion criteria. 
(2) Judgement of the severity and seriousness of AEs, causality, and related detailed description. 
(3) Detailed description of follow-up of discontinued (dropped out) subject.  
(4) Comment 
(5) A-aDO2 
 
22 Quality Control and Quality Assurance 
The sponsor will control and ensure quality of the study based on the standard operating procedures 
(SOP) to verify whether the quality of the clinical study is ensured. 
 

 
42 
 
22.1 Quality control 
The sponsor will confirm that the following major activities are appropriately performed according to 
each SOP.  
(1) In order to standardize the methods of the clinical study, the sponsor will explain the procedures for 
selection, enrollment, examination, evaluation, and others of subjects to the principal investigator 
and other relevant persons involved in the conduct of the clinical study before the start of the 
clinical study.  
(2) The monitor will periodically make monitoring visits during the study period to confirm the written 
informed consent and the conduct of the clinical study and others in compliance with the protocol.  
(3) The monitor will collect information on AEs during monitoring.  
(4) The monitor will check the entered data in the eCRF based on source documents such as medical 
records. 
(5) The data management manager or the person in charge of data management will check the entered 
data in the eCRF. 
(6) If there are any deficiencies or inquiries regarding (4) and (5), the monitor will issue a query, and 
request the investigators or study collaborator to reconfirm, add, change, or amend the entered data 
as necessary. When the subinvestigator or study collaborator makes additions, changes, or 
amendments, the principal investigator will finally check the details.  
(7) The sponsor will conduct a case review as needed, check the content and appropriateness of the 
entered data in the eCRF, and examine how to the handle the subject. 
(8) The data management manager and the person in charge of data management will operate data 
processing using a computer and ensure the reliability of data in accordance with the SOP. 
(9) The sponsor will check the descriptions when documents such as notification form for study plan, 
clinical study request form, contract form, and dispensing/retrieving records of the study drug and 
others are prepared.  
  
22.2 Quality assurance 
The audit manager will inspect whether the clinical study is being conducted in compliance with the 
protocol, SOPs, the Pharmaceuticals and Medical Devices Act, and related regulations such as GCP in 
accordance with the sponsor's SOP. Organizations to be audited will be the sponsor, CRO, and the 
medical institution.  
 
23 Ethics 
23.1 Compliance of GCP and others 
This clinical study will be conducted in compliance with the ethical principles based on the 
Declaration of Helsinki (1964) and its revised editions, the standards prescribed in Article 14, Paragraph 
3 and Article 80-2 of the Pharmaceuticals and Medical Devices Law, the Ministerial Ordinance on 
Standards for Conduct of Clinical studys of Drugs (MHW Ordinance No. 28 of March 27, 1997), and 
other relevant laws and regulations, and the protocol.  

 
43 
 
 
23.2 Review by IRB 
Prior to conducting a clinical study, the IRB established by the medical institution will obtain the 
protocol, informed consent form, investigator's brochure, and other documents requested by the IRB, 
judge the conduct and continuation of the clinical study from the viewpoint of ethical , scientific, and 
medical appropriateness, and notify the head of the participating medical institution of its opinion in 
writing.  
 
23.3 Subject confidentiality 
The investigators shall give due consideration to the confidentiality of the subject. Only the subject 
identification code is to be entered in the eCRF. If confidential information such as the name of the 
subject is displayed in other documents/materials to be submitted to the sponsor, such information 
should be deleted. In addition, when the test results are being published for academic purposes, the 
privacy protection of subjects shall be taken into consideration.  
The sponsor and CRO monitor and auditor should not inform a third person of any personal 
information obtained on the job related to the clinical study. The same shall apply after leaving from the 
job.  
 
23.4 Compensation for health damages 
The sponsor will be insured and take other measures to ensure the costs required for the treatment of 
study-related health damage and other loss compensation measures.  
 
23.5 Payment policy 
Payments of money related to the clinical study will be described separately in a written agreement or 
contract agreement between the sponsor and the medical institution. 
 
24 Retention of Record 
24.1 Retention of records and others 
24.1.1 Sponsor 
The study related documents that have to be retained will be specified in the GCP and SOP. 
  
24.1.2 Medical institution 
The study related documents that have to be retained will be specified in the GCP and the SOP of the 
medical institution. 

 
44 
 
 
24.2 Retention period  
24.2.1 Sponsor 
The sponsor will retain the specified study related documents until the day specified as (1) or (2), 
whichever comes later. 
 
(1) The day 5 years after the date of the manufacturing and marketing approval of the test drug. 
However, in the case of the drug that must be reexamined according to Article 14-4, Paragraph 1 of 
the Pharmaceuticals and Medical Devices Act (only the drug for which the period between the date 
of approval and the completion of reexamination is more than 5 years), the day on which the 
reexamination has been completed. 
(2) The day 3 years after discontinuation or completion of the clinical study. 
 
When retention of the specified study related documents is no longer required, the said effect will be 
notified to the head of the medical institution or the founder of the IRB.  
When the sponsor commissions duties, the sponsor will discuss the documents to be retained, the site, 
and the period with the outsourcing contractor.  
  
24.2.2 Medical institution 
The head of the medical institution will retain the prespecified study related documents until the day 
specified as (1) or (2), whichever comes later. If the sponsor requires a longer time period for retention, 
the head of the medical institution will discuss how long and how to retain the documents with the 
sponsor. When the records are retained, the responsible person for each record will be specified. 
 
(1) The date 3 years after the manufacturing and marketing approval of the test drug is obtained (or the 
date 3 years after notification of discontinuation of development is received). 
(2) The day 3 years after discontinuation or completion of the clinical study.  
 
24.2.3 Founder of IRB  
The founder of the IRB will retain the prespecified study related documents until the day specified as 
(1) or (2), whichever comes later. If the sponsor requires a longer time period for retention, the founder 
of the IRB will discuss how long and how to retain the documents with the sponsor. When the records 
are retained, the responsible person for each record will be specified. 
 
(1) The date 3 years after the manufacturing and marketing approval of the test drug is obtained (or the 
date 3 years after notification of discontinuation of development is received) 
(2) The day 3 years after discontinuation or completion of the clinical study.  
 

 
45 
 
25 Publication Policy 
The sponsor has the copyright for publications prepared or delegated on the basis of the results of the 
sponsored clinical study. The sponsor also possesses ownership of the information contained in this 
protocol (especially unpublished data). Therefore, even if the information is provided by the sponsor, the 
principal investigator who is willing to participate in the clinical study, other relevant persons involved 
in the clinical study, medical institution, IRB and others may not disclose the information to a third party 
without written agreement from the sponsor, except the case when the procedures to obtain informed 
consent from the subject are being taken. Moreover, data obtained from this clinical study are 
proprietary asset of the sponsor. When a part or all the results of this clinical study are to be published 
outside academic societies, medical journals, etc. (excluding disclosure to regulatory authorities), prior 
approval by the sponsor will be required. 
The results of this clinical study may be used by the sponsor as publications and submission 
documents for application to regulatory authorities. 
The outline of the clinical study will also be registered with the Clinical Research Protocol and 
Summary Disclosure System (https://jrct.niph.go.jp/) and/or the U.S. Clinical studys Database 
(https://Clinical studys.gov)  
 
26 List of Attachments  
Attachment 1：  Study Administrative Structure, Medical institutions, and Principal investigators 
 
27 Reference 
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Published online 2020 Jun 16