A Phase 1 Study in Healthy Participants to Evaluate the Safety, Tolerability, and Pharmacokinetics of Single-Ascending and Multiple-Ascending Doses of the Influenza A Virus Replication Inhibitor CC-42344
Phase: PHASE1
Conditions: Influenza A
Sponsor: Cocrystal Pharma, Inc.

 
 
 
 
 
 
Protocol Number: CC-42344-P1-001 
 
A Phase 1 Study in Healthy Participants to Evaluate the Safety, Tolerability, 
and Pharmacokinetics of Single-Ascending and Multiple-Ascending Doses 
of the Influenza A Virus Replication Inhibitor CC-42344 
Investigational Drug: CC-42344 
 
 
Sponsor: 
Cocrystal Pharma Australia Pty Ltd. 
 
Sponsor Contact: 
Sam Lee, PhD 
President and Interim Co-Chief Executive Officer  
Cocrystal Pharma Australia Pty Ltd. 
58 Gipps Street 
Collingwood, VIC 3066 
Tel: 011 (1) 425 750-7208 (U.S.) (mobile) 
E-mail: slee@cocrystalpharma.com 
  
 
Version 5.0, dated 17 December 2022 
 
The information contained in this protocol is confidential and intended for the use of the study 
staff.  The information in this document is the property of the sponsor and may not be disclosed 
unless federal or state law or regulations require such disclosure.  Subject to the foregoing, this 
information may be disclosed only to those persons involved in the study who need to know, 
with the obligation not to further disseminate this information.   
 

 
 
 
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1. 
PROTOCOL SYNOPSIS 
Protocol Number: CC-42344-P1-001 
Title: A Phase 1 Study in Healthy Participants to Evaluate the Safety, Tolerability, and 
Pharmacokinetics of Single-Ascending and Multiple-Ascending Doses of the Influenza A Virus 
Replication Inhibitor CC-42344  
Objectives 
Part 1: Single-Ascending Dose 
The primary objective of Part 1 is to assess the safety and tolerability of increasing doses of 
CC-42344 when given as a single oral dose to cohorts of healthy participants.  Secondary 
objectives are to assess the pharmacokinetics (PK) of CC-42344 following a single oral dose and 
to explore the effect of food on a single oral dose PK in healthy participants. 
Part 2: Multiple-Ascending Dose 
The primary objective of Part 2 is to assess the safety and tolerability of multiple-ascending 
doses of CC-42344 when administered orally to cohorts of healthy participants. A secondary 
objective is to assess the PK of CC-42344 when given as multiple oral doses to cohorts of 
healthy participants.   
Study Design 
This is a single-center, randomized, double-blind, placebo-controlled phase 1 study of the 
influenza A virus replication inhibitor CC-42344 given orally to healthy participants.   
Part 1: Participants will be randomly assigned within each cohort to receive a single dose of 
CC-42344 or placebo. Doses will escalate in sequential dose cohorts. It is planned that 4 cohorts 
will be dosed with 8 healthy participants per cohort (6 active and 2 placebo in each cohort). Each 
cohort in Part 1 will include the initial dosing of a sentinel group (1 CC-42344 and 1 placebo) at 
least 24 hours before dosing the remaining 6 subjects in the cohort (5 CC-42344 and 1 placebo). 
The remainder of the cohort will only be dosed if, in the opinion of the investigator, there is no 
significant safety concern identified in the sentinel subjects within the first 24 hours after 
administration of the dose (CC-42344 or placebo). The following regimens are planned: 
• Cohort 1A (N=8): 100 mg CC-42344 or placebo. 
• Cohort 1B (N=8): 200 mg CC-42344 or placebo. 
• Cohort 1C (N=8): 400 mg CC-42344 or placebo on Days 1 and 9 (food effect). 
• Cohort 1D (N=8): 800 mg CC-42344 or placebo.  
Cohort 1C will be a two-period sequential food-effect cohort in which participants will receive a 
single dose of study drug under fasted conditions on Day 1 and a single dose of study drug under 
fed conditions on Day 9. 

 
 
 
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After the study was conducted, it was found that the Cohort 1C PK data were not interpretable 
due to issues with the execution of the assay for plasma CC-42344 levels at the contracted 
laboratory. Therefore, an additional cohort (Cohort 1C-2) will be enrolled to generate the 400 mg 
PK and food-effect data. This cohort will comprise 6 participants, all of whom will receive a 
single 400-mg dose of open-label CC-42344 on Day 1 under fasted conditions and a single 
400-mg dose of open-label CC-42344 on Day 9 under fed conditions. The study entry criteria, 
activities, and assessments will be the same as those described for the main study. 
Part 2: Participants will be randomly assigned to receive repeated oral doses of CC-42344 or 
placebo. Doses will escalate between sequential dose cohorts. It is planned that 3 cohorts will be 
dosed for 14 days and 2 additional cohorts will be dosed for 5 days, with 8 healthy participants 
per cohort (6 active and 2 placebo). 
The following regimens are planned: 
• Cohort 2A (N=8): 50 mg CC-42344 or placebo once daily for 14 days.  
• Cohort 2B (N=8): 100 mg CC-42344 or placebo once daily for 14 days.  
• Cohort 2C (N=8): 200 mg CC-42344 or placebo once daily for 14 days.  
• Cohort 2D (N=8): 400 mg CC-42344 or placebo once daily for 5 days. 
• Cohort 2E (N=8): 400 mg CC-42344 or placebo twice daily for 5 days. 
Summary of Participant Eligibility Criteria 
Inclusion Criteria: 
1. Healthy males or healthy, non-pregnant, non-lactating females aged 18 to 55 years. 
2. Body weight of at least 50 kg.  
3. Body mass index ≥18.0 and ≤32.0 kg/m2. If outside this range, eligible at 
investigator’s discretion. 
4. Good state of health (mentally and physically) in the opinion of the investigator as 
indicated by a comprehensive clinical assessment (detailed medical history and a 
complete physical examination), electrocardiogram (ECG), vital signs, and laboratory 
investigations (hematology, clinical chemistry, coagulation, and urinalysis). 
5. Willing and able to refrain from alcohol and caffeine from 48 hours before the first 
dose through study confinement. 
6. Negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test, if 
required and per site policy. 
7. Female participants are eligible to participate if they are not pregnant, not 
breastfeeding, and at least 1 of the following conditions applies: 
• Not of childbearing potential, defined as surgically sterile (hysterectomy, 

 
 
 
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bilateral salpingectomy, tubal ligation or bilateral oophorectomy - verbal 
confirmation through medical history review acceptable) or postmenopausal 
(no menses for 12 months and confirmed by serum follicle-stimulating 
hormone (FSH) concentration ≥40 mIU/mL).  
• Of childbearing potential and agrees to practice true abstinence or agrees to 
use a highly effective method of contraception consistently from 30 days 
before Day 1 until at least 30 days after dosing. Highly effective contraception 
includes hormonal contraception (oral, injected, implanted, or transdermal) 
plus use of a condom, placement of an intrauterine device or intrauterine 
system plus use of a condom, or a vasectomized male partner (performed at 
least 6 months prior) who has been documented to no longer produce sperm - 
verbal confirmation through medical history review acceptable. Contraception 
requirements do not apply for participants in an exclusively same-sex 
relationship. Female participants should not donate eggs for 30 days after their 
last dose. 
8. Male participants must agree to practice true abstinence; be surgically sterilized 
(performed at least 6 months prior and documented to no longer produce sperm - 
verbal confirmation through medical history review acceptable); or agree to use a 
condom plus effective contraception (i.e. established use of hormonal contraception - 
started at least 30 days before Day 1; or placement or an intrauterine device or 
intrauterine system) for their female partner, if of childbearing potential, from 
screening and for at least 90 days after dosing and refrain from donating sperm during 
this period. Contraception requirements do not apply for participants in an exclusively 
same-sex relationship. Males with pregnant partners may participate if they agree to 
use a barrier method of contraception. 
9. Must provide written informed consent before any study procedure is performed. 
Exclusion Criteria: 
1. Participants who have received any investigational drug in a clinical research study 
within the previous 30 days before screening or 5 half-lives, whichever is longer. 
2. Participants who have received any vaccine within 7 days prior to randomization. 
3. Participants who are study site or sponsor employees, or immediate family members 
of a study site or sponsor employee. 
4. History of any drug or alcohol abuse in the past 2 years defined as >21 units of 
alcohol per week for males and >14 units of alcohol per week for females. Where 1 
unit = 360 mL of beer, 150 mL wine, or 45 mL of spirits. 
5. Current regular smokers or users of e-cigarettes or nicotine replacement products are 
excluded. Social smokers who have had 3 or less tobacco- or nicotine-containing 

 
 
 
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products (including tobacco, e-cigarettes and marijuana) in the 3 months prior to first 
study drug administration are permitted if willing to abstain from smoking during the 
confinement period. 
6. Females of childbearing potential who are pregnant or lactating or planning to 
become pregnant during the study (female participants of childbearing potential must 
have a negative pregnancy test at screening and Day -1). A woman is considered of 
childbearing potential unless she is permanently sterile (hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy - verbal confirmation through medical 
history review acceptable) or is postmenopausal (had no menses for 12 months 
without an alternative medical cause and a serum FSH concentration ≥40 mIU/L). 
7. Participants who do not have suitable veins for multiple venipunctures/cannulation as 
assessed by the investigator at screening. 
8. Clinically significant abnormal biochemistry, hematology, coagulation, or urinalysis 
as judged by the investigator.  
9. Positive alcohol breath test or urine test for drugs of abuse at screening or Day -1. 
10. Evidence of renal impairment at screening, as indicated by an estimated creatinine 
clearance of <80 mL/min using the Cockcroft-Gault equation. 
11. Abnormal liver function tests as indicated by alanine aminotransferase (ALT) >1.5x 
upper limit of normal (ULN), aspartate aminotransferase (AST) >1.5x ULN or total 
bilirubin >1.5x ULN. Note: may be repeated once at the discretion of the investigator. 
Participants with results consistent with Gilbert’s syndrome may be enrolled at the 
discretion of the investigator.  
12. Positive test result for hepatitis B, hepatitis C, or human immunodeficiency virus 
(HIV) at screening. 
13. Evidence or history of clinically significant allergic (except for untreated, 
asymptomatic, seasonal allergies at time of dosing), hematological, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, renal, psychiatric, or 
neurological disease. 
14. Acute illness (gastrointestinal, infection [e.g., influenza] or known inflammatory 
process) at screening or Day -1. 
15. Abnormal screening ECG, including QT intervals corrected with Fridericia’s formula 
>450 msec for males or >470 msec for females, or participant has any cardiac rhythm 
other than sinus rhythm that is interpreted by the investigator to be clinically 
significant. 
16. Supine resting bradycardia (pulse heart rate [HR] <40 bpm) or a supine resting 
tachycardia (HR >100 bpm) during vital sign measurements at screening or Day -1. 
Vital sign measurements may be repeated at the investigator’s discretion. 

 
 
 
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17. Hypertension, defined as a supine resting systolic blood pressure >140 mm Hg or a 
supine resting diastolic blood pressure >90 mm Hg during vital sign measurements at 
screening or Day -1. Vital sign measurements may be repeated at the investigator’s 
discretion. 
18. Hypotension, defined as a supine resting systolic blood pressure <90 mm Hg or a 
supine resting diastolic blood pressure <40 mm Hg during vital sign measurements at 
screening or Day -1. Vital sign measurements may be repeated at the investigator’s 
discretion. 
19. Known personal or family history of congenital long QT syndrome or known family 
history of sudden death. 
20. Has donated blood or plasma within 30 days prior to screening or had a loss of whole 
blood of more than 500 mL within the 30 days prior to screening, or receipt of a 
blood transfusion within one year prior to screening. 
21. Taking, or have taken, any prescribed medication in the 14 days before dosing or 
over-the-counter drug, including herbal remedies, in the 7 days before dosing. 
Exceptions are vitamins, minerals, paracetamol, hormone replacement therapy, and 
hormonal contraception. Additional exceptions may apply on a case-by-case basis if 
considered not to interfere with the objectives of the study, as agreed by the principal 
investigator and sponsor’s medical monitor. 
22. Failure to satisfy the investigator of fitness to participate for any other reason. 
Investigational Drug 
CC-42344 
Study Drug Doses and Route of Administration 
CC-42344 or placebo given orally.  Study drug will be provided in capsule form.  Part 1 will 
include single-ascending doses of CC-42344 100 mg, 200 mg, 400 mg, and 800 mg. The 400-mg 
food-effect cohort will receive a second dose on Day 9. Part 2 will include multiple doses of 
CC-42344 50 mg, 100 mg, and 200 mg once daily (QD) for 14 days, and 400 mg QD and 
400 mg BID for 5 days. 
Safety Assessments 
• Clinical chemistry, hematology, coagulation, and urinalysis. 
• Vital signs (blood pressure, heart rate, oral temperature, respiratory rate). 
• Electrocardiogram. 
• Physical examination. 
• Adverse events. 

 
 
 
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Pharmacokinetic Assessment 
Plasma CC-42344 concentration. 
Criteria for Dose Escalation 
● 
A Safety Monitoring Committee comprising 3 members will review safety and available 
PK data prior to dose escalation to the next dose cohort in Parts 1 and 2.   
● 
For dose escalation to proceed, safety data must be available from a minimum of 7 
participants who completed the planned safety assessments up to 48 hours after dosing to 
ensure that at least 5 participants received active study drug.  
● 
The following data are required for interim study decisions: adverse events, vital signs, 
safety laboratory values, and ECGs. 
● 
Dose escalation will not occur with any of the following: 
• 
a serious adverse reaction (i.e., a serious adverse event considered at least possibly 
related to the active drug) in one subject. 
• 
Grade 3 or higher nonserious adverse reactions (i.e., severe nonserious adverse event 
considered related to the active drug administration) in two participants in the same 
cohort, independent of whether they occurred within the same system organ class. 
Sample Size, Power, and Number of Sites 
● 
No formal sample size calculation was done. Based on experience from similar studies, 
the target number of participants to be enrolled is appropriate for the assessment of safety 
and tolerability. 
● 
In Part 1, 32 healthy participants will be enrolled into 4 cohorts, each with 8 participants. 
An additional 6 participants will be enrolled into an open-label cohort to repeat the Part 1 
PK and food-effect investigation with 400 mg. 
● 
 In Part 2, 24 healthy participants will be enrolled into 3 cohorts, each with 8 participants.   
● 
In both Parts 1 and 2, up to 2 replacement participants may be enrolled per cohort. 
Participants withdrawn due to an adverse event related to CC-42344 will be considered 
evaluable and will not be replaced.   
● 
Planned number of sites: one (Australia). 
Statistical Analysis 
Safety will be assessed based on the actual treatment received for all participants who have 
received study drug. Data will be summarized using descriptive statistics (number of 
participants, arithmetic mean, standard deviation, median, minimum, and maximum) for 
continuous variables and frequency and percentages for categorical variables.  In addition, for 
pharmacokinetic data, the geometric mean and geometric coefficient of variation will be 

 
 
 
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calculated. Where confidence intervals are presented, they will be two-sided 95% confidence 
intervals. 
Sponsor: Cocrystal Pharma Australia Pty Ltd. 

 
 
 
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2. 
SCHEDULE OF EVENTS 
2.1. 
Part 1: Single-Ascending Dose Schedule of Events 
 
Screening 
Clinical Unit  
End of Study 
Visit10 
 
Day -28 to -1 
Day -1 
Day 1 
Day 2 
Day 3 
Day 8  
Assessments 
 
 
Pre-dose 
Dosing 
Post-dose 
 
 
(+/-1 d) 
Unit Check-in 
 
X 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
X 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
 
 
 
 
 
Prior medication history 
X 
X 
 
 
 
 
 
 
Vein assessment 
X 
 
 
 
 
 
 
 
Physical examination1 
X 
X 
 
 
X (abbrev) 
 
X (abbrev) 
X (abbrev) 
Height 
X 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
12-lead ECG 2 
X 
X 
X 
 
X 
X 
X 
X 
Vital signs3 
X 
X 
X 
 
X 
X 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
Study Drug 
 
 
 
X 
 
 
 
 
Adverse event reporting4 
 
 
 
X 
X 
X 
X 
X 
Concomitant medications 
 
 
X 
 
 
X 
X 
X 
Alcohol breath test 11 
X 
X 
 
 
 
 
 
 
Drugs of abuse screen 
X 
X 
 
 
 
 
 
 
Pregnancy screen5 
X 
X 
 
 
 
 
 
X 
FSH6 
X 
 
 
 
 
 
 
 
Serology7 
X 
 
 
 
 
 
 
 
Clinical Safety Labs8 
X 
X 
 
 
X 
X 
 
X 
Plasma CC-42344 levels9 
 
 
X 
 
X 
X 
X 
 
Discharge from Unit 
 
 
 
 
 
 
X 
 

 
 
 
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Footnotes 
1 
Physical examination will include examination of general appearance, head, ears, eyes, nose, throat, neck (including thyroid), skin, cardiovascular system, respiratory 
system, gastrointestinal system, musculoskeletal system, lymph nodes, and nervous system. Abbreviated exam will include at a minimum assessment of general 
appearance, head, nose, throat, respiratory system, and cardiovascular system. 
2 
Electrocardiogram will be taken in triplicate (a least 1 minute apart and with all 3 completed within 5 minutes) with 12-lead ECG once during screening, on Day -1, on 
Day 1 pre-dose (within 2 hours) and 2 and 4 hours ±10 minutes after dosing, and on Days 2, 3, and 8. ECGs will be measured prior to vital sign measurements with 
participants in a supine position after a minimum 5-minute rest. 
3 
Vital signs include blood pressure, heart rate, respiratory rate, and oral temperature and will be collected prior to blood draws following a minimum 5-minute rest in a 
supine position. Vital signs will be measured at screening, on Day -1, on Day 1 prior to dosing (within 2 hours) and 2 and 4 hours ±10 minutes after dosing, and on Days 2, 
3, and 8. 
4 
Adverse event reporting will be continuous through end of study on Day 8. 
5 
Females of childbearing potential will be screened for pregnancy. The screening pregnancy test will be by blood sample to detect the presence of β-hCG (collected as part 
of clinical chemistry sample). On Day -1 and at end of study, pregnancy will be determined by urine dipstick. 
6 
Only for women of postmenopausal status. 
7 
Serology screening will include tests for hepatitis B surface antigen, hepatitis C virus, and human immunodeficiency virus. 
8 
Standard clinical safety labs will be collected non-fasted. 
9 
PK samples to be collected before dosing (within 30 minutes) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, and 48 h after dosing.  Additional samples to 
be collected at 72 and 96 hours postdose for Cohorts 1C and 1D. Sampling windows are ±5 minutes for samples through 4 h postdose, ±10 minutes for samples at 6 and 8 
h, ±30 minutes for samples from 12 to 48 h,  and ±4 h for samples at 72 and 96 h. When ECGs and vital signs are scheduled at the same time as PK samples, the sample 
will be taken at the scheduled time point, with the ECGs and vital signs obtained as close as possible prior to the blood draw. 
10 End of study visit for all cohorts except for the food-effect cohort, Cohort 1C. See Section 2.2 for schedule of events for days 8-16 for Cohort 1C. 
11 Alcohol breath testing may be replaced with a question asking that participants confirm that they have refrained from any alcohol intake for the time period outlined in the 
protocol 

 
 
 
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2.2. 
Part 1 Cohort 1C Schedule of Events – Period 2 
 
Clinical Unit 
EOS Visit9 
 
Day 8 
Day 9 
Day 10 
Day 11 
Day 16 
Assessments 
 
Pre-dose 
Dosing 
Post-dose 
 
 
(+/-1 d) 
Unit Check-in 
X 
 
 
 
 
 
 
Informed consent 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
Demographic data 
 
 
 
 
 
 
 
Medical history 
 
 
 
 
 
 
 
Prior medication history 
 
 
 
 
 
 
 
Vein assessment 
 
 
 
 
 
 
 
Physical examination1 
X 
 
 
X (abbrev) 
 
X (abbrev) 
X (abbrev) 
Height 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
12-lead ECG 2 
X 
X 
 
X 
X 
X 
X 
Vital signs3 
X 
X 
 
X 
X 
X 
X 
High-fat breakfast4 
 
X 
 
 
 
 
 
Study Drug 
 
 
X 
 
 
 
 
Adverse event reporting5 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
X 
X 
 
 
X 
X 
X 
Alcohol breath test 10 
X 
 
 
 
 
 
 
Drugs of abuse screen 
X 
 
 
 
 
 
 
Pregnancy screen6 
X 
 
 
 
 
 
X 
Clinical Safety Labs7 
X 
 
 
X 
X 
 
X 
Plasma CC-42344 levels8 
 
X 
 
X 
X 
X 
 
Discharge from Unit 
 
 
 
 
 
X 
 

 
 
 
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Footnotes 
Note: The washout window between Period 1 and Period 2 may be optionally extended for up to 3 days, with other Period 2 visits adjusted accordingly. Thus, dosing for 
Period 2 may occur between Day 9 and Day 12. 
1 
Physical examination will include examination of general appearance, head, ears, eyes, nose, throat, neck (including thyroid), skin, cardiovascular system, respiratory 
system, gastrointestinal system, musculoskeletal system, lymph nodes, and nervous system. Abbreviated exam will include at a minimum assessment of general 
appearance, head, nose, throat, respiratory system, and cardiovascular system. 
12 Electrocardiogram will be taken in triplicate (at least 1 minute apart and with all 3 completed within 5 minutes) with 12-lead ECG on Day 8, on Day 9 pre-dose (within 2 
hours) and 2 and 4 hours after dosing ±10 minutes, and on Days 10, 11, and 16. ECGs will be measured prior to vital sign measurements with participants in a supine 
position after a minimum 5-minute rest. 
13 Vital signs include blood pressure, heart rate, respiratory rate, and oral temperature and will be collected prior to blood draws following a minimum 5-minute rest in a 
supine position. Vital signs will be measured on Day 8, on Day 9 prior to dosing (within 2 hours) and 2 and 4 hours ±10 minutes after dosing, and on Days 10, 11, and 16. 
14 High-fat breakfast started and finished within 30 minutes prior to dosing. 
15 Adverse event reporting will be continuous to end of study on Day 16. 
16 On Day 8 and at end of study, pregnancy will be determined by urine dipstick. 
17 Standard clinical safety labs will be collected non-fasted. 
18 PK samples to be collected before dosing (within 1 hour) and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 36, 48, 72, and 96 h after dosing.  Sampling windows 
are ±5 minutes for samples through 4 h postdose, ±10 minutes for samples at 6 and 8 h, ±30 minutes for samples at 12 to 48 h, and ±4 h for samples at 72 and 96 h. When 
ECGs and vital signs are scheduled at the same time as PK samples, the sample will be taken at the scheduled time point, with the ECGs and vital signs obtained as close 
as possible prior to the blood draw. 
19 End of study visit. 
20 Alcohol breath testing may be replaced with a question asking that participants confirm that they have refrained from any alcohol intake for the time period outlined in the 
protocol 

 
 
 
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2.3. 
Part 2: Multiple-Ascending Dose Schedule of Events (Cohorts 2A, 2B, and 2C) 
 
Screen-
ing 
Day -
28 to -1 
Clinical Unit 
Day 
17-18 
EOS 
Visit 11 
Day 21 
 
Day 
-1 
Day 1 
Day 2-4 
Day 5-13 
Day 14 
Day 
15-16 
or ET 
Assessments 
 
 
Pre-
dose 
Dosing 
Post-
Dose 
Pre-
dose 
Dosing 
Post-
Dose 
Pre-
dose 
Dosing 
Post-
Dose 
Pre-
dose 
Dosing 
Post-
Dose 
 
 
(+/-1 d) 
Check-in 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic 
data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior 
medication 
history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vein 
assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination 1 
X 
X 
 
 
X 
abbrev 
 
 
X 
abbrev 
 
 
 
 
 
X 
abbrev 
 
 
X 
abbrev 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 2 
X 
X 
X 
 
X 
 
 
X 
 
 
 
 
 
X 
 
 
 
Vital signs 3 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Adverse event 
reporting4 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
medications 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

 
 
 
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Screen-
ing 
Day -
28 to -1 
Clinical Unit 
Day 
17-18 
EOS 
Visit 11 
Day 21 
 
Day 
-1 
Day 1 
Day 2-4 
Day 5-13 
Day 14 
Day 
15-16 
or ET 
Assessments 
 
 
Pre-
dose 
Dosing 
Post-
Dose 
Pre-
dose 
Dosing 
Post-
Dose 
Pre-
dose 
Dosing 
Post-
Dose 
Pre-
dose 
Dosing 
Post-
Dose 
 
 
(+/-1 d) 
Alcohol breath 
test 12 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Drugs of abuse 
screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
screen 5 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
FSH 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Safety 
Labs 8 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Plasma CC-
42344 levels9 
 
 
X 9 
 
X 9 
X 9 
 
 
X 9 
 
 
X 9 
 
X 9 
X 9 
X 9 
 
Discharge10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Footnotes 
1 
Physical examination will include examination of general appearance, head, ears, eyes, nose, throat, neck (including thyroid), skin, cardiovascular system, respiratory 
system, gastrointestinal system, musculoskeletal system, lymph nodes, and nervous system. Abbreviated exam will include at a minimum assessment of general 
appearance, head, nose, throat, respiratory system, and cardiovascular system. 
2 
Electrocardiogram will be taken in triplicate (a least 1 minute apart and with all 3 completed within 5 minutes) with 12-lead ECG during screening, on Day -1, on Day 1 
pre-dose (within 2 hours) and 2 and 4 hours ±10 minutes after dosing, and 2 hours ±10 minutes after dosing on Days 2-4 and Day 14. ECGs will be measured prior to vital 
sign measurements with participants in a supine position after a minimum 5-minute rest. 
3 
Vital signs include blood pressure, heart rate, respiratory rate, and oral temperature and will be collected prior to blood draws following a minimum 5-minute rest in a 
supine position. Vital signs will be measured at screening, on Day -1, on Day 1 prior to dosing (within 2 hours) and 2 and 4 hours ±10 minutes after dosing, on Days 2-16 
and Day 21. 
4 
Adverse event reporting will be continuous to end of study on Day 21. 
5 
Females of childbearing potential will be screened for pregnancy. The screening pregnancy test will be by blood sample to detect the presence of β-hCG (collected as part 
of clinical chemistry sample). On Day -1 and at end of study, pregnancy will be determined by urine dipstick. 
6 
Only for women of postmenopausal status. 
7 
Serology screening will include tests for hepatitis B surface antigen, hepatitis C virus, and human immunodeficiency virus. 
8 
Standard clinical safety labs will be collected on Day -1, 1-4, 10, 14, and 21. 
9 
PK sampling to be conducted as follows: 
• 
Day 1: before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, and 24 h after dosing 

 
 
 
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• 
Days 2, 4, 8, 12, and 13: before dosing; note that the Day 2 predose sample serves as the Day 1 24-hour sample  
• 
Day 14: before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 72, and 96 h after dosing 
Sampling windows are within 1 hour predose, ±5 minutes for samples through 4 h post dose, ±10 minutes for samples at 6 and 8 h, and ±30 minutes for samples at 12 to 
48 h, and ±4 h for samples at 72 and 96 h. When ECGs and vital signs are scheduled at the same time as PK samples, the sample will be taken at the scheduled time point, 
with the ECGs and vital signs obtained as close as possible prior to the blood draw. 
10 Discharge from unit following assessment on Day 16 or early termination (ET). 
11 End of study visit. 
12 Alcohol breath testing may be replaced with a question asking that participants confirm that they have refrained from any alcohol intake for the time period outlined in the 
protocol 

 
 
 
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2.4. 
Part 2: Multiple-Ascending Dose Schedule of Events (Cohorts 2D and 2E) 
 
Screen-
ing 
Day -
28 to -1 
Clinical Unit 
Day  
8-9 
EOS 
Visit 11 
Day 12 
 
Day 
-1 
Day 1 
Day 2-4 
Day 5 
Day 
6-7 or 
ET 
Assessments 
 
 
Pre-
dose 
Dosing 
Post-
Dose 
Pre-
dose 
Dosing 
Post-
Dose 
Pre-
dose 
Dosing 
Post-
Dose 
 
 
(+/-1 d) 
Check-in 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ exclusion criteria 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior medication history 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Vein assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 1 
X 
X 
 
 
X 
abbrev 
 
 
X 
abbrev 
 
 
X 
abbrev 
 
 
X 
abbrev 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
12-lead ECG 2 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
 
 
 
Vital signs 3 
X 
X 
X 
 
X 
 
 
X 
 
 
X 
X 
 
X 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Study Drug 13 
 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
Adverse event reporting4 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant medications 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Alcohol breath test 12 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
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Screen-
ing 
Day -
28 to -1 
Clinical Unit 
Day  
8-9 
EOS 
Visit 11 
Day 12 
 
Day 
-1 
Day 1 
Day 2-4 
Day 5 
Day 
6-7 or 
ET 
Assessments 
 
 
Pre-
dose 
Dosing 
Post-
Dose 
Pre-
dose 
Dosing 
Post-
Dose 
Pre-
dose 
Dosing 
Post-
Dose 
 
 
(+/-1 d) 
Drugs of abuse screen 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy screen 5 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
FSH 6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serology7 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinical Safety Labs 8 
X 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
Plasma CC-42344 levels9 
 
 
X 9 
 
X 9 
X 9 
 
 
X 9 
 
X 9 
X 9 
X 9 
 
Discharge10 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
Footnotes 
1 
Physical examination will include examination of general appearance, head, ears, eyes, nose, throat, neck (including thyroid), skin, cardiovascular system, respiratory system, 
gastrointestinal system, musculoskeletal system, lymph nodes, and nervous system. Abbreviated exam will include at a minimum assessment of general appearance, head, 
nose, throat, respiratory system, and cardiovascular system. 
2 
Electrocardiogram will be taken in triplicate (a least 1 minute apart and with all 3 completed within 5 minutes) with 12-lead ECG during screening, on Day -1, on Day 1 pre-
dose (within 2 hours) and 2 and 4 hours ±10 minutes after dosing, and 2 hours ±10 minutes after dosing on Days 2-5. ECGs will be measured prior to vital sign measurements 
with participants in a supine position after a minimum 5-minute rest. 
3 
Vital signs include blood pressure, heart rate, respiratory rate, and oral temperature and will be collected prior to blood draws following a minimum 5-minute rest in a supine 
position. Vital signs will be measured at screening, on Day -1, on Day 1 prior to dosing (within 2 hours) and 2 and 4 hours ±10 minutes after dosing, on Days 2-7 and Day 12. 
4 
Adverse event reporting will be continuous to end of study on Day 12. 
5 
Females of childbearing potential will be screened for pregnancy. The screening pregnancy test will be by blood sample to detect the presence of β-hCG (collected as part of 
clinical chemistry sample). On Day -1 and at end of study, pregnancy will be determined by urine dipstick. 
6 
Only for women of postmenopausal status. 
7 
Serology screening will include tests for hepatitis B surface antigen, hepatitis C virus, and human immunodeficiency virus. 
8 
Standard clinical safety labs will be collected on Day -1, 1-5, and 12. 
9 
PK sampling to be conducted as follows: 
• 
Cohort 2D (QD dosing) 
o 
Day 1: before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, and 24 h after dosing.  
o 
Days 2, 4: before dosing; note that the Day 2 predose sample serves as the Day 1 24-hour sample  
o 
Day 5: before dosing and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 72, and 96 h after dosing 

 
 
 
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• 
Cohort 2E (BID dosing) 
o 
Day 1: before dose 1 at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, and 12 h after dose 1 (pre-dose 2); 12 hours after dose 2.  
o 
Days 2, 4: before each dose; note that the Day 2 pre-dose 1 sample serves as the Day 1 dose 2 12-hour sample  
o 
Day 5: before the final dose (administered the morning of Day 5), and at 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 3.5, 4, 6, 8, 12, 24, 48, 72, and 96 h after the final dose 
• 
Sampling windows are within 30 minutes predose, ±5 minutes for samples through 4 h post dose, ±10 minutes for samples at 6 and 8 h, and ±30 minutes for samples at 
12 to 48 h, and ±4 h for samples at 72 and 96 h. When ECGs and vital signs are scheduled at the same time as PK samples, the sample will be taken at the scheduled time 
point, with the ECGs and vital signs obtained as close as possible prior to the blood draw. 
10 Discharge from unit following assessment on Day 7 or early termination (ET). 
11 End of study visit. 
12 Alcohol breath testing may be replaced with a question asking that participants confirm that they have refrained from any alcohol intake for the time period outlined in the 
protocol 
13 Study drug to be administered beginning on Day 1 (Time 0) through Day 5 inclusive: 
• 
Cohort 2D: every 24 hours (±30 minutes) for a total of 5 doses 
• 
Cohort 2E: every 12 hours (±30 minutes) with the final dose the morning of Day 5 for a total of 9 doses 
 

 
 
 
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TABLE OF CONTENTS 
1. 
PROTOCOL SYNOPSIS .................................................................................................. 2 
2. 
SCHEDULE OF EVENTS ................................................................................................ 9 
2.1. 
Part 1: Single-Ascending Dose Schedule of Events ................................................ 9 
2.2. 
Part 1 Cohort 1C Schedule of Events – Period 2 ................................................... 11 
2.3. 
Part 2: Multiple-Ascending Dose Schedule of Events (Cohorts 2A, 2B, and 2C) 13 
2.4. 
Part 2: Multiple-Ascending Dose Schedule of Events (Cohorts 2D and 2E) ........ 16 
3. 
LIST OF ABBREVIATIONS .......................................................................................... 22 
4. 
INTRODUCTION ........................................................................................................... 23 
4.1. 
Seasonal Influenza ................................................................................................. 23 
4.2. 
CC-42344............................................................................................................... 23 
4.3. 
Risk/Benefit Assessment ....................................................................................... 25 
5. 
OBJECTIVES AND ENDPOINTS ................................................................................. 26 
6. 
INVESTIGATIONAL PLAN .......................................................................................... 27 
6.1. 
Summary of Study Design ..................................................................................... 27 
6.2. 
Discussion of Design ............................................................................................. 28 
7. 
STUDY POPULATION .................................................................................................. 30 
7.1. 
Inclusion and Exclusion Criteria ........................................................................... 30 
7.1.1. 
Inclusion Criteria ............................................................................................... 30 
7.1.2. 
Exclusion Criteria .............................................................................................. 31 
7.2. 
Removal of Participants from Study Drug or Assessment .................................... 33 
7.2.1. 
Early Discontinuation of Study Drug ................................................................ 33 
7.2.2. 
Participant Withdrawal from the Study ............................................................. 33 
7.2.3. 
Participant Replacement .................................................................................... 33 
8. 
TREATMENTS ............................................................................................................... 34 
8.1. 
Participant Assignment .......................................................................................... 34 
8.2. 
Method of Assignment to Treatment ..................................................................... 34 
8.3. 
Materials and Supplies........................................................................................... 34 
8.3.1. 
Formulation, Packaging, and Labeling .............................................................. 34 
8.3.2. 
Storage and Handling ......................................................................................... 35 
8.3.3. 
Final Disposition of Clinical Supplies ............................................................... 35 
8.4. 
Dosage Administration .......................................................................................... 35 
8.5. 
Blinding and Unblinding ....................................................................................... 36 
8.6. 
Concomitant Therapy ............................................................................................ 36 

 
 
 
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9. 
STUDY ASSESSMENTS ............................................................................................... 37 
9.1. 
Pharmacokinetic Assessments ............................................................................... 37 
9.2. 
Safety Assessments................................................................................................ 37 
9.2.1. 
Physical Examination......................................................................................... 37 
9.2.2. 
Vital Signs .......................................................................................................... 37 
9.2.3. 
Electrocardiograms ............................................................................................ 37 
9.2.4. 
Clinical Laboratory Tests ................................................................................... 37 
9.3. 
Adverse Events ...................................................................................................... 38 
9.3.1. 
Definition of Adverse Event .............................................................................. 38 
9.3.2. 
Reporting Procedures for All Adverse Events ................................................... 39 
9.3.3. 
Adverse Event Severity...................................................................................... 39 
9.3.4. 
Adverse Event Relationship to Study Drug ....................................................... 40 
9.3.5. 
Serious Adverse Event Definition and Reporting Procedures ........................... 40 
9.4. 
Safety Monitoring .................................................................................................. 41 
10. QUALITY CONTROL AND QUALITY ASSURANCE ............................................... 43 
11. DATA ANALYSIS METHODS ..................................................................................... 44 
11.1. 
Determination of Sample Size ............................................................................... 44 
11.2. 
Statistical and Analytical Plans ............................................................................. 44 
11.2.1. 
General Considerations .................................................................................. 44 
11.2.2. 
Handling of Missing Data .............................................................................. 44 
11.2.3. 
Participant Disposition ................................................................................... 44 
11.2.4. 
Participant Characteristics .............................................................................. 44 
11.2.5. 
Treatment Compliance ................................................................................... 44 
11.2.6. 
Pharmacokinetic Analyses ............................................................................. 44 
11.2.7. 
Safety Analyses .............................................................................................. 45 
11.2.8. 
Interim Analyses ............................................................................................ 46 
12. ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS .......... 47 
12.1. 
Ethical Review ....................................................................................................... 47 
12.2. 
Regulatory Considerations .................................................................................... 47 
12.2.1. 
Investigator Information ................................................................................. 47 
12.2.2. 
Protocol Amendments and Study Termination .............................................. 48 
12.2.3. 
Study Documentation, Privacy, and Records Retention ................................ 48 
12.3. 
Study Finances ....................................................................................................... 48 
12.4. 
Publications ........................................................................................................... 48 

 
 
 
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13. REFERENCES ................................................................................................................ 50 
14. DOCUMENT HISTORY................................................................................................. 51 
14.1. 
Summary of Changes from Version 4.0 to Version 5.0 ........................................ 52 
14.2. 
Summary of Changes from Version 3.0 to Version 4.0 ........................................ 53 
14.3. 
Summary of Changes from Version 2.0 to Version 3.0 ........................................ 54 
14.4. 
Summary of Changes from Version 1.1 to Version 2.0 ........................................ 55 
14.5. 
Summary of Changes from Version 1.0 to Version 1.1 ........................................ 57 
 
List of Appendices 
Appendix A: 
Sponsor Protocol Approval ............................................................................ 58 
Appendix B: 
Investigator Protocol Signature Page ............................................................. 59 
 
List of Tables 
Table 1: 
Study Drug Treatment (Part 1, Single-Ascending Dose) ...................................... 34 
Table 2: 
Study Drug Treatment (Part 2, Multiple-Ascending Dose) ................................... 35 
 

 
 
 
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3. 
LIST OF ABBREVIATIONS 
ABBREVIATION 
DEFINITION 
AE 
adverse event 
ALT 
alanine transaminase  
ANOVA 
analysis of variance  
AST 
aspartate aminotransferase 
AUC 
area under the plasma concentration-time curve 
BID 
twice per day (bis in die) 
Cmax 
maximum plasma concentration 
COVID-19 
coronavirus disease 2019 
CRF 
case report form 
DAIDS 
Division of AIDS 
EC 
Ethics Committee  
ECG 
electrocardiogram 
EOS 
end of study 
ET 
early termination 
FSH 
follicle-stimulating hormone 
hCG 
human chorionic gonadotropin  
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
human immunodeficiency virus 
HR 
heart rate 
MedDRA 
Medical Dictionary for Regulatory Activities  
PK 
pharmacokinetic(s) 
QD 
once a day (quaque die) 
SAE 
serious adverse event 
SARS-CoV-2 
severe acute respiratory syndrome coronavirus 2 
SDD 
spray-dried dispersion 
SMC 
Safety Monitoring Committee 
t1/2 
terminal elimination half-life 
Tmax 
time of maximum plasma concentration 
ULN 
upper limit of normal 
λz 
elimination rate constant 

 
 
 
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4. 
INTRODUCTION 
4.1. 
Seasonal Influenza 
Seasonal influenza is a global acute respiratory illness caused by influenza A or B viruses. 
Influenza A virus is the sole cause of influenza pandemics and is responsible for seasonal 
influenza epidemics in humans. Although usually a self-limited infection, influenza A can 
result in pneumonia, respiratory failure, and death, especially in persons at increased risk for 
influenza complications (such as very young, elderly, and those with comorbid conditions). 
The time from infection to illness (incubation period) is approximately 2 days but ranges 
from one to four days (World Health Organization 2021). Worldwide, influenza results in 
estimates of about 3 to 5 million cases of severe illness and up to 650,000 respiratory deaths 
annually (World Health Organization 2021). 
Two classes of antiviral drugs are approved for the treatment of influenza: (1) the 
neuraminidase inhibitors (inhaled zanamivir, oral oseltamivir, and intravenous peramivir), 
which are active against both influenza A and B, and (2) the selective inhibitor of influenza 
cap-dependent endonuclease, oral baloxavir, which is active against influenza A and B. A 
third class of drugs, the adamantanes (amantadine and rimantadine), is only active against 
influenza A and is not recommended by the World Health Organization due to a marked 
increase in resistant isolates (World Health Organization 2021).  
Antiviral treatment is recommended as soon as possible for any patient with suspected or 
confirmed influenza who is hospitalized; has severe, complicated, or progressive illness; or is 
at higher risk for influenza complications (US Centers for Disease Control and Prevention 
2021). In contrast, consideration of early empiric antiviral treatment of non-high-risk 
outpatients with suspected influenza is recommended to be made based upon clinical 
judgment, if treatment can be initiated within 48 hours of illness onset (US Centers for 
Disease Control and Prevention 2021). Antiviral therapy for influenza is considered 
underused in high-risk patients (World Health Organization 2021). Antiviral therapy for 
influenza can also be critical for the prevention of illness in household contacts of infected 
patients (Ikematsu et al., 2020). 
Resistance, drug interactions, adverse events, timing of initiation of antiviral influenza 
therapy, route of administration, and duration of therapy are important considerations in 
choice of antiviral therapy for influenza (Uyeki et al., 2018). In particular, emergence of 
resistance can limit the therapeutic utility of anti-influenza treatments (Abed et al., 2021; 
Beigel and Hayden, 2020; Uehara et al., 2020). 
4.2. 
CC-42344 
CC-42344 is a novel oral, potent, and broad-spectrum anti-influenza A agent that targets the 
cap-binding PB2 domain of the viral polymerase, thereby blocking the viral replication cycle.  

 
 
 
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In vitro pharmacology studies demonstrated CC-42344 to be a potent and selective influenza 
A virus inhibitor with low nanomolar potency. It exhibits a high level of viral selectivity for 
influenza A and has no relevant in vitro inhibitory effects against native human DNA 
polymerases. In vitro studies with CC-42344 studies indicate that it has a high barrier to 
resistance. CC-42344 also exhibits synergism in combination with current influenza drugs. In 
vitro combination of CC-42344 with other anti-influenza or antiviral drugs for other 
indications showed synergism for influenza A activity. In addition, CC-42344 showed 
excellent anti-influenza activity against oseltamivir- and baloxavir-resistant influenza A 
H1N1. In a mouse model of influenza A infection, an oral formulation was tolerated without 
adverse effects and protected the infected mice from the virus-related pattern of body weight 
loss and improved their survival at doses ≥25 mg/kg/day. 
CC-42344 demonstrated no- to low-level cytotoxicity across a range of proliferating and 
nonproliferating human cells, no signs of mitochondrial toxicity with proliferating HepG2 
liver cells, and no off-target in vitro interactions at likely clinical concentrations. Safety 
pharmacology testing confirmed that the central nervous and respiratory systems in rats were 
unaffected, while some slight, non-adverse, and reversible decreases were observed in 
systolic blood pressure and heart rate in conscious dogs at single oral doses of 1000 mg/kg. 
Metabolic profiling using hepatocytes detected 9 metabolites formed from CC-42344 across 
mouse, rat, dog, monkey, and human; a glucuronide metabolite was the most abundant. 
CC-42344 showed inhibitory potency in vitro towards all the major human cytochrome P-450 
isoforms.  
Safety assessments were conducted using rat and dog as the selected species based on 
coverage for human metabolites observed with hepatocytes. No adverse effects of CC-42344 
were identified after single oral doses up to 1000 mg/kg. Repeated oral administration over 14 
days identified the liver (hepatocellular cholestasis and necrosis with increased bilirubin and 
liver enzyme activities), kidneys (renal tubular degeneration with increased serum urea and 
decreased serum chloride), and meninges (mononuclear inflammation) as target organs 
associated with adverse effects. These adverse effects reversed after a 7-day recovery period 
apart from a single case of mononuclear inflammation in the meninges. The no-observed-
adverse-effect level (NOAEL) was determined to be 70 mg/kg/day in the dog, the most 
sensitive species. CC-42344 was negative for mutagenicity in the bacterial reverse mutation 
assay and for structural chromosomal aberration in cultured Chinese hamster ovary cells, both 
with and without metabolic activation. 
More detailed information about nonclinical and preclinical studies with CC-42344 can be 
found in the Investigator’s Brochure. 

 
 
 
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4.3. 
Risk/Benefit Assessment 
Anticipated risks of CC-42344 are low based on the mechanism of action and preclinical 
safety data that includes cytotoxicity and genotoxicity evaluations, safety pharmacology 
studies, and single- and repeated-dose toxicity studies in rat and dog.  The risk-benefit 
balance for this study is considered favorable given the overall limited risks to study 
participants in this sequential-cohort dose-escalation study. 

 
 
 
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5. 
OBJECTIVES AND ENDPOINTS 
Part 1: Single-Ascending Dose 
Objectives 
Endpoints 
Primary 
• To assess the safety and tolerability 
of increasing doses of CC-42344 
when given as single oral dose to 
cohorts of healthy participants 
• Incidence of treatment-emergent AEs 
• Incidence of clinically significant laboratory 
abnormalities 
• Incidence of clinically significant changes 
from baseline in vital signs 
• Incidence of clinically significant changes 
from baseline in ECGs 
Secondary 
• To assess the PK of CC-42344 
following a single oral dose 
• PK parameters: Cmax, Tmax, AUC(0-t), AUC(inf), 
λz, t1/2 
• To explore the effect of food on the 
single oral dose PK of CC-42344 
• Difference between fasted and fed conditions 
in systemic exposure to CC-42344: Cmax, 
Tmax, AUC(0-t), AUC(inf) 
 
Part 2: Multiple-Ascending Dose 
Objectives 
Endpoints 
Primary 
• To assess the safety and tolerability 
of multiple-ascending doses of 
CC-42344 when administered 
orally to cohorts of healthy 
participants 
• Incidence of treatment-emergent AEs 
• Incidence of clinically significant laboratory 
abnormalities 
• Incidence of clinically significant changes 
from baseline in vital signs 
• Incidence of clinically significant changes 
from baseline in ECGs 
Secondary 
• To assess the PK of CC-42344 
when given as multiple oral doses 
• PK parameters: Cmax, Tmax, AUC(0-24) on Days 
1 and 14 and λz and t1/2 after the last dose; 
predose concentrations on Days 2, 4, 8, 12, 
and 13. 
 

 
 
 
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6. 
INVESTIGATIONAL PLAN 
6.1. 
Summary of Study Design 
This is a single-center, randomized, double-blind, placebo-controlled phase 1 study of the 
influenza A virus replication inhibitor CC-42344 given orally to healthy participants at a 
single site in Australia. Participants will be recruited by Linear Clinical Research Ltd. 
Screening assessments must be done to determine participant eligibility.  Written consent 
must be obtained before conducting any study procedures. 
Part 1: Single-Ascending Dose 
Participants will be randomly assigned within each cohort to receive a single dose of 
CC-42344 or placebo. Doses will escalate in sequential dose cohorts. It is planned that 4 
cohorts will be dosed with 8 healthy participants per cohort (6 active and 2 placebo in each 
cohort). Each cohort in Part 1 will include the initial dosing of a sentinel group (1 CC-42344 
and 1 placebo) at least 24 hours before dosing the remaining 6 subjects in the cohort (5 
CC-42344 and 1 placebo). The remainder of the cohort will only be dosed if, in the opinion of 
the investigator, there is no significant safety concern identified in the sentinel subjects within 
the first 24 hours after administration of the dose (CC-42344 or placebo). The following 
regimens are planned: 
• Cohort 1A (N=8): 100 mg CC-42344 or placebo. 
• Cohort 1B (N=8): 200 mg CC-42344 or placebo. 
• Cohort 1C (N=8): 400 mg CC-42344 or placebo on Days 1 and 9 (food effect). 
• Cohort 1D (N=8): 800 mg CC-42344 or placebo. 
Cohort 1C will be a two-period sequential food-effect cohort in which participants will 
receive a single dose of study drug under fasted conditions on Day 1 and a single dose of 
study drug under fed conditions on Day 9.  
After the study was conducted, it was found that the Cohort 1C PK data were not 
interpretable due to issues with the execution of the assay for plasma CC 42344 levels at the 
contracted laboratory. Therefore, an additional cohort (Cohort 1C-2) will be enrolled to 
generate the 400 mg PK and food-effect data. This cohort will comprise 6 participants, all of 
whom will receive a single 400-mg dose of open-label CC-42344 on Day 1 under fasted 
conditions and a single 400-mg dose of open-label CC-42344 on Day 9 under fed conditions. 
The study entry criteria, activities, and assessments will be the same as those described for the 
main study. 
Additional dose cohort(s) may be added if all previous dosages are well tolerated and 
accumulated PK and safety data support the addition of higher dose(s). 

 
 
 
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Part 2: Multiple-Ascending Dose 
Part 2 of the study may be opened after satisfactory review of the safety and PK data from the 
first dose in Cohort 1C.  
Participants will be randomly assigned to receive once-daily oral doses of CC-42344 or 
placebo for 14 days. Doses will escalate between sequential dose cohorts. It is planned that up 
to 3 cohorts will be dosed with 8 healthy participants per cohort (6 active and 2 placebo).   
The following regimens are planned: 
• Cohort 2A: 50 mg CC-42344 or placebo once daily for 14 days.  
• Cohort 2B: 100 mg CC-42344 or placebo once daily for 14 days.  
• Cohort 2C: 200 mg CC-42344 or placebo once daily for 14 days.  
• Cohort 2D: 400 mg CC-42344 or placebo once daily for 5 days. 
• Cohort 2E: 400 mg CC-42344 or placebo twice daily for 5 days. 
6.2. 
Discussion of Design 
Study Design: The randomized, double-blind, placebo-controlled design provides the optimal 
opportunity to differentiate potential adverse events associated with CC-42344 from 
background events in healthy volunteers. Dose escalation in sequential cohorts with interim 
review by a Safety Monitoring Committee (SMC) mitigates risk to study participants in this 
first-in-human study. 
Dose Rationale: The lowest NOAEL of 70 mg/kg/day from the rat and dog 14-day repeated 
dose GLP toxicology studies provides a human equivalent dose of 1894 mg to a 50-kg 
person. This corresponds to a 19X safety factor over the proposed Part 1 (single-ascending 
dose) starting dose of 100 mg and a 2.4X safety factor over the proposed maximum dose of 
800 mg. 
The doses initially selected for Part 2 (multiple-ascending dose)—50 mg, 100 mg, and 200 
mg QD × 14 days—were supported based on the favorable safety profile of single doses of 
100 to 800 mg in Part 1 of the study. In addition, at the NOAEL of 70 mg/kg in the 14-day 
dog study, the most sensitive species, the Day 14 Cmax and AUC(0-24) were 8,475 ng/mL and 
15,450 hr×ng/mL, respectively (mean of males and females). Based on the 200 mg single-
dose cohort, and assuming an ~1.5-fold accumulation with QD dosing, the steady-state Cmax 
and AUC(0-24) in humans for a 200 mg QD regimen are projected to be 1,410 ng/mL and 
3,182 hr×ng/mL, respectively. This provides safety margins of ~6-fold and ~5-fold, 
respectively. The starting dose of 50 mg is anticipated to result in trough plasma 
concentrations well in excess of the CC-42344 EC90 (concentration resulting in 90% viral 
activity inhibition) based on modeling of the single-dose PK data. 

 
 
 
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The additional cohorts planned for Part 2 (multiple-ascending dose)—400 mg QD and 
400 mg BID for 5 days—are supported based on the favorable safety profile seen with 
repeated dosing at up to 200 mg/day for 14 days and single doses of up to 800 mg in the 
current study. No significant accumulation was seen with QD dosing at up to 200 mg. 
Entry Criteria: Participants will be healthy adults and receive standard assessments to 
determine eligibility.  
Safety Endpoints: The safety assessments of physical examination, vital signs, clinical 
laboratories, electrocardiogram, and adverse event collection used in this trial are standard 
assessments for phase 1 studies evaluating the safety of single and repeated dosing.   
 

 
 
 
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7. 
STUDY POPULATION 
The participants will comprise healthy adults between the ages of 18 and 55. 
Participation in this study is voluntary.  The nature of the study will be fully explained to each 
participant during the informed consent.  The participants will have the opportunity to ask 
questions.  An informed consent document will then be signed by the participant and the 
person performing the consent discussion and retained by the investigator according to Good 
Clinical Practice.  A copy of the signed informed consent document will be given to the 
participant. 
Eligibility for enrollment will be based on the results of screening for the following inclusion 
and exclusion criteria.  
7.1. 
Inclusion and Exclusion Criteria 
7.1.1. 
Inclusion Criteria  
1) 
Healthy males or healthy, non-pregnant, non-lactating females aged 18 to 55 years. 
2) 
Body weight of at least 50 kg. 
3) 
Body mass index between ≥18.0 and ≤32.0 kg/m2. If outside this range, eligible at 
investigator’s discretion. 
4) 
Good state of health (mentally and physically) in the opinion of the investigator as 
indicated by a comprehensive clinical assessment (detailed medical history and a 
complete physical examination), electrocardiogram (ECG), vital signs, and 
laboratory investigations (hematology, clinical chemistry, coagulation, and 
urinalysis). 
5) 
Willing and able to refrain from alcohol and caffeine from 48 hours before first dose 
through study confinement. 
6) 
Negative severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test, if 
required and per site policy. 
7) 
Female participants are eligible to participate if they are not pregnant, not 
breastfeeding, and at least 1 of the following conditions applies: 
• 
Not of childbearing potential, defined as surgically sterile (hysterectomy, 
bilateral salpingectomy, tubal ligation or bilateral oophorectomy - verbal 
confirmation through medical history review acceptable) or postmenopausal (no 
menses for 12 months and confirmed by follicle-stimulating hormone (FSH) 
level ≥40 mIU/mL).  
• 
Of childbearing potential and agrees to practice true abstinence or agrees to use 
a highly effective method of contraception consistently from 30 days prior to 
Day 1 until at least 30 days after dosing. Highly effective contraception includes 
hormonal contraception (oral, injected, implanted or transdermal) plus use of a 
condom, placement of an intrauterine device or intrauterine system plus use of a 

 
 
 
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condom, or a vasectomized male partner (performed at least 6 months prior) 
who has been documented to no longer produce sperm - verbal confirmation 
through medical history review acceptable. Contraception requirements do not 
apply for participants in an exclusively same-sex relationship. Female 
participants should not donate eggs for 30 days after their last dose. 
8) 
Male participants must agree to practice true abstinence; be surgically sterilized 
(performed at least 6 months prior and documented to no longer produce sperm - 
verbal confirmation through medical history review acceptable); or agree to use a 
condom plus effective contraception (i.e. established use of hormonal contraception 
- started at least 30 days before Day 1; or placement or an intrauterine device or 
intrauterine system) for their female partner, if of childbearing potential, from 
screening and for at least 90 days after dosing and refrain from donating sperm 
during this period. Contraception requirements do not apply for participants in an 
exclusively same-sex relationship. Males with pregnant partners may participate if 
they agree to use a barrier method of contraception. 
9) 
Must provide written informed consent before any study procedure is performed.  
7.1.2. 
Exclusion Criteria 
1) 
Participants who have received any investigational drug in a clinical research study 
within the previous 30 days before screening or 5 half-lives, whichever is longer. 
2) 
Participants who have received any vaccine within 7 days prior to randomization. 
3) 
Participants who are study site or sponsor employees, or immediate family members 
of a study site or sponsor employee. 
4) 
History of any drug or alcohol abuse in the past 2 years defined as >21 units of 
alcohol per week for males and >14 units of alcohol per week for females. Where 1 
unit = 360 mL of beer, 150 mL wine, or 45 mL of spirits. 
5) 
Current regular smokers or users of e-cigarettes or nicotine replacement products are 
excluded. Social smokers who have had 3 or less tobacco- or nicotine-containing 
products (including tobacco, e-cigarettes and marijuana) in the 3 months prior to 
first study drug administration are permitted if willing to abstain from smoking 
during the confinement period. 
6) 
Females of childbearing potential who are pregnant or lactating or planning to 
become pregnant during the study (female participants of childbearing potential 
must have a negative pregnancy test at screening and Day -1). A woman is 
considered of childbearing potential unless she is permanently sterile (hysterectomy, 
bilateral salpingectomy, and bilateral oophorectomy) or is postmenopausal (had no 
menses for 12 months without an alternative medical cause and a serum FSH 
concentration ≥40 mIU/L). 
7) 
Participants who do not have suitable veins for multiple venipunctures/cannulation 
as assessed by the investigator at screening. 

 
 
 
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8) 
Clinically significant abnormal biochemistry, hematology, coagulation, or urinalysis 
as judged by the investigator. 
9) 
Positive alcohol breath test and/or urine test for drugs of abuse at screening or 
Day -1. 
10) Evidence of renal impairment at screening, as indicated by an estimated creatinine 
clearance of <80 mL/min using the Cockcroft-Gault equation. 
11) Abnormal liver function tests as indicated by alanine aminotransferase (ALT) > 1.5x 
upper limit of normal (ULN), aspartate aminotransferase (AST) > 1.5x ULN or total 
bilirubin >1.5x ULN. Note: may be repeated once at the discretion of the 
investigator. Participants with results consistent with Gilbert’s syndrome may be 
enrolled at the discretion of the investigator. 
12) Positive test result for hepatitis B, hepatitis C, or human immunodeficiency virus 
(HIV) at screening 
13) Evidence or history of clinically significant allergic (except for untreated, 
asymptomatic, seasonal allergies at time of dosing), hematological, endocrine, 
pulmonary, gastrointestinal, cardiovascular, hepatic, renal, psychiatric, or 
neurological disease. 
14) Acute illness (gastrointestinal, infection [e.g., influenza] or known inflammatory 
process) at screening or Day -1. 
15) Abnormal screening ECG, including QT intervals corrected with Fridericia’s 
formula >450 msec for males or >470 msec for females, or participant has any 
cardiac rhythm other than sinus rhythm that is interpreted by the investigator to be 
clinically significant. 
16) Supine resting bradycardia (pulse heart rate [HR] <40 bpm) or a supine resting 
tachycardia (HR >100 bpm) during vital sign measurements at screening or Day -1. 
Vital sign measurements may be repeated at the investigator’s discretion. 
17) Hypertension, defined as a supine resting systolic blood pressure >140 mm Hg or a 
supine resting diastolic blood pressure >90 mm Hg during vital sign measurements 
at screening or Day -1. Vital sign measurements may be repeated at the 
investigator’s discretion. 
18) Hypotension, defined as a supine resting systolic blood pressure <90 mm Hg or a 
supine resting diastolic blood pressure <40 mm Hg during vital sign measurements 
at screening or Day -1. Vital sign measurements may be repeated at the 
investigator’s discretion. 
19) Known personal or family history of congenital long QT syndrome or known family 
history of sudden death. 
20) Has donated blood or plasma within 30 days prior to screening or had a loss of 
whole blood of more than 500 mL within the 30 days prior to screening, or receipt 
of a blood transfusion within one year prior to screening. 

 
 
 
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21) Taking, or have taken, any prescribed medication in the 14 days before dosing or 
over-the-counter drug, including herbal remedies, in the 7 days before dosing. 
Exceptions are vitamins, minerals, paracetamol, hormone replacement therapy, and 
hormonal contraception. Additional exceptions may apply on a case-by-case basis if 
considered not to interfere with the objectives of the study, as agreed by the 
principal investigator and sponsor’s medical monitor. 
22) Failure to satisfy the investigator of fitness to participate for any other reason. 
7.2. 
Removal of Participants from Study Drug or Assessment 
7.2.1. 
Early Discontinuation of Study Drug 
A participant must prematurely discontinue study drug under any of the following 
circumstances: 
● 
The participant wishes to discontinue study drug. 
● 
The investigator wishes the participant to discontinue study drug, especially but not 
limited to the investigator concluding that further treatment puts the participant at 
unacceptable risk. 
● 
The participant develops a condition or begins a therapy that would have excluded 
entry into the study. 
● 
The participant becomes pregnant during the study period. In this circumstance, the 
pregnancy must be immediately reported to the sponsor. 
● 
The participant develops an adverse event with the Division of AIDS (DAIDS) Table 
for Grading the Severity of Adult and Pediatric Adverse Events that is grade 3 or 
greater toxicity and related to study drug in the judgment of the investigator.   
Participants who discontinue study drug prematurely should continue to have the planned 
study assessments unless consent to do so is withdrawn. 
7.2.2. 
Participant Withdrawal from the Study 
A participant must be withdrawn from the study (and discontinue any study drug) if: 
● 
the participant requests such study discontinuation. 
The reason for study withdrawal, if available, must be recorded in the participant’s case 
report form (CRF). An early termination visit will be conducted unless consent to do so is 
withdrawn. 
7.2.3. 
Participant Replacement 
In both Parts 1 and 2, up to 2 replacement participants may be enrolled per cohort. An 
exception is participants withdrawn due to an adverse event related to CC-42344, who will be 
considered evaluable and will not be replaced. 

 
 
 
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The PK data from the additional participants enrolled in Cohort 1C-2 will replace the 
uninterpretable PK data from Cohort 1C; however, the safety data from both Cohorts 1C and 
1C-2 will be analyzed and included in the clinical study report.  
8. 
TREATMENTS 
8.1. 
Participant Assignment 
After informed consent has been obtained and study eligibility has been established, 
participants will be admitted to the Linear Clinical Research Unit the day before the first dose 
of study drug. 
8.2. 
Method of Assignment to Treatment 
In both parts of this study, participants will be assigned a screening number and randomized 
to receive CC-42344 or placebo prior to dosing.  CC-42344 dosage is determined based on 
cohort assignment.  A participant is considered randomized after they are confirmed as 
eligible for dosing and when a pharmacy personnel or designee assigns a randomization 
number/treatment allocation.   
8.3. 
Materials and Supplies 
8.3.1. 
Formulation, Packaging, and Labeling 
Study drug (CC-42344 or matching placebo) will be administered orally to the participant in 
capsule form (Shanghai STA Pharmaceutical Product Co., Ltd, Shanghai, China) through the 
site pharmacy.  
The active drug product is manufactured using spray-dried dispersion (SDD) of CC-42344 
and hydroxypropyl methylcellulose acetate succinate. The SDD will be filled into capsules, 
using excipients such as mannitol, microcrystalline cellulose, colloidal silicon dioxide and 
magnesium stearate (or other excipients commonly used in capsule formulations).  
The drug product is a 50-mg dose strength capsule with visually matching placebo. The 
capsules are packaged in 30-count bottles. Study drug treatment by cohort is summarized in 
Table 1 and Table 2. See the Pharmacy Manual for additional information. 
Table 1: 
Study Drug Treatment (Part 1, Single-Ascending Dose) 
Cohort 
Study Drug 
No. Capsules 
Frequency 
1A 
CC-42344 (50 mg/capsule) or placebo 
2 
Single dose on Day 1 
1B 
CC-42344 (50 mg/capsule) or placebo 
4 
Single dose on Day 1 
1C 
CC-42344 (50 mg/capsule) or placebo 
8/dose 
Single doses on Days 1 and 9 
1D 
CC-42344 (50 mg/capsule) or placebo 
16 
Single dose on Day 1 
1C-2 
CC-42344 (50 mg/capsule) open label 
8/dose 
Single doses on Days 1 and 9 
 

 
 
 
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Table 2: 
Study Drug Treatment (Part 2, Multiple-Ascending Dose) 
Cohort 
Study Drug 
No. Capsules 
Frequency 
2A 
CC-42344 (50 mg/capsule) or placebo 
1/dose 
Once daily on Days 1 through 14 
2B 
CC-42344 (50 mg/capsule) or placebo 
2/dose 
Once daily on Days 1 through 14 
2C 
CC-42344 (50 mg/capsule) or placebo 
4/dose 
Once daily on Days 1 through 14 
2D 
CC-42344 (50 mg/capsule) or placebo 
8/dose 
Once daily on Days 1 through 5 
2E 
CC-42344 (50 mg/capsule) or placebo 
8/dose 
Twice daily on Days 1 through 5 A 
A. Final dose the morning of Day 5 (9 planned doses total) 
8.3.2. 
Storage and Handling 
The study drug will be stored at 2ºC to 8ºC (35.6ºF to 46.4ºF).  No other special handling is 
required.   
8.3.3. 
Final Disposition of Clinical Supplies 
At the end of the study, study drug supply and accountability records will be reconciled as to 
drug shipped, drug consumed, and drug remaining. Any discrepancies noted will be 
documented.  Final drug accountability reconciliation will be performed at the visit occurring 
at the end of treatment or early discontinuation.  Unused study drug will be destroyed on site 
with permission of the sponsor.   
8.4. 
Dosage Administration 
The investigator (or designee) will administer a single dose of study drug in Part 1 (2 doses in 
Cohort 1C), every day for 14 days in Part 2, Cohorts 2A-2C, every day for 5 days in Cohort 
2D, and twice per day for 5 days in Cohort 2E (last dose the morning of Day 5).  
Part 1, Cohorts 1A-1D Day 1 dosing: Administer oral study drug in a fasted state (at least 8 
hours of fasting).  Study drug will be given with a 240 mL glass of water. Additional water 
(up to a total of 480 mL) may be given if needed to ingest all of the capsules in the dose. 
Dosing should be completed within 5 minutes of ingesting the first capsule. Subjects are 
required to fast for 4 hours postdose.  Except for water given with the dose, subjects will not 
be allowed fluids from 1 hour prior to until 2 hours after dosing. 
Part 1, Cohort 1C Day 9 dosing: Drug will be administered within 30 minutes after ingesting 
a standard high-fat/high-calorie breakfast. The breakfast must be started and finished within 
30 minutes prior to dosing. Postdose, subjects are required to fast for 4 hours and are not 
allowed fluids for 2 hours. 
Part 2, Cohorts 2A-2D: Drug will be administered within 30 minutes after ingesting a 
standardized breakfast. The breakfast must be started and finished within 30 minutes prior to 
dosing. Postdose, subjects are required to fast for 4 hours and are not allowed fluids for 2 
hours.  

 
 
 
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Part 2, Cohort 2E (BID dosing): Study drug will be administered within 30 minutes after 
ingesting a standardized breakfast (morning dose) or snack (evening dose). The breakfast or 
snack must be started and finished within 30 minutes prior to dosing. Postdose, subjects are 
required to fast for 4 hours and are not allowed fluids for 2 hours. The final dose will be given 
the morning of the last day of dosing (Day 5). 
The investigator (or designee) is responsible for the correct use of the study drug to the 
participants, confirming that instructions are followed properly, maintaining accurate records 
of study drug dispensing, and collection of all unused study drug, including empty drug 
packaging.   
8.5. 
Blinding and Unblinding 
This is a randomized, double-blind, placebo-controlled study. Neither the participants nor the 
study personnel with direct contact with the participant will know which study drug 
(CC-42344 or placebo) is being administered during the treatment period. Placebo and active 
drug will be the same in appearance, taste, and quantity.  To preserve the blinding of the 
study, a minimum number of study personnel who do not have direct interactions with the 
participant’s study procedures will see the randomization table before the study is complete. 
All data will be reviewed blinded by the SMC for the purposes of escalation of dose cohorts 
unless the SMC considers it necessary to unblind the data for safety concerns. 
Emergency unblinding for adverse events (AEs) will be performed through the code break 
envelopes.  Emergency unblinding for AEs may be used only if a participant’s medical care 
requires knowledge of the participant’s treatment assignment.  The investigator should make 
every effort to contact the sponsor before unblinding a participant’s treatment assignment. If a 
participant’s treatment assignment is unblinded, the sponsor must be immediately notified. In 
this situation, the sponsor’s medical monitor may also become unblinded to the participant’s 
treatment assignment. 
In the additional cohort (1C-2) being enrolled to repeat the 400 mg PK and food effect data, 
no placebo group will be required, thus CC-42344 will be administered in an open-label 
manner with no blinding or randomization.  
8.6. 
Concomitant Therapy 
No concomitant medications are allowed except for vitamins, minerals, paracetamol, oral 
contraceptives, and hormone replacement therapy. Exceptions may apply on a case-by-case 
basis, if considered not to interfere with the objectives of the study as agreed by the principal 
investigator and sponsor’s medical monitor. 

 
 
 
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9. 
STUDY ASSESSMENTS 
9.1. 
Pharmacokinetic Assessments 
Plasma levels of CC-42344 will be measured by LC-MS/MS  to determine the extent of 
systemic exposure and standard pharmacokinetic (PK) parameters (such as Cmax, Tmax, AUC, 
and t1/2) will be estimated. Plasma samples for PK assessments will be obtained as detailed in 
the Schedule of Events (see Section 2). 
9.2. 
Safety Assessments 
Safety evaluations will include physical examination, vital signs, electrocardiograms, clinical 
laboratory data, and collection of adverse events (see Section 9.3).  
9.2.1. 
Physical Examination 
Physical examinations will be conducted at the times indicated in the Schedule of Events (see 
Section 2). 
Physical examination will include examination of general appearance, head, ears, eyes, nose, 
throat, neck (including thyroid), skin, cardiovascular system, respiratory system, 
gastrointestinal system, musculoskeletal system, lymph nodes, and nervous system.  
Abbreviated exam will include at a minimum assessment of general appearance, head, nose, 
throat, respiratory system, and cardiovascular system. 
9.2.2. 
Vital Signs 
Vital signs, including blood pressure, heart rate, respiratory rate, and oral temperature, will be 
monitored in a supine position after a 5-minute rest period according to the Schedule of 
Events (see Section 2). 
9.2.3. 
Electrocardiograms 
Triplicate 12-lead ECG(s) will be obtained with participants in a supine position as outlined 
in the Schedule of Events (see Section 2) using a digital ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTc intervals. There will be a 5-
minute rest period before commencing ECGs and at least 1 minute between triplicate 
measurements with all 3 completed within 5 minutes. 
9.2.4. 
Clinical Laboratory Tests 
Clinical laboratory tests will be performed at the times specified in the Schedule of Events 
(see Section 2).  The following tests will be performed: 
● 
Hematology: hemoglobin, hematocrit, erythrocyte count, mean cell volume, white 
blood cell count, neutrophils, lymphocytes, monocytes, eosinophils, basophils, 
platelets, reticulocyte count  

 
 
 
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● 
Clinical chemistry: Serum concentrations of sodium, potassium, chloride, total 
bilirubin, indirect bilirubin (screening only), direct bilirubin (screening only), alkaline 
phosphatase, alanine transaminase (ALT), aspartate transaminase (AST), urea, 
creatinine, uric acid, phosphorous, calcium, plasma glucose, total protein, albumin, 
cholesterol, creatinine kinase, creatinine clearance (screening only)  
● 
Coagulation: prothrombin time, activated partial thromboplastin time, international 
normalized ratio  
● 
Urinalysis: specific gravity, pH, protein, glucose, blood, nitrites, leukocyte esterase. 
Microscopy will be performed if abnormalities noted for protein, blood, or leukocytes, 
or if clinically indicated 
● 
Serology: hepatitis B surface antigen, hepatitis C virus, and human immunodeficiency 
virus 
● 
Reproduction (females only): serum β-hCG or FSH (screening) and urine hCG 
(females of child-bearing potential) 
All clinical laboratory assessments will be analyzed at the participating site’s local laboratory.  
Investigators must document their review of each laboratory report by signing or initialing 
and dating each report. 
9.3. 
Adverse Events 
9.3.1. 
Definition of Adverse Event 
For purposes of this trial, an AE will be defined as any new unfavorable or unintended sign, 
symptom, or disease or change of an existing condition, which occurs during or after 
treatment, whether or not considered treatment-related.  A clinically significant laboratory 
value should be reported as an adverse event.  Lack of drug effect is not an adverse event in 
clinical trials because the purpose of the clinical trial is to establish drug effect. 
After informed consent and before treatment with study drug, study site personnel will note 
the occurrence and nature of each participant’s medical condition(s) in the Medical History 
section of the CRF.  During the remainder of the study, site personnel will again note any 
change in the condition(s) and the occurrence and nature of any adverse events. 
If the study drug is discontinued for a participant, study site personnel must report and clearly 
document the circumstances and data leading to any such discontinuation, using designated 
case report forms. For adverse events, the participant should be followed until the event 
resolves or stabilizes, with frequency of follow-up at the discretion of the investigator. 
In cases where the investigator notices an unanticipated benefit to the participant, study site 
personnel should enter “unexpected benefit” with the actual event term (for example, the 
complete actual term would be “unexpected benefit—sleeping longer”). 

 
 
 
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Cases of pregnancy that occur during maternal or paternal exposures to study drug should be 
reported for tracking purposes.  Data on fetal outcome and breastfeeding are collected for 
regulatory reporting and drug safety evaluation. 
9.3.2. 
Reporting Procedures for All Adverse Events 
Investigators are responsible for monitoring the safety of participants who have entered this 
study and noting any event that seems unusual, even if this event may be considered an 
unanticipated benefit to the participant. The investigator is responsible for appropriate 
medical care of participants during the study. 
The investigator remains responsible for following, through an appropriate health care option, 
adverse events that are serious or that caused the participant to discontinue the study.  The 
participant should be followed until the event is resolved or explained.  Frequency and 
method of follow-up are left to the discretion of the investigator and site policy.  
Adverse event information will be collected through Day 8 (Part 1), Day 16 (Cohort 1C), and 
Day 21 (Part 2).  Participants who discontinue study drug at any time will have adverse events 
collected through the planned end of study visit, provided consent to continue in the study has 
not been withdrawn. 
The investigator is responsible for assessing and recording all adverse experiences.  Each AE 
will be recorded and classified for intensity, seriousness, and causality. All AEs either 
observed by the investigator or reported by the participant will be recorded regardless of 
causality. The investigator will follow the participant until an AE resolves or stabilizes. 
9.3.3. 
Adverse Event Severity 
The Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric 
Adverse Events version 2.1 (July 2017) will be used to assess and grade AE severity, 
including laboratory abnormalities judged to be clinically significant.  If the experience is not 
covered in the DAIDS criteria, the following guidelines should be used to grade severity: 
● 
Mild (grade 1): Mild symptoms causing no or minimal interference with usual social 
and functional activities with intervention not indicated. 
● 
Moderate (grade 2): Moderate symptoms causing greater than minimal interference 
with usual social and functional activities with intervention indicate. 
● 
Severe (grade 3): Severe symptoms causing inability to perform usual social and 
functional activities with intervention or hospitalization indicated. 
● 
Life-threatening (grade 4): Potentially life-threatening symptoms causing inability to 
perform basic self-care functions with intervention indicated to prevent permanent 
impairment, persistent disability, or death. 
The term “severe” is a measure of intensity and a severe AE is not necessarily serious. 

 
 
 
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9.3.4. 
Adverse Event Relationship to Study Drug 
The relationship of an AE to the study drug should be based on the judgment of the 
investigator and assessed using the following guidelines: 
● 
Related: Previously known toxicity of agent; or an event that follows a reasonable 
temporal sequence from administration of the drug; that follows a known or expected 
response pattern to the suspected drug; that is confirmed by stopping or reducing the 
dosage of the drug; and that is not explained by any other reasonable hypothesis. 
● 
Probably related: An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected response pattern to the 
suspected drug; that is confirmed by stopping or reducing the dosage of the drug; and 
that is unlikely to be explained by the known characteristics of the participant’s 
clinical state or by other interventions. 
● 
Possibly related: An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected response pattern to that 
suspected drug; but that could readily have been produced by a number of other 
factors. 
● 
Unrelated: An event that can be determined with certainty to have no relationship to 
the study drug. 
9.3.5. 
Serious Adverse Event Definition and Reporting Procedures 
Any AE that meets the definition of serious noted below and occurs in a participant during 
the course of the study must be reported to the sponsor by telephone within 24 hours of the 
investigator becoming aware of the event. In addition, a serious adverse event form (SAE) 
must be completed by the investigator or designee and faxed to the study sponsor within 24 
hours of the investigator becoming aware of the event.  In addition, the site investigator or 
designee must report SAEs to their local Ethics Committee (EC) in accordance with the EC’s 
standard operating procedures and policies.  
An SAE is defined as an adverse event that suggests a significant hazard or side effect, 
regardless of the relationship to study drug.  An SAE includes, but may not be limited to, any 
event that: 
● 
Results in death. 
● 
Is life-threatening. This definition implies that the participant, in the view of the 
investigator, is at immediate risk of death from the event. It does not include an event 
that, had it occurred in a more serious form, might have caused death. 
● 
Requires inpatient hospitalization or prolongs existing hospitalization. 
● 
Results in persistent or significant disability/incapacity. 

 
 
 
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● 
Results in a congenital anomaly or birth defect. This serious criterion applies if a 
participant exposed to an investigational product gives birth to a child with a 
congenital anomaly or birth defect. 
Medical and scientific judgment will be exercised in deciding whether classification of an AE 
as serious is appropriate in other situations, such as important medical events that may not be 
immediately life-threatening or result in death or hospitalization but may jeopardize the 
participant or require intervention to prevent one of the outcomes listed in the definition 
above.  These should also usually be considered serious.  Examples of such events include 
allergic bronchospasm requiring intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient hospitalization, or the development of 
drug dependence or abuse. 
Serious adverse events occurring after a participant is discontinued from the study will only 
be reported if the investigator believes that the event may have been caused by the study drug 
or a protocol procedure. 
For the purpose of expedited reporting to regulatory agencies, an investigator will be 
responsible for identifying any adverse event that is serious, unexpected, and believed to be 
related to study drug.  An adverse event or suspected adverse reaction is considered 
“unexpected” if it is not consistent with the risk information described in the Investigator’s 
Brochure. For example, under this definition, hepatic necrosis would be unexpected (by virtue 
of greater severity) if the investigator brochure or investigational drug application referred 
only to elevated hepatic enzymes or hepatitis. Similarly, cerebral thromboembolism and 
cerebral vasculitis would be unexpected (by virtue of greater specificity) if the investigator 
brochure or investigational drug application listed only “cerebral vascular accidents.  
9.4. 
Safety Monitoring 
A medically qualified person will monitor blinded safety data throughout the study. The 
sponsor (or designee) will review SAEs within time frames mandated by regulatory 
requirements and will review trends and adverse events at periodic intervals. 
A Safety Monitoring Committee (SMC) comprising 3 members will review safety and 
available PK data prior to dose escalation to the next dose cohort in Parts 1 and 2, as well as 
between the fasted and fed periods in Part 1, Cohort C.  The SMC will be composed of the 
independent medical monitor, principal investigator, and sponsor’s medical representative. 
Other members of the investigational team may join the SMC as non-voting attendees as 
deemed appropriate.  Before dose escalation in the single-ascending dose and multiple-
ascending dose cohorts, the SMC will review all available safety and tolerability data for a 
minimum of 7 participants who have completed the planned safety assessments up to 48 
hours after dosing to ensure that at least 5 participants received active study drug. The 

 
 
 
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following data are required for interim study decisions: adverse events, vital signs, safety 
laboratory values, and ECGs 
Dose escalation will not occur with any of the following: 
● 
a serious adverse reaction (i.e., a serious adverse event considered at least possibly 
related to the active drug) in one subject. 
● 
Grade 3 or higher nonserious adverse reactions (i.e., severe nonserious adverse event 
considered related to the active drug administration) in two participants in the same 
cohort, independent of whether they occurred within the same system organ class. 
The data will be reviewed blinded unless the SMC considers it necessary to unblind the data 
for safety concerns. Before breaking the code (per standard procedures), the potential 
decisions and actions will be determined.  
SMC decisions on dose escalation will be taken in consensus between the SMC members. If 
consensus cannot be reached, the principal investigator, who has the ultimate responsibility 
for the safety of participants, will make the final decision on whether to continue or stop the 
study. The SMC’s decisions and their rationale will be documented. 

 
 
 
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10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
The investigator agrees to be responsible for implementing and maintaining quality control 
and quality assurance systems to ensure that trials are conducted and data are generated, 
documented, and reported in compliance with the protocol, accepted standards of Good 
Clinical Practice, and all applicable federal, state, and local laws, rules and regulations 
relating to the conduct of the clinical study. 
The investigator also agrees to conduct the study in an efficient and diligent manner and in 
conformance with this protocol; generally accepted standard of Good Clinical Practice; and 
all applicable federal, state, and local laws, rules, and regulations relating to the conduct of 
the clinical study. 
The investigator must allow study-related monitoring, audits, and inspection by the EC, 
sponsor (or designee), government regulatory agencies, and, if applicable, University 
compliance and quality assurance groups of all trial-related documents and procedures.   
The investigator shall prepare and maintain accurate study documentation in compliance with 
Good Clinical Practice standards and applicable federal, state, and local laws, rules, and 
regulations.  

 
 
 
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11. 
DATA ANALYSIS METHODS 
11.1. 
Determination of Sample Size 
No formal sample size calculation was done. Based on experience from previous similar 
studies, the target number of participants to be enrolled is appropriate for the assessment of 
safety and tolerability. 
11.2. 
Statistical and Analytical Plans 
11.2.1. 
General Considerations 
The analysis of safety variables will include all participants who receive study drug, including 
participants in the additional 400 mg food-effect cohort (Cohort 1C-2).   
All variables will be summarized by descriptive statistics for each treatment group.  The 
statistics for continuous variables will include mean, median, standard deviation, and number 
of observations.  Categorical variables will be tabulated using frequencies and percentages. 
Where confidence intervals are presented, they will be two-sided 95% confidence intervals.   
11.2.2. 
Handling of Missing Data 
Missing data will not be imputed for safety analyses.   
11.2.3. 
Participant Disposition 
Study participant disposition will be summarized by treatment group.  Participants who 
discontinued study drug prematurely or withdrew from the study will be summarized and 
listed, with reason for early termination/withdrawal. 
11.2.4. 
Participant Characteristics 
Demographic and other baseline characteristics will be summarized by treatment group. 
11.2.5. 
Treatment Compliance 
As all study drug dosing is administered at the clinical unit, treatment compliance will be 
evaluated based on the dosing data recorded by the study personnel.  
11.2.6. 
Pharmacokinetic Analyses 
The following PK parameters will be estimated from serial plasma CC-42344 concentration 
data using noncompartmental analysis. 
Single Dose:  maximum plasma concentration (Cmax) and time to Cmax (Tmax), the elimination 
rate constant (λz) and half-life (t1/2), area under the curve (AUC) to the last time with a 
concentration ≥ lower limit of quantitation (LLOQ) [AUC(0-t)] and to infinity [AUC(inf)]. 
Multiple Dose:  Cmax, Tmax, AUC over the 24-hour dosing interval [AUC(0-24)] on Days 1 and 
14, and the elimination rate constant (λz) and half-life (t1/2) after the last dose on Day 14. 

 
 
 
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All analyses will be done using the actual elapsed sampling times. Plasma concentrations and 
PK parameters will be summarized using descriptive statistics. 
The PK parameters Cmax, AUC(0-t), and AUC(inf) will be compared between the fed and fasted 
cohorts using an analysis of variance (ANOVA) model with treatment as a fixed effect and 
subject as a random effect.  The geometric mean ratios and associated 90% confidence 
intervals will be estimated from the statistical model and used to assess the effect of food. 
The attainment of steady-state for each dose level in the multiple-ascending dose phase will 
be assessed by a comparison of the predose plasma concentrations obtained as indicated in 
the Schedule of Events (see Sections 2.3 and 2.4) using an ANOVA model with day as a 
fixed effect and subject as a random effect.  Paired comparisons will be done to determine 
when steady-state has been reached. 
Pharmacokinetic parameters will be compared among doses in the single-ascending dose and 
multiple-ascending dose phases and between phases using descriptive statistics and graphical 
displays.  Relationships between Cmax and the AUCs and dose for both phases will be 
assessed using the power model: 
𝑃𝑃= 𝑎𝑎× 𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝐷𝑏𝑏 
where P represents the parameter and a and b are constants.  A value of b of ~1 with a 95% 
confidence interval  that includes 1 indicates linearity or dose proportionality.  The power 
model will be fit to the individual subject data using nonlinear least squares regression, i.e., 
SAS PROC NLIN or equivalent. 
11.2.7. 
Safety Analyses 
Treatment-emergent AEs are defined as AEs occurring after the first dose of study drug 
through Day 8 in Part 1 (Day 16 in cohort 1C) and Day 21 (Day 12 in Cohorts 2D and 2E) in 
Part 2. Duration of treatment will be summarized by treatment group. 
The incidence of all reported AEs and treatment-related AEs will be tabulated by treatment 
group. Adverse events will be classified by system organ class and preferred term using the 
Medical Dictionary for Regulatory Activities (MedDRA). 
Adverse events will be listed and summarized by treatment group, MedDRA preferred term, 
severity, seriousness, and relationship to study drug. In the event of multiple occurrences of 
the same AE with the same preferred term in one participant, the AE will be counted once as 
the worst occurrence. The incidence of AEs will be tabulated by system organ class and 
treatment group. AEs leading to premature discontinuation of study drug or withdrawal from 
the study will be summarized and listed in the same manner. 

 
 
 
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Summary statistics for actual values and for change from baseline will be summarized for 
laboratory results by treatment group and scheduled visit. Participants with laboratory values 
outside of the normal reference range at any postbaseline assessment will be identified. 
Data to be listed by subject and summarized by treatment will include AEs, vital signs, ECG 
parameters, and clinical laboratory evaluations. All values outside the clinical reference 
ranges will be flagged on the data listings. Other data to be listed by subject will include 
physical examination findings and concomitant medications.  
11.2.8. 
Interim Analyses 
As described in Section 9.4, before dose escalation in the single-ascending dose and multiple-
ascending dose cohorts, an SMC will review safety and available PK data to determine 
whether dose escalation may proceed.  

 
 
 
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12. 
ADMINISTRATIVE, ETHICAL, AND REGULATORY CONSIDERATIONS 
The investigator is responsible for presenting the risks and benefits of study participation to 
the participant in simple terms using the informed consent document. The investigator will 
ensure that written informed consent is obtained from each participant by obtaining the 
appropriate signatures and dates on the informed consent document before the performance of 
protocol evaluations or procedures.  
12.1. 
Ethical Review 
The investigator will obtain documentation of the EC approval of the protocol and the 
informed consent document before the study may begin at the investigative site(s). The name 
and address of the reviewing EC are provided in the investigator file. 
The sponsor will supply the following to the investigative site for submission to the EC: 
• Protocol and amendments. 
• Informed consent document and updates. 
• Relevant curricula vitae, if required. 
• Required safety and SAE reports. 
• Any additional submissions required by the site’s EC. 
The investigator must provide the following documentation to the sponsor or its designee: 
• The EC periodic (e.g., quarterly, annual) reapproval of the protocol. 
• The EC approvals of any amendments to the protocol or revisions to the informed 
consent document. 
• The EC receipt of safety and SAE reports, as appropriate. 
12.2. 
Regulatory Considerations 
This study will be conducted in accordance with the protocol and ethical principles stated in 
the 2013 version of the Declaration of Helsinki or the applicable guidelines on Good Clinical 
Practice, and all applicable federal, state, and local laws, rules, and regulations. 
After reading the protocol, the investigator will sign the protocol signature page and return it 
to the sponsor or designee. 
12.2.1. 
Investigator Information 
The contact information and qualifications of the principal investigator and subinvestigators, 
and name and address of the research facility are included in the investigator file. 

 
 
 
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12.2.2. 
Protocol Amendments and Study Termination 
The sponsor will initiate changes to the protocol as necessary (except for changes to eliminate 
an immediate hazard to a study participant) and seek approval by the EC before 
implementing.  The investigator is responsible for enrolling participants who have met 
protocol eligibility criteria. Protocol violations must be reported to the local EC in accordance 
with EC policies.  
The sponsor may terminate the study at any time. The EC must be advised in writing of study 
completion or early termination. 
12.2.3. 
Study Documentation, Privacy, and Records Retention 
All records connected with this clinical study will be retained for at least 2 years following 
the date of an approved marketing application or at least 3 years from the formal 
discontinuation of CC-42344 development; or 7 years from the end of the study, whichever is 
longer.  All local laws regarding retention of records must also be followed.  The study site is 
required to retain all records until written notification allowing destruction is received from 
Cocrystal Pharma Australia Pty Ltd.  
To protect the safety of participants in the study and to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and participant 
medical records in the participant files as original source documents for the study. If 
requested, the investigator will provide the applicable regulatory agencies and applicable EC 
with direct access to original source documents. 
Records containing participant medical information must be handled in accordance with the 
requirements of the Health Insurance Portability and Accountability Act (HIPAA) Privacy 
Rule or equivalent (e.g., Privacy Act of 1988) and consistent with the terms of the participant 
authorization contained in the informed consent document for the study. Care should be taken 
to ensure that such records are not shared with any person or for any purpose not 
contemplated by the informed consent document. Furthermore, CRFs and other documents 
should be completed in strict accordance with the instructions provided by the sponsor, 
including the instructions regarding the coding of participant identities. 
12.3. 
Study Finances 
This study is financed by Cocrystal Pharma Australia Pty Ltd.   
12.4. 
Publications 
Cocrystal Pharma Australia Pty Ltd. Assures that the key design elements of this protocol will 
be posted in a publicly accessible registry. Neither the complete nor any part of the results of 
the study carried out under this protocol, nor any of the information provided by the sponsor 
for the purposes of performing the study, will be published or passed on to any third party 
without the consent of the study sponsor.  Any investigator involved with this study is 

 
 
 
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obligated to provide the sponsor with complete test results and all data derived from the 
study. 

 
 
 
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13. 
REFERENCES 
Abed Y, Saim-Mamoun A, Boivin G. Fitness of influenza A and B viruses with reduced 
susceptibility to baloxavir: A mini-review. Rev Med Virol. 2021;31(3):e2175. Doi: 
10.1002/rmv.2175. Epub 2020 Sep 25. 
Beigel JH, Hayden FG. Influenza Therapeutics in Clinical Practice-Challenges and Recent 
Advances. Cold Spring Harb Perspect Med. 2021;11(4):a038463. Doi: 
10.1101/cshperspect.a038463. 
Ikematsu H, Hayden FG, Kawaguchi K, et al. Baloxavir Marboxil for Prophylaxis against 
Influenza in Household Contacts. N Engl J Med. 2020;383(4):309-320.  Doi: 
10.1056/NEJMoa1915341. Epub 2020 Jul 8. 
Uehara T, Hayden FG, Kawaguchi K, et al. Treatment-Emergent Influenza Variant Viruses 
With Reduced Baloxavir Susceptibility: Impact on Clinical and Virologic Outcomes in 
Uncomplicated Influenza. J Infect Dis. 2020;221(3):346-355. Doi: 10.1093/infdis/jiz244. 
U.S. Centers for Disease Control and Prevention. Influenza Antiviral Medications: Summary 
for Clinicians. Available at: https://www.cdc.gov/flu/professionals/antivirals/summary-
clinicians.htm [Accessed July 9, 2021]. 
Uyeki TM, Bernstein HH, Bradley JS. Clinical Practice Guidelines by the Infectious Diseases 
Society of America: 2018 Update on Diagnosis, Treatment, Chemoprophylaxis, and 
Institutional Outbreak Management of Seasonal Influenza. Clin Infect Dis. 2019; 68(6):895-
902. Doi: 10.1093/cid/ciy874. 
 
World Health Organization. Influenza (seasonal). Available at:  https://www.who.int/news-
room/fact-sheets/detail/influenza-(seasonal) [Accessed July 9, 2021]. 
 

 
 
 
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14. 
DOCUMENT HISTORY 
Document Version 
Date 
Version 5.0 
17-Dec-2022 
Version 4.0 
12-Dec-2022 
Version 3.0 
18-Jun-2022 
Version 2.0 
17-Jan-2022 
Version 1.1 
21-Sep-2021 
Version 1.0 
26-Aug-2021  

 
 
 
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14.1. 
Summary of Changes from Version 4.0 to Version 5.0 
Section  
Change 
Rationale 
6.1 Summary of Study 
Design 
Synopsis 
Table 2 
Added Cohorts 2D and 2E to the 
multiple-ascending dose (MAD) 
portion of the study. 
Obtain safety and PK data for 400 mg 
QD and BID dosing of CC-42344 for 5 
days to explore additional dosing 
regimens. 
2 Schedule of Events 
Added Section 2.4 to define the 
schedule of events for Cohorts 2D and 
2E.  
Added additional schedule of events to 
accommodate the shorter length of 
treatment for MAD cohorts 2D and 2E (5 
days versus 14 days in the initial MAD 
cohorts). The general scheme for 
assessments is the same. 
6.2 Dose Rationale 
Added text supporting 400 mg QD and 
BID dose regimens. 
Provide rationale for additional MAD 
cohorts (2D and 2E). 
8.4 Dosage 
Administration 
Added instructions for BID dosing. 
Provide required operational information. 
11.2 Statistical and 
Analytical Plans 
Edited to reflect the additional cohorts 
to be included in the analyses. 
Clarity and consistency. 

 
 
 
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14.2. 
Summary of Changes from Version 3.0 to Version 4.0 
Section  
Change 
Rationale 
6.1 Summary of 
Study Design 
Synopsis 
Added Cohort 1C-2, an additional cohort to 
generate replacement 400 mg PK and food-
effect data. Six participants will be treated 
with CC-42344 in a 2-period food design. 
Obtain required PK data.  
7.2.3 Participant 
Replacement  
11.2 Statistical and 
Analytical Plans 
Stated that the Cohort 1C-2 participants’ PK 
data will replace the uninterpretable PK data 
from Cohort 1C, however the safety data 
from both cohorts will be included in the 
analyses. 
Define plans for use of data from 
addition participants; confirm that 
safety analyses will include all 
participants treated with CC-42344. 
8.5 Blinding and 
Unblinding  
Noted that CC-42344 will be administered 
in an open-label manner in Cohort 1C-2. 
Specify that treatment assignment will 
not be blinded in the additional 
cohort. 

 
 
 
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14.3. 
Summary of Changes from Version 2.0 to Version 3.0 
Section  
Change 
Rationale 
2 Schedule of Events 
Optional replacement of alcohol breath 
testing with a question confirming 
abstinence 
Mitigate risk of COVID-19 in the 
study clinic, as initially specified in 
Protocol Clarification Letter 3, dated 
21-Feb-22 
2 Schedule of Events 
Add 72- and 96- hour postdose PK sample 
for Cohorts 1C and 1D 
Better define the terminal elimination 
half-life, as initially specified in 
Protocol Clarification Letter 4, dated 
24-Mar-22 
2.2 Part 1 Cohort 1C 
Schedule of Events – 
Period 2 
Allow optional extension of washout period 
between fasted and fed periods in Cohort 
1C 
Provide operational flexibility, as 
initially specified in Protocol 
Clarification Letter 2, dated 04-Feb-
22 
2.3 Part 2: Multiple-
Ascending Dose 
Schedule of Events 
Added specific PK sampling timepoints for 
Part 2 
Provide PK data to support analysis of 
the multidose PK profile 
6.1 Summary of 
Study Design (and 
Synopsis) 
Changed the planned dose cohorts for the 
multiple-ascending dose part of the study 
(Part 2) from 200, 400, and 600 mg QD to 
50, 100, and 200 mg QD 
Favorable safety profile in Part 1, 
with PK data supporting predicted 
trough concentrations above the EC90 
at the 50-mg QD dose level 
6.2 Discussion of 
Design 
Added text regarding the safety of the dose 
levels planned for Part 2 of the study 
Provide rationale for dosing regimens 
for the multiple-ascending dose 
cohorts 
7.1.2 Exclusion 
Criteria (and 
Synopsis) 
Criterion 2: Change the allowable length of 
time between COVID-19 vaccination and 
randomization from 2 weeks to 7 days and 
expand the exclusion to cover all vaccines  
Relax the COVID-19 vaccination 
timeframe, as initially specified in 
Protocol Clarification Letter 3, dated 
21-Feb-22; include all vaccines for 
consistency 
8.3.1 Formulation, 
Packaging, and 
Labeling 
Adjust the number of capsules per dose in 
Part 2 to match the planned dose levels 
Consistency with updated dose levels 
8.4 Dosage 
Administration 
Added instructions for a standardized 
breakfast prior to dosing 
Specify controlled predose food 
intake 
General 
Editorial, formatting, and/or administrative 
corrections 
Accuracy and consistency 
 

 
 
 
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14.4. 
Summary of Changes from Version 1.1 to Version 2.0 
Section  
Change 
Rationale 
2 Schedule of Events 
Changed the window for the End of Study 
Visit from +1 day to +/-1 day for all cohorts 
Provide operational flexibility 
2.2 Part 1 Cohort 1C 
Schedule of Events – 
Period 2 
Changed the windows for predose 
assessments in the fed period of the food 
effect cohort (Cohort 1C, Day 9): 
• ECGs and vital sign windows from 30 
minutes to 2 hours pre-dose 
• PK blood draw window from 30 minutes 
to 1 hour pre-dose 
 
 
 
• Make consistent with other cohorts 
 
• Allow time for the completion of a 
high-fat breakfast prior to dosing 
7.1.1 Inclusion 
Criteria 
Changed the upper limit of BMI in 
inclusion criterion 3 from 30.0 to 
32.0 kg/m2  
Correction for consistency with the 
synopsis 
7.1.2 Exclusion 
Criteria 
Changed the required negative pregnancy 
test in exclusion criterion 6 from Day 1 to 
Day -1 
Changed exclusion criterion 11 by adding 
the underlined text: 
Participants with results consistent with 
Gilbert’s syndrome may be enrolled at the 
discretion of the investigator. 
Correction for consistency with the 
schedule of events 
 
Clarification 
8.3.1 Formulation, 
Packaging, and 
Labeling 
Changed the CC-42344 spray-dried 
dispersion drug product form from 100-mg 
tablets to 50-mg capsules 
Updated the number of capsules per dose in 
Tables 1 and 2 
Update drug product information with 
the planned dose form and strength 
8.3.2 Storage and 
Handling 
Changed the storage temperature from 
20ºC–25ºC to 2ºC–8ºC  
Reflect the actual planned storage 
temperatures 
8.4 Dosage 
Administration 
Added text: 
Additional water (up to a total of 480 mL) 
may be given if needed to ingest all of the 
capsules in the dose. Dosing should be 
completed within 5 minutes of ingesting the 
first capsule. 
Provide additional details regarding 
dosing procedures 
9.2.4 Clinical 
Laboratory Tests 
Added white blood cell count to the list of 
required clinical laboratory tests 
Correct oversight 
9.4 Safety 
Monitoring 
Added the stopping rules that are presented 
in the synopsis: 
Dose escalation will not occur with any of 
the following: 
• a serious adverse reaction (i.e., a serious 
adverse event considered at least possibly 
related to the active drug) in one subject. 
Consistency and completeness 

 
 
 
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Section  
Change 
Rationale 
• Grade 3 or higher nonserious adverse 
reactions (i.e., severe nonserious adverse 
event considered related to the active drug 
administration) in two participants in the 
same cohort, independent of whether they 
occurred within the same system organ 
class. 
1 Protocol Synopsis 
Updated to reflect changes noted above  
Provide consistency 
General 
Editorial, formatting, and/or administrative 
corrections 
Accuracy and consistency  

 
 
 
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14.5. 
Summary of Changes from Version 1.0 to Version 1.1 
Section  
Change 
Rationale 
6.2 Discussion of 
Design 
Changed the dose rationale as follows: 
The lowest NOAEL of 70 mg/kg/day 
from the rat and dog 14-day repeated 
dose GLP toxicology studies provides a 
human equivalent dose of 2333 1894 mg 
to a 60 50-kg person. This corresponds 
to a 2319X safety factor over the 
proposed starting dose of 100 mg and a 
2.92.4X safety factor over the proposed 
maximum dose of 800 mg. 
Provide the exposure multiples for a 50-
kg person, in alignment with the study 
inclusion criteria.  
14 Document History 
Added document history and list of 
changes. 
Provide summary and rationale for 
changes to approved versions of the 
protocol. 
 

 
 
 
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Appendix A: Sponsor Protocol Approval 
 
 
Protocol Title: 
A Phase 1 Study in Healthy Participants to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of Single-Ascending and 
Multiple-Ascending Doses of the Influenza A Virus Replication 
Inhibitor CC-42344 
Protocol Number: 
CC-42344-P1-001 
 
 
 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use, Good Clinical Practice and applicable regulatory 
requirements  
 
This study protocol has been approved by the following persons: 
 
 
 
Signed: 
 
 
 
 
  
Sam Lee, PhD 
President and Interim Co-Chief Executive Officer  
Cocrystal Pharma Australia Pty Ltd. 
 
Date 
 

 
 
 
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Appendix B: Investigator Protocol Signature Page 
 
Protocol Title: 
A Phase 1 Study in Healthy Participants to Evaluate the Safety, 
Tolerability, and Pharmacokinetics of Single-Ascending and 
Multiple-Ascending Doses of the Influenza A Virus Replication 
Inhibitor CC-42344   
Protocol Number: 
CC-42344-P1-001 
 
 
By signing this protocol, the investigator agrees to conduct the study in accordance with the 
protocol, generally accepted standards of Good Clinical Practice, and all applicable federal, 
state, and local laws, rules, and regulations relating to the conduct of the clinical study. In 
addition, the investigator agrees to provide the sponsor with accurate financial information to 
allow the sponsor to submit complete and accurate certification and disclosure statements as 
required by federal regulations. 
By signing this protocol, the investigator agrees to be responsible for implementing and 
maintaining quality control and quality assurance systems with written procedures to ensure 
that the trials are conducted and data are generated, documented, and reported in compliance 
with the protocol, accepted standards of Good Clinical Practice, and all applicable federal, 
state, and local laws, rules, and regulations relating to the conduct of the study. 
 
 
 
 
 
 
 
 
Investigator’s Signature 
 
Print Name 
 
Date 
 
 
 
 
 
Site Address and Telephone