Conditions: HIV Infections
Keywords: D-peptide HIV entry inhibitor
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 32
Healthy volunteers: yes

Brief summary:
This first-in-human study will evaluate the safety, tolerability, immunogenicity, and pharmacokinetics of the HIV entry inhibitor CPT31 (cholesterol-PIE12-2-trimer) in healthy adults. This is a randomized, placebo-controlled, double-blind, single ascending dose study.

Detailed description:
This is a single subcutaneous (SC) dose study. Doses will be administered in an escalating manner following satisfactory review by a Protocol Safety Review Team (PSRT) of the safety, tolerability and pharmacokinetic (PK) data through Day 6 from the lower dose levels. 32 healthy subjects will be studied in 4 groups (Groups A1 to A4).

This study will comprise a placebo-controlled, double-blind, single-dose, sequential-group design in healthy subjects. Each subject will participate in 1 treatment period and reside in the Clinical Research Unit (CRU) from Day -1 through Day 6. It is planned for 6 subjects per dose level group to receive SC CPT31 and 2 subjects to receive matching placebo. Each group will be divided into 2 cohorts, with each cohort being dosed 72 hours apart. Sentinel dosing will take place in the first cohort, which will comprise 2 subjects, with 1 subject receiving CPT31 and 1 subject receiving placebo. The second cohort will comprise 6 subjects, with 5 subjects receiving CPT31 and 1 subject receiving placebo. Blood samples for PK analysis and assessment of immunogenicity will be collected predose and up to 5 days postdose, with an additional immunogenicity sample taken at the Follow-up visit.

Arms:
arm 1: 6 subjects receiving a single subcutaneous injection of CPT31 (0.01 mg/kg) and 2 subjects receiving matching placebo SC injection arm 2: 6 subjects receiving a single subcutaneous injection of CPT31 (0.04 mg/kg) and 2 subjects receiving matching placebo SC injection arm 3: 6 subjects receiving a single subcutaneous injection of CPT31 (0.12 mg/kg) and 2 subjects receiving matching placebo SC injection arm 4: 6 subjects receiving a single subcutaneous injection of CPT31 (0.24 mg/kg) and 2 subjects receiving matching placebo SC injection

Interventions: intervention 1: CPT31 intervention 2: Placebo
Intervention descriptions: intervention 1: CPT31 (cholesterol-PIE12-2-trimer) is a novel D-peptide HIV entry inhibitor that binds with high affinity to a conserved hydrophobic pocket within the gp41 trimer intervention 2: matching placebo

Protocol document:
Prot_000.pdf: 
Title 
A Phase Ia Clinical Study of HIV Entry Inhibitor CPT31: Single Ascending Dose Study of 
Safety, Tolerability, Immunogenicity, and Pharmacokinetics in Healthy Adults 
 
NCT Number 
NCT04672083 
 
Document Date 
July 27, 2020 


TITLE PAGE 
Protocol 
A Phase Ia Clinical Study of HIV Entry Inhibitor CPT31: Single Ascending 
Dose Study of Safety, Tolerability, Immunogenicity, and Pharmacokinetics 
in Healthy Adults 
Protocol Status: Final 
Protocol Date: 12 December 2019 
Revised 14 February 2020 
Revised 13 July 2020 
Revised 27 July 2020 
Protocol Version: 4 
Investigational Product: CPT31 
Navigen Study Number: CPT31-001 
Covance Study Number: 8405732 
IND Number: 144625 
Sponsor: 
Navigen Inc. 
675 Arapeen Drive, Suite 103 
Salt Lake City, UT 84108 
USA 
Study Site: 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 32117 
USA 
Sponsor Signatory: 
Alan L. Mueller, Ph.D. 
Principal Investigators: 
Hugh A. Coleman. DO. 
Information described herein is confidential and may be disclosed only with the express 
written permission of the Sponsor. 


Protocol 
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 Reference: CPT31-001 
Protocol Version 4, 27 July 2020 
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SPONSOR APPROVAL 
I have read the protocol and approve it: 
 
 
 
Electronic signature appended to first page of Viewable Rendition  
 
 
Alan L. Mueller, Ph.D. 
 
Date 
VP Research, Navigen Inc. 
 




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STUDY IDENTIFICATION 
Sponsor 
Navigen, Inc. 
675 Arapeen Drive, Suite 103 
Salt Lake City, UT 84108 
USA 
Sponsor’s Study Contact 
Alan L. Mueller, Ph.D.  
VP Research 
Navigen, Inc. 
675 Arapeen Drive, Suite 103 
Salt Lake City, UT 84108 
USA 
Study Site 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 32117 
USA 
Principal Investigator 
Hugh A. Coleman, DO 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 32117 
USA 
Tel: +1 386 366 6446 
Clinical Laboratory 
LabCorp 
4200 North 29th Avenue 
Hollywood, FL 33020  
USA 
Statistician 
Martin Johnson MSc 
Covance Clinical Research Unit Ltd 
Springfield House, Hyde Street 
Leeds, LS2 9LH 
UK 


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SYNOPSIS 
Title of study: A Phase Ia clinical study of HIV entry inhibitor CPT31: single ascending dose study 
of safety, tolerability, immunogenicity, and pharmacokinetics in healthy adults 
Objectives:  
The primary objective of the study is: 
 
to assess the safety and tolerability of single subcutaneous (SC) doses of CPT31 in healthy 
subjects. 
The secondary objectives of the study are: 
 
to characterize the single SC dose pharmacokinetics (PK) of CPT31 
 
to identify and characterize antibodies to CPT31 
Study design: 
This will be a single SC dose study. 
Doses will be administered in an escalating manner following satisfactory review by a Protocol 
Safety Review Team (PSRT) of the safety, tolerability and PK data through Day 6 from the lower 
dose levels. 
This study will comprise a placebo-controlled, double-blind, single-dose, sequential-group design in 
healthy subjects. Each subject will participate in 1 treatment period and reside in the Clinical 
Research Unit (CRU) from Day -1 through Day 6. It is planned for 6 subjects per dose level group 
to receive SC CPT31 and 2 subjects to receive matching placebo. Each group will be divided into 
2 cohorts, with each cohort being dosed 72 hours apart. Sentinel dosing will take place in the first 
cohort, which will comprise 2 subjects, with 1 subject receiving CPT31 and 1 subject receiving 
placebo. The second cohort will comprise 6 subjects, with 5 subjects receiving CPT31 and 1 subject 
receiving placebo.  
Blood samples for PK analysis and assessment of immunogenicity will be collected predose and up 
to 5 days postdose, with an additional immunogenicity sample taken at the Follow-up visit. 
Number of subjects: 
32 healthy subjects will be studied in 4 groups (Groups A1 to A4). 
Diagnosis and main criteria for inclusion: 
Healthy male and female subjects aged 18 to 55 years (inclusive) with a body mass index of 18.0 to 
32.0 kg/m2 (inclusive). 
Investigational products, dose, and mode of administration: 
Test products: 15 mg/mL CPT31 solution  
Proposed dose levels: 0.01, 0.04, 0.12, and 0.24 mg/kg 
Administration route: SC 
Reference product and mode of administration: 
Reference product: placebo solution 
Administration route: SC 
Duration of subject participation in the study: 
Planned Screening duration: approximately 4 weeks 
Planned study duration (Screening to Follow-up): approximately 8 weeks 


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Endpoints: 
Pharmacokinetics: 
Blood and urine samples will be collected for the analysis of plasma and urinary concentrations of 
CPT31. Pharmacokinetic parameters will be derived by noncompartmental analysis. The PK 
parameters will include area under the plasma concentration-time curve (AUC) from time zero to 
infinity (AUC0-∞), AUC from time zero to the time of the last quantifiable concentration (AUC0-tlast), 
maximum observed plasma concentration (Cmax), time of the maximum observed plasma 
concentration (Tmax), apparent plasma terminal elimination half-life (t1/2), apparent total plasma 
clearance (CL/F), apparent volume of distribution (Vz/F), amount of drug excreted in the urine (Ae), 
percentage of dose excreted unchanged (Fe) in urine, and renal clearance (CLR). 
Other PK parameters may also be added. 
Safety: 
Adverse events, clinical laboratory evaluations (hematology, clinical chemistry, urinalysis), 12-lead 
electrocardiograms, vital signs measurements, physical examinations, and anti-CPT31 antibodies, 
e.g., immunoglobulin (Ig)G, IgM. 
Statistical methods: 
Pharmacokinetics: 
Individual plasma concentrations of CPT31 and PK parameters will be listed and summarized using 
descriptive statistics. Individual urine concentrations of CPT31 will be listed. Individual and mean 
CPT31 concentration-time profiles will be presented graphically.  
Where data are available, CPT31 dose proportionality will be examined across the dose groups. The 
PK parameters will be analyzed for dose proportionality using a power model approach or analysis 
of variance (ANOVA) model, as appropriate.  
Safety: 
Safety parameters will be listed and summarized using descriptive statistics. The frequency of 
subjects with QTcB >470 ms or change from baseline >30 ms will be summarized for each 
treatment. No formal statistical analysis of safety data is planned. 


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TABLE OF CONTENTS 
TITLE PAGE .............................................................................................................................1 
SPONSOR APPROVAL ...........................................................................................................2 
INVESTIGATOR AGREEMENT.............................................................................................3 
STUDY IDENTIFICATION .....................................................................................................4 
SYNOPSIS .................................................................................................................................5 
TABLE OF CONTENTS ...........................................................................................................7 
LIST OF TABLES AND FIGURES..........................................................................................9 
LIST OF ABBREVIATIONS ..................................................................................................10 
1. 
INTRODUCTION ...........................................................................................................12 
1.1. 
Overview ................................................................................................................12 
1.2. 
Summary of Nonclinical Pharmacology ................................................................13 
1.3. 
Summary of Safety Pharmacology ........................................................................14 
1.4. 
Summary of Toxicology ........................................................................................15 
1.4.1. 
Toxicology in Rats .......................................................................................15 
1.4.2. 
Toxicology in Monkeys ...............................................................................16 
1.5. 
Summary of Nonclinical Pharmacokinetics ...........................................................17 
1.6. 
Study Rationale ......................................................................................................18 
1.7. 
Benefit-risk Assessment .........................................................................................19 
2. 
OBJECTIVES AND ENDPOINTS .................................................................................19 
2.1. 
Objectives ..............................................................................................................19 
2.2. 
Endpoints ...............................................................................................................19 
2.2.1. 
Primary Endpoints .......................................................................................19 
2.2.2. 
Secondary Endpoints ...................................................................................20 
3. 
INVESTIGATIONAL PLAN ..........................................................................................20 
3.1. 
Overall Study Design and Plan ..............................................................................20 
3.2. 
Study Start and End of Study Definitions ..............................................................22 
3.3. 
Additional Groups ..................................................................................................22 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups .................22 
3.4.1. 
Dose Interval ................................................................................................23 
3.5. 
Selection of Doses in the Study .............................................................................23 
3.6. 
Dose Escalation ......................................................................................................24 
3.7. 
Dose Escalation Stopping Rules ............................................................................25 
3.8. 
Overall Study Stopping Rules ................................................................................25 
4. 
SELECTION OF STUDY POPULATION .....................................................................25 
4.1. 
Healthy Subjects ....................................................................................................25 
4.1.1. 
Inclusion Criteria .........................................................................................25 
4.1.2. 
Exclusion Criteria ........................................................................................26 
4.2. 
Subject Number and Identification ........................................................................27 


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4.3. 
Subject Withdrawal and Replacement ...................................................................28 
5. 
STUDY TREATMENTS .................................................................................................28 
5.1. 
Description, Storage, Packaging, and Labeling .....................................................28 
5.2. 
Study Treatment Administration ............................................................................29 
5.3. 
Randomization .......................................................................................................29 
5.4. 
Blinding..................................................................................................................29 
5.5. 
Treatment Compliance ...........................................................................................30 
5.6. 
Drug Accountability...............................................................................................30 
6. 
CONCOMITANT THERAPIES AND OTHER RESTRICTIONS ................................30 
6.1. 
Concomitant Therapies ..........................................................................................30 
6.2. 
Diet .........................................................................................................................31 
6.3. 
Smoking .................................................................................................................31 
6.4. 
Exercise ..................................................................................................................31 
6.5. 
Blood Donation ......................................................................................................32 
7. 
STUDY ASSESSMENTS AND PROCEDURES ...........................................................32 
7.1. 
Pharmacokinetic Assessments ...............................................................................32 
7.1.1. 
Sample Collection and Processing ...............................................................32 
7.1.2. 
Analytical Methodology ..............................................................................32 
7.2. 
Immunogenicity Assessments ................................................................................33 
7.3. 
Safety and Tolerability Assessments .....................................................................33 
7.3.1. 
Adverse Events ............................................................................................33 
7.3.2. 
Clinical Laboratory Evaluations ..................................................................33 
7.3.3. 
Vital Signs ....................................................................................................34 
7.3.4. 
Electrocardiogram ........................................................................................34 
7.3.5. 
Physical Examination...................................................................................35 
7.3.6. 
Body Weight ................................................................................................35 
8. 
SAMPLE SIZE AND DATA ANALYSIS ......................................................................35 
8.1. 
Determination of Sample Size ...............................................................................35 
8.2. 
Analysis Populations ..............................................................................................35 
8.2.1. 
Pharmacokinetic Population ........................................................................35 
8.2.2. 
Safety Population .........................................................................................35 
8.3. 
Pharmacokinetic Analyses .....................................................................................35 
8.4. 
Safety Analysis ......................................................................................................36 
8.5. 
Interim Analysis .....................................................................................................36 
9. 
REFERENCES ................................................................................................................36 
10.  APPENDICES .................................................................................................................37 
Appendix 1: Adverse Event Reporting ..............................................................................38 
Appendix 2: Clinical Laboratory Evaluations ...................................................................42 
Appendix 3: Total Blood Volume ......................................................................................44 


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Appendix 4: Contraception Guidance ................................................................................45 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations ............................47 
Appendix 6: Schedule of Assessments ..............................................................................51 
Appendix 7: Protocol Amendment(s)/Administrative Change(s) ......................................55 
 
LIST OF TABLES AND FIGURES 
Table 1: Pharmacokinetic Parameters of CPT31 in Cynomolgus Macaques ....................18 
Table 2: Human Safety Margin Estimates for CPT31 .......................................................23 
Table 3: Planned Investigational Medicinal Product Dose Levels ....................................24 
Table 4: Injection Volumes ................................................................................................29 
 
Figure 1: Study Schematic .................................................................................................21 
Figure 2: Planned Dose Levels ..........................................................................................22 
 


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LIST OF ABBREVIATIONS 
Abbreviation Definition 
Ae 
amount of drug excreted in the urine 
AE 
adverse event 
AIDS 
Acquired Immune Deficiency Syndrome 
ANOVA 
analysis of variance 
ART 
antiretroviral therapy 
AUC 
area under the plasma concentration-time curve 
AUC0- 
area under the plasma concentration-time curve from time zero to infinity 
AUC0-tlast 
area under the plasma concentration-time curve from time zero to the time 
of the last quantifiable concentration 
AUC0-24 
area under the plasma concentration-time curve from time zero to 24 hours 
postdose 
AUC0-τ 
area under the plasma concentration-time curve over a dosing interval 
cART 
combination antiretroviral therapy 
CFR 
Code of Federal Regulations 
CL/F 
apparent total plasma clearance 
CLR 
renal clearance 
Cmax 
maximum observed plasma concentration 
Cmin 
minimum observed plasma concentration 
CRO 
Contract Research Organization 
CRU 
Clinical Research Unit 
CSA 
clinical study agreement 
CNS 
central nervous system 
Da 
Daltons 
DAIDS 
Division of AIDS 
ECG 
electrocardiogram 
eCRF 
electronic Case Report Form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
Fe 
percentage of drug excreted unchanged 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
hr 
hour 
HED 
human equivalent dose 
HIV 
human immunodeficiency virus 
IB 
Investigator’s Brochure 


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IC50 
Concentration producing 50% inhibition 
IC90 
Concentration producing 90% inhibition 
ICF 
Informed Consent Form 
ICH 
International Council for/Conference on Harmonisation 
Ig 
immunoglobulin  
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
ISR 
injection site reaction 
IUD 
intrauterine device 
IV 
Intravenous(ly) 
kg 
kilogram 
Mg  
milligram 
MATE 
multidrug and toxin extrusion 
MTD 
maximum tolerated dose 
NIH 
National Institutes of Health 
NOAEL 
no observed adverse effect level 
OATP 
organic anion transporting polypeptide 
OCT 
organic cation transporter 
PBMC 
Peripheral blood mononuclear cells 
PD 
pharmacodynamic(s) 
PK 
pharmacokinetic(s) 
PrEP 
pre-exposure prophylaxis 
PSRT 
Protocol Safety Review Team 
QTc 
QT interval corrected for heart rate 
QTcF 
QT interval corrected for heart rate using Fridericia’s method 
RAAUC0-τ 
observed accumulation ratio based on AUC0-τ 
RACmax 
observed accumulation ratio based on Cmax 
SAE 
serious adverse event 
SC 
subcutaneous(ly) 
SHIV 
simian/human immunodeficiency virus 
STI 
sexually transmitted infection 
t1/2 
apparent plasma terminal elimination half-life 
TCID50 
concentration producing 50% infection in tissue culture 
TK 
toxicokinetic(s) 
Tmax 
time of the maximum observed plasma concentration 
TMF 
Trial Master File 
Vz/F 
apparent volume of distribution 
 
 


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1. INTRODUCTION 
1.1. 
Overview 
Human immunodeficiency virus (HIV) infection and acquired immune deficiency syndrome 
(AIDS) remain serious global health issues. Since the epidemic began, 77 million people 
have become infected with HIV (1.8 million in the U.S.), and 35 million people have died 
from AIDS-related illnesses (~700,000 in the U.S.). In 2017, the most current year for which 
data are available, 1.8 million new cases of HIV infection were diagnosed (~40,000 in the 
U.S.). Globally, about 9.4 million or ~25% of HIV-positive individuals are not yet diagnosed 
(170,000 or ~15% in the U.S.)1,2. 
For many patients, combination antiretroviral therapy (cART) has transformed HIV into a 
chronic manageable illness, however, despite cART approximately 20% of patients do not 
achieve complete viral suppression3. Many cART patients experience serious side effects 
(including liver toxicity, pancreatitis, cardiotoxicity, central nervous system [CNS] toxicity, 
rash, and loss of bone density) that reduce quality of life. Additionally, patients often struggle 
with lifelong daily dosing. These factors negatively affect patient adherence to cART. In a 
national survey of HIV clinicians, 72 respondents indicated that ~21% of their patients are 
poorly adherent (Navigen unpublished clinician survey). Published reports estimate 
adherence as low as 53% in certain populations 4. Poor adherence results in suboptimal viral 
suppression, which can lead to drug resistance, virologic failure, and increased HIV 
transmission rates. 
CPT31 is a novel D-peptide HIV entry inhibitor that binds to the gp41 trimer pocket region 
and addresses many of the limitations of current cART. Natural L-peptides, composed of 
L-amino acids, are often poor drugs because they are susceptible to proteolytic degradation. 
The resulting high dose requirements, cost, and delivery challenges have limited the 
otherwise outstanding potential of peptides to block protein-protein interaction interfaces in 
diverse diseases. D-peptides, composed entirely of mirror-image D-amino acids, hold great 
promise as therapeutic agents, since they are resistant to proteolysis. D-peptides also have the 
advantage of being minimally immunogenic, likely due to their inability to be processed for 
major histocompatibility complex presentation5.  
D-peptides are ideal HIV entry inhibitors since the HIV fusion machinery (i.e., gp41) is an 
accessible extracellular target and has been clinically validated by Fuzeon® (enfuvirtide) 
studies. Fuzeon is an L-peptide derived from the gp41 C-peptide region that binds the gp41 
N-trimer and prevents a critical conformation change that drives virus and target-cell 
membrane fusion. It represented a therapeutic breakthrough as the first Food and Drug 
Administration (FDA)-approved HIV entry inhibitor but has had limited lasting impact on 
HIV treatment due to the practical limitations of L-peptide drugs. Two other entry inhibitors 
are currently approved for use. Selzentry® (maraviroc) blocks HIV entry by binding to a 
cellular coreceptor, CCR5, and thus does not inhibit strains that use an alternative coreceptor, 
CXCR4, necessitating expensive and time-consuming tropism testing prior to initiation of 
therapy. Trogarzo® is a recently approved (2018) monoclonal antibody that inhibits entry by 
binding the primary HIV receptor CD4. It is currently approved for patients with multidrug 
resistant HIV and is administered every 14 days.  


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Navigen, Inc. is developing CPT31 to both treat patients with HIV type 1 infection and 
prevent HIV infection in healthy individuals. The study outlined in this protocol exclusively 
focuses on establishing the safety, tolerability, pharmacokinetic, pharmacodynamic, and 
immunologic profiles of a simple (non-depot) subcutaneous (SC) injectable formulation. 
However, nonclinical studies with a long-acting formulation of CPT31 (CPT31-LA) are 
underway in parallel, and we ultimately envision CPT31 to be administered as a long-acting 
injectable in an extended-release (depot) formulation, differentiating it from current marketed 
treatments that require one or more pills to be administered daily. Based on current 
nonclinical data for CPT31, expected advantages over current and pipeline anti-HIV 
compounds include the following: 
 
High potency against all major circulating HIV clades and no cross-resistance 
with existing entry inhibitors; 
 
Strong barrier to resistance resulting from an exceptionally high binding 
affinity to a highly conserved region of HIV; 
 
Low antigenicity; 
 
Minimal side effects due to high specificity to an extracellular HIV-specific 
target; 
 
Pharmacokinetic (PK) profile that potentially supports monthly dosing with 
extended-release formulation; and 
 
More convenient dosing that will lead to better compliance in some patient 
populations. 
These advantages support CPT31 use (especially as a long-acting injectable) as a component 
in a first-line combination therapy in HIV+ individuals. Additionally, because CPT31 has a 
unique mechanism of action, it could be used as “salvage” therapy for multi-drug-resistant 
HIV patients. Finally, CPT31’s advantages make is a candidate for use by HIV negative 
individuals as pre-exposure prophylaxis (PrEP) to reduce the likelihood of HIV transmission.  
This study will be the first time that CPT31 is administered to humans.  
1.2. 
Summary of Nonclinical Pharmacology 
The in vitro antiviral activity of CPT31 against laboratory and clinical isolates of HIV-1 was 
assessed in peripheral blood lymphocytes, human osteosarcoma cells expressing CCR5 (HOS 
CCR5), and CXCR4-positive HeLa cells (TZM-bl). In vitro, CPT31 has a concentration 
producing 90% inhibition (IC90) ≤10 nM in 96% of HIV strains in an international panel of 
60 primary isolates representing clades A, B, C, and D, and circulating recombinant forms 
CRF01_AE and CRF02_AG, in TZM-B1 cells.  
In human peripheral blood mononuclear cells (PBMCs), CPT31 inhibited HIV-1NL4-3 with an 
IC90 of ~0.06 nM (reverse transcriptase assay). There was a 3.5-12.8-fold potency loss 
against HIV-1NL4-3 in the presence of 10-40% dialyzed human serum. Extrapolation to 100% 
human serum predicts an IC90 of ~2 nM. The average potency of CPT31 in PBMCs infected 
with additional isolates from various clades (in the absence of human serum) was ~2-fold less 
than measured against HIV-1NL4-3 (comparing concentration producing 50% inhibition [IC50] 
since it is less susceptible than IC90 due to the relatively large PBMC assay variability). 


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To achieve full virologic suppression, Navigen is targeting a trough CPT31 serum 
concentration of ≥4× the serum-adjusted mean IC90 of diverse strains in human PBMCs, 
which, based on the above data, gives an estimated target trough CPT31 serum concentration 
of ~16 nM (145 ng/mL). 
The efficacy of CPT31 in a rhesus macaque model was assessed using both pre-exposure 
prophylactic and treatment protocols. A virulent simian/human immunodeficiency virus 
(SHIV) strain was developed for evaluating the effectiveness of HIV envelope-targeting 
inhibitors such as CPT316. This SHIV-AD8 contains the HIV R5-tropic env AD8, derived 
from a primary clade B strain. SHIV-AD8 is more pathogenic than commonly used SHIV 
strains; therefore, it provides a more robust test for CPT31 efficacy. As expected, this strain is 
highly sensitive to CPT31 with an IC50 <20 pM in a standard pseudovirion entry assay.  
Male rhesus macaques (n = 4) were given CPT31 via intramuscular injection daily for a total 
of 10 days at dose levels of 3, 0.5, and 0.125 mg/kg/day. The animals were challenged on 
Day 4 intrarectally with 1000 × concentration producing 50% infection in tissue culture 
(TCID50) SHIV-AD8. Treatment continued after challenge through Day 10. Animals first 
were dosed at 3 mg/kg/day for 10 days, and plasma virus levels were monitored for 12 weeks 
post-challenge. After documenting lack of infection, the study was repeated in the same 
4 animals at a dose level of 0.5 mg/kg/day. After 12 weeks and absence of seroconversion, 
the study was repeated at a dose level of 0.125 mg/kg/day. At this dose level, 3/4 animals 
seroconverted within 10 days. One hundred percent of historical vehicle control animals 
seroconvert within 1-week post-challenge in this model.  
A therapeutic efficacy study was also completed. Three naïve rhesus macaques were infected 
with SHIV-AD8 (1000× TCID50, rectal challenge) and monitored for 14 weeks until stable 
viremia was achieved (median 105 copies/mL). CPT31 was then dosed at 3 mg/kg/day for 
30 days. Rapid ~2-log reductions in plasma viremia were observed. However, as expected, 
virus levels rebounded after ~2 weeks due to drug resistance (as confirmed by sequencing). A 
similar result is observed with modern first-line HIV drugs when used as monotherapy 
against uncontrolled infection7.  
To more closely mimic a traditional therapeutic setting where virus is suppressed by a 
combination of highly active drugs, a monotherapy maintenance study was performed in 
which CPT31 was introduced when virus was undetectable. Combination ART was utilized 
to suppress virus levels in infected rhesus macaques to undetectable levels, and then 
treatment was transitioned to CPT31 monotherapy to determine if it could prevent viral 
rebound. CPT31 (3 mg/kg/day) maintained viral suppression in all 4 animals for the duration 
of the 12 weeks of monotherapy. Significantly, there were no clinical signs of toxicity 
observed in these animals (including injection site reactions [ISRs]), and clinical chemistry 
and hematology parameters were all within normal ranges.  
1.3. 
Summary of Safety Pharmacology 
Following single doses of up to 20 mg/kg/day CPT31, there were no effects on 
cardiovascular, respiratory, or central nervous systems in cynomolgus monkeys. No effects 
on respiratory and central nervous systems were observed in Sprague-Dawley rats at doses up 
to 60/40 mg/kg/day.  


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Detailed descriptions of the studies can be found in the Investigator’s Brochure (IB)8. 
1.4. 
Summary of Toxicology 
1.4.1. 
Toxicology in Rats 
A study was conducted to evaluate toxicity after a single dose of CPT31 when administered 
via SC injection to male Sprague-Dawley rats at 0, 10, 30, 60, and 100 mg/kg. 
All animals survived to scheduled sacrifice at 24 hours postdose. In the 100 mg/kg dose 
group, 1/3 animals appeared slow and sensitive to touch at 8 hours postdose, and 3/3 animals 
were slightly lethargic with increased respiration rates at 24 hours postdose. All 
CPT31-treated animals had mild to moderate ISRs. No other adverse clinical or necropsy 
findings were observed. Based on these results, the maximum tolerated dose (MTD) of 
CPT31 in male Sprague-Dawley rats following single-dose SC administration is 100 mg/kg. 
A Good Laboratory Practice (GLP)-compliant 14-day repeat-dose toxicity study evaluated 
the toxicity (including respiratory and CNS safety pharmacology endpoints) as well as the 
toxicokinetics (TK) of CPT31 in male and female Sprague-Dawley rats at dose levels of 0, 
10, 20, or 60/40 mg/kg/day, administered daily via SC injection. The dose solution strength 
for all groups was 15 mg/mL. The 60 mg/kg/day dose was not tolerated, and several animals 
were found dead or were sacrificed moribund on Days 4-8. Dosing in this group was 
suspended on Day 4 and resumed on Day 7 at the reduced dose of 40 mg/kg/day in surviving 
animals (although these animals were inadvertently not dosed on Day 10 due to a protocol 
deviation). All animals that survived past Day 8 survived until their scheduled sacrifice on 
Day 15.  
CPT31 was well tolerated in 63/64 animals in the 10 and 20 mg/kg/day dose groups. A single 
male animal (R0110) in the low (10 mg/kg/day) dose group was sacrificed moribund on 
Day 6. In all dose groups, the cause of either death or moribund condition in 16 of 18 animals 
that did not survive the dosing phase (including Animal R0110) was renal tubular 
degeneration with correlating clinical pathology changes. The cause of death in the other 2 of 
18 animals was hepatic coagulative necrosis. No safety pharmacology (respiratory and CNS) 
findings were observed even in the high-dose group animals (60/40 mg/kg/day). The findings 
in Animal R0110 prevented assignment of a no observed adverse effect level (NOAEL) in 
this study. Notably, Animal R0110 was a statistical outlier in terms of its plasma drug level at 
terminal sacrifice (24-hours post last dose), which was ~3-fold higher than its dose-group 
peers (Grubb’s test, GraphPad Prism® software). 
A 28-day GLP-compliant repeat-dose study evaluated the toxicity and TK of CPT31 in 
Sprague-Dawley rats at dose levels of 0, 1, 3, and 6 mg/kg/day, administered once daily by 
SC injection. All CPT31 dose solutions were 5 mg/mL. All animals survived until their 
scheduled sacrifice. CPT31-related effects included an increased incidence of nodules at the 
dose sites in males administered 6 mg/kg/day and increased incidence of scabs in the cervical 
and thoracic skin area of females administered ≥ 3 mg/kg/day; decreased body weight gain in 
females administered ≥ 3 mg/kg/day and males administered 6 mg/kg/day; decreased food 
consumption for animals administered 6 mg/kg/day; clinical pathology effects of minimal to 
mild severity consistent with inflammatory response (higher neutrophil count and fibrinogen 


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and lower albumin and albumin:globulin ratio) in males administered ≥1 mg/kg/day and 
females administered ≥ 3 mg/kg/day; and increases in mean IL-1β levels on Day 7 in animals 
administered 6 mg/kg/day and on Day 28 in males administered ≥ 1 mg/kg/day and females 
administered ≥ 3 mg/kg/day. CPT31-related non-adverse microscopic findings were observed 
in the SC injection sites, kidney, and spleen. Microscopic findings included edema and/or 
macrophage infiltrates in the SC injection sites (correlating with macroscopic thickening) in 
animals administered ≥ 1 mg/kg/day, slight to moderate focal renal tubular degeneration in 
males administered ≥ 3 mg/kg/day, minimal to slight focal mononuclear cell infiltration in 
kidney of males administered ≥ 1 mg/kg/day, and slightly to moderately increased 
extramedullary hematopoiesis in spleen of males administered ≥ 1 mg/kg/day. All effects 
exhibited full or partial (SC injection site findings) recovery during the recovery phase. Due 
to the mild severity of findings and the lack of impact on the health and wellbeing of animals 
administered up to 6 mg/kg/day, effects for doses up to 6 mg/kg/day were considered non-
adverse. Thus, the NOAEL in this study was 6 mg/kg/day. This dose level corresponded to 
maximum observed plasma concentration (Cmax) and area under the concentration-time curve 
(AUC) from time zero to 24 hours postdose (AUC0-24) values of 6,900 ng/mL (764 nM) and 
92,300 hr*ng/mL (10,223 hr*nM), respectively, on Day 28 of the dosing phase. 
1.4.2. 
Toxicology in Monkeys 
A study was conducted to evaluate the toxicity of escalating SC doses of 10, 20, 40, and 
80 mg/kg CPT31 doses on Days 1, 4, 8, and 12, respectively to one male and one female 
cynomolgus monkey. The 3- to 4-day interval between the dose days served as a washout 
period. The dose level of 80 mg/kg was well tolerated in the male animal. The female animal 
administered 80 mg/kg CPT31 showed midline hemorrhage with swelling, and the animal 
was sacrificed as scheduled on Day 15. The cause of hemorrhage was not identified. Other 
clinical pathology findings in this female animal were consistent with inflammation, 
including increased white blood cell and neutrophil counts, moderately decreased total 
protein, albumin, albumin:globulin ratio, and mildly increased globulin. Based on the clinical 
observations and correlating clinical pathology changes, a dose level of 80 mg/kg/day was 
considered adverse; therefore, 40 mg/kg/day is the MTD when CPT31 is administered as a 
single dose.  
Another study was conducted to evaluate the toxicity of CPT31 when given as repeat doses 
via SC injection to cynomolgus monkeys. Dose groups were 10, 40, or 80 mg/kg/day CPT31 
for 14 days via SC injection in the scapular region. Administration of 40 or 80 mg/kg/day 
was terminated after Day 2 due to toxicity. CPT31-related unscheduled sacrifice or death 
occurred for males administered 40 or 80 mg/kg/day and females administered 80 mg/kg/day. 
CPT31-related clinical observations for these animals included hypoactivity, hunched 
posture, decreased reactivity to stimulus, pallor, high or subnormal temperature, lethargy, 
irregular respiration, reduced food consumption, and moribund condition. Clinical 
observations at the dose sites included moderate edema and bruising which were localized to 
the dose site or spread across the entire quadrant designated for injection, although only 2 of 
4 dose sites were utilized. Clinical observations correlated with major clinical pathology 
findings in animals administered ≥40 mg/kg/day, which were generally consistent with 
inflammation and coagulopathy. Bone marrow hypocellularity in males administered 
40 mg/kg/day correlated with decreased peripheral blood cell counts. CPT31-related, 
non-adverse, SC dose site reactions were observed in both sexes administered 10 mg/kg/day 


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and males administered 40 mg/kg/day. Effects for animals administered 10 mg/kg/day were 
considered non-adverse. Thus, the NOAEL is 10 mg/kg/day.  
A GLP-compliant 14-day repeat-dose study evaluated the toxicity (including cardiovascular, 
respiratory, and CNS safety pharmacology endpoints) as well as TK of CPT31 in cynomolgus 
monkeys at dose levels of 0, 5, 10, or 20 mg/kg/day administered daily via SC injection. Two 
groups of animals were treated at 10 mg/kg/day: one at 5 mg/mL and one at 15 mg/mL 
CPT31 solution to compare the effects of dose concentration. All remaining groups were 
treated at 15 mg/mL CPT31 solution. The study also evaluated the reversibility, persistence, 
or delayed occurrence of any effects during a 14-day recovery phase. All animals survived 
until scheduled sacrifice. Major findings included CPT31-related renal tubular degeneration 
and necrosis with correlating clinical chemistry changes, and dose-dependent clinical 
laboratory changes suggestive of inflammation that correlated with SC ISRs. CPT31-related 
increases in mean IL-6 levels above the lower limit of quantitation and above control means 
were noted at 3 hours postdose on Day 7 of the dosing phase in females administered 10 
mg/kg/day (15 mg/mL) and animals administered 20 mg/kg/day. The finding in animals 
administered 20 mg/kg/day was consistent with the increase in C-reactive protein on Days 7 
and 15 of the dosing phase. No CPT31-related changes were noted in IL-1, IL-1, or 
TNF- in animals administered ≥5 mg/kg/day. The NOAEL in this study was 10 mg/kg/day 
regardless of dose solution strength. This dose level corresponded to mean (across male and 
female groups) Cmax and AUC0-24 values of 25,400 ng/mL (2,813 nM) and 380,000 hr*ng/mL 
(42,086 hr*nM), respectively on Day 14 of the dosing phase. 
1.5. 
Summary of Nonclinical Pharmacokinetics 
Following intravenous (IV) or SC administration (1 mg/kg) in Sprague-Dawley rats, the 
apparent plasma terminal elimination half-life (t1/2) of CPT31 was 3.2 and 5.5 hours, 
respectively, and SC bioavailability was 53%. Similarly, following IV or SC administration 
(1 or 3 mg/kg, respectively) in cynomolgus macaques, the t1/2 of CPT31 was 7 and 
18.6 hours, respectively, and SC bioavailability was 78%. CPT31 given IV to Sprague-
Dawley rats or monkeys has a low volume of distribution (134 mL/kg and 96 mL/kg, 
respectively), suggesting that it is largely confined to the plasma compartment. Plasma 
protein binding studies revealed that 5 μM CPT31 is ≥96% bound in rat, minipig, dog, 
monkey, and human plasma. 
Both Cmax and AUC of CPT31 upon SC administration to Sprague-Dawley rats are linear (but 
not fully dose proportional) at increasing dose levels up to 40 mg/kg. Terminal half-life is 
consistently between 4 and 8 hours at dose levels ranging from 3-75 mg/kg. 
A distribution/excretion study using radioactive [125I]-CPT31 suggested that CPT31 is 
eliminated via renal clearance, as expected for a mid-molecular weight compound (average 
9,029 Daltons). Composed of D-peptides, CPT31 is not expected to enter peptide catabolic 
pathways.  
Non-parametric superposition of available cynomolgus macaques PK data (Table 1) and 
allometric scaling to humans predicts that a 0.03 mg/kg SC injection every third day would 
give a trough level ~13-22 nM (117-199 ng/mL). Therefore, this dose is tentatively set as the 
expected human therapeutic dose in order to achieve a trough CPT31 level of ≥4 × the 


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serum-adjusted IC90 against diverse strains in human PBMCs (~16 nM), as described above. 
However, the PK profile in humans remains to be established, and the estimated effective 
dosing will change accordingly. 
Table 1: Pharmacokinetic Parameters of CPT31 in Cynomolgus Macaques 
Day 
Dose 
(mg/kg/day) 
Sex 
AUC0-24 
(hr*ng/mL) 
Cmax 
(ng/mL) 
1 
5 
M 
252 000 
15 100 
 
 
F 
248 000 
16 100 
 
10 
M 
356 000 
23 000 
 
 
F 
393 000 
25 700 
 
20 
M 
686 000 
41 600 
 
 
F 
627 000 
37 800 
14 
5 
M 
264 000 
16 700 
 
 
F 
270 000 
17 500 
 
10 
M 
369 000 
25 500 
 
 
F 
391 000 
25200 
 
20 
M 
396 000 
30 800 
 
 
F 
676 000 
54 500 
Abbreviations: AUC0-24 = area under the plasma concentration-time curve from time zero to 24 hours postdose; 
Cmax = maximum observed plasma concentration; hr = hour; Tmax = time of the maximum observed plasma concentration. 
 
There is little potential for significant CPT31 drug-drug interactions involving cytochrome 
P450 based on direct inhibition studies in liver microsomes. There is also low intrinsic 
clearance of CPT31 in microsomes as well as low to medium CPT31 intrinsic clearance in 
hepatocytes. In all species tested (rat, minipig, dog, monkey, and human), clearance rates are 
greater in hepatocytes than in liver microsomes, indicating the possibility of a 
non-cytochrome P450-mediated mechanism of biotransformation. Furthermore, CPT31 did 
not significantly inhibit key cell transporters (P-glycoprotein, Breast Cancer Resistance 
Protein, organic anion transporting polypeptide ([OATP]1B1, OATP1B3, organic cation 
transporter [OCT]2, OAT1, OAT3, multidrug and toxin extrusion [MATE]1, MATE2-K), 
indicating low therapeutic potential for drug-drug interactions as a result of transporter 
inhibition.  
Putative metabolites formed during non-NADPH-dependent CPT31 clearance observed in 
rat, monkey, and human microsomes were sought and not detected in a study using liver 
microsomes. By contrast, another study sought putative CPT31 metabolites formed during 
clearance in rat, monkey, and human hepatocytes. While partial degradation in all species 
was observed, no specific species attributable to CPT31 metabolism were detected. 
1.6. 
Study Rationale 
This is the first time CPT31 will be administered to humans. The principal aim of this study 
is to obtain safety and tolerability data when CPT31 is administered SC as a single dose to 
healthy subjects. This information, together with the PK data, will help establish the doses 
and dosing regimen suitable for future studies in patients. 


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1.7. 
Benefit-risk Assessment 
Subjects in this study will not gain any clinical benefits. Study subjects and others may 
benefit in the future from information learned from this study. Specifically, information 
learned in this study may lead to the development of safe and effective interventions to treat 
and/or prevent HIV transmission. 
The risks of participation are primarily those associated with adverse reactions to the 
investigational medicinal product (IMP), although there may also be some discomfort from 
collection of blood samples and other study procedures.  
Phlebotomy may lead to discomfort, feelings of dizziness or faintness, and/or bruising, 
swelling and/or infection. Good venipuncture practices reduce the pain and likelihood of 
bruising and secondary infection. Precautions will be taken with subjects who have a history 
of fainting or other vasovagal events during blood draws, including having the subject lie 
down during the procedure. 
Subcutaneous injections can cause injection site swelling, warmth, and discomfort. These 
ISRs generally resolve within 3 days. Inadvertent administration of study product into a vein 
or into a nerve can occur. Injections are only administered by trained designated study 
personnel, and numerous precautions are taken to minimize this risk. 
Electrocardiograms (ECGs) have no major risks. However, mild pain may be associated with 
removal of the electrodes and mild skin irritation may develop at the sites of electrode 
attachment. 
2. OBJECTIVES AND ENDPOINTS 
2.1. 
Objectives 
The primary objective of the study is: 
 to assess the safety and tolerability of a single SC dose of CPT31 in healthy subjects 
The secondary objectives of the study are: 
 to characterize the single SC dose PK of CPT31 
 to identify and characterize antibodies to CPT31 
2.2. 
Endpoints  
2.2.1. 
Primary Endpoints 
The primary safety endpoints for this study are as follows: 
 incidence and severity of adverse events (AEs) 
 incidence of laboratory abnormalities, based on hematology, clinical chemistry, and 
urinalysis test results 


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 12-lead electrocardiogram (ECG) parameters 
 vital signs measurements 
 physical examinations 
 anti-CPT31 antibodies, e.g., immunoglobulin (Ig)G, IgM 
2.2.2. 
Secondary Endpoints 
The single ascending dose PK outcome endpoints of CPT31 are as follows: 
 AUC from time zero to infinity (AUC0-∞) 
 AUC from time zero to the time of the last quantifiable concentration (AUC0-tlast) 
 Cmax 
 time of the maximum observed plasma concentration (Tmax) 
 t1/2 
 apparent total plasma clearance (CL/F) 
 apparent volume of distribution (Vz/F) 
 renal clearance (CLR) 
 amount of drug excreted in the urine (Ae) 
 percentage of dose excreted unchanged in the urine (Fe) 
Other PK parameters may also be reported. 
3. INVESTIGATIONAL PLAN 
This will be a single SC dose study. 
3.1. 
Overall Study Design and Plan 
This study will comprise a placebo-controlled, double-blind, single-dose, sequential-group 
design. Overall, it is planned for 32 healthy subjects to be studied in 4 groups (Groups A1 to 
A4), with each group consisting of 8 subjects. In each group, 6 subjects will be randomized to 
receive SC CPT31 and 2 subjects will be randomized to receive matching placebo. 
Potential subjects will be screened to assess their eligibility to enter the study within 28 days 
prior to the first dose administration.  
Each subject will participate in 1 treatment period only. Subjects will reside at the Clinical 
Research Unit (CRU) from Day -1 (the day before dosing) to Day 6. All subjects will return 
for a Follow-up visit 28 to 30 days after dosing.  
Based on the ongoing review of the safety, tolerability, and PK results, additional 
nonresidential visits may be required. The number of additional visits per subject will not 
exceed 3 and will not extend beyond 30 days after dose administration. 


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All groups will be divided into 2 cohorts, with each cohort being dosed 72 hours apart. The 
first (sentinel) cohort will comprise 2 subjects, with 1 subject receiving CPT31 and 1 subject 
receiving placebo. The second cohort will comprise 6 subjects, with 5 subjects receiving 
CPT31 and 1 subject receiving placebo.  
The maximum total duration of study participation for each subject (from Screening through 
Follow-up visit) is anticipated to be approximately 8 weeks. 
Dose escalation will occur a minimum of 7 days after all subjects complete all Day 6 
assessments in the previous dose group.   
An overview of the study design is shown in Figure 1 and the planned dose levels in are 
shown in Figure 2. A Schedule of Assessments is presented in Appendix 6. 
 
Figure 1: Study Schematic 
Abbreviations: CRU = Clinical Research Unit, N = number of subjects. 
 


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Figure 2: Planned Dose Levels 
 
Abbreviations: N = number of subjects; SC = subcutaneous. 
3.2. 
Study Start and End of Study Definitions 
The start of the study is defined as the date the first enrolled subject signs an Informed 
Consent Form (ICF). The point of enrollment occurs at the time of subject number allocation. 
The end of the study is defined as the date of the last subject’s last assessment (scheduled or 
unscheduled). 
3.3. 
Additional Groups 
Following review of the safety, tolerability, and PK data, additional dose groups may be 
added to the study. Up to 3 further groups of 8 subjects (6 active:2 placebo) may be included.  
The requirement for additional groups will be decided by the Protocol Safety Review Team 
(PSRT), comprised of the Investigator, Sponsor Representative, Medical Monitor, and NIH 
Division of AIDS (DAIDS) Medical Monitor). Changes will be documented in the Trial 
Master File (TMF), and the IRB will be notified. 
3.4. 
Discussion of Study Design, Including the Choice of Control Groups 
A sequential-group, ascending-dose design has been chosen for safety reasons as CPT31 is in 
the early stages of clinical development, with this study being the first time it will be 
administered to humans. Subcutaneous doses have been chosen for the study, as this is the 
intended clinical route of administration.  
Continuous 12-lead ECG monitoring will be included for Groups A3 and A4 in order to 
allow assessment of the relationship between CPT31 concentrations and QT interval 


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corrected for heart rate (QTc), with a view to supporting a potential thorough QT study 
waiver.   
Based upon the nonclinical data, the planned duration of the study is considered adequate to 
achieve the study objectives.  
This study will be double-blind and placebo-controlled in order to avoid bias in the collection 
and evaluation of data during its conduct. Placebo has been chosen as the control treatment to 
assess whether any observed effects are treatment-related or simply reflect the study 
conditions. 
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications.   
3.4.1. 
Dose Interval 
Dosing at each dose level will be such that 2 subjects (1 CPT31 and 1 placebo) will be dosed 
72 hours before the remaining 6 subjects. After dosing the first 2 subjects on a separate day, a 
minimum of a 5-minute dosing interval for the remaining 6 subjects in each dose-ascending 
cohort is considered acceptable. Continuation to dose the remaining 6 subjects will be made 
by the PSRT.  
3.5. 
Selection of Doses in the Study 
Based on activity in human PBMCs infected with diverse primary isolates, the estimated 
effective serum trough concentration of CPT31 is 16 nM (145 ng/mL) (4x the serum-adjusted 
IC90 in PBMCs).  
Human PK modeling predicts that a dose of 0.03 mg/kg administered every third day will be 
optimal to maintain CPT31 serum trough levels in a narrow range (~13-22 nM, 
117-199 ng/mL) that is close to the target trough concentration of 16 nM while minimizing 
total exposure (Cmax ~50 nM, 452 ng/mL) over the course of an envisioned future 
short-duration (~2-week) multiple ascending dose human study. We propose a starting dose 
of 0.01 mg/kg in this first-in-human single ascending dose study, with subsequent dose 
escalations to 0.04 mg/kg (4-fold increase), 0.12 mg/kg (3-fold increase), and 0.24 mg/kg (2-
fold increase). The safety margins for the 0.01 mg/kg human dose relative to rat and monkey 
NOAELs are 97 and 320, respectively (Table 2).  
Table 2: Human Safety Margin Estimates for CPT31 
Study Type 
Species 
Duration 
NOAEL 
HED 
(mg/kg)* 
Human 
Safety 
Margins** 
mg/kg 
mg/m2 
Safety Pharmacology 
CNS 
Rat 
Single dose 
60 
360 
9.7 
970 
CNS 
Monkey 
14 days 
20 
240 
6.5 
650 
Respiratory 
Rat 
Single dose 
60 
360 
9.7 
970 
Respiratory 
Monkey 
14 days 
20 
240 
6.5 
650 
Cardiovascular 
Monkey 
14 days 
20 
240 
6.5 
650 


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General Toxicology 
Repeat-dose 
Rat 
14 days 
ND 
ND 
ND 
ND 
Rat 
28 days 
6 
36 
0.97 
97 
Monkey 
14 days 
10 
120 
3.2 
320 
CNS = central nervous system; HED = human equivalent dose; ND = not determined; NOAEL = no observed 
adverse effect level. 
* 
Based on allometric conversion between species based on mg/kg dose levels. Allometric conversion factors 
used for rat and monkey were 6.2 and 3.1, respectively. Assumes body weights for rat, monkey, and human 
of 0.15, 3, and 60 kg, respectively9,10. 
** Calculated by dividing the HED by the proposed CPT31 clinical start dose of 0.01 mg/kg. 
The planned IMP dose levels for the study are shown in Table 3. 
Table 3: Planned Investigational Medicinal Product Dose Levels 
Group 
Subject Numbers 
Dose  
A1 
0101 – 0108 
0.01 mg/kg or placebo 
A2 
0109 – 0116 
0.04 mg/kg or placebo 
A3 
0117 –0124 
0.12 mg/kg or placebo 
A4 
0125 – 0132 
0.24mg/kg or placebo 
Dose levels should not increase by more than 5-fold for predicted nonpharmacologically 
active dose levels and by more than 3-fold for predicted pharmacologically active dose levels 
(≥0.03 mg/kg by SC injection every third day).  
The highest dose level may exceed the top dose shown in the above table, provided the dose 
escalation stopping rules are not exceeded (Section 3.7).  
Details of all doses administered in the study will be documented in the TMF. 
3.6. 
Dose Escalation 
Doses will be administered in an escalating manner following satisfactory review by the 
PSRT of the safety, tolerability, and PK data (up to 5 days postdose) from the lower dose 
levels. Any clinically significant results will be discussed before dose escalation continues. 
Interim PK data will also be reviewed in terms of dose escalation and to confirm that the 
study design remains appropriate. Doses may be reduced and may be lower than the starting 
dose. There will be a minimum of 7 days between completion of Day 6 assessments in the 
previous dose group and dosing in the next dose group to allow sufficient time for an 
adequate safety review. 
Dose escalation will only occur if data from all participants in the dosing group have been 
reviewed by the PSRT. 
An interim safety report, summarizing results from all available safety assessments, will be 
sent to the Sponsor prior to the start of each successive group.  


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3.7. 
Dose Escalation Stopping Rules 
Following discussion among the PSRT, dose escalation will stop if: 
 Clinically relevant signs or symptoms of similar nature occur in 2 or more subjects in 
a group that, in the opinion of the Investigator, warrant stopping of dose escalation. 
 One or more subjects experience a serious AE (SAE) that is considered to be related 
to IMP. 
  Two or more subjects experience a Grade 3 or 4 AE or laboratory abnormality that is 
considered to be at least possibly related to IMP. 
 There is evidence of clinically significant increases in liver function tests (aspartate 
aminotransferase, alanine aminotransferase, alkaline phosphatase, bilirubin, and/or 
gamma-glutamyl transferase), defined as 3 times the upper limit of normal in 3 or 
more subjects in a group (confirmed with repeat testing). 
 Clinically significant increases in serum creatinine or blood urea nitrogen, defined as 
1.5 times and 2 times the upper limit of normal, respectively (confirmed with repeat 
testing), in 3 or more subjects in a group. 
3.8. 
Overall Study Stopping Rules 
The study may be discontinued at the discretion of the PSRT if any of the following criteria 
are met: 
 AEs unknown to date (i.e., not previously reported in any similar investigational study 
drug trial with respect to their nature, severity, and/or duration) 
 increased frequency, severity, and/or duration of known, anticipated, or previously 
reported AEs (this may also apply to AEs defined at Day -1 as baseline signs and 
symptoms) 
 medical or ethical reasons affecting the continued performance of the study 
 difficulties in the recruitment of subjects 
 cancelation of drug development. 
The study will be discontinued if 2 or more subjects experience a Grade 3 or 4 AE or 
laboratory abnormality that is considered to be at least possibly related to IMP. 
The study may be stopped at any time prior to completion by the sponsor, FDA, IRB, and/or 
doctors participating in the study. 
4. SELECTION OF STUDY POPULATION 
4.1. 
Healthy Subjects 
4.1.1. 
Inclusion Criteria 
Subjects must satisfy all the following criteria at the Screening Visit unless otherwise stated: 


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1. Males or females, of any race, between 18 and 55 years of age, inclusive.  
2. Body mass index between 18.0 and 32.0 kg/m2, inclusive.  
3. In good health, determined by no clinically significant findings from medical and 
surgical history, physical examination, 12-lead ECG, vital signs measurements, and 
clinical laboratory evaluations (congenital nonhemolytic hyperbilirubinemia [e.g., 
suspicion of Gilbert’s syndrome based on total and direct bilirubin] is not acceptable) 
at Screening and/or Day -1 as assessed by the Investigator (or designee).  
4. Females will not be pregnant or have been within the previous 3 months, or lactating, 
and females of childbearing potential and males will agree to use contraception, as 
detailed in Appendix 4. 
5. Able to comprehend and willing to sign an ICF and to abide by the study restrictions. 
4.1.2. 
Exclusion Criteria 
Subjects will be excluded from the study if they satisfy any of the following criteria at the 
Screening Visit unless otherwise stated: 
1. Significant history or clinical manifestation of any metabolic, allergic, dermatological, 
hepatic, renal, hematological, pulmonary, cardiovascular, gastrointestinal, 
neurological, respiratory, endocrine, or psychiatric disorder, as determined by the 
Investigator (or designee). 
2. A ≥Grade 2 laboratory abnormality at Screening or Day -1 as defined by the Division 
of AIDS Table for Grading the Severity of Adult and Pediatric Adverse Events, 
Version 2.1 dated July 2017. 
3. Estimated glomerular filtration rate (eGFR per CKD-Epi equation) of 
<90 ml/min/1.73 m2. 
4. Known sensitivity to CPT31 or any of its components. 
5. History of significant hypersensitivity, intolerance, or allergy to any drug compound, 
food, or other substance, unless approved by the Investigator (or designee). 
6. History of alcoholism or drug/chemical abuse within 2 years prior to Day -1. 
7. Alcohol consumption of > 21 units per week for males and > 14 units for females. 
One unit of alcohol equals 12 oz (360 mL) beer, 1½ oz (45 mL) liquor, or 5 oz 
(150 mL) wine.  
8. Positive urine drug screen at Screening or positive alcohol breath test result or 
positive urine drug screen on Day -1.  
9. Positive HIV test as documented by Combo Ag/Ab HIV-1/HIV-2 immunoassay.  
10. Positive hepatitis B surface antigen, positive hepatitis B core antibody with negative 
hepatitis B surface antibody test result, or positive hepatitis C antibody at Screening 
or within 3 months before first dose of study treatment. 
11. Participation in a clinical study involving administration of an investigational drug in 
the past 30 days prior to dosing.  


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12. Use or intend to use any prescription or over the counter medications/products 
(including HIV medications being used for pre-exposure prophylaxis) other than 
hormone replacement therapy, oral, implantable, transdermal, injectable, or 
intrauterine contraceptives or acetaminophen up to 2 grams per day for no more than 
3 consecutive days within 14 days prior to dosing, unless deemed acceptable by the 
Investigator (or designee).  
13. Use of tobacco- or nicotine-containing products within 3 months prior to Day -1, or 
positive cotinine at Screening or Day -1.  
14. Receipt of blood products within 2 months prior to Day -1. 
15. Donation of blood from 3 months prior to Screening, plasma from 2 weeks prior to 
Screening, or platelets from 6 weeks prior to Screening.  
16. Poor peripheral venous access. 
17. Have previously completed or withdrawn from this study or any other study 
investigating CPT31 and have previously received the investigational product.  
18. Subjects who, in the opinion of the Investigator (or designee), should not participate 
in this study. 
4.1.2.1. 
Additional Exclusion Criteria 
19. Have any clinically significant abnormal ECG results constituting a risk while taking 
the investigational product, as determined by the Investigator, such as any of the 
following, as determined by single 12-lead ECG:  
a. QT interval corrected for heart rate using Fridericia’s method (QTcF) >450 ms 
for males and >470 ms for females, confirmed by calculating the mean of the 
original value and 2 repeats.  
b. QRS duration >120 ms confirmed by calculating the mean of the original 
value and 2 repeats. 
c. PR interval >220 ms confirmed by calculating the mean of the original value 
and 2 repeats. 
d. findings which would make QTc measurements difficult or QTc data 
uninterpretable. 
e. history of additional risk factors for torsades de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
f. Risks related to bradycardia, for example, second or third degree 
atrioventricular block or sick sinus syndrome 
4.2. 
Subject Number and Identification 
Subjects will have a unique identification number used at Screening. Subjects will be 
assigned a subject number at the time of their randomization. Assignment of subject numbers 
will be in ascending order and no numbers will be omitted (e.g., Subjects 0101, 0102, etc.). 
Replacement subjects (Section 4.3) will be assigned a subject number corresponding to the 


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number of the subject he/she is replacing plus 1000 (e.g., Subject 1101 replaces 
Subject 0101). 
Subjects will be identified by identification or subject number only on all study 
documentation. A list identifying the subjects by subject number will be kept in the Site 
Master File. Photos of subjects may be taken for subject identification. 
4.3. 
Subject Withdrawal and Replacement 
A subject is free to withdraw from the study at any time. In addition, a subject will be 
withdrawn if any of the following criteria are met: 
 change in compliance with any inclusion/exclusion criterion that is clinically relevant 
and affects subject safety as determined by the Investigator (or designee) 
 noncompliance with the study restrictions that might affect subject safety or study 
assessments/objectives, as considered applicable by the Investigator (or designee) 
 any clinically relevant sign or symptom that, in the opinion of the Investigator (or 
designee), warrants subject withdrawal. 
If a subject is withdrawn, the Sponsor will be notified and the date and reason(s) for the 
withdrawal will be documented in the subject’s electronic Case Report Form (eCRF). If a 
subject is withdrawn, efforts will be made to perform all follow-up assessments, if possible 
(Appendix 6). Other procedures may be performed at the Investigator’s (or designee’s) and/or 
Sponsor’s discretion. If the subject is in-house, these procedures should be performed before 
the subject is discharged from the clinic. The Investigator (or designee) may also request that 
the subject return for an additional Follow-up visit. All withdrawn subjects will be followed 
until resolution of all their AEs or until the unresolved AEs are judged by the Investigator (or 
designee) to have stabilized. 
Subjects who are withdrawn for reasons not related to study drug may be replaced following 
discussion of the PSRT Subjects withdrawn as a result of AEs thought to be related to the 
study drug will generally not be replaced. 
5. STUDY TREATMENTS 
5.1. 
Description, Storage, Packaging, and Labeling 
The IMPs (15 mg/mL CPT31 histidine formulation [50 mM histidine, 200 mM mannitol, 
pH 7.2 solution for SC injection] and placebo) will be supplied by the Sponsor (or designee), 
along with the batch/lot numbers and Certificates of Analysis. All IMPs will be provided in 
single-use vials. 
All IMPs will be stored at 2oC to 8oC at the study site in a location that is locked with 
restricted access. 
The IMPs will be labeled in accordance with national laws and regulations.  


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5.2. 
Study Treatment Administration 
All IMP vials will be removed from storage at 2oC to 8oC for between 5 to 60 minutes prior 
to dose preparation. The IMP vials will be swirled for approximately 3-5 seconds, IMP will 
be drawn up into 1 or more BD tuberculin syringes (0.3 or 1.0 mL), and syringes containing 
IMP will be used within 6 hours after dose preparation. Each dose of CPT31 and placebo will 
be administered by SC injection into the abdomen while the subject is in a semi-supine or 
sitting position. Subjects will be fasted for at least 8 hours prior to dosing and for at least 2 
hours after dosing; a meal will be provided after the 2-hour postdose assessments are 
completed. 
Subjects will be administered the IMP while semi-supine or seated and will remain 
semi-supine or seated for at least 30 minutes after dosing, except as necessitated by the 
occurrence of an AE(s) and/or study procedures.   
The doses and estimated injection volumes are detailed in Table 4. Rounding may be used 
based on measurable volumes in the appropriate syringe. 
Table 4: Injection Volumes 
Group 
Dose Level (mg/kg) 
Frequency 
Estimated Injection 
Volumea (mL) 
A1 
0.01 
Once 
0.047 
A2 
0.04 
Once 
0.187 
A3 
0.12 
Once 
0.56 
A4 
0.24 
Once 
1.12 
a 
Assuming a 70 kg subject.   
5.3. 
Randomization 
The randomization code will be produced by the Statistics Department at Covance using a 
computer-generated pseudo-random permutation procedure. Two subjects per group will be 
randomly assigned to receive placebo. For all groups, sentinel dosing will occur whereby 
2 subjects (1 active and 1 placebo) will be dosed on 1 day and, providing no safety concerns 
arise, the remaining 6 subjects (5 active and 1 placebo) will be dosed after 72 hours. 
Prior to the start of the study, the live randomization will be distributed according to the 
randomization specification form and will include the Covance CRU pharmacy staff. 
5.4. 
Blinding 
The following controls will be employed to maintain the double-blind status of the study: 
 The placebo solution may not be identical in appearance to the CPT31 solution. The 
unblinded pharmacy staff member will prepare syringes for injection (placebo and 
CPT31 solution) and an unblinded study nurse will perform the injections. If color 
differences are apparent between active and placebo in dosing syringes, then subjects 
will be blindfolded prior to and during study drug/placebo injection. Other Covance 
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 The Investigator and other members of staff involved with the study will remain 
blinded to the treatment randomization code during the assembly procedure. 
 Interim bioanalytical data will be provided to the PSRT in a blinded manner. 
To maintain the blind, the Investigator will be provided with a sealed randomization code for 
each subject, containing details of their treatment. These individual sealed envelopes will be 
kept in a limited access area that is accessible 24 hours a day. In order to manage subject 
safety or to support dose escalation decisions (in the event of possibly treatment-related SAEs 
or Grade ≥3 AEs), the decision to unblind resides solely with the Investigator. Whenever 
possible and providing it does not interfere with or delay any decision in the best interest of 
the subject, the Investigator will discuss the intended code-break with the Sponsor. If it 
becomes necessary to break the code during the study, the date, time, and reason will be 
recorded in the subject’s source data and on the individual envelope and will be witnessed by 
a second person. 
5.5. 
Treatment Compliance 
The following measures will be employed to ensure treatment compliance: 
 All doses will be administered under the supervision of suitably qualified study site 
staff. 
 At each dose preparation occasion, a predose and postdose inventory of IMP will be 
performed.  
5.6. 
Drug Accountability 
The Investigator (or designee) will maintain an accurate record of the receipt of the study 
supplies received. In addition, an accurate drug disposition record will be kept, specifying the 
amount dispensed to each subject and the date of dispensing. This drug accountability record 
will be available for inspection at any time. At the completion of the study, the original drug 
accountability record will be available for review by the Sponsor upon request. 
Empty or partially used IMP vials will be discarded upon satisfactory completion of the 
compliance and accountability procedures. Any unused IMP vials will be retained until 
completion of the study. 
At the completion of the study, all unused supplies will be returned to the Sponsor or 
disposed of by the study site, per the Sponsor’s written instructions. 
6. CONCOMITANT THERAPIES AND OTHER RESTRICTIONS 
6.1. 
Concomitant Therapies 
Subjects will refrain from use of any prescription or nonprescription medications/products 
(including HIV medications being used for pre-exposure prophylaxis) within 14 days of 
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Paracetamol/acetaminophen (2 g/day for up to 3 consecutive days), hormone replacement 
therapy, oral, implantable, transdermal, injectable, or intrauterine contraceptives are 
acceptable concomitant medications. The administration of any other concomitant 
medications during the study is prohibited without prior approval of the Investigator (or 
designee), unless its use is deemed necessary for treatment of an AE. Any medication taken 
by a subject during the course of the study and the reason for its use will be documented in 
the source data. 
All concomitant medications, over-the-counter preparations, vitamins and nutritional 
supplements, recreational drugs, and herbal preparations reported throughout the course of 
the study will be recorded in the source documents and on eCRFs designated for that purpose. 
6.2. 
Diet 
While confined at the study site, subjects will receive a standardized diet at scheduled times 
that do not conflict with other study-related activities. Subjects will be fasted overnight (at 
least 8 hours) before collection of blood samples for clinical laboratory evaluations that 
include the lipid panel (see Appendix 6).  
On the days with intensive PK assessments (Day 1), meals will be identical for each group. 
On Day 1, subjects will be fasted for at least 8 hours prior to dosing, and at least 2 hours after 
dosing; a light breakfast will be provided after the 2-hour postdose assessments are 
completed. Breakfast time will be staggered between subjects to ensure that it is taken at the 
same time with respect to dosing. 
Meals will be provided as appropriate at other times. Water will be freely available at all 
times. 
Caffeine-containing foods and beverages will not be allowed from 48 hours before Day -1 
until Discharge.  
Consumption of alcohol will not be permitted from 72 hours prior to Day -1 until the 
Follow-up visit. 
6.3. 
Smoking 
Subjects will not be permitted to use tobacco- or nicotine-containing products within 
3 months prior to Day -1 until the Follow-up visit. 
6.4. 
Exercise 
Subjects are required to refrain from strenuous exercise from 7 days before Day -1 until the 
Follow-up visit and will otherwise maintain their normal level of physical activity during this 
time (i.e., will not begin a new exercise program nor participate in any unusually strenuous 
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6.5. 
Blood Donation 
Subjects are required to refrain from donation of blood from 3 months prior to Screening, 
plasma from 2 weeks prior to Screening, and platelets from 6 weeks prior to Screening until 
3 months after the Follow-up visit.  
7. STUDY ASSESSMENTS AND PROCEDURES 
Every effort will be made to schedule and perform the procedures as closely as possible to the 
nominal time, giving considerations to appropriate posture conditions, practical restrictions, 
and the other procedures to be performed at the same timepoint. 
The highest priority procedures will be performed closest to the nominal time. The order of 
priority for scheduling procedures around a timepoint is (in descending order of priority): 
 dosing 
 blood samples 
 urine samples (for CPT31 assay, males only) 
 any other procedures (ECGs will be scheduled before vital signs measurements). 
Where activities at a given timepoint coincide, consideration must be given to ensure that the 
following order of activities is maintained: ECGs, vital signs, blood draws. 
7.1. 
Pharmacokinetic Assessments 
7.1.1. 
Sample Collection and Processing 
Blood samples (approximately 2 × 1 mL) will be collected by venipuncture or cannulation at 
the times indicated in the Schedule of Assessments in Appendix 6. Furthermore, up to 
3 additional blood samples may be taken from each subject, with the maximum volume of 
blood withdrawn per subject not exceeding the limit detailed in Appendix 3. Any changes to 
the scheduled times of PK assessments will be agreed with the Sponsor and documented in 
the TMF. Samples taken from subjects who received placebo will not be analyzed.  
Procedures for collection, processing, and shipping of PK blood samples will be detailed in a 
separate document.  
Urine samples, for male subjects only, will be collected into pre-weighed polyethylene 
containers over the time intervals indicated in the Schedule of Assessments in Appendix 6. 
Procedures for collection, processing, and shipping of urine samples will be detailed in a 
separate document. 
7.1.2. 
Analytical Methodology 
Plasma and urine concentrations of CPT31 will be determined using validated analytical 
procedures. Specifics of the analytical methods will be provided in separate documents. 


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7.2. 
Immunogenicity Assessments 
Blood samples (approximately 2 × 1 mL) will be collected by venipuncture or cannulation at 
the times indicated in the Schedule of Assessments in Appendix 6. The timings may be 
subject to change based on the ongoing review of the data. 
7.3. 
Safety and Tolerability Assessments 
7.3.1. 
Adverse Events 
Adverse event definitions, assignment of severity and causality, and procedures for reporting 
SAEs are detailed in Appendix 1. 
The condition of each subject will be monitored from the time of signing the ICF to final 
discharge from the study. Subjects will be observed for any signs or symptoms and asked 
about their condition by open questioning, such as “How have you been feeling since you 
were last asked?”, at least once each day while resident at the study site and at each study 
visit. Subjects will also be encouraged to spontaneously report AEs occurring at any other 
time during the study. 
All nonserious AEs, whether reported by the subject voluntarily or upon questioning, or 
noted on physical examination, will be recorded from initiation of study drug until study 
completion. Serious AEs will be recorded from the time the subject signs the ICF until study 
completion. The nature, time of onset, duration, and severity will be documented, together 
with an Investigator’s (or designee’s) opinion of the relationship to study drug. Photos may 
be taken of visible side effects, such as a skin rash, for the study records. 
Adverse events recorded during the course of the study will be followed up, where possible, 
until resolution or until the unresolved AEs are judged by the Investigator (or designee) to 
have stabilized. This will be completed at the Investigator’s (or designee’s) discretion. 
7.3.2. 
Clinical Laboratory Evaluations 
Blood and urine samples will be collected for clinical laboratory evaluations (including 
clinical chemistry, hematology, urinalysis, coagulation, and serology) at the times indicated 
in the Schedule of Assessments in Appendix 6. Clinical laboratory evaluations are listed in 
Appendix 2. Additional clinical laboratory evaluations will be performed at other times if 
judged to be clinically appropriate or if the ongoing review of the data suggests a more 
detailed assessment of clinical laboratory safety evaluations is required. 
Subjects will be asked to provide urine samples for drugs of abuse screen and cotinine test, 
and will undergo an alcohol breath test at the times indicated in the Schedule of Assessments 
in Appendix 6. For all female subjects, a pregnancy test will be performed at the times 
indicated in the Schedule of Assessments in Appendix 6.  
An Investigator (or designee) will perform a clinical assessment of all clinical laboratory 
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7.3.3. 
Vital Signs 
Supine blood pressure, supine pulse rate, respiratory rate, and oral body temperature will be 
assessed at the times indicated in the Schedule of Assessments in Appendix 6. Vital signs 
may also be performed at other times if judged to be clinically appropriate or if the ongoing 
review of the data suggests a more detailed assessment of vital signs is required. 
Day 1 predose blood pressure, pulse rate, and respiratory rate will be measured in triplicate at 
approximately 2-minute intervals. The median value will be used as the baseline value in the 
data analysis. All subsequent measurements will be performed singly and repeated once if 
outside the relevant clinical reference ranges. Oral body temperature will be measured singly. 
Subjects must be supine for at least 5 minutes before blood pressure and pulse rate 
measurements. 
7.3.4. 
Electrocardiogram 
7.3.4.1. 
12-Lead Electrocardiogram 
Resting 12-lead ECGs will be recorded after the subject has been supine and at rest for at 
least 5 minutes at the times indicated in the Schedule of Assessments in Appendix 6. Single 
12-lead ECGs will be repeated 2 more times, and an average taken of the 3 readings, if either 
of the following criteria apply: 
 QTcF value > 500 msec 
 QTcF change from the baseline (predose) is > 60 msec. 
Additional 12-lead ECGs may be performed at other times if judged to be clinically 
appropriate or if the ongoing review of the data suggests a more detailed assessment of ECGs 
is required. The Investigator (or designee) will perform a clinical assessment of each 12-lead 
ECG.  
Day 1 predose 12-lead ECGs will be measured in triplicate at approximately 2-minute 
intervals. The mean value will be used as the baseline value in the data analysis. All 
subsequent measurements will be performed singly and repeated 2 more times if outside the 
relevant clinical reference ranges, as described above. 
7.3.4.2. 
Continuous 12-lead Electrocardiogram Monitoring 
Continuous 12-lead ECG monitoring (Groups A3 and A4 only) using a digital recorder will 
take place at the times indicated in the Schedule of Assessments in Appendix 6. 
All Continuous ECG data collected on study will be archived without extraction or analysis 
and will not be reported in the scope of this study.  
Subjects will be supine for at least 10 minutes before the extraction timepoint and for 
5 minutes from the start of each extraction timepoint (each extraction will last for 5 minutes). 
Environmental distractions (e.g., television, radio, conversation) should be avoided during the 
pre-ECG resting period and during ECG recording.  


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When coinciding, vital signs assessments and PK sampling should always be performed after 
the ECG extraction time window. If a separate ECG machine is being used for safety 
assessments described in Section 7.3.4.1, that machine should be in place prior to the 
extraction window to permit safety ECGs to be recorded irrespective of the extraction 
window. If the machine is not in place prior to the extraction window, safety ECGs must be 
recorded after the extraction window. If an integral system is used, safety ECGs may be 
recorded irrespective of the extraction window.  
7.3.5. 
Physical Examination 
A full physical examination or symptom-directed physical examination will be performed at 
the timepoints specified in the Schedule of Assessments in Appendix 6. 
7.3.6. 
Body Weight 
Body weight (in light clothing) will be recorded at the times indicated in the Schedule of 
Assessments in Appendix 6. 
8. SAMPLE SIZE AND DATA ANALYSIS 
8.1. 
Determination of Sample Size 
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time CPT31 is being administered to humans. However, the number of subjects in the 
present study is common in early clinical pharmacology studies and is considered sufficient 
to achieve the objectives of the study. A common distribution between active and placebo 
subjects is 6+2. Buoen et al. (Evaluation of the Cohort Size in Phase I Dose Escalation Trials 
Based on Laboratory Data, J Clin Pharmacol (2003) 43:470-476) investigated the impact of 
cohort size on Type I error and power in Phase I dose escalation trials based on laboratory 
data and concluded that “the active cohort size in Phase I dose escalation trials should be 
between 6 and 10 active subjects.” 
8.2. 
Analysis Populations 
8.2.1. 
Pharmacokinetic Population 
The PK population will include all subjects who received at least 1 dose of CPT31 and have 
evaluable PK data.  
8.2.2. 
Safety Population 
The Safety population will include all subjects who received at least 1 dose of study 
treatment (CPT31 or placebo). 
8.3. 
Pharmacokinetic Analyses 
Noncompartmental PK analysis will be performed on individual plasma and urine 
concentration data, using commercial software such as Phoenix® WinNonlin®. Plasma 
concentrations of CPT31 and PK parameters will be listed and summarized using descriptive 


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statistics. Urine concentrations of CPT31 will be listed. Individual and mean CPT31 
concentration-time profiles will also be presented graphically. 
Where data are available, CPT31 dose proportionality will be examined across dose groups. 
The PK parameters will be analyzed for dose proportionality using a power model approach 
or analysis of variance (ANOVA) model, as appropriate. 
8.4. 
Safety Analysis 
Safety parameters will be listed and summarized using descriptive statistics.  The frequency 
of subjects with QTcB >470 ms or change from baseline >30 ms will be summarized for each 
treatment.  No formal statistical analysis of safety data is planned. Each AE will be coded 
using the Medical Dictionary for Regulatory Activities. 
8.5. 
Interim Analysis 
No formal interim statistical analyses are planned for this study. 
9. REFERENCES 
1 
UNAIDS. 2017 Global HIV Statistics.  Fact Sheet (Dec. 2018). 
2 
Avert. HIV and AIDS in the United States of America.  Fact Sheet (Dec. 2018). 
3 
Division_of_HIV/AIDS_Prevention. HIV in the United States and Dependent Areas.  Fact 
Sheet (Jan. 2019). 
4 
Kim, S. H., Gerver, S. M., Fidler, S. & Ward, H. Adherence to antiretroviral therapy in 
adolescents living with HIV: systematic review and meta-analysis. AIDS 28, 1945-1956, 
doi:10.1097/QAD.0000000000000316 (2014). 
5 
Dintzis, H. M., Symer, D. E., Dintzis, R. Z., Zawadzke, L. E. & Berg, J. M. A comparison of 
the immunogenicity of a pair of enantiomeric proteins. Proteins 16, 306-308 (1993). 
6 
Gautam, R. et al. Pathogenicity and mucosal transmissibility of the R5-tropic simian/human 
immunodeficiency virus SHIV(AD8) in rhesus macaques: implications for use in vaccine 
studies. J Virol 86, 8516-8526, doi:10.1128/JVI.00644-12 (2012). 
7 
Bar, K. J. et al. Effect of HIV Antibody VRC01 on Viral Rebound after Treatment 
Interruption. N Engl J Med 375, 2037-2050, doi:10.1056/NEJMoa1608243 (2016). 
8 
Navigen_Inc. CPT31 - Investigator’s Brochure.  (Oct. 2019). 
9 
FDA_Guidance_Document.     (2005). 
10 
Nair, A. B. a. J. S. A simple practical guide for dose conversion between animals and humans. 
J Basic Clin Pharma 7, 27-31 (2016). 
 
 


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10. APPENDICES 


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Appendix 1: Adverse Event Reporting 
Definitions 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product, which does not necessarily have 
a causal relationship with this treatment. An AE can therefore be any unfavorable and/or 
unintended sign (including a clinically significant abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a study drug, whether or not related to the study 
drug. 
Assessment of Severity 
The Investigator will be asked to provide an assessment of the severity of the AE using the 
following criteria defined by the Division of AIDS Table for Grading the Severity of Adult 
and Pediatric Adverse Events, Version 2.1 dated July 2017:  
 Grade 1, Mild: Usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 
 Grade 2, Moderate: Usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
 Grade 3, Severe: Interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
 Grade 4, Potentially Life-threatening: The subject was at immediate risk of death 
from the event as it occurred (i.e., does not include a reaction that might have caused 
death if it had occurred in a more serious form). For instance, drug-induced hepatitis 
that resolved without evidence of hepatic failure would not be considered 
life-threatening even though drug-induced hepatitis can be fatal. 
 Grade 5, Death. 
Relationship to Study Treatment 
The Investigator (or designee) will make a determination of the relationship of the AE to the 
study drug using a 4-category system according to the following guidelines: 
 Not Related: The AE is definitely caused by the subject’s clinical state or the study 
procedure/conditions. 
 Unlikely Related: The temporal association between the AE and the drug is such that 
the drug is not likely to have any reasonable association with the AE. 
 Possibly Related: The AE follows a reasonable temporal sequence from the time of 
drug administration but could have been produced by the subject’s clinical state or the 
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 Related: The AE follows a reasonable temporal sequence from administration of the 
drug, abates upon discontinuation of the drug, follows a known or hypothesized 
cause-effect relationship, and (if appropriate) reappears when the drug is reintroduced.  
Follow-up of Adverse Events 
Every reasonable effort will be made to follow up with subjects who have AEs. Any subject 
who has an ongoing AE that is possibly related or related to the IMP or study procedures at 
the Follow-up visit will be followed up, where possible, until resolution or until the 
unresolved AE is judged by the Investigator (or designee) to have stabilized. This will be 
completed at the Investigator’s (or designee’s) discretion. Any subject who has an ongoing 
AE that is not related or unlikely related to the IMP or study procedures at the Follow-up visit 
can be closed out as ongoing at the Investigator’s discretion.  
Adverse Drug Reactions 
All noxious and unintended responses to an IMP (i.e., where a causal relationship between an 
IMP and an AE is at least a reasonable possibility) related to any dose should be considered 
as adverse drug reactions. 
For marketed medicinal products, a response to a drug which is noxious and unintended, and 
which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases 
or for modification of physiological function is to be considered an adverse drug reaction. 
An unexpected adverse drug reaction is defined as an adverse reaction, the nature or severity 
of which is not consistent with the applicable product information (e.g., Investigator’s 
Brochure for an unapproved IMP). 
Serious Adverse Events 
A serious AE (SAE) is defined as any untoward medical occurrence that at any dose either: 
 results in death 
 is life-threatening 
 requires inpatient hospitalization or prolongation of existing hospitalization 
 results in persistent or significant disability/incapacity (disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions) 
 results in a congenital anomaly/birth defect 
 results in an important medical event (see below). 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered SAEs when, based upon appropriate medical judgment, 
they may jeopardize the subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 


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Instances of death or congenital abnormality, if brought to the attention of the Investigator at 
any time after cessation of the study treatment and considered by the Investigator to be 
possibly related to the study treatment, will be reported to the Protocol Safety Review Team 
(PSRT). 
Definition of Life-threatening 
An AE is life-threatening if the subject was at immediate risk of death from the event as it 
occurred (i.e., does not include a reaction that might have caused death if it had occurred in a 
more serious form). For instance, drug-induced hepatitis that resolved without evidence of 
hepatic failure would not be considered life-threatening even though drug-induced hepatitis 
can be fatal. 
Definition of Hospitalization 
Adverse events requiring hospitalization should be considered serious. In general, 
hospitalization signifies that the subject has been detained (usually involving an overnight 
stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate at the Clinical Research Unit (CRU). When in doubt as to whether 
hospitalization occurred or was necessary, the AE should be considered as serious. 
Hospitalization for elective surgery or routine clinical procedures, which are not the result of 
an AE, need not be considered AEs and should be recorded on a Clinical Assessment Form 
and added to the electronic Case Report Form. If anything untoward is reported during the 
procedure, this must be reported as an AE and either ‘serious’ or ‘nonserious’ attributed 
according to the usual criteria. 
Serious Adverse Event Reporting 
Food and Drug Administration reportable AEs are AEs that are associated with the use of the 
drug and are serious and unexpected. Food and Drug Administration-reportable AEs will be 
reported by the study site to the PSRT and the responsible Institutional Review Board (IRB). 
The PSRT will be notified in writing (e.g., facsimile) within 24 hours of when an AE that is 
potentially FDA-reportable is first recognized or reported. 
Subsequently, a written confirmation or summary of the AE (using FDA Form 3500A or 
equivalent) will be sent to the Sponsor within 3 working days of the original notification.  
The IRB will be notified of any FDA-reportable AEs within the timeframe required by the 
IRB. The IRB Serious and Unexpected Adverse Experience Submission Form will be 
completed and submitted with the copy of the written confirmation or summary of the AE. 
The responsibility for reporting SAEs will be transferred to the Sponsor 30 days after the end 
of the study. 
 
 


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 Reference: CPT31-001 
Protocol Version 4, 27 July 2020 
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Pregnancy 
Pregnancy (maternal or paternal exposure to study drug) does not meet the definition of an 
AE. However, to fulfill regulatory requirements any pregnancy should be reported following 
the serious AE process to collect data on the outcome for both mother and fetus. 
 
 


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 Reference: CPT31-001 
Protocol Version 4, 27 July 2020 
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Appendix 2: Clinical Laboratory Evaluations 
Clinical chemistry: 
Hematology: 
Urinalysis: 
Alanine aminotransferase 
Albumina 
Alkaline phosphatase 
Aspartate aminotransferase 
Blood urea nitrogen  
Calcium 
Chloride 
Creatinine 
Gamma-glutamyl transferase 
Glucose (random) 
Potassium  
Sodium  
Total bilirubinb 
Total proteina 
Uric acid 
Fibrinogen 
C-reactive protein 
 
Cytokine panel 
IL-1 
IL-6 
TNF- 
 
Lipid panel (fasted)c 
Cholesterol 
Low density lipoprotein 
High density lipoprotein 
Triglycerides 
Hematocrit  
Hemoglobin 
Mean cell hemoglobin 
Mean cell hemoglobin 
concentration 
Mean cell volume 
Platelet count 
Red blood cell (RBC) count 
RBC distribution width  
White blood cell (WBC) count 
WBC differential: 
   Basophils 
   Eosinophils 
   Lymphocytes 
   Monocytes 
   Neutrophils 
 
Coagulation profile: 
Activated partial thromboplastin 
time 
International normalized ratio 
Prothrombin time 
 
Bilirubin  
Blood 
Color and appearance  
Glucose 
Ketones 
Leukocyte esterase  
Nitrite  
pH 
Protein 
Specific gravity 
Urobilinogen 
Microscopic examination (if 
protein, leukocyte esterase, 
nitrite, or blood is positive)  
 
Serologyd: 
Drug screene: 
Hormone panel - females 
only: 
Anti-hepatitis B surface antibody 
Anti-hepatitis B core antibody  
Hepatitis B surface antigen 
Hepatitis C antibody 
Human immunodeficiency 
(HIV-1 and HIV-2) Combo 
Ag/Ab HIV-1/HIV-2 
immunoassay 
Including but not limited to:  
Amphetamines/methamphetamines 
Barbiturates 
Benzodiazepines 
Cocaine (metabolite) 
Methadone 
Phencyclidine 
Opiates 
Tetrahydrocannabinol/ 
Cannabinoids 
cotinine 
Alcoholf 
Alcohol breath testf   
Follicle-stimulating hormoned 
(postmenopausal females only) 
Serum pregnancy test (human 
chorionic gonadotropin)g 
 
a Calculated globulin and albumin:globulin ratio will be derived.  
b Direct and indirect bilirubin will be analyzed if total bilirubin is elevated. 
c Fasted lipid panel only included as indicated in the Schedule of Assessments (Appendix 6). 
d Only analyzed at Screening. 


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e Urine test to include cotinine.  
f Alcohol breath test (not included at Screening). 
g Performed at Screening, Day -1, and Follow-up for all females.  


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Covance Study: 8405732 
 
 Reference: CPT31-001 
Protocol Version 4, 27 July 2020 
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Appendix 3: Total Blood Volume 
The following blood volumes will be withdrawn for each subject. 
 
Volume per blood 
sample (mL) 
Maximum number of 
blood samples 
Total amount of 
blood (mL) 
Clinical laboratory 
evaluations 
12.5 
8 
100 
Serology 
3.5 
1 
3.5 
Coagulation 
2.7 
8 
21.6 
CPT31 
pharmacokinetics 
2 
18 
36 
Immunogenicity 
2 
4 
8 
Total: 
169.1 
If extra blood samples are required, the maximum blood volume to be withdrawn per subject 
will not exceed 400 mL. 


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Covance Study: 8405732 
 
 Reference: CPT31-001 
Protocol Version 4, 27 July 2020 
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Appendix 4: Contraception Guidance 
Definitions 
Women of Childbearing Potential: premenopausal females who are anatomically and 
physiologically capable of becoming pregnant following menarche. 
Women of Nonchildbearing Potential:  
1. Surgically sterile: females who are permanently sterile via hysterectomy, 
bilateral salpingectomy, and/or bilateral oophorectomy by reported medical 
history and/or medical records. Surgical sterilization to have occurred a minimum 
of 6 weeks, or at the Investigator’s discretion, prior to Screening. 
2. Postmenopausal: Females at least 45 years of age with amenorrhea for 12 months 
without an alternative medical reason with confirmatory follicle-stimulating 
hormone (FSH) levels of ≥ 40 mIU/mL. The amenorrhea should not be induced by 
a medical condition such as anorexia nervosa, hypothyroid disease or polycystic 
ovarian disease, or by extreme exercise. It should not be due to concomitant 
medications that may have induced the amenorrhea such as oral contraceptives, 
hormones, gonadotropin-releasing hormones, anti-estrogens, or selective estrogen 
receptor modulators. Women aged > 60 years old whose FSH values are not 
≥ 40 mIU/L may be included at the discretion of the Investigator and in 
consultation with the Sponsor.  
Fertile male: a male that is considered fertile after puberty. 
Infertile male: permanently sterile male via bilateral orchiectomy. 
Contraception Guidance 
Female Subjects 
Female subjects who are of nonchildbearing potential will not be required to use 
contraception. Female subjects of childbearing potential must be willing to use 2 methods 
(1 primary and 1 secondary method) of birth control from the time of signing the Informed 
Consent Form (ICF) until 90 days after the Follow-up visit. Primary (non-barrier) methods of 
contraception include: 
 hormonal injection (as prescribed) 
 combined oral contraceptive pill or progestin/progestogen-only pill (as prescribed) 
 combined hormonal patch (as prescribed) 
 combined hormonal vaginal ring (as prescribed) 
 hormonal IUD 
 surgical method performed at least 3 months prior to the Screening Visit: 
o 
bilateral tubal ligation 


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o 
Essure® (hysteroscopic bilateral tubal occlusion) with confirmation of 
occlusion of the fallopian tubes 
 hormonal implant 
 vasectomized male partner (sterilization performed at least 90 days prior to the 
Screening Visit, with verbal confirmation of surgical success, and the sole partner for 
the female subject)  
Secondary (barrier) methods of contraception include: 
 male condom with spermicide 
 female condom with spermicide 
 over-the-counter sponge with spermicide 
 cervical cap with spermicide (as prescribed) 
 hormonal or non-hormonal intrauterine device (IUD) 
 diaphragm with spermicide (as prescribed). 
Female subjects of childbearing potential should refrain from donation of ova from Check-in 
(Day -1) until 90 days after the Follow-up visit. 
Male Subjects 
Male subjects will be surgically sterile for at least 90 days, with documented azoospermia, or 
when sexually active with female partners of childbearing potential will be required to use a 
male condom with spermicide (even if subject has a history of vasectomy) from Check-in 
until 90 days after the Follow-up visit. Sexual intercourse with female partners who are 
pregnant or breastfeeding should be avoided unless condoms are used from the time of the 
first dose until 90 days after the Follow-up visit. Male subjects are required to refrain from 
donation of sperm from Check-in until 90 days after the Follow-up visit.  
Sexual Abstinence and Same-sex Relationships 
For subjects who practice true abstinence, subjects must be abstinent for at least 6 months 
prior to Screening and must agree to remain abstinent from the time of signing the ICF until 
90 days after the Follow-up visit. 
A subject in a same-sex relationship at the time of signing the ICF must agree to refrain from 
engaging in a heterosexual relationship from the time of signing the ICF until 90 days after 
the Follow-up visit. 


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 Reference: CPT31-001 
Protocol Version 4, 27 July 2020 
Page 47 of 55 
Appendix 5: Regulatory, Ethical, and Study Oversight Considerations 
Regulatory and Ethical Considerations 
This study will be conducted in accordance with the protocol and with the following: 
 Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences International Ethical Guidelines. 
 Applicable International Conference on Harmonisation (ICH) Good Clinical Practice 
(GCP) Guidelines. 
 Applicable laws and regulations. 
The protocol, protocol amendments, Informed Consent Form (ICF), Investigator Brochure, 
and other relevant documents (e.g., advertisements) must be submitted to an Institutional 
Review Board (IRB) by the Investigator and reviewed and approved by the IRB before the 
study is initiated. 
Any amendments to the protocol will require IRB and regulatory authority (as locally 
required) approval before implementation of changes made to the study design, except for 
changes necessary to eliminate an immediate hazard to study subjects. All protocol 
amendments must be approved by the NIAID Division of AIDS at the National Institutes of 
Health. 
The Investigator will be responsible for the following: 
 Providing written summaries of the status of the study to the IRB annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB. 
 Notifying the IRB of SAEs or other significant safety findings as required by IRB 
procedures. 
 Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 Code of Federal Regulations (CFR), ICH guidelines, the IRB, 
European Regulation 536/2014 for clinical studies (if applicable), and all other 
applicable local regulations. 
Finances and Insurance 
Financing and insurance will be addressed in a separate agreement. 
Informed Consent 
Prior to starting participation in the study, each subject will be provided with a study-specific 
ICF giving details of the study drugs, procedures, and potential risks of the study. Subjects 
will be instructed that they are free to obtain further information from the Investigator (or 
designee) and that their participation is voluntary and they are free to withdraw from the 


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 Reference: CPT31-001 
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study at any time. Subjects will be given an opportunity to ask questions about the study prior 
to providing consent for participation. 
Following discussion of the study with Clinical Research Unit (CRU) personnel, subjects will 
sign 2 copies of the ICF in the presence of a suitably trained member of staff to indicate that 
they are freely giving their informed consent. One copy will be given to the subject, and the 
other will be maintained in the subject’s records. 
Subjects must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 
Subject Data Protection 
Subjects will be assigned a unique identifier and will not be identified by name in electronic 
Case Report Forms (eCRFs), study-related forms, study reports, or any related publications. 
Subject and Investigator personal data will be treated in compliance with all applicable laws 
and regulations. In the event the study protocol, study report, or study data are included in a 
public registry, all identifiable information from individual subjects or Investigators will be 
redacted according to applicable laws and regulations.  
The subject must be informed that his/her personal study-related data will be used by the 
Sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the subject. The subject must also be informed that his/her study-related data 
may be examined by Sponsor or Contract Research Organization (CRO) auditors or other 
authorized personnel appointed by the Sponsor, by appropriate IRB members, and by 
inspectors from regulatory authorities such as the Food and Drug Administration (FDA).  
Disclosure 
All information provided regarding the study, as well as all information collected and/or 
documented during the course of the study, will be regarded as confidential. The Investigator 
(or designee) agrees not to disclose such information in any way without prior written 
permission from the Sponsor. 
Data Quality Assurance 
The following data quality steps will be implemented: 
 All relevant subject data relating to the study will be recorded on eCRFs unless 
directly transmitted to the Sponsor or designee electronically (e.g., laboratory data). 
The Investigator is responsible for verifying that data entries are accurate and correct 
by electronically signing the eCRF.  
 The Investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.  
 The Investigator must permit study-related monitoring, audits, IRB review, and 
regulatory agency inspections and provide direct access to source data documents.  


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 Reference: CPT31-001 
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 The Sponsor or designee is responsible for the data management of this study 
including quality checking of the data. Predefined agreed risks, monitoring thresholds, 
quality tolerance thresholds, controls, and mitigation plans will be documented in a 
risk management register. Additional details of quality checking to be performed on 
the data may be included in a Data Management Plan.  
 A Study Monitor will perform ongoing source data verification to confirm that data 
entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of subjects are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
 Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained by the Investigator in accordance with 21 CFR 312.62(c) unless local 
regulations or institutional policies require a longer retention period. No records may 
be destroyed during the retention period without the written approval of the Sponsor. 
No records may be transferred to another location or party without written notification 
to the Sponsor.  
Investigator Documentation Responsibilities 
All individual, subject-specific study data will also be entered into a 21 CFR 
Part 11-compliant electronic data capture (EDC) system on an eCRF in a timely fashion. 
All data generated from external sources (e.g., laboratory and bioanalytical data), and 
transmitted to the Sponsor or designee electronically, will be integrated with the subject’s 
eCRF data in accordance with the Data Management Plan.  
An eCRF must be completed for each enrolled subject who undergoes any Screening 
procedures, according to the eCRF completion instructions. The Sponsor, or CRO, will 
review the supporting source documentation against the data entered into the eCRFs to verify 
the accuracy of the electronic data. The Investigator will ensure that corrections are made to 
the eCRFs and that data queries are resolved in a timely fashion by the study staff. 
The Investigator will sign and date the eCRF via the EDC system’s electronic signature 
procedure. These signatures will indicate that the Investigator reviewed and approved the 
data on the eCRF, data queries, and site notifications. 
Publications 
If on completion of the study the data warrant publication, the Investigator may publish the 
results in recognized (refereed) scientific journals subject to the provisions of the clinical 
study agreement (CSA). Unless otherwise specified in the CSA, the following process will 
occur: 
If the Investigator expects to participate in the publication of data generated from this site, the 
institution and Investigator will submit reports, abstracts, manuscripts, and/or other 
presentation materials to the Sponsor for review before submission for publication or 


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 Reference: CPT31-001 
Protocol Version 4, 27 July 2020 
Page 50 of 55 
presentation. The Sponsor will have 60 days to respond with any requested revisions 
including, without limitation, the deletion of confidential information. The Investigator will 
act in good faith upon requested revisions, except the Investigator will delete any confidential 
information from such proposed publications. The Investigator will delay submission of such 
publication or presentation materials for up to an additional 90 days in order to have a patent 
application(s) filed. 


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 Reference: CPT31-001 
Protocol Version 4, 27 July 2020 
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Appendix 6: Schedule of Assessments 


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Protocol Version 4, 27 July 2020 
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Schedule of Assessments 
Study Procedures 
Screening 
Day -28 to 
Day -2 
 
Treatment Period 
Follow-up 
(28-30 days 
postdose) 
Day -1 
Days 1 to 6 
Informed consent 
X 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
Demographic data 
X 
 
 
 
Medical and surgical history 
X 
Xa 
 
 
Urinary drug screen 
X 
X 
 
 
Alcohol breath test 
 
X 
 
 
HIV, hepatitis B, and 
hepatitis C tests 
X 
 
 
 
Serum pregnancy testb 
X 
X 
 
X 
Height and body weight 
Xc 
X 
 
 
Study residency: 
 
 
 
 
Check-in 
 
X 
 
 
Check-out 
 
 
Day 6 
 
Nonresidential visit 
X 
 
 
X 
Study drug 
administration: 
 
 
 
 
CPT31or placebo 
 
 
Day 1 (0 h)  
 
Pharmacokinetics:  
 
 
 
 
Blood samplingd 
 
 
Day 1 predose, 0.5 h (±3 min), 1 h (±6 min), 2 h (±12 min), 4 h (±30 min), 6 h 
(±30 min), 8 h (±30 min), 10 h (±30 min), 12 h (±30 min), 16 h (±30 min), Day 2 
(24 h, ±30 min), Day 3 (48 h, ±4 h), Day 4 (72 h, ±4 h), Day 5 (96 h, ±4 h), and 
Day 6 (120 h, ±4 h)  
 
Urine samplingd, i 
 
 
Day 1 predose (spot collection) and 0 to 4 h (±15 min), 4 to 8 h (±15 min), Day 1 
to Day 2 (8 to 24 h, ±15 min), Day 2 to Day 3 (24 to 48 h, ±15 min), and Day 3 to 
Day 4 (48 h to 72 h ±15 min) 
 


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 Reference: CPT31-001 
Protocol Version 4, 27 July 2020 
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Schedule of Assessments 
Study Procedures 
Screening 
Day -28 to 
Day -2 
 
Treatment Period 
Follow-up 
(28-30 days 
postdose) 
Day -1 
Days 1 to 6 
Immunogenicity: 
 
 
 
 
Blood samplingd 
 
 
Day 1 predose, Day 2 (24 h), Day 5 (96 h)  
X 
Safety and tolerability: 
 
 
 
 
Adverse event recording 
X 
X 
Ongoing 
X 
Prior/concomitant 
medication monitoring 
X 
X 
Ongoing 
X 
Clinical laboratory 
evaluations (including 
coagulation)d 
Xe 
Xe 
Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 (120 he) 
X 
Supine blood pressure, 
supine pulse rate, 
respiratory rate and oral 
body temperatured 
X 
X 
Day 1 predose, 2 h, 4 h, 12 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 
(96 h), and Day 6 (120 h) 
X 
12-lead ECGd 
X 
 
Day 1 predose, 2 h, 4 h, 12 h, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 
(96 h), and Day 6 (120 h) 
X 
Continuous 12-lead ECG 
 
 
Xf 
 
Physical examinationd 
Xg 
 
Day 1 predose, Day 2 (24 h), Day 3 (48 h), Day 4 (72 h), Day 5 (96 h), and Day 6 
(120 h)h 
Xh 
Abbreviations: ECG = electrocardiogram, h = hour; HIV = human immunodeficiency virus; min = minute.  
a Interim medical history. 
b In all females.  
c Height measured at Screening only. 
d Times (h) relative to dosing. 
e Clinical laboratory tests to include lipid panel (fasted). 
f Monitor for 12-lead ECG recording will be worn from 2 hours predose to 25 hours postdose on Day 1. Extraction timepoints will be 60, 45, and 30 minutes predose and at and 0.25 hours, 
0.5 hours, 1 hour, 2 hours, 4 hours, 6 hours, 8 hours, 10 hours, 12 hours, 24 hours postdose. Continuous 12-lead ECG will be performed on Groups A3 and A4 only. 
g Performed between the Screening Visit and predose assessments. 
h Symptom-directed physical examination at all timepoints other than Screening. 


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 Reference: CPT31-001 
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iPK urine sampling for males only


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 Reference: CPT31-001 
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Appendix 7: Protocol Amendment(s)– Summary of Changes 
Protocol Amendment 2 (Protocol Version 3)  
PURPOSE: To update wording related to the appearance and blinding requirements of 
CPT31 and placebo solutions. 
MODIFICATIONS TO PROTOCOL:  
General Revisions:  
Section 3.5: Wording revised as no systemic exposure specifically defined in section 3.7 
Section 5.2: Correction/clarification of timings 
Section 5.4: Updates to appearance of CPT31 and placebo solution information and 
potential for required study blinding actions/processes. 
ADDITIONAL RISK TO THE SUBJECT: There are no additional risks to the 
subjects. 
Protocol Amendment 3 (Protocol Version 4)  
PURPOSE: To update urine PK assessment to males only. 
MODIFICATIONS TO PROTOCOL:  
General Revisions:  
Section 7 and 7.1.1: Wording updated to state urine samples for males only (for CPT-31 
assay) 
Appendix 6: Urine sampling information for PK updated to detail males only. 
ADDITIONAL RISK TO THE SUBJECT: There are no additional risks to the 
subjects.

SAP_001.pdf: 
Statistical Analysis Plan 
A Phase Ia Clinical Study of HIV Entry Inhibitor CPT31: Single Ascending Dose Study of 
Safety, Tolerability, Immunogenicity, and Pharmacokinetics in Healthy Adults 
 
NCT Number 
NCT04672083 
 
Document Date 
August 13, 2020 


TITLE PAGE 
Statistical Analysis Plan 
A Phase Ia Clinical Study of HIV Entry Inhibitor CPT31: Single Ascending 
Dose Study of Safety, Tolerability, Immunogenicity, and Pharmacokinetics 
in Healthy Adults  
 
 
 
SAP Status: Final 
SAP Version: 1.0 
SAP Date: 13 August 2020 
Investigational Product: CPT31 
Protocol Reference: CPT31-001 
Covance Study: 8405732 
 
 
Sponsor: 
Navigen Inc 
675 Arapeen Drive, Suite 103 
Salt Lake City, Utah 84108 
USA  
 
Study Site: 
Covance Clinical Research Unit Inc. 
1900 Mason Avenue, Suite 140 
Daytona Beach, FL 32117 
USA 
 
 
 
 
 
 
 
 
Principal Investigator: 
Hugh A. Coleman. DO. 
 
 
 
Information described herein is confidential and may be disclosed only with the express 
written permission of the sponsor. 
 


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TABLE OF CONTENTS 
TITLE PAGE ............................................................................................................................. 1 
TABLE OF CONTENTS ........................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................... 4 
1. INTRODUCTION ................................................................................................................. 6 
2. STUDY OBJECTIVES .......................................................................................................... 6 
3. STUDY ENDPOINTS ........................................................................................................... 6 
3.1. Primary Endpoints ........................................................................................................... 6 
3.2. Secondary Endpoints ....................................................................................................... 7 
4. STUDY DESIGN................................................................................................................... 7 
5. SAMPLE SIZE JUSTIFICATION ........................................................................................ 9 
6. STUDY TREATMENTS ....................................................................................................... 9 
7. DEFINITIONS OF POPULATIONS .................................................................................. 10 
7.1. All Subjects Population ................................................................................................. 10 
7.2. Safety Population .......................................................................................................... 10 
7.3. Pharmacokinetic Population ......................................................................................... 10 
8. STATISTICAL METHODOLOGY .................................................................................... 10 
8.1. General .......................................................................................................................... 10 
8.1.1. Calculation of the Summary Statistics ................................................................... 11 
8.1.2. Triplicate Readings................................................................................................. 11 
8.1.3. Repeat and Unscheduled Readings ........................................................................ 11 
8.1.4. Definitions of Baseline and Change from Baseline ............................................... 12 
8.2. Subject Disposition and Population Assignment .......................................................... 12 
8.3. Screening Demographics .............................................................................................. 12 
8.4. Prior and Concomitant Medication ............................................................................... 12 
8.5. Pharmacokinetic Assessments ...................................................................................... 13 
8.5.1. Pharmacokinetic Analysis ...................................................................................... 13 
8.5.2. Presentation of Pharmacokinetic Data ................................................................... 15 
8.5.3. Pharmacokinetic Statistical Methodology .............................................................. 16 
8.6. Safety and Tolerability Assessments ............................................................................ 17 
8.6.1. Adverse Events ....................................................................................................... 17 
8.6.2. Clinical Laboratory Parameters .............................................................................. 19 
8.6.3. Vital Signs Parameters ........................................................................................... 19 


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8.6.4. 12-lead Electrocardiogram Parameters .................................................................. 20 
8.6.5. Other Assessments ................................................................................................. 20 
8.6.6. Safety and Tolerability Statistical Methodology .................................................... 20 
8.7. Immunogenicity Assessments ....................................................................................... 20 
8.7.1. Immunogenicity Endpoints .................................................................................... 20 
8.7.2. Immunogenicity Statistical Methodology .............................................................. 21 
9. INTERIM ANALYSES ....................................................................................................... 21 
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES ........ 21 
11. REFERENCES .................................................................................................................. 21 
12. APPENDICES ................................................................................................................... 22 


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Final, Version 1.0, 13 August 2020 
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LIST OF ABBREVIATIONS 
Abbreviations pertain to the statistical analysis plan (SAP) only (not the tables, figures, and 
listings [TFLs]).  
 
  
ADaM 
analysis data model 
%AUCextrap 
percentage of AUC due to extrapolation from the last quantifiable 
concentration to infinity 
AE 
adverse event 
Ae 
amount of drug excreted in the urine at each collection interval and 
cumulative amount of drug excreted in the urine at each collection 
interval 
ANOVA 
analysis of variance 
AUC0-∞ 
area under the curve from time 0 to infinity 
AUC0-tlast 
area under the curve from time 0 to the time of the last measurable  
concentration 
BLQ 
below the limit of quantification 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CL/F 
apparent total plasma clearance   
CLR 
renal clearance  
Cmax 
maximum concentration  
CSR 
clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
ECG 
Electrocardiogram 
Fe 
percentage excreted in urine at each collection interval and cumulative 
percentage excreted in urine at each collection interval 
GLSM 
geometric least squares mean 
ICH 
International Council for/Conference on Harmonisation of Technical 
Requirements for Registration of Pharmaceuticals for Human Use 
LLOQ 
lower limit of quantification 
Ln 
natural log 
LSM 
least squares mean 
MedDRA 
Medical Dictionary for Regulatory Activities 
PK 
pharmacokinetic(s) 
QTc 
QT interval corrected for heart rate 
QTcB 
QT interval corrected for heart rate using Bazett’s formula 
QTcF 
QT interval corrected for heart rate using Fridericia’s formula 
SAP 
statistical analysis plan 


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Protocol Reference: CPT31-001 
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SD 
standard deviation 
t1/2 
apparent terminal elimination half-life 
TEAE 
treatment-emergent adverse event 
TFL 
table, figure, and listing 
Tlast 
time of the last quantifiable plasma concentration 
Tmax 
time to maximum concentration 
Vz/F 
Apparent volume of distribution during the terminal elimination phase 
WHODrug 
World Health Organization Drug Dictionary  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1. INTRODUCTION 
This SAP has been developed after review of the clinical study protocol (Final Version 4.0 
dated 27 July 2020) and electronic case report form.  
This SAP describes the planned analysis of the pharmacokinetic (PK) and safety and 
tolerability data from this study. A detailed description of the planned TFLs to be presented 
in the clinical study report (CSR) is provided in the accompanying TFL shells document.  
In general, the analyses are based on information from the protocol, unless they have been 
modified by agreement with Navigen Inc. A limited amount of information about this study 
(eg, objectives, study design) is given to help the reader’s interpretation. This SAP must be 
finalized prior to the lock of the clinical database for this study. When the SAP and TFL 
shells are approved, they will serve as the template for this study’s CSR.  
This SAP supersedes any statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed 
and will be identified accordingly in the CSR. Any substantial deviations from this SAP will 
be agreed with Navigen Inc. and identified in the CSR.  
This SAP is written with consideration of the recommendations outlined in the International 
Conference on Harmonisation (ICH) E9 guideline Statistical Principles for Clinical Trials 
and ICH E3 guideline Structure and Content of Clinical Study Reports.1,2  
The document history is presented in Appendix 1.  
2. STUDY OBJECTIVES  
The primary objective of the study is: 
• to assess the safety and tolerability of a single SC dose of CPT31 in healthy subjects 
The secondary objectives of the study are: 
• to characterize the single SC dose PK of CPT31 
• to identify and characterize antibodies to CPT31 
3. STUDY ENDPOINTS  
3.1. Primary Endpoints 
The primary safety endpoints for this study are as follows: 
• incidence and severity of adverse events (AEs) 
• incidence of laboratory abnormalities, based on hematology, clinical chemistry, and 
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• 12-lead electrocardiogram (ECG) parameters 
• vital signs measurements 
• physical examinations 
• anti-CPT31 antibodies, e.g., immunoglobulin (Ig)G, IgM 
3.2. Secondary Endpoints 
The single ascending dose PK outcome endpoints of CPT31 are as follows: 
• AUC from time zero to infinity (AUC0-∞) 
• AUC from time zero to the time of the last quantifiable concentration (AUC0-tlast) 
• Cmax 
• time of the maximum observed plasma concentration (Tmax) 
• t1/2 
• apparent total plasma clearance (CL/F) 
• apparent volume of distribution (Vz/F) 
• renal clearance (CLR) 
• amount of drug excreted in the urine (Ae) 
• percentage of dose excreted unchanged in the urine (Fe) 
Other PK parameters may also be reported. 
4. STUDY DESIGN  
This study will comprise a placebo-controlled, double-blind, single-dose, sequential-group 
design. Overall, it is planned for 32 healthy subjects to be studied in 4 groups (Groups A1 to 
A4), with each group consisting of 8 subjects. In each group, 6 subjects will be randomized to 
receive SC CPT31 and 2 subjects will be randomized to receive matching placebo. 
 
All groups will be divided into 2 cohorts, with each cohort being dosed 72 hours apart. The 
first (sentinel) cohort will comprise 2 subjects, with 1 subject receiving CPT31 and 1 subject 
receiving placebo. The second cohort will comprise 6 subjects, with 5 subjects receiving 
CPT31 and 1 subject receiving placebo.Potential subjects will be screened to assess their 
eligibility to enter the study within 28 days 
prior to the first dose administration. 
 
Each subject will participate in 1 treatment period only. Subjects will reside at the Clinical 
Research Unit (CRU) from Day -1 (the day before dosing) to Day 6. All subjects will return 


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for a Follow-up visit 28 to 30 days after dosing. 
 
Based on the ongoing review of the safety, tolerability, and PK results, additional 
nonresidential visits may be required. The number of additional visits per subject will not 
exceed 3 and will not extend beyond 30 days after dose administration. 
 
 
The maximum total duration of study participation for each subject (from Screening through 
Follow-up visit) is anticipated to be approximately 8 weeks. 
 
Dose escalation will occur a minimum of 7 days after all subjects complete all Day 6 
assessments in the previous dose group. 
An overview of the study design is shown in Figure 1 and the planned dose levels are shown 
in Figure 2.  
 
Figure 1: Study Schematic 
Abbreviations: CRU = Clinical Research Unit, N = number of subjects. 
 


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Figure 2: Planned Dose Levels 
 
Abbreviations: N = number of subjects; SC = subcutaneous. 
5. SAMPLE SIZE JUSTIFICATION  
No formal statistical assessment, in terms of sample size, has been conducted as this is the 
first time CPT31 is being administered to humans. However, the number of subjects in the 
present study is common in early clinical pharmacology studies and is considered sufficient 
to achieve the objectives of the study. A common distribution between active and placebo 
subjects is 6+2. Buoen et al. (Evaluation of the Cohort Size in Phase I Dose Escalation Trials 
Based on Laboratory Data, J Clin Pharmacol (2003) 43:470-476) investigated the impact of 
cohort size on Type I error and power in Phase I dose escalation trials based on laboratory 
data and concluded that “the active cohort size in Phase I dose escalation trials should be 
between 6 and 10 active subjects.” 
 
6. STUDY TREATMENTS  
The study treatment names, abbreviations, and ordering to be used in the TFLs are presented 
in Table 1.  
Table 1: 
Presentation of Study Treatment Sequences in TFLs  
Study Treatment Name 
Treatment Order on TFLs 
Placebo  
1 
0.01 mg/kg SC CPT31  
2 


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0.04 mg/kg SC CPT31  
3 
0.12 mg/kg SC CPT31  
4 
0.24 mg/kg SC CPT31  
5 
 
7. DEFINITIONS OF POPULATIONS  
Any protocol deviations will be considered prior to database lock for their importance and 
taken into consideration when assigning subjects to populations.  
7.1. All Subjects Population  
The all-subjects population will include all subjects who signed the informed consent form 
and had any study assessment recorded in the database per the protocol.  
7.2. Safety Population  
The safety population will include all subjects who received at least 1 dose of study treatment 
(CPT31 or placebo).  
7.3. Pharmacokinetic Population  
The PK population will include all subjects who received at least 1 dose of CPT31 and have 
evaluable PK data.   
8. STATISTICAL METHODOLOGY  
8.1. General  
Listings will be provided for all data captured in the database. Listings will include all 
subjects assigned to the all-subjects population and include data up to the point of study 
completion or discontinuation. Subjects are generally considered to have completed the study 
if they completed all protocol-specified procedures and assessments for the end-of-treatment 
visit. Any subject who discontinued the study will be identified accordingly in the listings. 
Summaries and statistical analyses will include the subjects assigned to the relevant 
population based on data type. 
Data analysis will be performed using the SAS® statistical software package Version 9.4 (or 
higher if upversioned during the study).  
Analysis Data Model (ADaM) datasets will be prepared using Clinical Data Interchange 
Standards Consortium (CDISC) ADaM Version 2.1 (or higher if upversioned during the 
study) and CDISC ADaM Implementation Guide Version 1.2 (or higher if upversioned 
during the study). Pinnacle 21 Community Validator Version 2.2.0 (or higher if upversioned 
during the study) will be utilized to ensure compliance with CDISC standards.  


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Caution should be used when interpreting results from the statistical analyses conducted in 
this study because the sample size is not based on power calculations.  
Where reference is made to ‘all calculations’, this includes, but is not limited to, summary 
statistics, statistical analyses, baseline derivation, changes from baseline, percentage changes 
from baseline, and any parameter derivations. 
8.1.1. Calculation of the Summary Statistics  
For continuous data the following rules will be applied:  
● Missing values will not be imputed, unless specifically stated otherwise.  
● Unrounded data will be used in the calculation of summary statistics.  
● If the number of subjects with valid observations (n) <3, summary statistics will not be 
calculated, with the exception of n, minimum, and maximum. 
● As Early Termination data is not associated with any scheduled timepoint, it will be 
excluded from all calculations of summary statistics.  
For categorical data the following rules will be applied:  
● If the categories of a parameter are ordered (eg, AE severity), all categories between the 
possible minimum and maximum categories will be included, even if n = 0 for a given 
category. If the categories are not ordered (eg, race), only those categories for which 
there is at least 1 subject represented will be included.  
● Missing values will not be imputed, with the exception of AEs where the ‘worst-case’ 
approach will be taken (see Section 8.6.1), or unless specifically stated otherwise. A 
‘missing’ category will be included for any parameter for which information is missing. 
This will ensure that the population size totals are consistent across different 
parameters.  
8.1.2. Triplicate Readings  
For vital signs data only, where triplicate readings are taken, the median of triplicate readings 
will replace the original readings in all calculations.  
For electrocardiogram (ECG) data only, where triplicate readings are taken, the mean of 
triplicate readings will replace the original readings in all calculations.  
In case of incomplete triplicate readings (eg, only 2 out of 3 readings were recorded), the 
mean and/or medians will be calculated based on the number of readings available.  
8.1.3. Repeat and Unscheduled Readings  
For vital signs and ECG data only, any predose value recorded in addition to the original 
value or a postdose value recorded within 15 minutes of the original value will be defined as 
a repeat value; any postdose value recorded more than 15 minutes after the original value will 


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be defined as an unscheduled value. For all other data types (eg, laboratory parameters), any 
value recorded in addition to the original value will be defined as an unscheduled value.  
The original value will be replaced by the last associated repeat value in all calculations. 
As unscheduled values are not associated with any scheduled timepoint, they will be 
excluded from all calculations, with the exception of the baseline derivation (see 
Section 8.1.4).  
8.1.4. Definitions of Baseline and Change from Baseline  
The baseline will be defined as the last value recorded prior to dosing. If the date/time of the 
value is incomplete or missing, it will be excluded from the baseline calculation, unless the 
incomplete date/time indicates the value was recorded prior to dosing.   
Individual changes from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The mean change from baseline will be 
defined as the mean of the individual changes from baseline for all subjects. 
See Section 8.1.3 for more detail on handling repeat and unscheduled readings in the 
calculations. See Section 8.1.2 for more detail on handling of triplicate readings in the 
calculations.  
8.2. Subject Disposition and Population Assignment  
Subject disposition and population assignment will be listed.  
A summary table by treatment will be provided, based on the all-subjects population.  
8.3. Screening Demographics  
The screening demographics including age, sex, race, ethnicity, height, body weight, and 
body mass index will be listed.  
A summary table by treatment will be provided, based on the safety population. 
8.4. Prior and Concomitant Medication  
Prior medication will be defined as medication that ends prior to dosing. Concomitant 
medication will be defined as medication that starts during or after dosing or starts but does 
not end prior to dosing.  
Prior and concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHODrug) Global, Format B3, Version March 2020 (or later if upversioned 
during the study). Prior and concomitant medications will be listed. 


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8.5. Pharmacokinetic Assessments  
8.5.1. Pharmacokinetic Analysis  
The following PK parameters will be determined where possible from the plasma 
concentrations of CPT31, using non-compartmental methods in validated software program, 
Phoenix WinNonlin (Certara USA, Inc., Version 8.1 or higher): 
Parameter 
 Units 
Definition 
AUC0-tlast 
h*xg/mL 
area under the curve from time 0 to the time of the last 
measurable concentrationa 
AUC0-∞ 
h*xg/mL 
area under the curve from time 0 to infinityb 
Cmax 
xg/mL 
maximum concentration  
Tmax 
h 
time to maximum concentration 
Tlast 
h 
time of the last quantifiable plasma concentration 
t1/2 
h 
apparent terminal elimination half-life 
CL/F 
L/h 
apparent total plasma clearance   
Vz/F 
L 
Apparent volume of distribution during the terminal 
elimination phase 
%AUCextrap % 
percentage of AUC due to extrapolation from the last 
quantifiable concentration to infinity 
Ae 
mg 
amount of drug excreted in the urine at each collection 
interval and cumulative amount of drug excreted in the urine 
at each collection interval 
Fe 
% 
percentage excreted in urine at each collection interval and 
cumulative percentage excreted in urine at each collection 
interval   
 
CLR 
h*xg/mL/mg renal clearance  
 
 
 
a AUC will be calculated using the linear trapezoidal rule for increasing concentrations and the logarithmic rule for 
decreasing concentrations (linear up/log down rule). Additional pharmacokinetic parameters may be determined where 
appropriate.  
b Based on last observed quantifiable concentration 
Additional PK parameters may be determined where appropriate. 
Actual elapsed time from dosing will be used to estimate all individual PK parameters. If 
actual times are missing, nominal times may be used by default.  
If AUC0- cannot be determined for all subjects, an alternative AUC measure, such as AUC to 
a fixed time point, may be used in the statistical analysis. 
Cmax, Tmax and Tlast will be obtained directly from the concentration-time profiles.  For 
multiple peaks, the highest postdose concentration will be reported as Cmax. In the case that 
multiple peaks are of equal magnitude, the earliest Tmax will be reported.  
The amount of drug excreted in urine (Ae) and percentage of dose excreted (Fe) will be 
calculated for each urine collection (t1-t2); cumulative Ae and Fe will be calculated by 


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summing the t1-t2 values over the 0-t2 period where t2 = end of the study collection period.  
Ae will be calculated using a urine density of 1.0 g/mL. 
CLR will be calculated over the same collection interval according to the following formula, 
at the time interval (0-t2) where concentrations are quantifiable for both parameters: 
CLR =
Ae0-t2
AUC0−t2
 
 
8.5.1.1. Criteria for Handling Concentrations Below the Limit of Quantification or 
Missing Concentrations in Pharmacokinetic Analysis 
For the non-compartmental analysis (NCA) and individual plot, if a BLQ value occurs before 
the first measurable concentration, it will be assigned a value of 0, otherwise it will be treated 
as missing. The following rules apply with special situations defined below:  
 Where 2 or more consecutive concentrations are BLQ at the end of a profile, the profile 
will be deemed to have terminated and any further quantifiable concentrations will be 
set to missing for the calculation of the PK parameters unless they are considered to be 
a true characteristic of the profile of the drug. 
 If an entire concentration-time profile is BLQ, the profile will be excluded from the PK 
analysis. 
 If a pre-dose measurement for the first dose is missing, the value will be set to zero. 
8.5.1.2. Criteria for Calculating an Apparent Terminal Elimination Half-life 
The start of the terminal elimination phase for each subject will be defined by visual 
inspection and will be the first point at which there is no systematic deviation from the 
log-linear decline in plasma concentrations. 
The apparent terminal elimination rate constant (λz) will only be calculated when a reliable 
estimate can be obtained using at least 3 data points, preferably not including Cmax, and the 
adjusted coefficient for determination of exponential fit (R2-adj) of the regression line is ≥0.7. 
Parameters requiring λz in their calculation (eg, AUC0-inf, t1/2, CL/F and Vz/F) will only be 
calculated if the R2-adj value of the regression line is ≥0.7.  
The following regression-related diagnostic PK parameters will be determined:  
Parameter 
Units 
Definition 
λz 
h-1 
apparent terminal elimination rate constant 
λz Upper 
h 
end of exponential fit 
λz Lower 
h 
start of exponential fit 
λz N 
NA 
number of data points included in the log-linear regression 
λz Span Ratio NA 
time period over which λz was determined as a ratio of t1/2 
R2-adj 
NA 
adjusted coefficient for determination of exponential fit 


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The time period used for the estimation of apparent terminal elimination half-lives, where 
possible, will be over at least two half-lives.  For t1/2 estimates where λz was calculated over a 
time period less than twice their resultant half-life, the reliability of t1/2 and any PK parameters 
derived from λz will be discussed in CSR. 
8.5.1.3. Criteria for Calculating AUC 
The minimum requirement for the calculation of AUC will be the inclusion of at least 3 
consecutive concentrations above the lower limit of quantification. If there are only 3 
consecutive concentrations, at least 1 should follow Cmax.  
If the extrapolated area is 30%, AUC0-∞ (and derived parameters CL/F, Vz/F, t1/2 etc) may be 
excluded from summary statistics and statistical analysis at the discretion of the sponsor or 
PK analyst.  
8.5.1.4. Treatment of Outliers in Pharmacokinetic Analysis 
If a value is considered to be anomalous due to being inconsistent with the expected PK 
profile, it may be appropriate to exclude this point from the PK analysis. However, the 
exclusion of data must have strong justification and will be documented in CSR.   
Quantifiable predose concentration values in the first dosing will be considered anomalous 
and set to missing for the PK analysis.  
8.5.2. Presentation of Pharmacokinetic Data 
8.5.2.1.  Presentation of Plasma Drug Concentration Data  
If the actual time of sample collection deviates from the nominal time by more than ±10%, 
the concentration will be flagged and excluded from the summary statistics. Individual 
concentrations deemed to be anomalous will be flagged in the listings and excluded from the 
summary statistics. 
For PK concentration data the following rules will apply: 
 Values that are BLQ will be set to 0 for the calculation of summary statistics. 
 Arithmetic mean or median values that are BLQ will be presented as 0. 
 If any BLQ results (treated as 0) are in a series of summarized data, geometric mean 
and coefficient of variation (CV%) of geometric mean will be reported as not 
calculated (NC).  
8.5.2.2. Presentation of Plasma Pharmacokinetic Parameter Data  
The PK parameters will be listed and summarized descriptively by treatment (arithmetic and 
geometric means; standard deviation and CV%; minimum, maximum, and median values; and 
geometric CV). For Tmax and Tlast, no geometric mean and geometric CV will be calculated. 
For the calculation of summary statistics of PK parameters, all not reported (NR) and NC 
values in a data series will be set to missing. 
 


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8.5.3. Pharmacokinetic Statistical Methodology  
All PK concentrations and parameters will be listed.  
Summary tables, mean (± standard deviation [SD]) figures, overlaying individual figures, and 
individual figures by treatment and time postdose will be provided for plasma PK 
concentrations. All figures will be produced on both linear and semi-logarithmic scales, with 
the exception of figures across all days, which will be produced on the linear scale only. The 
+SD bars will only be displayed on the linear scale.  
Summary tables by treatment will be provided for all PK parameters, with the exception of 
diagnostic regression-related PK parameters. Separate summary tables by treatment and time 
interval will be provided for excretion parameters and cumulative excretion parameters.  
Where data are available, CPT31 dose proportionality will be examined across dose 
groups. The PK parameters (Cmax, AUC0-tlast, AUC0-∞) will be analysed for dose 
proportionality using a power model approach or analysis of variance (ANOVA) model, as 
appropriate. The PK parameters will be analyzed using a power model3 that will have the 
following form: 
parameter = intercept × dose^slope + random error 
Using the natural log (ln) transformation,4 a power model can be expressed as a linear 
regression equation: 
ln(parameter) = intercept + slope × ln(dose) + random error 
For dose proportionality, the slope of the regression line is equal to 1; for dose independence, 
it is equal to 0.  
For each PK parameter separately, a pooled estimate (across all doses) of slope, 
corresponding 95% confidence interval (CI), and between-subject CV will be calculated. 
Figures (on the logarithmic scale) containing individual values, power model line (95% CI), 
and dose proportionality line (defined as the power model line with slope of 1) will be created 
for each PK parameter; figures (on the semi-logarithmic scale) containing individual values 
and geometric means will be created for each corresponding PK parameter normalized by 
dose administered.  
The lack of fit test will be conducted for the statistical assessment of linearity assumption, 
and thus appropriateness of a power model. The lack of fit model will be the same as the 
power model fitted, but with dose included as additional fixed effect. The statistical 
assessment will rule the linearity assumption acceptable if the diagnostic plots appear 
reasonable and the lack of fit p-value >0.05 (dose effect is not significant at the 0.05 level of 
significance). The assessment of linearity assumption may also occur via visual examination 
of the figures by the pharmacokineticist. This assessment may override the statistical 
assessment; where this occurs, it will be detailed in the CSR.  
It will be concluded that PK parameter is dose proportional for the dose range studied if the 
assumption of linearity is ruled acceptable and the 95% CI for the slope spans 1.  


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If the assumption of linearity is ruled unacceptable for any PK parameter, its corresponding 
PK parameter normalized by dose administered will be ln-transformed and analyzed using an 
analysis of variance (ANOVA) model.6 The model will include dose as a factor.  
For each PK parameter separately, the geometric least squares mean (GLSM) for each dose, 
p-values for the overall, and pairwise dose comparisons will be calculated. Residual plots will 
be produced to assess the adequacy of the model(s) fitted.  
Examples of the SAS code that will be used are as follows: 
Power Model Analysis  
proc mixed data = <data in> alpha = 0.05; 
 by parcat1n parcat1 pkday paramn param; 
 class usubjid; 
 model lpk = ldose / cl residual ddfm = kr; 
 random intercept / subject = usubjid; 
 ods output solutionf = <data out>; 
run; 
Power Model Analysis (Lack of Fit Test) 
proc mixed data = <data in>; 
 by parcat1n parcat1 pkday paramn param; 
 class dose usubjid; 
 model lpk = ldose dose / htype = 1 ddfm = kr; 
 random intercept / subject = usubjid; 
 ods output tests1 = <data out>; 
run; 
ANOVA Model Analysis  
proc mixed data = <data in> alpha = 0.05; 
 by parcat1n parcat1 pkday paramn param; 
 class dose; 
 model ldnpk = dose / cl residual ddfm = kr; 
 lsmeans dose / cl pdiff;  
 ods output lsmeans = <data out>;  
 ods output diffs = <data out>; 
 ods output tests3 = <data out>; 
run; 
No inferential statistical analyses are planned. 
8.6. Safety and Tolerability Assessments  
8.6.1. Adverse Events  
All AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 23.0 (or higher if upversioned during the study). All AEs will be assigned severity 
grade using the following criteria defined by the Division of AIDS Table for Grading the 
Severity of Adult and Pediatric Adverse Events, Version 2.1 dated July 2017: 
 Grade 1, Mild: Usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual activities of 
daily living. 


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 Grade 2, Moderate: Usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the subject. 
 Grade 3, Severe: Interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
 Grade 4, Potentially Life-threatening: The subject was at immediate risk of death 
from the event as it occurred (i.e., does not include a reaction that might have caused 
death if it had occurred in a more serious form). For instance, drug-induced hepatitis 
that resolved without evidence of hepatic failure would not be considered 
life-threatening even though drug-induced hepatitis can be fatal. 
 Grade 5, Death. 
A treatment-emergent adverse event (TEAE) will be defined as an AE that starts during or 
after dosing, or starts prior to dosing and increases in severity after dosing. 
A treatment-related TEAE will be defined as a TEAE with a relationship of possibly, 
probably, or definitely related to the study treatment, as determined by the investigator.  
All AEs will be listed. In addition to the data recorded in the database, the listings will 
include derived onset time and duration. Onset time will be calculated from the time of 
dosing for TEAEs only. 
The frequency of subjects with TEAEs and the number of TEAEs will be summarized for the 
following categories:  
● TEAEs (overall, serious, leading to discontinuation, and leading to death) by treatment  
● TEAEs by severity and treatment  
● Treatment-related TEAEs (overall, serious, leading to discontinuation, and leading to 
death) by treatment  
● Treatment-related TEAEs by severity and treatment  
The frequency of subjects will be summarized separately for TEAEs and treatment-related 
TEAEs by the following:  
● System organ class, preferred term, and treatment  
● Preferred term and treatment  
For the AE data the following rules will apply:  
● For the derivation of TEAE status: If the start date/time of an AE is incomplete or 
missing, an AE will be assumed to be a TEAE, unless the incomplete start date/time or 
the end date/time indicates an AE started prior to dosing.  


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● For the derivation of treatment-related TEAE status: If the study treatment relationship 
for a TEAE is missing, a TEAE will be assumed to be a treatment-related TEAE.  
● For the derivation of onset time: If the start date/time of an AE is missing, onset time 
will not be calculated. If the start date/time of an AE is incomplete, where possible, the 
minimum possible onset time will be calculated and presented in ‘≥DD:HH:MM’ 
format (eg, if the date/time of dosing is 01MAY2019/08:00 and recorded start date/time 
of an AE is 03MAY2019, then the minimum possible onset time will be calculated by 
assuming the AE started at the first hour and minute of 03MAY2019 
[03MAY2019/00:00], thus will be presented as onset time ≥01:16:00 in the listing).  
● For the derivation of duration: If the end date/time of an AE is missing, duration will 
not be calculated. If the start or end date/time of an AE is incomplete, where possible, 
the maximum possible duration will be calculated and presented in ‘≤DD:HH:MM’ 
format (eg, if the start of an AE date/time is 01MAY2019/08:00 and its recorded end 
date/time is 03MAY2019, then the maximum possible duration will be calculated by 
assuming the AE ended at the last hour and minute of 03MAY2019 
[03MAY2019/23:59], thus will be presented as duration ≤02:15:59 in the listing).  
● For the calculation of summary statistics: If the severity of a TEAE is missing, a TEAE 
will be counted under the maximum severity possible.  
● For the calculation of summary statistics: If a subject experienced multiple TEAEs with 
the same preferred term for the same treatment, this will be counted as 1 TEAE for that 
treatment under the maximum severity recorded.  
8.6.2. Clinical Laboratory Parameters  
All clinical laboratory (clinical chemistry, hematology, urinalysis, coagulation, serology, and 
cytokines) parameters, with changes from baseline, will be listed; any value outside the 
clinical reference range will be flagged. Separate listings will be provided for any parameter 
for which there is any individual subject value outside the respective clinical reference range.  
Summary tables and boxplots by treatment and timepoint will be provided for clinical 
chemistry, hematology, serology, urinalysis, coagulation parameters and cytokines, with 
changes from baseline.  
Values recorded as <x, ≤x, >x, or ≥x will be displayed in the listings as recorded. For the 
derivation of listing flags, calculation of summary statistics, and presentation in the figures, 
<x and ≤x values will be set to [0/half of x], whereas >x and ≥x values will be set to x. 
8.6.3. Vital Signs Parameters  
All vital signs parameters, with changes from baseline will be listed; any value outside the 
clinical reference range will be flagged. 
Summary tables and boxplots by treatment and timepoint will be provided for all vital signs 
parameters, with changes from baseline.   


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8.6.4. 12-lead Electrocardiogram Parameters  
All 12-lead ECG parameters, with changes from baseline, will be listed; any value outside the 
clinical reference range will be flagged. 
Summary tables and boxplots by treatment and timepoint will be provided for all 12-lead 
ECG parameters, with changes from baseline. An outlier analysis will be performed for QT 
interval corrected for heart rate using Bazett’s formula (QTcB) and QT interval corrected for 
heart rate using Fridericia’s formula (QTcF). The analysis will include all individual original, 
repeat, and unscheduled postdose values.  
The maximum postdose values will be summarized by treatment according to the following 
categories:  
● ≤450 ms  
● >450 and ≤480 ms (all instances flagged in the listing)  
● >480 and ≤500 ms (all instances flagged in the listing)  
● >500 ms (all instances flagged in the listing)  
The maximum increases from baseline will be summarized by treatment according to the 
following categories:  
● ≤30 ms  
● >30 and ≤60 ms (all instances flagged in the listing)  
● >60 ms (all instances flagged in the listing)  
8.6.5. Other Assessments  
Medical history will be listed. 
All other safety and tolerability assessments not detailed in the above sections will be listed 
only.  
8.6.6. Safety and Tolerability Statistical Methodology  
No inferential statistical analyses are planned.  
8.7. Immunogenicity Assessments 
8.7.1. Immunogenicity Endpoints 
The immunogenicity endpoints are anti-CPT31 antibodies, e.g., immunoglobulin (Ig)G, IgM. 
Immunogenicity samples will be collected on Day 1 predose, Day 2 (24 h), Day 5 (96 h) with 
an additional immunogenicity sample taken at the Follow-up visit. 


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Protocol Reference: CPT31-001 
Final, Version 1.0, 13 August 2020 
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8.7.2. Immunogenicity Statistical Methodology 
All immunogenicity data will be listed. 
The anti-CPT31 antibodies, e.g., immunoglobulin (Ig)G, IgM will be summarized. 
Summary tables by treatment and timepoint will be provided for all immunogenicity data. 
9. INTERIM ANALYSES  
No formal interim statistical analyses are planned for this study.  
10. SIGNIFICANT CHANGES FROM THE PROTOCOL-SPECIFIED ANALYSES  
There were no significant changes from the protocol-specified analyses.  
11. REFERENCES  
1. ICH. ICH Harmonised Tripartite Guideline: Statistical principles for clinical trials (E9). 
5 February 1998.  
2. ICH. ICH Harmonised Tripartite Guideline: Structure and content of clinical study reports 
(E3). 30 November 1995.  
3. Gough K, Hutchinson M, Keene O, et al. Assessment of dose proportionality: report from 
the statisticians in the pharmaceutical industry/Pharmacokinetics UK Joint Working 
Party. Drug Inf J. 1995;29(3):1039-1048. 
4. Keene ON. The log transformation is special. Stat Med. 1995;14(8):811-819. 
5. Brown H, Prescott R. Applied Mixed Models in Medicine. Chichester: John Wiley & 
Sons, 1999. 
6. Snedecor GW, Cochran WG. Statistical Methods. 8th ed. Ames, IA: Iowa State University 
Press, 1989. 
7. Lehmann EL. Nonparametrics: Statistical Methods Based on Ranks. San Francisco, CA: 
Holden-Day; 1975. 


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CONFIDENTIAL 
Covance Study: 8405732 
Protocol Reference: CPT31-001 
Final, Version 1.0, 13 August 2020 
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12. APPENDICES 
Appendix 1: 
Document History 
Status, Version 
Date of Change 
Summary/Reason for Changes 
Final, Version 1.0 
NA 
NA; the first version. 
NA = not applicable