Clinical trial NCT03960541
Conditions: HIV Infections Dyslipidemias
Keywords: HIV Dyslipidemias CD24Fc HIV Chronic Inflammation LDL Reduction
Sponsor: Oncoimmune, Inc., a subsidiary of Merck & Co., Inc. (Rahway, New Jersey USA)
Start date: 2020-08-31; Completion date: 2021-05-27
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a phase 2, randomized, double-blinded, placebo-controlled clinical trial. The intervention drug will be efprezimod alfa (intravenous \[IV\] infusion). A cohort of 64 patients with HIV on antiretroviral therapy (ART) will be randomized in a 1:1 fashion to be administered 3 doses of efprezimod alfa (240mg IV infusion) or placebo once every 2 weeks (q2w) during a 4-week window, followed by a 24-week follow-up window to assess the changes in LDL.

Detailed description:
This study is a phase 2, randomized, placebo-control, double-blinded clinical trial to assess the effect of efprezimod alfa on reduction in low-density lipoprotein (LDL) among patients with HIV. The effect of efprezimod alfa on total cholesterol and triglycerides, markers of immune activation (T cell activation, sCD14, and inflammatory cytokines), size of HIV reservoirs, hemoglobin (HbA1c) and leptin, and hepatic steatosis will be evaluated.

It is hypothesized that therapy with efprezimod alfa will result in significant decreases in LDL in HIV patients. In addition, efprezimod alfa may reduce leptin and cholesterol, HbA1c, hepatic steatosis and fibrosis, and markers of inflammation in patients with chronic HIV who are virally suppressed on ART.

In this phase 2 study, a cohort of 64 HIV patients virally suppressed on ART will be randomized in a 1:1 fashion to receive an intravenous infusion of 240 mg of efprezimod alfa vs. placebo administered every 2 weeks during a 4-week treatment window, followed by a 24- week follow-up period. Patients will be followed for safety and adverse events as well as changes in lipid metabolism and inflammatory markers during a 24-week follow-up period. This investigation will take place at the University of Maryland.

Arms: arm 1: Participants received an intravenous infusion of 240 mg of efprezimod alfa on Days 0, 14, and 28. arm 2: Participants received an intravenous infusion of placebo (sterile saline solution) on Days 0, 14, and 28.
Interventions: intervention 1: Efprezimod alfa (human CD24 extracellular domain and human IgG1 Fc fusion protein) intervention 2: Saline Solution
Intervention descriptions: intervention 1: Efprezimod alfa will be given as IV infusion, 240 mg per infusion, on Days 0, 14, and 28. intervention 2: Sterile saline solution (0.9% sodium chloride) will be given as placebo via IV infusion, 100 ml per infusion, on Days 0, 14, and 28.

Protocol documents:
Prot_SAP_000.pdf: 
Official Protocol Title: 
NCT number: 
NCT03960541 
Document Date: 
12-Nov-2020
CD24Fc Administration to Decrease LDL and Inflammation in 
HIV Patients, Both as Markers of Efficacy and Cardiovascular Risk 
Reduction (CALIBER)


C D 2 4 Fc  Ad mi nistr ati o n t o D ecr e as e  LDL a n d  Infl a m m ati o n i n HI V P ati e nts,  Bot h 
as M ar k ers of  Effic ac y a n d C ar di o v asc ul ar Ri s k R e d ucti o n  
( C ALI B E R) 
Pr ot oc ol N u m b er: H P -0 0 0 8 6 0 2 9  
Pri nci p al I n v esti g at or:   
S h y a m as u n d ar a n  K ottilil, M D  P h D  
Pr of ess or of M e dici n e  
I nstit ut e of H u m a n Vir ol o g y 
U ni v ersit y of M ar yl a n d Sc h o ol of M e dici n e  
7 2 5 W L o m b ar d Str e et, R o o m N 5 6 2  
B alti m or e M D 2 1 2 0 1  
P h o n e: 
 
I N D n u m b er: 1 3 6 2 5 4  
I N D S p o ns or:  
O nc oI m m u n e, I nc.  
R oc kvill e, M D  
O nc oI m m u n e I nc. Pr ot oc ol #:  
 C D 2 4 Fc -0 0 3  
N C T #:   N C T 0 3 9 6 0 5 4 1  
F u n d e d b y : N HL BI  
V e rsi o n N u m b er:  v. 5 , N o v e m b er 1 2 , 2 0 2 0 
1
1
0 6 F 3 4 9
P P D
0 7 X N D S


CALIBER OncoImmune CD24Fc-003 
Version 5.0 
Protocol HP-00086029 
November 12, 2020 
 
 
2 
STATEMENT OF COMPLIANCE ............................................................................................................................. 5 
STUDY TEAM ............................................................................................................................................................. 5 
1 
PROTOCOL SUMMARY .................................................................................................................................. 6 
1.1 
Synopsis ................................................................................................................................................ 6 
1.2 
Schema ................................................................................................................................................. 8 
1.3 
Schedule of Activities (SoA) ............................................................................................................... 9 
2 
INTRODUCTION ............................................................................................................................................. 10 
2.1 
Study Rationale .................................................................................................................................. 10 
2.2 
Background......................................................................................................................................... 10 
2.2.1 
Pharmacology and toxicology of CD24Fc .................................................................. 11 
2.2.2 
Safety of CD24Fc in animal studies ............................................................................ 11 
2.2.3 
CD24Fc in HUMAN STUDIES ..................................................................................... 12 
2.2.4 
Rationale for Use of CD24Fc to reduce LDL ............................................................. 19 
2.3 
Risk/Benefit Assessment .................................................................................................................. 19 
2.3.1 
Known Potential Risks ................................................................................................... 19 
2.3.2 
Known Potential Benefits .............................................................................................. 23 
2.3.3 
Assessment of Potential Risks and Benefits .............................................................. 23 
3 
OBJECTIVES AND ENDPOINTS ................................................................................................................. 23 
3.1.1 
Primary Objectives ......................................................................................................... 23 
3.1.2 
Secondary Objectives ................................................................................................... 23 
3.1.3 
Exploratory Objectives .................................................................................................. 24 
3.1.4 
PRIMARY ENDPOINTS ................................................................................................ 24 
3.1.5 
SECONDARY ENPOINTS ............................................................................................ 24 
3.1.6 
EXPLORATORY ENDPOINT ....................................................................................... 24 
4 
STUDY DESIGN .............................................................................................................................................. 25 
4.1 
Overall Design .................................................................................................................................... 25 
4.2 
Justification for Dose ......................................................................................................................... 25 
4.3 
End of Study Definition ..................................................................................................................... 26 
5 
STUDY POPULATION ................................................................................................................................... 26 
5.1 
Inclusion Criteria ................................................................................................................................ 26 
5.2 
Exclusion Criteria ............................................................................................................................... 28 
5.3 
Lifestyle Considerations .................................................................................................................... 29 
5.4 
Screen Failures .................................................................................................................................. 29 
5.5 
Strategies for Recruitment and Retention ...................................................................................... 30 
6 
STUDY INTERVENTION ............................................................................................................................... 31 
6.1 
Study Intervention(s) Administration ............................................................................................... 31 
6.1.1 
Study Intervention Description ..................................................................................... 31 
6.1.2 
Dosing and Administration ............................................................................................ 31 
6.2 
Preparation/Handling/Storage/Accountability ................................................................................ 32 
6.2.1 
Acquisition and accountability ...................................................................................... 32 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ................................................ 32 
6.2.3 
Product Storage and Stability ....................................................................................... 33 
6.2.4 
Preparation ...................................................................................................................... 33 
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November 12, 2020 
 
 
3 
6.3 
Measures to Minimize Bias: Randomization and Blinding ........................................................... 34 
6.4 
Study Intervention Compliance ........................................................................................................ 34 
6.5 
Concomitant Therapy ........................................................................................................................ 34 
6.5.1 
Rescue Medicine ............................................................................................................ 34 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL .................................................................................................................... 34 
7.1 
Discontinuation of Study Intervention ............................................................................................. 34 
7.2 
Participant Discontinuation/Withdrawal from the Study ............................................................... 35 
7.3 
Lost to Follow-Up ............................................................................................................................... 36 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................................................ 37 
8.1 
Study visits .......................................................................................................................................... 37 
8.2 
Assays ................................................................................................................................................. 39 
8.3 
Safety and Other Assessments ....................................................................................................... 43 
8.4 
Adverse Events and Serious Adverse Events ............................................................................... 44 
8.4.1 
Definition of Adverse Events (AE) ............................................................................... 44 
8.4.2 
Definition of Serious Adverse Events (SAE) .............................................................. 44 
8.4.3 
Classification of an Adverse Event .............................................................................. 45 
8.4.4 
Time Period and Frequency for Event Assessment and Follow-Up ....................... 46 
8.4.5 
Adverse Event Reporting .............................................................................................. 47 
8.4.6 
Follow-up of Adverse Events and Serious Adverse Events .................................... 48 
8.4.7 
Serious Adverse Event Reporting ............................................................................... 48 
8.4.8 
Reporting of Pregnancy ................................................................................................ 48 
8.4.9 
Pausing and Halting Rules ........................................................................................... 49 
8.5 
Unanticipated Problems .................................................................................................................... 49 
8.5.1 
Definition of Unanticipated Problems (UP) ................................................................. 49 
8.5.2 
Unanticipated Problem Reporting ................................................................................ 49 
9 
STATISTICAL CONSIDERATIONS ............................................................................................................. 50 
9.1 
Statistical Hypotheses ....................................................................................................................... 50 
9.2 
Sample Size Determination .............................................................................................................. 51 
9.3 
Populations for Analyses .................................................................................................................. 51 
9.4 
Statistical Analyses............................................................................................................................ 51 
9.4.1 
General Approach .......................................................................................................... 51 
9.4.2 
Analysis of the Primary Efficacy and secondary Endpoints ..................................... 52 
9.4.3 
Safety Analyses .............................................................................................................. 52 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ................................. 52 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................... 53 
10.1.1 
Informed Consent Process ........................................................................................... 53 
10.1.2 
Study Discontinuation and Closure ............................................................................. 53 
10.1.3 
Confidentiality and Privacy ........................................................................................... 54 
10.1.4 
Future Use of Stored Specimens and Data ............................................................... 54 
10.1.5 
Key Roles and Study Governance .............................................................................. 55 
10.1.6 
Safety Oversight ............................................................................................................. 55 
10.1.7 
Clinical Monitoring .......................................................................................................... 56 
10.1.8 
Quality Assurance and Quality Control ....................................................................... 56 
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CALIBER OncoImmune CD24Fc-003 
Version 5.0 
Protocol HP-00086029 
November 12, 2020 
 
 
4 
10.1.9 
Data Handling and Record Keeping ............................................................................ 57 
10.1.10 
Protocol Deviations ........................................................................................................ 57 
10.1.11 
Publication and Data Sharing Policy ........................................................................... 58 
10.1.12 
Conflict of Interest Policy .............................................................................................. 58 
10.2 
Additional Considerations ................................................................................................................. 59 
10.3 
Abbreviations ...................................................................................................................................... 60 
10.4 
Protocol Amendment History ........................................................................................................... 62 
11 
REFERENCES ................................................................................................................................................ 63 
 
 
NIH Addendum 
1 
NUMBER OF PATIENTS TO BE ENROLLED AT THE NIH .................................................................... 69 
2 
NIH PATIENT REGISTRATION .................................................................................................................... 69 
2.1 
Registration Procedures ................................................................................................................... 69 
2.1.1 
Registration Process at NIH ......................................................................................... 69 
3 
CRITERIA FOR REMOVAL FROM SPONSOR PROTOCOL .................................................................. 69 
4 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN (THIS 
REPORTING SECTION OUTLINES THE REPORTING REQUIREMENTS THAT ARE REQUIRED TO 
THE NIH AND ARE IN ADDITION TO THE REPORTING REQUIREMENTS FOR THE UMB IRB.) ......... 70 
4.1 
NIH Definitions ................................................................................................................................... 70 
4.2 
NIH IRB and Clinical Director Reporting ........................................................................................ 70 
4.2.1 
NIH Intramural IRB ......................................................................................................... 70 
4.2.2 
Reporting to NIH Intramural IRB .................................................................................. 70 
4.2.3 
NIH CC Clinical Director Reporting ............................................................................. 70 
4.3 
Data and Safety Monitoring Plan ..................................................................................................... 70 
4.3.1 
Principal Investigator/Research Team ........................................................................ 70 
5 
DATA COLLECTION AND EVALUATION ................................................................................................... 70 
5.1 
Data Collection ................................................................................................................................... 70 
5.2 
Future use of Stored Data/Samples................................................................................................ 71 
6 
HUMAN SUBJECTS PROTECTIONS ......................................................................................................... 71 
6.1 
Rationale For Subject Selection ...................................................................................................... 71 
6.2 
Risk/Benefit Assessment .................................................................................................................. 71 
6.2.1 
Known Potential Risks ................................................................................................... 71 
7 
COLLABORATIVE AGREEMENTS ............................................................................................................. 71 
7.1 
Agreement Type ................................................................................................................................ 71 
8 
CERTIFICATE OF CONFIDENTIALITY ...................................................................................................... 72 
9 
INSURANCE BILLING .................................................................................................................................... 72 
10 
COMPENSATION, REIMBURSEMENT, AND PAYMENT ....................................................................... 72 
APPENDIX A: SAFETY MONITORING BOARD ................................................................................................. 73 
 
 
 
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C A LI B E R O n c oI m m u n e C D 2 4 Fc -0 0 3  
Versi o n 5. 0  
Pr ot o c ol H P -0 0 0 8 6 0 2 9  
N o v e m b er 1 2 , 2 0 2 0 
 
 
5  
S T A T E M E N T O F C O M P LI A N C E  
T h e tri al will b e c o n d uct e d i n acc or d a nc e wit h t h e Int er n ati o n al C o nf er e nc e o n H ar m o nis ati o n  G o o d 
Cli nic al Pr actic e ( I C H G C P),  a p plic a bl e U nit e d St at es ( US) C o d e of F e d er al R e g ul ati o ns  ( C F R), a n d t h e 
N HL BI T er ms a n d C o n diti o ns of A w ar d. T h e Pri nci p al I nv esti g at or will ass ur e t h at n o d evi ati o n fr o m, or 
c h a n g es t o t h e pr ot oc ol will t a k e pl ac e wit h o ut pri or a gr e e m e nt fr o m t h e I nv esti g ati o n al N e w Dr u g (I N D) 
s p o ns or, f u n di n g a g e nc y a n d d oc u m e nt e d a p pr ov al fr o m t h e I nstit uti o n al R e vi e w B o ar d (I R B), exc e pt 
w h er e n ec ess ar y t o eli mi n at e a n i m m e di at e h az ar d(s) t o t h e tri al p artici p a nts. All p ers o n n el i nv olv e d i n 
t h e c o n d uct of t his stu dy h av e c o m pl et e d H u m a n S u bj ects Pr ot ecti o n a n d I C H G C P Tr ai ni n g.  
 
T h e pr ot oc ol, i nf or m e d c o ns e nt f or m, r ecr uit m e nt m at eri als, a n d all p artici p a nt m at eri als will b e 
s u b mitt e d t o t h e I R B f or r evi e w a n d a p pr ov al.  A p pr o v al of b ot h t h e pr ot oc ol a n d t h e c o ns e nt f or m m ust 
b e o bt ai n e d b ef or e a ny p artici p a nt is e nr oll e d.  A ny a m e n d m e nt t o t h e pr ot oc ol will r e q uir e r e vi e w a n d 
a p pr o v al by t h e I R B b ef or e t h e c h a n g es ar e i m pl e m e nt e d t o t h e st u dy.  All c h a n g es t o t h e c o ns e nt f or m 
will b e I R B a p pr ov e d; a d et er mi n ati o n will b e m a d e r e g ar di n g w h et h er  a n e w c o ns e nt n e e ds t o b e 
o bt ai n e d fr o m p artici p a nts w h o pr o vi d e d c o ns e nt, usi n g a pr e vi o usl y  a p pr ov e d c o ns e nt f or m. 
 
S T U D Y T E A M  
 
Pri nci p al I n v esti g at or : 
S hy a m as u n d ar a n  K ottilil, M D, P h D  
 
L e a d Ass oci at e I n v esti g at or: 
P o o n a m M at h ur, D O, M P H  
 
Ass oci at e I n v esti g at ors:  
J o el C h u a, M D 
J e n nif er H off m a n, M S N, M P H, C R N P  
J e n nif er H uss o n, M D, M H S 
A m y N els o n, R N, M S  
A n gi e Pric e, A N P -C, D N P  
L y di a T a n g, MB C h B  
 
St u d y Sit es : 
I nstit ut e of H u m a n Vir ol o gy, U niv ersity of 
M ar yl a n d, B alti m or e, M D  
7 2 5 W est L o m b ar d Str e et  
B alti m or e, M D  
 
N ati o n al I nstit ut es of H e alt h  
1 0 C e nt er Driv e  
B et h es d a, M D  
 
 
Pr ot oc ol St atistici a n : 
 
 
NI H L e a d I n v esti g at or:  
H e nr y M as ur, M D ( NI H/ C C M D)  
 
C oll a b or ati n g I n v esti g at ors : 
B h a w n a P o o ni a, P h D  
T a e -W o ok C h u n, P h D ( NI H/ NI AI D)  
N e h al N. M e ht a, M D, M S C E, F A H A  ( NI H/ N HL BI) 
A mit D ey, M D ( NI H/ N HL BI)  
 
M e dic al M o nit or: 
 
 
P h ar m acist: 
 
 
I R B of R ec or d: U ni v ersity of M aryl a n d H R P O  
 
 
 
0 6 F 3 4 9
P P D
P P D
P P D
0 7 X N D S


CALIBER OncoImmune CD24Fc-003 
Version 5.0 
Protocol HP-00086029 
November 12, 2020 
 
 
6 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
CD24Fc Administration to Decrease LDL and Inflammation in HIV Patients, 
Both as Markers of Efficacy and Cardiovascular Risk Reduction (CALIBER) 
 
Study Description: 
This is a phase 2, randomized, double-blinded, placebo-controlled clinical 
trial. The intervention drug will be CD24Fc (IV infusion). A cohort of 64 
subjects with HIV on antiretroviral therapy will be randomized in a 1:1 
fashion to be administered 3 doses of CD24Fc (240mg IV infusion) or 
placebo q2w during a 4-week window, followed by a 24-week follow-up 
window to assess safety and changes in LDL.   
 
Objectives: 
Primary Objectives:   
1. To determine the safety and tolerability of CD24Fc during the 4-week 
dosing period and a 24-week follow-up period in a cohort of HIV 
patients.  
2. To evaluate the change in LDL during a 4-week dosing period of 
CD24Fc and a 24-week follow-up period. 
 
Secondary Objectives:    
To evaluate the effect of CD24Fc on the following variables between the 
placebo and intervention arms in comparison with baseline values:  
1. Levels of total cholesterol, HDL, and triglycerides  
2. Markers of immune activation (CD4 and CD8 T cells, IFN, TNF, 
sCD14) 
3. Size of HIV reservoirs  
4. Myocardial damage (measured by Troponin I and T) 
5. Hepatic steatosis, as determined by transient elastography  
6. Leptin 
7. Hemoglobin A1c 
8. Presence of anti-drug antibody (ADA) and temporal correlation to 
any adverse events, and its effect on PK (For first 6 subjects). 
9. The pharmacokinetics (PK) and pharmacodynamics (PD) of CD24Fc 
in the first 6 randomized subjects.  
 
Exploratory Objectives: 
1. To assess the effect of CD24Fc on aortic vascular inflammation as 
measured by standardized uptake value of arterial FDG by 
PET/CT. We will select 12 subjects with an LDL>125 to have the 
imaging study.  
2. To assess the effect of CD24Fc on the inflammatory markers hs-
CRP and GlycA. 
3. To assess the effect of CD24Fc on the CEC and NMR lipoproteins. 
4. To assess the effect of CD24Fc on endothelin-1. 
 
 
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CALIBER OncoImmune CD24Fc-003 
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Protocol HP-00086029 
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7 
Endpoints: 
Primary Endpoints:  
1. Incidence and severity of any adverse events (AEs) during the 
administration of drug and 24 weeks after completion. Safety will be 
evaluated by assessment of clinical laboratory tests, physical 
examination at various time points during the study, and by the 
documentation for AEs. 
2. The percentage reduction in LDL level from the baseline (predosing) to 
2 weeks after the last treatment. 
 
Secondary Endpoints:  
1. Percent change in levels of total cholesterol, HDL, and triglycerides 
from baseline to Weeks 6 and 28 between placebo and intervention 
arms.  
2. Percent change in markers of immune activation (CD4 and CD8 T 
cells, IFN, TNF, sCD14) from baseline to Week 6 and 28 between 
placebo and intervention arms. 
3. Change in proviral DNA from baseline to Week 6 and Week 28 
between placebo and intervention arms. 
4. Percent change from baseline to week 28 in Troponin I and T 
between placebo and intervention arms.  
5. Change in percent of hepatic steatosis (by CAP measurement) and 
fibrosis (by KPA) as determined by transient elastography from 
baseline to week 28 between placebo and intervention arms.  
6. Percent change in leptin from baseline to Week 6 and Week 28 
between placebo and intervention arms.  
7. Percent change in hemoglobin A1c from baseline to Week 6 and 28 
between placebo and intervention arms.  
8. PK and PD assessments (For 6 subjects) 
9. Presence of ADA in all subject with temporal correlation to any adverse 
events, and its effect on PK (For first 6 subjects). 
10. Changes in IL-6, apoB, Lp(a), urine albumin to creatinine ratio before 
and after treatment.  
 
Exploratory Endpoints:  
1.    Change in vascular inflammation as evidenced by aortic FDG uptake by 
FDG-PET/CT will be assessed before and after therapy. The arterial 
uptake of FDG is measured by the standardized uptake value (SUV) 
max divided by the venous SUV mean yielding a target to background 
ratio (TBR).  
2.   Changes in hs-CRP and GlycA before and after treatment. 
3.   Changes in CEC and NMR lipoproteins before and after treatment.  
4. Changes in endothelin-1 before and after treatment. 
 
Study Population: 
64 adults with HIV infection (age 50 and older) on antiretroviral therapy  
(ART) with HIV viral suppression for at least 2 years. Subjects will be 
recruited from the Baltimore, MD and Washington, DC regions.  
 
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CALIBER OncoImmune CD24Fc-003 
Version 5.0 
Protocol HP-00086029 
November 12, 2020 
 
 
8 
Phase: 
2 
Description of 
Sites/Facilities Enrolling 
Participants: 
University of Maryland 
Institute of Human Virology Clinical Research Unit (IHV/CRU) 
725 West Lombard Street 
Baltimore MD 21201 
 
National Institutes of Health 
Clinical Center Radiology (Bldg 10) 
10 Center Dr.  
Bethesda, MD 20814 
 
Description of Study 
Intervention: 
Human CD24 (also known as cluster of differentiation 24 or heat stable 
antigen (HSA)) is an 80 amino acid glycosyl-phosphatidyl-inositol (GPI)-
anchored glycoprotein expressed on the membrane surfaces of 
hematopoietic and non-hematopoietic cells. Recombinant fusion protein, 
CD24Fc, is composed of the extracellular domain (ECD) of human CD24 
fused to the hinge and Fc region of human IgG. It has been used for the 
treatment of autoimmune diseases and Graft vs Host Disease. Doses of 
240mg have been shown to be safe, well-tolerated, and effective in 
reducing LDL.  
 
Study Duration: 
2 years 
 
Participant Duration: 
28 weeks 
 
 
1.2 
SCHEMA 
 
 
 
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CALIBER OncoImmune CD24Fc-003 
Version 5.0 
Protocol HP-00086029 
November 12, 2020 
 
 
9 
1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
Screening+ 
Day -55 to -
14 
Day -55 
to -1 
Day -55 
to -1#  
Day 
0 
Wk 
2* 
Wk 
4* 
Wk 
6^ 
Wk 
16^ 
Wk 
28^ 
Informed Consent  
X 
 
 
 
 
 
 
 
 
Medical History & Physical Exam1 
X 
 
 
X 
 
 
X 
X 
X 
Height, Weight, and BMI 
X 
 
 
 
 
 
 
 
X 
Vital Signs  
X 
 
 
X 
X 
X 
X 
X 
X 
Medication Reconciliation 
X 
 
 
X 
X 
X 
X 
X 
X 
Adverse Event Review and Evaluation 
 
 
 
X 
X 
X 
X 
X 
X 
CMP, CBC with diff, PT/INR, Urinalysis 
X 
 
 
X 
X 
X 
X 
X 
X 
CD4 count and HIV VL 
X 
 
 
X 
X 
X 
X 
X 
X 
Hepatitis B panel (surface antigen, core antibody, 
surface antibody) 
X 
 
 
 
 
 
 
 
 
Hepatitis C Ab with reflex RNA 
X 
 
 
 
 
 
 
 
 
Hemoglobin A1c 
X 
 
 
 
 
 
X 
 
X 
Lipid panel (Fasting) 
X 
 
X 
X 
X 
X 
X 
X 
X 
Troponin I and T 
X 
 
 
 
 
 
X 
 
X 
Leptin (Fasting) 
X 
 
X 
 
 
 
X 
 
X 
ECG (once at Screening and Wk 6; pre-dose and 2 hrs 
post-dose during dosing visits) 
X 
 
 
X 
X 
X 
X 
 
 
Serum hCG (women of child-bearing potential) 
X 
 
 
 
 
 
 
 
X 
POC Urine hCG (women of child-bearing potential) 
 
 
 
X 
X 
X 
X 
X 
 
PK of ART and CD24Fc before (and 2 hrs post-dose for 
Day 0 to Week 4)- first 6 subjects 
 
 
 
X 
X 
X 
X 
X 
X 
Anti-drug antibody% 
 
 
 
X 
 
 
X 
 
X 
Immunology labs (for CD4:CD8, sCD14, proviral DNA), 
inflammatory cytokines 
X 
 
  
X 
X 
X 
X 
X 
X 
GlycA, CEC, NMR lipoproteins2 
 
 
 
X 
 
 
X 
 
X 
hsCRP, IL-6, apoB, Lp(a), UACR  
X 
 
  
X 
X 
X 
X 
X 
X 
Endothelin-1 
X 
 
 
 
 
 
 
 
X 
CD24Fc Infusion  
 
 
 
X 
X 
X 
 
 
 
Transient elastography with CAP 
X 
 
X 
 
 
 
 
 
X 
FDG PET/CT (NIH)3 
 
X 
 
 
 
 
 
 
X 
+ Screening tests within the last 8 weeks prior to screening visit that have been done as part of routine medical care or at an outside 
facility can be used.  Screening window of 8 weeks with more than 2 weeks between screening and Day 0. 
*Study Visits for Weeks 2-4 include a window of +/-4 days 
^Study Visit for Weeks 6, 16 and 28 include a window of +/- 1 week except for FDG PET/CT, which will include a window of +/-30 days 
1 Targeted history and exam will be performed as needed for symptoms or lab abnormalities 
2 Only for subjects completing the optional FDG-PET/CT testing 
3 See protocol section 8.1.1.2 for criteria leading to FDG PET/CT testing 
# If subject is not fasting at screening, may return for fasting labs and Transient Elastography prior to Day 0 
% also done for suspected immune-related adverse events.  
 
 
 
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2 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
Infection with Human Immunodeficiency Virus (HIV) affects an estimated 36.7 million worldwide. In the 
United States, an estimated 1.1 million are infected, and as access to antiretroviral treatment (ART) has 
increased, the population of people infected with HIV ages. Patients with viral suppression have 
increased life expectancy, therefore, they are apt to develop comorbidities seen in age-matched 
individuals without HIV, including cardiovascular disease (CVD). Among people living with HIV, CVD and 
its risk factors are an important cause of morbidity and mortality1. With the use of antiretroviral therapy 
(ART), the life expectancy of people with HIV has increased, making management of these comorbidities 
an important focus in prevention of cardiovascular disease. Findings from the SMART2 study showed the 
consequences of untreated HIV infection, including an increased relative risk for CVD by 60% in those 
who received episodic therapy, composed to those who received continuous ART2.  
 
HIV infection affects lipid metabolism by increasing triglycerides (TG) and low-density lipoprotein 
(LDL)3,4. In addition to HIV itself changing lipid concentrations5, antiretroviral therapy can also be pro-
arthrogenic1, and chronic inflammation from HIV (even in virally suppressed patients) can alter lipid 
metabolism profiles4. Studies have shown that compared to uninfected controls, patients with HIV who 
were on ART have an increased risk of CVD6,7. ART regimens have been studied extensively to determine 
their risk on lipid metabolism, and some classes of medications, such as protease inhibitors and older 
nucleoside reverse transcriptase inhibitors, may have more impact on lipid metabolism than newer 
classes of medications, such as integrase inhibitors7,8. 
 
Persistent inflammation and chronic immune activation are seen in HIV even when ART use leads to viral 
suppression4,9, increasing the risk for cardiovascular disease. The SMART study2 found that plasma levels 
of interleukin-6 (IL-6), C-reactive protein (CRP), and D-dimer products of fibrinolysis are independent 
predictors of mortality in HIV, including CVD-related deaths, and this has been supported by other 
studies, including that by Duprez et al10. Also, chronic immune activation may increase LDL levels by 
altering how lipids are processed and transported and/or by modifying lipids through the activity of 
reactive oxygen species11, rendering these lipids more inflammatory through their activation of 
monocytes and endothelial cells12,13. Oxidized LDL levels in HIV have been linked to markers of 
monocyte/macrophage activation13, coronary calcium14, noncalcified coronary artery plaques15, and 
arterial inflammation in HIV-infected patients16, indicating that oxidized LDL is an important contributor 
of blood vessel inflammation in HIV infection.  
 
In an effort to decrease effects of dyslipidemia and inflammation on cardiovascular health, use of statins 
in HIV patients has become a method to prevent CVD14,17. However, studies show that use of statins in 
patients with HIV is underutilized17,18, suggesting that there is a need for alternative lipid-lowering 
therapies in this population. In addition, delineating immune pathways that form the basis for abnormal 
lipid metabolism observed in HIV-infected patients seem to be vital in our efforts to reduce morbidity 
and mortality of this population.   
 
 
2.2 
BACKGROUND  
Human CD24 (also known as cluster of differentiation 24 or heat stable antigen (HSA)) is an 80 amino 
acid glycosyl-phosphatidyl-inositol (GPI)-anchored glycoprotein expressed on the membrane surfaces of 
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hematopoietic and non-hematopoietic cells encoded by a coding sequence (CDS) of 240 base pairs.  The 
first 26 amino acids constitute the signal peptide, while the last 23 serve as a signal for cleavage to allow 
for the attachment of the GPI tail. As a result, the mature human CD24 molecule has only 31 amino 
acids. CD24 is highly expressed in many cell types involved in the pathogenesis of Rheumatoid Arthritis 
(RA) and Multiple Sclerosis (MS). Furthermore, a single-nucleotide polymorphism of the CD24 gene 
results in replacement of alanine (CD24a) with valine (CD24v) in the mature protein and is an important 
genetic modifier for risk of several autoimmune diseases, including RA, MS and Systemic Lupus 
Erythematous. 
   
OncoImmune, Inc. has developed a recombinant fusion protein, CD24Fc, composed of the extracellular 
domain (ECD) of human CD24 fused to the hinge and Fc region of human IgG1, for the treatment of 
autoimmune diseases and Graft vs Host Disease (GVHD). CD24 (and CD24Fc) is highly glycosylated and 
based on the structural analysis of the saccharides, we identified lectins as relevant CD24 ligands that 
regulate innate and adaptive immunity. Furthermore, OncoImmune, Inc. has demonstrated that CD24Fc 
reduces production of multiple cytokines involved in the pathogenesis of RA and is highly effective in 
treating experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. CD24Fc has also 
been shown to be highly effective in preventing graft versus host disease (GVHD) in mice. 
 
The nonclinical program has been designed to support the ongoing clinical program. A first-in-human 
(FIH), single ascending dose clinical trial in healthy subjects has been successfully completed. A second, 
single ascending dose (Phase IIa) clinical trial with CD24Fc for the prevention of acute GVHD following 
myeloablative allogeneic hematopoietic stem cell transplant was completed in December 2018.  
Additional clinical studies for a metabolic disorder in prediabetic patients is planned. 
 
For more information on the background and development of CD24Fc, please see section 2 of the 
Investigator Brochure (IB). 
2.2.1 PHARMACOLOGY AND TOXICOLOGY OF CD24FC 
PK information from human studies is further described in section 2.2.3. In human studies, The Cmax and 
AUCs of plasma CD24Fc increased proportionally to the doses administered, consistent with data in 
mouse and monkey. The plasma CD24Fc reached Tmax between 1.01 and 1.34 hours. The t½ of plasma 
CD24Fc ranged between 280.83 and 327.10 hours. More information is available in section 5 of the IB.  
 
For information about nonclinical pharmacokinetics, please refer to sections 1.3 and 4.2 of the IB. 
 
For more information about nonclinical pharmacology, please refer to section 4.1 of the IB. 
 
For more information about toxicology in animals, please refer to section 4.3 of the IB. 
 
For more information about safety pharmacology, please refer to section 4.4 of the IB.  
2.2.2 SAFETY OF CD24FC IN ANIMAL STUDIES 
 
In a multi-dose intravenous toxicity study of CD24Fc in mice, no adverse effects were noted at doses of 
12.5, 35 or 125 mg/kg once weekly for 4 weeks with a 4-week recovery period. The no-observed-
adverse-effect-level (NOAEL) was considered to be equal to or greater than 125 mg/kg. In a multi-dose 
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toxicity study in cynomolgus monkeys, CD24Fc administered via 1-hour intravenous infusion once 
weekly for 4 consecutive weeks at 12.5 mg/kg/week, 35 mg/kg/week, or 125 mg/kg/week was generally 
well tolerated in male and female cynomolgus monkeys through a 4-week dosing period with a 10-week 
recovery period. On Day 28, one male administered 35 mg/kg/week had an approximate 13% decrease 
in hemoglobin concentration. On Day 98 (76 days after the last dose), changes in hematology for this 
animal included a 21% decrease in hemoglobin, a 16% increase in red blood cell counts, a 21% decrease 
in mean cell volume (MCV), a 32% decrease in mean cell hemoglobin (MCH), a 14% decrease in mean 
cell hemoglobin concentration (MCHC), a 24% increase in red cell distribution width (RDW), and an 
approximately 2-fold increase in platelet and reticulocyte counts compared to prestudy (Day  -2) levels. 
Day 98 blood smear analysis documented hypochromic red blood cells, microcytosis, anisocytosis, 
schistocytes, poikilocytes, and spherocytes, as well as an apparent increase in platelet numbers; these 
hematology changes are not considered typical findings in cynomolgus monkeys. However, no 
corresponding histopathology abnormalities were identified, and these hematology findings were not 
observed in any other animals in the study. Based on the hematology findings, the NOAEL for CD24Fc 
was considered to be 12.5 mg/kg/week under the conditions of this study when administered once 
weekly for four weeks. 
 
In the multi-dose studies, anti-drug antibodies (ADA) were raised in CD24Fc-treated mice and monkeys, 
respectively.  However, ADA were not associated with accelerated drug clearance or with any 
toxicological findings. 
 
In the tissue cross-reactivity study, cross-reactivity was determined using biotinylated CD24Fc and found 
to be widespread in tissues from normal human and cynomolgus monkeys. The staining intensity of 
CD24Fc binding and its distribution varied from minimal to marked, but the cytoplasmic staining pattern 
is consistent in all cell types with occasional membrane staining primarily in epithelial cells. Specific 
CD24Fc binding was detected in the similar tissues from human and monkeys, including lymphoid 
system, central nervous system, squamous cells of multiple tissues, epithelia of glands and goblet cells 
of digestive tract. Except the intensity of the specific staining is slightly stronger in cynomolgus monkey 
tissues, the cross-reactivity of CD24Fc with tissues from human and cynomolgus monkey tissues was 
considered similar under the study conditions. 
 
2.2.3 CD24FC IN HUMAN STUDIES 
 
FIRST IN-HUMAN STUDY (PHASE I) 
A Phase I, randomized, double-blind, placebo-controlled, single ascending dose study was conducted to 
assess the safety, tolerability, and PK of CD24Fc in healthy male and female adult subjects. A total of 40 
subjects in 5 cohorts of 8 subjects each were enrolled in this study. Six of the 8 subjects in each cohort 
received study drug and 2 subjects received placebo (0.9% sodium chloride, saline). The first cohort was 
dosed with 10 mg. Succeeding cohorts received 30 mg, 60 mg, 120 mg, and 240 mg of CD24Fc or 
matching placebo. Dosing was based on a fixed amount of CD24Fc and not based weight or BSA. 
 
Safety:  
In total, 18 (45.0%) subjects had a treatment-emergent adverse event (TEAE) during the study: 6 (60.0%) 
subjects in the placebo group, 2 (33.3%) subjects in the CD24Fc 10 mg group, 3 (50.0%) subjects in the 
CD24Fc 30 mg group, 2 (33.3%) subjects in the CD24Fc 60 mg group, 3 (50.0%) subjects in the CD24Fc 
120 mg group, and 2 (33.3%) subjects in the CD24Fc 240 mg group. All TEAEs in the study were 
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considered mild or moderate in severity by the Investigator except for 1 subject in the placebo group 
who experienced a severe headache. The most common TEAEs were headache (6 [15.0%] subjects), 
burns, second degree (3 [7.5%] subjects), ventricular tachycardia (2 [5.0%] subjects), and upper 
respiratory tract infection (2 [5.0%] subjects). 
 
Overall, 5 (12.5%) subjects had a study drug-related TEAE: 1 (10.0%) subject in the placebo group, 2 
(33.3%) subjects in the CD24Fc 10 mg group, 1 (16.7%) subject in the CD24Fc 30 mg group, and 1 
(16.7%) subject in the CD24Fc 60 mg group. The study drug-related TEAEs during the study were 
headache (4 [10.0%] subjects) and ventricular tachycardia (1 [2.5%] subject). 
 
A drug-related SAE of non-sustained ventricular tachycardia was experienced by 1 (16.7%) subject in the 
CD24Fc 60 mg group approximately 4 hours post-dose. The SAE was considered mild in severity by the 
Investigator and did not lead to discontinuation of the subject from the study. The Investigator 
considered the event to be drug related due to its close temporal proximity to dosing, though similar 
short, isolated episodes of non-sustained ventricular tachycardia may be seen in up to 4% of normal, 
healthy populations undergoing continuous cardiac monitoring. The other episode of non-sustained 
ventricular tachycardia was not considered related to study drug administration, and occurred without 
symptoms the second night post-infusion. 
 
No deaths or adverse events leading to discontinuation occurred during the study. No clinically 
meaningful changes from baseline in laboratory parameters, vital signs, or ECGs occurred. 
 
Exploratory Pharmacodynamic Markers: 
As surrogate markers for treatment-emergent changes in basal levels of inflammation, pre- and post-
dose levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein (hs-CRP) were analyzed. 
Changes in fasting low-density lipoprotein cholesterol (LDL-C) levels were also analyzed. 
Interleukin-6 levels were determined from samples collected on Day -1; Day 1, 8 hours after dosing; Day 
2; Day 7; and Day 42. The pre-dose levels of IL-6 were generally extremely low among the subjects, 
which did not allow for its use as a surrogate marker for CD24Fc anti­inflammatory activity in a normal, 
healthy population. 
 
High-sensitivity C-reactive protein levels were determined from samples collected on Day -1, Day 7, and 
Day 42. Two additional time points (Day 1, 8 hours and Day 2) were added beginning with the last 6 
subjects dosed in Cohort 2 (CD24Fc 30 mg group). The Day ­1 hs-CRP levels were normal in all except 
4 subjects. Overall, there were no significant treatment-emergent reductions in hs-CRP levels. 
Fasting LDL-C levels were determined from samples collected on Day -1, Day 7, and Day 42 for Cohort 1 
(CD24Fc 10 mg group). Beginning with Cohort 2 (CD24Fc 30 mg group), this lipid sampling was expanded 
to include Day 14. At Day 14, the CD24Fc 240 mg group had a statistically significant percent change 
decrease in LDL-C from baseline.  
 
PK: 
This study also characterized the single-dose PK of CD24Fc in healthy subjects. The mean plasma 
concentration of CD24Fc increased proportionally to the doses administered with t½ of 280.83 to 327.10 
hours. 
 
 
 
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Immunogenicity: 
Anti-CD24Fc antibodies were detectable at Day 28 and Day 42 in 1 subject in each of the 5 dose cohorts; 
however, for the subject in the CD24Fc 120 mg group and the subject in the CD24Fc 240 mg group, anti-
CD24Fc antibodies were also detectable pre-dose at levels higher than post-dose levels. Except for those 
subjects with significant pre-dose anti-CD24Fc antibody levels, all post-dose anti-CD24Fc antibody levels 
were modest. No deviations in PK were found in any subjects with detectable anti-CD24Fc antibody 
levels. 
 
Conclusions:  
This study showed that the single dose of IV administration of CD24Fc up to 240 mg was safe and well 
tolerated in healthy subjects. A drug-related SAE of non-sustained ventricular tachycardia was 
experienced by 1 subject in the CD24Fc 60 mg group. The SAE occurred at a rate comparable with 
normal populations, was considered mild by the Investigator, and did not lead to discontinuation from 
the study. There were no clinically meaningful changes from baseline in laboratory parameters, vital 
signs, ECGs, or physical exams during the study.  
 
For more information, please see section 5.1 of the IB. 
 
CD24FC FOR THE PREVENTION OF ACUTE GRAFT-VERSUS-HOST DISEASE FOLLOWING MYELOABLATIVE 
ALLOGENEIC HEMATOPOIETIC STEM CELL (PHASE II) 
A randomized, placebo-controlled Phase IIa dose escalation trial was conducted to evaluate the addition 
of CD24Fc to standard of care acute GVHD prophylaxis in cancer patients undergoing allogeneic 
myeloablative hematopoietic stem cell transplantation (HCT). The trial was designed to define the 
recommended phase II dose (RP2D) or Maximum Tolerated Dose (MTD) of CD24Fc for acute GVHD 
prophylaxis. The trial enrolled patients receiving transplants from matched unrelated donors undergoing 
allogeneic HCT according to institutional practice. This trial exclusively utilized myeloablative 
conditioning regimens and standard of care prophylaxis comprising tacrolimus and methotrexate since 
these patients experience the most severe tissue injury and drug will likely have the strongest biological 
effect in this setting.  
 
The Phase IIa trial comprised two single ascending dose cohorts (240 mg and 480 mg) and a single multi-
dose cohort of CD24Fc in addition to standard-of-care GVHD prophylaxis. In the single dose cohort, the 
study agent, CD24Fc, was administered intravenously on day -1 pre-transplant. In the multi-dosing 
cohort, patients received 3 biweekly administrations of CD24Fc of 480 mg (day -1), 240 mg (day +14) 
and 240 mg (day +28). Dosing was based on a fixed amount and not based on weight or BSA. Each 
dosing cohort enrolled 8 subjects using a randomized 3:1 ratio (6 CD24Fc subjects and 2 placebo) design 
for a total enrollment of 24 patients.  
 
The primary objectives of the study were: 
• 
To evaluate the safety and tolerability of CD24Fc in subjects undergoing myeloablative 
allogeneic hematopoietic cell transplantation (HCT)  
• 
To determine the recommended Phase II dose (RP2D) or maximum tolerable dose (MTD) of 
CD24Fc in patients undergoing HCT  
 
The secondary objectives of the study were: 
• 
To estimate grade II-IV acute GVHD free survival (GFS) at day 180 following HCT.  
• 
To estimate grade III-IV acute GVHD free survival (GFS) at day 180 following HCT. 
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• 
To describe incidence of chronic GVHD at one year following HCT  
• 
To describe incidence of relapse at one year following HCT 
• 
To describe incidence of transplant-related mortality (TRM) at one year following HCT 
• 
To describe rates of infection at day 100 following HCT 
• 
To evaluate overall survival (OS) and disease-free survival (DFS) at one year following HCT 
 
The correlative and biologic study objectives of the study were: 
• 
To assess the pharmacokinetic (PK) profile of single-dose CD24Fc and anti-drug antibodies in the 
target patient population 
• 
To examine functional responses of antigen presenting cells and T cells before and after 
administration of CD24Fc  
• 
To perform phenotyping of T cells, B cells, NK cells and other cellular immune subsets before 
and after donor cell infusion (HCT)  
• 
To assess plasma concentrations of pro-inflammatory cytokines, damage-associated molecular 
patterns (DAMPs), Low-density lipoprotein (LDL), High-density lipoprotein (HDL), Triglycerides, 
Total cholesterol and GVHD biomarkers before and after administration of CD24Fc 
• 
To assess genetic polymorphism of CD24 and Siglec10 genes, and microRNAs such as mir29, in 
both donor and recipients 
 
Efficacy:  
Overall, treatment with CD24Fc resulted in trends toward a higher Grade III to IV acute GFS rate at 
Day 180 (94.4% and 50.0%, respectively) (hazard ratio = 0.1), higher DFS rate at 1 year post-HCT (83.3% 
and 50.0%, respectively) (hazard ratio = 0.2), better OS rate at 1 year post-HCT (83.3% and 50.0%, 
respectively) (hazard ratio = 0.2), and higher Grade III to IV acute GFS and relapse-free survival (GRFS) 
rate at Day 180 (83.3% and 33.3%, respectively) (hazard ratio = 0.2) compared to placebo. 
 
Additionally, there were overall trends toward a lower cumulative incidence rate of relapse at 1 year 
post-HCT (11.1% and 33.3%, respectively) (hazard ratio = 0.3) and a lower cumulative incidence rate of 
TRM at Day 180 (0.0% and 16.7%, respectively) and 1 year (5.6% and 16.7%, respectively) (hazard 
ratio = 0.3) for the CD24Fc treatment group compared to the placebo group. 
 
Overall, there was a trend toward a lower incidence of Grade III to IV acute GVHD by Day 180 in CD24Fc-
treated patients when compared to patients receiving placebo (5.6% and 33.3%, respectively) (hazard 
ratio = 0.1) but a higher cumulative incidence of Grade II to IV acute GVHD by Day 100 for the CD24Fc 
treatment group compared to the placebo group (38.9% and 16.7%, respectively) (hazard ratio = 2.6).  
Overall, the Grade II to IV acute GFS rate at Day 180 was slightly higher in the CD24Fc treatment group 
compared to the placebo group (61.1% and 50.0%, respectively). 
 
Overall, there was a trend toward a higher incidence of chronic GVHD at 1 year post-HCT in CD24Fc-
treated patients when compared to patients receiving placebo (63.3% and 33.3%, respectively) (hazard 
ratio = 2.1) and a similar GRFS rate at 1 year post-HCT (32.4% and 33.3%, respectively) (hazard ratio = 
0.7). 
 
In total, 13 (72.2%) patients who received CD24Fc and 2 (33.3%) patients who received placebo had an 
infection through Day 100. The majority of the infections were bacterial or viral and occurred in the 
blood or urine. The majority of the bacteria recovered from blood culture were common skin 
inhabitants and low virulence pathogens (i.e., coagulase negative staphylococci). 
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In total, there was a reduced rate of cytomegalovirus (CMV) reactivation at Day 100 in the CD24Fc 
treatment group over the placebo group (22.2% and 50.0%, respectively) among high risk populations 
(pre-transplantation CMV status as D+/R+, D-/R+, or unknown D/R+). The CMV reactivation in the 2 
patients in the CD24Fc group occurred after systemic steroid treatment. The 1 patient in the placebo 
group with CMV reactivation did not receive steroid treatment prior to CMV reactivation. 
 
PK: 
Following a single IV administration of CD24Fc (240 and 480 mg CD24Fc single dose cohorts), the 
geometric mean plasma exposure (Cmax,-1d, AUC0-42d, AUC0-last,-1d, and AUC0-inf) increased with increasing 
CD24Fc doses. The mean t½ and λz were similar between the 240 and 480 mg doses of CD24Fc. The 
mean values of t½ were 414.739 and 406.648 h and the mean values of λz were 0.0018 and 0.0017 h-1 for 
the 240 and 480 mg CD24Fc single dose cohorts, respectively. Additionally, there was an increase in the 
mean Vz and CL between the 240 and 480 mg doses of CD24Fc. 
 
Following multiple IV administrations of CD24Fc (960 mg CD24Fc multiple dose cohort), the exposure of 
CD24Fc was sustained over time. Additionally, the mean plasma CD24Fc concentration on Day 100 was 
higher for the 480, 240, and 240 mg (ie, 960 mg) CD24Fc multiple dose cohort (850.84 ng/mL) compared 
to the single dose cohorts (216.38 ng/mL and 330.96 ng/mL for the 240 and 480 mg CD24Fc single dose 
cohorts, respectively). Furthermore, the geometric mean AUC0-last,overall value was higher for the 480, 240, 
and 240 mg (ie, 960 mg) CD24Fc multiple dose cohort (37,363,953.5 ng⋅h/mL) compared to the single 
dose cohorts (AUC0-last,-1d of 10,156,549.9 ng⋅h/mL and 15,522,686.2 ng⋅h/mL for the 240 and 480 mg 
CD24Fc single dose cohorts, respectively). 
 
The median tmax,-1d (2.10 h for both the 240 and 480 mg CD24Fc single dose cohorts and 2.13 h for the 
960 mg CD24Fc multiple dose cohort) was similar across all of the CD24Fc doses. For the 960 mg CD24Fc 
multiple dose cohort, the median tmax,-1d and tmax,28d were similar (2.13 and 2.52 h, respectively).  
 
Safety:  
No patients experienced a DLT during the study. The MTD was not reached. The highest dose in this 
study, 960 mg CD24Fc multiple dose (ie, 480 mg, 240 mg, and 240 mg on Days -1, 14, and 28), is 
considered safe and recommended for future studies. 
 
The incidence of TEAEs from Day -1 to 30/60 days after the last dosing was the same between all 
treatments: 6 (100.0%) patients in the 240 mg CD24Fc single dose cohort, 6 (100.0%) patients in the 480 
mg CD24Fc single dose cohort, 6 (100.0%) patients in the 960 mg multiple dose cohort, and 6 (100.0%) 
patients who received placebo experienced TEAEs.  
 
The most common TEAEs were stomatitis (6 [100.0%] patients in the 240 mg CD24Fc single dose cohort, 
6 [100.0%] patients in the 480 mg CD24Fc single dose cohort, 5 [83.3%] patients in the 960 mg CD24Fc 
multiple dose cohort, and 6 [100.0%] patients who received placebo); platelet count decreased 
(6 [100.0%] patients in the 240 mg CD24Fc single dose cohort, 6 [100.0%] patients in the 480 mg CD24Fc 
single dose cohort, 5 [83.3%] patients in the 960 mg CD24Fc multiple dose cohort, and 5 [83.3%] 
patients who received placebo); and white blood cell count decreased (6 [100.0%] patients in the 240 
mg CD24Fc single dose cohort, 6 [100.0%] patients in the 480 mg CD24Fc single dose cohort, 5 [83.3%] 
patients in the 960 mg CD24Fc multiple dose cohort, and 4 [66.7%] patients who received placebo). 
Severe stomatitis (≥ Grade 3) occurred in 3 (50.0%) patients in the 240 mg CD24Fc single dose cohort, 
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C A LI B E R O n c oI m m u n e C D 2 4 Fc -0 0 3  
Versi o n 5. 0  
Pr ot o c ol H P -0 0 0 8 6 0 2 9  
N o v e m b er 1 2 , 2 0 2 0 
 
 1 7  
4 ( 6 6. 7 %) p ati e nts i n t h e 4 8 0 m g C D 2 4 Fc si n gl e d os e c o h ort, 2 ( 3 3. 3 %) p ati e nts i n t h e 9 6 0 m g C D 2 4 Fc 
m ulti pl e d os e c o h ort, a n d 5 ( 8 3. 3 %) p ati e nts w h o r ec ei v e d pl ac e b o, wit h a cl e ar i nv ers e c orr el ati o n 
b et w e e n C D 2 4 Fc d os es a n d d ur ati o n of s ev er e st o m atitis.  
 
O n e ( 1 6. 7 %) p ati e nt i n t h e 4 8 0  m g C D 2 4 Fc si n gl e d os e c o h ort a n d 2 ( 3 3. 3 %) p ati e nts w h o r ec ei v e d 
pl ac e b o ex p eri e nc e d a st u dy dr u g -r el at e d T E A E. T h e m ost c o m m o n st u dy dr u g-r el at e d T E A E w as 
di arr h e a ( 1  [ 1 6. 7 %] p ati e nt i n t h e 4 8 0 m g C D 2 4 Fc si n gl e d os e c o h ort a n d 2  [ 3 3. 3 %] p ati e nts w h o 
r ec eiv e d pl ac e b o). N o p ati e nts i n ot h er c o h orts ex p eri e nc e d a st u dy dr u g-r el at e d T E A E. 
 
T h e i nci d e nc e of Gr a d e 3/ 4/ 5 T E A Es w as t h e s a m e b et w e e n all tr e at m e nts: 6 ( 1 0 0. 0 %) p ati e nts i n t h e 
2 4 0  m g C D 2 4 Fc si n gl e d os e c o h ort, 6 ( 1 0 0. 0 % ) p ati e nts i n t h e 4 8 0 m g C D 2 4 Fc si n gl e d os e c o h ort, 
6 ( 1 0 0. 0 %) p ati e nts i n t h e 9 6 0 m g C D 2 4 Fc m ulti pl e d os e c o h ort, a n d 6 ( 1 0 0. 0 %) p ati e nts w h o r ec ei v e d 
pl ac e b o. O n e ( 1 6. 7 %) p ati e nt i n t h e 4 8 0 m g C D 2 4 Fc si n gl e d os e c o h ort ex p eri e nc e d hy p er gl yc e mi a t h at 
w as c o nsi d er e d a st u dy dr u g-r el at e d Gr a d e 3/ 4/ 5 T E A E.  
 
I n t ot al, 1 ( 4. 2 %) p ati e nt di e d d uri n g t h e st u dy d u e t o T E A Es. P ati e nt 
 r ec ei v e d pl ac e b o a n d 
ex p eri e nc e d Gr a d e 4 p n e u m o m e di asti n u m a n d Gr a d e 5 p n e u m o ni a T E A Es t h at r es ult e d i n d e at h. P er 
t h e I nv esti g at or, it w as c o nsi d er e d u nli k ely t h at t h es e T E A Es w er e r el at e d t o st u dy dr u g. 
 
I n t ot al, 9 ( 3 7. 5 %) p ati e nts ex p eri e nc e d a tr e at m e nt-e m er g e nt s eri o us a dv ers e ev e nt ( S A E): 2  ( 3 3. 3 %) 
p ati e nts i n t h e 2 4 0  m g C D 2 4 Fc si n gl e d os e c o h ort, 1  ( 1 6. 7 %) p ati e nt i n t h e 4 8 0 m g C D 2 4 Fc si n gl e d os e 
c o h ort, 4 ( 6 6. 7 %) p ati e nts i n t h e 9 6 0 m g C D 2 4 Fc m ulti pl e d os e c o h ort, a n d 2 ( 3 3. 3 %) p ati e nts w h o 
r ec eiv e d pl ac e b o. Tr e at m e nt-e m er g e nt S A Es r e p ort e d f or p ati e nts w h o r ec ei v e d C D 2 4 Fc w er e n a us e a, 
st o m atitis, a b d o mi n al p ai n, d e hy dr ati o n, d ecr e as e d a p p etit e, d e vic e r el at e d i nf ecti o n, art hritis, 
p ol y m y al gi a r h e u m atic a, w ei g ht d ecr e as e, c o g nitiv e dis or d er, a n d p ul m o n ar y e m b olis m.  
 
N o  p ati e nts  ex p eri e nc e d a st u dy dr u g -r el at e d tr e at m e nt-e m er g e nt S A E.  
 
I n t ot al, t h e i nci d e nc e of T E A Es of al a ni n e a mi n otr a nsf er as e i ncr e as e a n d bl o o d alk ali n e p h os p h at as e 
i ncr e as e w er e si mil ar b et w e e n p ati e nts w h o r ec eiv e d C D 2 4 Fc a n d p ati e nts w h o r ec eiv e d pl ac e b o. T h e 
i nci d e nc e of T E A Es of as p art at e a mi n otr a nsf er as e i ncr e as e w as hi g h er f or p ati e nts w h o r ec ei v e d C D 2 4 Fc 
c o m p ar e d t o p ati e nts w h o r ec eiv e d pl ac e b o. Tr e at m e nt -e m er g e nt a dv ers e ev e nts of bl o o d c h ol est er ol 
i ncr e as e w er e o nl y r e p ort e d by p ati e nts i n t h e 9 6 0 m g C D 2 4 Fc m ulti pl e d os e c o h ort ( 2 [ 3 3. 3 %] p ati e nts). 
Tr e at m e nt -e m er g e nt a dv ers e ev e nts of bl o o d cr e ati ni n e i ncr e as e w er e o nl y r e p ort e d by p ati e nts w h o 
r ec eiv e d pl ac e b o ( 2 [ 3 3. 3 %] p ati e nts). A T E A E of bl o o d bilir u bi n i ncr e as e d w as r e p ort e d by 1 ( 1 6. 7 %) 
p ati e nt w h o r ec eiv e d pl ac e b o.  
 
I n t ot al, t h e i nci d e nc e of T E A Es of w hit e bl o o d c ell c o u nt d ecr e as e, ly mp h ocyt e c o u nt d ecr e as e, a n d 
n e utr o p hil c o u nt d ecr e as e  w er e hi g h er i n p ati e nts w h o r ec eiv e d C D 2 4 Fc c o m p ar e d t o p ati e nts w h o 
r ec eiv e d pl ac e b o. T h e i nci d e nc e of T E A Es of pl at el et c o u nt d ecr e as e w as si mil ar b et w e e n p ati e nts w h o 
r ec eiv e d C D 2 4 Fc a n d p ati e nts w h o r ec eiv e d pl ac e b o. 
 
N o p ati e nt h a d a l a b or at ory a b n or m ality t h at w as c o nsi d er e d a n S A E or r es ult e d i n disc o nti n u ati o n of 
st u dy dr u g.  
 
N o p ati e nts w h o r ec eiv e d eit h er si n gl e or m ulti pl e d osi n g of C D 2 4 Fc h a d p ositiv e A D A r es ults at a ny ti m e 
p oi nt s a m pl e d pr e- or p ost -i nf usi o n. 
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A TEAE of weight increase was reported by 1 (16.7%) patient who received placebo and a TEAE of weight 
decrease was reported by 3 (16.7%) patients who received CD24Fc. A TEAE of ECG QT prolonged was 
reported by 1 (16.7%) patient who received placebo. 
 
The mean percent change from baseline in the blast percentage in bone marrow at Day 100 
was -57.11%, -12.50%, 1433.33%, and -51.33% for the 240 mg CD24Fc single dose cohort, 480 mg 
CD24Fc single dose cohort, 960 mg CD24Fc multiple dose cohort, and placebo group, respectively. 
 
Engraftment: 
In total, 18 (100.0%) patients who received CD24Fc and 6 (100.0%) patients who received placebo 
experienced neutrophil engraftment. In total, 18 (100.0%) patients who received CD24Fc and 5 (83.3%) 
patients who received placebo experienced platelet engraftment. The median times to neutrophil and 
platelet engraftment were similar between all treatment groups. No patients experienced primary 
engraftment failure. 
 
The mean CD3 and CD33 cell chimerism on Day 28/Day 30 was 73.0% donor cells and 100.0% donor 
cells, respectively, for patients who received CD24Fc and 77.4% donor cells and 100.0% donor cells, 
respectively, for patients who received placebo. The mean CD3 and CD33 cell chimerism on Day 100 was 
80.9% donor cells and 99.4% donor cells, respectively, for patients who received CD24Fc and 73.8% 
donor cells and 96.6% donor cells, respectively, for patients who received placebo. 
 
Conclusions: 
• 
The safety profile of CD24Fc did not appear to be affected by increasing dose or multiple 
administrations. 
• 
No patients experienced a dose-limiting toxicity (DLT) during the study. The MTD was not reached. 
The highest dose in this study, 960 mg CD24Fc multiple dose (ie, 480 mg, 240 mg, and 240 mg on 
Days -1, 14, and 28, respectively), is considered safe and recommended for future studies. 
• 
Treatment with CD24Fc resulted in trends toward a higher Grade III to IV acute GFS rate at Day 180 
(hazard ratio = 0.1), higher DFS rate at 1 year post-HCT (hazard ratio = 0.2), better OS rate at 1 year 
(hazard ratio = 0.2), and higher Grade III to IV acute GRFS rate at Day 180 (hazard ratio = 0.2) 
compared to treatment with placebo. 
• 
There was a trend toward a lower incidence of Grade III to IV acute GVHD by Day 180 for the CD24Fc 
treatment group compared to the placebo group (hazard ratio = 0.1). 
• 
There was a trend toward a higher cumulative incidence of Grade II to IV acute GVHD by Day 100 for 
the CD24Fc treatment group compared to the placebo group (hazard ratio = 2.6). 
• 
The Grade II to IV acute GFS rate at Day 180 was slightly higher in the CD24Fc treatment group 
compared to the placebo group. 
• 
Treatment with CD24Fc resulted in a trend toward a lower cumulative incidence rate of relapse at 1 
year post-HCT compared to treatment with placebo (hazard ratio = 0.3). 
• 
There was a lower rate of CMV reactivation among the at risk populations but a higher rate of 
infection with CD24Fc treatment compared to placebo.  
• 
The majority of the bacteria recovered from blood culture were common skin inhabitants and low 
virulence pathogens. 
• 
Multiple doses of CD24Fc induced more sustained exposure over time and resulted in higher mean 
plasma CD24Fc concentrations on Day 100 compared to the single dose cohorts. 
• 
The median tmax,-1d and tmax,28d remained consistent across all of the CD24Fc doses. 
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• 
No patients who received either single or multiple dosing of CD24Fc had positive ADA results at any 
time point sampled pre- or post-infusion. 
 
For more information, please see section 5.2 of the IB.  
2.2.4 RATIONALE FOR USE OF CD24FC TO REDUCE LDL  
During OncoImmune’s Phase I trial, serum 
samples were taken and the level of LDL was 
measured over time; the 240mg dose 
significantly reduced LDL (see Figure) and IB 
section 2.4.2 for more information).  
 
CD24Fc has also been used in Phase II testing 
for the prophylaxis of acute GVHD in cancer 
patients undergoing allogeneic myeloablative 
hematopoietic stem cell transplantation (HCT). 
In the Phase IIa portion of the trial 
(ClinicalTrials.gov Identifier: NCT02663622), 
patients were sequentially double-blind 
randomized into three cohorts with 2 placebo 
and 6 in CD24Fc treatment. The two single ascending dose cohorts (240 mg and 480 mg) and one multi-
dose cohort (480 mg (day -1), 240 mg (day +14) and 240 mg (day +28)) were given CD24Fc in addition to 
standard of care GVHD prophylaxis with tacrolimus and methotrexate. The LDL levels were examined 
and recorded at pre-dosing baseline and Day 14 post-HCT. The D14 samples in the multi-dose cohort 
were taken before the D14 CD24Fc administration. The D14 results in the multi-dose cohort are 
combined with the 480mg single dose cohort as both groups of patients received 480mg at Day-1. In this 
Phase IIa clinical trial, HCT patients underwent myeloablative conditioning treatment with intensive 
chemotherapy before the HCT. Some patients had additional total body irradiation. The placebo group 
had an average 78+19% of the D14 LDL level to the pre-dosing level. The CD24Fc 240mg group had an 
average of 50+10% of the D14 LDL level to the pre-dosing level. The CD24Fc 480mg group (including the 
single dosing and multi-dosing groups) had an average of 60+20% of the D14 LDL level to the pre-dosing 
level. When compared with placebo control, both 240mg and 480mg of CD24Fc significantly reduced 
LDL-C at Day 14 post-HCT. These results suggest that LDL is significantly reduced with use of CD24Fc; this 
investigation aims to see if a similar reduction occurs in HIV positive patients who are virally suppressed, 
thus serving as a surrogate marker for CVD risk reduction. For more information, please see section 
2.4.2 of the IB. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
To date, CD24Fc has been tested in a Phase I clinical study in healthy subjects, and in a Phase IIa trial for 
the prevention of acute GvHD following myeloablative allogeneic HSCT.  
Phase I Study: The Phase I study was a randomized, double-blind, placebo-controlled, single ascending 
dose study to assess the safety, tolerability, and PK of CD24Fc in healthy male and female adult subjects. 
A total of 40 subjects in 5 cohorts of 8 subjects each were enrolled in this study. Six of the 8 subjects in 
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each cohort received study drug and 2 subjects received placebo (0.9% sodium chloride, saline). The first 
cohort was dosed with 10 mg and succeeding cohorts received 30 mg, 60 mg, 120 mg, and 240 mg of 
CD24Fc or matching placebo and were dosed at least 3 weeks apart to allow for review of safety and 
tolerability data for each prior cohort.  
The Phase I study showed that the single dose of CD24Fc up to 240 mg by IV administration was 
generally well tolerated in healthy subjects. The most common TEAEs reported by subjects included 
headache and second-degree burns. However, no statistically significant difference was observed 
between those who received placebo vs those who received CD24Fc.  All TEAEs in the study were 
considered mild or moderate in severity by the Investigator except for 1 subject in the placebo group 
who experienced a severe headache. A drug-related SAE of ventricular tachycardia was experienced by 1 
subject in the CD24Fc 60 mg group. The SAE was considered mild in severity by the Investigator and did 
not lead to discontinuation from the study, and occurred at a rate comparable with normal populations, 
was considered mild by the Investigator, and did not lead to discontinuation from the study. There were 
no infusion reactions or injection site reactions reported.  
Phase II study: The Phase IIa GvHD study was also a randomized, double-blind, placebo-controlled trial 
that evaluated the safety and tolerability of the addition of CD24Fc to standard GVHD prophylaxis in 
healthy male and female adult subjects in subjects undergoing myeloablative allogeneic hematopoietic 
cell transplantation (HCT). The Phase IIa trial comprised two single ascending dose cohorts (240 mg and 
480 mg) and a single multi-dose cohort (480/240/240 mg)of CD24Fc to define the recommended phase 
IIb dose (RP2D) or maximum tolerated dose (MTD). A total of 24 subjects in 3 cohorts of 8 subjects were 
enrolled in this study. Six of the 8 subjects in each cohort received study drug and 2 subjects received 
placebo (0.9% sodium chloride, saline).  
The safety profile of CD24Fc did not appear to be affected by increasing dose or multiple 
administrations. No patients experienced a DLT during the study. The MTD was not reached. One 
patient in the 480 mg CD24Fc single dose cohort and 2 patients who received placebo experienced a 
study drug-related TEAE. The most common study drug-related TEAE was diarrhea. No patients in other 
cohorts experienced a study drug related TEAE. The highest dose in this study, 960 mg CD24Fc multiple 
dose (ie, 480 mg, 240 mg, and 240 mg on Days -1, 14, and 28, respectively), is considered safe and 
recommended for future studies. The most common adverse events (AEs) observed included 
hematologic AEs (i.e. anemia, thrombocytopenia, leukopenia, neutropenia), nausea and oral mucositis, 
which are expected based on the patient population and/or treatment procedure.  
As with the FIH study and the Phase II GvHD study, the planned studies include many precautions that 
are being taken to ensure subject safety. The protocol has been designed to exclude subjects who are at 
heightened risk of adverse events (AE) and ensure that clinical sites are equipped to manage any 
toxicities.  
Based on the known biology of the CD24-Siglec pathways and its importance in the immune system, 
immune-related adverse events (irAE) are the most likely class of toxicity that could be observed in 
humans. As in the FIH and Phase IIs GvHD study, potential risks, and plans to mitigate these risks are 
incorporated into the design of future studies. 
Ventricular Tachycardia: An SAE of ventricular tachycardia was observed in one healthy subject that 
received CD24Fc in the Phase 1 trial. This SAE was considered mild in severity by the investigator and did 
not lead to discontinuation of the subject from the study. This SAE was considered to be drug related 
due to its close temporal proximity to dosing, though similar short, isolated episodes of non-sustained 
ventricular tachycardia may be seen in up to 4% of normal, healthy populations. No deaths or adverse 
events leading to discontinuation occurred during the study. 
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During the Phase IIa trial, all patients had 12-line EKG before and after each CD24Fc or placebo I.V. 
infusion. The 24 patients in Phase IIa trial did not have abnormal EKG when compared with baseline pre-
dosing EKG.  
Based on the mechanism of action and pre-clinical data, there is no reason to believe that CD24Fc 
administration would lead to ventricular tachycardia or any other cardiac-related adverse events. 
Inclusion criteria for the CD24Fc in preventing GVHD study includes having a Hematopoietic Cell 
Transplant-Co-morbidity Index (HCT-CI) of ≤ 4, which includes an assessment of arrhythmia and cardiac 
co-morbidities. Vital signs will be monitored before and during each infusion of CD24Fc in this trial, and 
an assessment of arrhythmia and cardiac co-morbidities will be done in the screening period.   
Adverse Immune Suppression: Preclinical studies indicate that CD24Fc is not broadly 
immunosuppressive. Preclinical data have demonstrated that CD24 negatively regulates host 
inflammatory response to cellular Danger-Associated Molecular Patterns (DAMPs) that are released as a 
result of tissue injury and, through interaction with its receptor, Siglec G, CD24 provides a powerful 
negative regulation for host response to tissue injuries. This mechanism is particularly relevant to the 
lead indication, GVHD and extensive preclinical studies have demonstrated that CD24Fc prevents GVHD 
in a mouse model.  Tissue injury is caused by hematopoietic stem cell transplantation conditioning 
regimens, including high-dose chemotherapy and/or total body irradiation (TBI), and is considered to be 
the first step in the development of acute GVHD. In contrast, host response to pathogen-associated 
molecular patterns (PAMPs) is unaffected by CD24-Siglec G interaction and thus the CD24-Siglec G 
interaction appears to play a critical role in discriminating DAMPs from PAMPs. 
Importantly, the drug has advantages over conventional immunosuppressants as it does not cause 
general immune suppression and use of high doses of CD24Fc does not block antibody response in non-
human primates.  Furthermore, an important function of allogeneic stem cell transplantation is to use 
donor T cells to eliminate allogeneic leukemia cells. This effect is called GVL.  Importantly, treatment of 
CD24Fc, which prevented GVHD had no effect of GVL in the mouse model. Finally, extensive studies in 
non-human primate demonstrate that CD24Fc does not suppress antigen-specific immune response, 
which suggest that CD24Fc will not likely increase risk of infection. Regardless, eligibility criteria in this 
study excludes subjects that are considered at risk for uncontrolled infections. Serum samples will be 
evaluated for autoantibodies as indicated in the SOA. In the Phase IIa trial, the rate of fungal, bacterial 
and viral infections was not significantly increased. Instead, there seemed to be a trend of reduced CMV 
reactivation.  
In this trial, HIV patients with anti-retroviral treatment may have increased risk of infections. However, 
the eligibility criteria in the planned study exclude subjects that are considered at risk for uncontrolled 
infections.  
Infusion Reactions:  Infusion reactions have not been observed in the Phase 1 or Phase IIa clinical trials. 
However, the administration of any recombinant protein has the potential to elicit infusion reactions. 
CD24Fc includes the Fc portion of human IgG1. After target binding, CD24Fc may induce FcγR cross-
linking, which has been associated with infusion reactions for some therapeutics.  
Infusion reactions may include events such as changes in vital signs, fever, difficulty breathing, 
hypotension, generalized or facial edema, nausea, chills, mental status changes, urticaria or vomiting 
during or up to 2 hours following infusion. The Phase IIa Clinical Protocol incorporated generalized 
procedures designed to closely monitor, minimize and manage any potential infusion reactions and 
initially was administered only on an inpatient hospital unit. However, the protocol was amended to 
allow CD24Fc dosing to be administrated in outpatient clinics for the multi-dosing cohort of 8 patients. 
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in this study, patients will be monitored before, during, and for 2 hours post infusion to assess for 
infusion-related reactions.  
Exacerbation of Immune Responses:  
CD24 has wide-spread expression among both hematopoietic and non-hematopoietic cells and, as a 
rule, CD24 tends to express at higher levels among immature immune cells than their terminally 
differentiated products. Therefore, CD24 has been widely used as a marker to track the development of 
both T and B cells.   
CD24 was initially identified as a costimulatory molecule on activated B cells by functional screening for 
monoclonal antibodies that inhibit T cell activation driven by activated B cells.  One of the most potent 
antibodies was identified as recognizing CD24 on B cells.  When expressed on CHO cells, CD24 can 
provide costimulatory activity for clonal expansion of naïve CD4 T cells.  Enk and Katz demonstrated that 
the CD24 functions as a costimulatory molecule on Langerhans cells (Enk and Katz 1994) 19, as anti-CD24 
blocks proliferation and induces clonal anergy of cloned Th1 cells.  The function of CD24 in CD8 T cell 
priming was demonstrated in two models.  First, CD24 was rapidly induced on macrophages following 
the phagocytosis of latex beads (De Bruijn et al 1996)20.  The induction of CD24 was essential for the in 
vitro priming of naïve CD8 T cells, as such priming was completely abrogated by anti-CD24 antibodies.  
Second, transfection of CD24 into tumor cells resulted in enhanced priming of CD8 T cells in vivo (Want 
et al 1987)21.  These results demonstrated that CD24 is a costimulatory molecule capable of promoting 
the priming of both CD4 and CD8 T cells. Therefore, there is a theoretical risk that CD24Fc could 
exacerbate immune responses. 
Pre-clinical animal models of disease, including GVHD, did not show any exacerbation of immune 
responses. Clinical observations during the FIH study did not suggest an exacerbation of immune 
responses. The Phase IIa clinical trial provided evidence that CD24Fc suppresses the severe acute GVHD 
while preserving the graft vs leukemia effect. There was no increase of infection in this highly 
susceptible population.  In the planned trial, serum samples will be collected evaluated for anti-drug 
antibodies, and the eligibility criteria exclude those that are at high risk for uncontrolled infections. 
Other Risks:  
The primary risks of phlebotomy include occasional bleeding or bruising of the skin at the site of needle 
puncture, and the sensation of transient lightheadedness, or rarely, fainting and infection. The amount 
of blood drawn will be within the limits allowed for adult subjects.   
 
The risks of intravenous catheters used to give the study drug or placebo includes local bleeding, 
infection, or local inflammation of the skin and vein with pain and swelling. 
 
After the ECG, subjects may experience mild skin irritation, slight redness or itching where the recording 
patches were placed.  They may also need to have chest hair shaved for the procedure. 
 
The risks with transient elastography are minimal since it is a non-invasive procedure. Patients may feel 
discomfort from the cold temperature of the gel that is applied for sonography, or from the pressure the 
probe transducer elicits against the skin with sound wave.  
 
The study involves exposure to radiation from the radioactive sugar, but the radiation from 2 FDG 
PET/CT scans will be less than the radiation safety limit for research. There is no medical risk from lying 
in the scanner, although subjects may become uncomfortable or restless. Subjects will also have to fast 
6 hours before the appointment due to the use of radioactive glucose, which may also cause discomfort. 
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In addition to any radiation concern, there could be psychological distress caused by an incidental 
finding of asymmetric FDG uptake that would likely necessitate additional investigation to exclude 
cancer. Additional minimal risks include bleeding or bruising at the venous site of FDG administration. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
 
The potential benefits of CD24Fc in patients with HIV infection included in the current study population 
are: 
• 
Use of an agent as lipid-lowering therapy in the growing number of chronically infected HIV 
patients who have risk factors for cardiovascular disease and have underutilization of statins, 
resulting in sub-optimal cardiovascular disease risk modification 
• 
Addressing the unmet medical need for decreasing immune activation and inflammation in 
patients infected with HIV, in order to reduce the risk of additional comorbidities and possibly 
lead to immune reconstitution  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
There is no intravenous treatment available to patients with HIV which is able to lower LDL and 
reduce inflammation/immune activation. Statins remain the standard of care for dyslipidemia, but 
are underutilized and may be ineffective in some cases. Other approaches, including ezetimibe, 
fibrates, and PCSK9 inhibitors, are approved therapies to lower LDL. However, CD24Fc has been 
found to lower LDL through different molecular mechanisms than statins and other approved drugs. 
CD24Fc may modulate the antigen presenting cells and promote immune reconstitution in HIV 
patients undergoing ART treatment.  If favorable changes in immune activation, inflammatory 
markers, and LDL can be achieved in patients who receive a 4-week regimen of CD24Fc, the 
anticipated value of lowering cardiovascular risk with a safe and tolerable regimen offers a favorable 
risk-benefit determination. 
 
3 
OBJECTIVES AND ENDPOINTS 
3.1.1 PRIMARY OBJECTIVES 
1. To determine the safety and tolerability of CD24Fc during the 4-week dosing period and a 24-week 
follow-up period in a cohort of HIV patients.  
2. To evaluate the change in LDL during a 4-week dosing period of CD24Fc and a 24-week follow-up 
period. 
3.1.2 SECONDARY OBJECTIVES 
To evaluate the effect of CD24Fc on the following variables between the placebo and intervention arms 
in comparison with baseline values:  
1. Levels of total cholesterol, HDL, and triglycerides  
2. Markers of immune activation (CD4 and CD8 T cells, IFN, TNF, sCD14) 
3. Size of HIV reservoirs  
4. Myocardial damage (measured by Troponin I and T) 
5. Hepatic steatosis, as determined by transient elastography  
6. Leptin 
7. Hemoglobin A1c 
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8. Presence of anti-drug antibody (ADA) and temporal correlation to any adverse events, and its 
effect on PK (For first 6 subjects). 
9. The pharmacokinetics (PK) and pharmacodynamics (PD) of CD24Fc in the first 6 randomized 
subjects. 
10. Changes in IL-6, apoB, Lp(a), urine albumin to creatinine ratio before and after treatment.  
3.1.3 EXPLORATORY OBJECTIVES 
1. To assess the effect of CD24Fc on aortic vascular inflammation as measured by standardized 
uptake value of arterial FDG by PET/CT. We will select 12 subjects with an LDL>125 to have the 
imaging study.  
2. To assess the effect of CD24Fc on the inflammatory markers hs-CRP and GlycA. 
3. To assess the effect of CD24Fc on the CEC and NMR lipoproteins. 
4. To assess the effect of CD24Fc on endothelin-1. 
 
3.1.4 PRIMARY ENDPOINTS 
 
1. Incidence and severity of any adverse events (AEs) during the administration of drug and 24 weeks 
after completion. Safety will be evaluated by assessment of clinical laboratory tests, physical 
examination at various time points during the study, and by the documentation for AEs. 
2. The percentage reduction in LDL level from the baseline (predosing) to 2 weeks after the last 
treatment. 
 
3.1.5 SECONDARY ENPOINTS 
1. Percent change in levels of total cholesterol, HDL, and triglycerides from baseline to Week 6 and 
28 between placebo and intervention arms.  
2. Percent change in markers of immune activation (CD4 and CD8 T cells, IFN, TNF, sCD14) from 
baseline to Week 6 and 28 between placebo and intervention arms. 
3. Change in proviral DNA from baseline to Week 6 and Week 28 between placebo and intervention 
arms. 
4. Percent change from baseline to week 28 in Troponin I and T between placebo and intervention 
arms.  
5. Change in percent of hepatic steatosis (by CAP measurement) and fibrosis (by KPA) as determined 
by transient elastography from baseline to week 28 between placebo and intervention arms.  
6. Percent change in leptin from baseline to Week 6 and Week 28 between placebo and 
intervention arms.  
7. Percent change in hemoglobin A1c from baseline to Week 6 and week 28 between placebo and 
intervention arms.  
8. PK and PD assessments (For 6 subjects) 
9. Presence of ADA and its effect on PK in all subjects 
 
3.1.6 EXPLORATORY ENDPOINT 
1. Change in vascular inflammation as evidenced by aortic FDG uptake by FDG-PET/CT will be assessed 
before and after therapy. The arterial uptake of FDG is measured by the standardized uptake value 
(SUV) max divided by the venous SUV mean yielding a target to background ratio (TBR).  
2. Changes in hs-CRP and GlycA before and after treatment. 
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3. Changes in CEC and NMR lipoproteins before and after treatment.  
4. Changes in endothelin-1 before and after treatment. 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This study is a phase 2, randomized, placebo-control, double-blinded clinical trial to assess the safety 
and tolerability of CD24Fc among patients with HIV, and the effect of CD24Fc on change in low-density 
lipoprotein (LDL) among patients with HIV. We will also evaluate the effect of CD24Fc on total 
cholesterol and triglycerides, markers of immune activation (T cell activation, sCD14, and inflammatory 
cytokines), size of HIV reservoirs, HbA1c and leptin, and hepatic steatosis, among other inflammatory 
markers.  
 
We hypothesize that therapy with CD24Fc will be safe and tolerable in HIV patients on ART and result in 
significant decreases in LDL. In addition, we hypothesize that CD24Fc will reduce cholesterol, leptin, 
HbA1c, hepatic steatosis and fibrosis, and markers of inflammation in patients with chronic HIV who are 
virally suppressed on ART.  
 
In this phase 2 study, a cohort of 64 HIV patients virally suppressed on ART will be randomized in a 1:1 
fashion to receive an intravenous infusion of 240mg of CD24Fc vs. placebo administered every 2 weeks 
during a 4-week treatment window, followed by a 24- week follow-up period. Patients will be followed 
for safety and adverse events as well as changes in lipid metabolism and inflammatory markers during a 
24-week follow-up period. This investigation will take place at the University of Maryland and National 
Institutes of Health.  
 
4.2 
JUSTIFICATION FOR DOSE 
This study will use the 240 mg dose as it has been proven to be safe in both healthy volunteers and 
GVHD patients. Importantly, 240 mg has been shown to significantly reduce LDL-C levels in clinical trials 
(see section 2.4.2 of IB).  Since LDL-C is an important endpoint for the study, we believe this a safe and 
likely effective dose.  In the Phase IIa CD24Fc in prevention of GVHD study, a multi-dosing cohort of 6 
patients given 480 mg, 240 mg and 240 mg of CD24Fc with 2 week intervals, none of the patients 
showed drug-related adverse effects.  Notably, multiple dosing studies in non-human primate involving 
125 mg/kg showed no adverse effect.  Since this is 30-40-fold higher than the proposed human dose (3-
4 mg/kg), there is large window for safety for the proposed dosing (biologics of 50kD or more is 
normally translated directly using body weight). 
 
The proposed dosing number (3 doses) and window (4 weeks) will be the same as the number of dosing 
in clinical trials (3 doses) and non-human primates (4 doses), all within 4 weeks of dosing.  We believe 
this is well-justified, since total exposures in proposed trial will be less than the dosing schedule in the 
Phase IIa multi-dosing cohort (480-240-240 mg at Day -1, 14, and 28).  
 
 
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4.3 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit or the last scheduled procedure shown in the Schedule of Activities (SoA), 
Section 1.3. 
 
5 
STUDY POPULATION 
 
The target population is patients age 50 or older with chronic HIV infection who have achieved viral 
suppression with use of ART for at least 2 years. The study is designed to target a demographic of people 
in the United States who are at risk for cardiovascular disease but have different risk factors than that of 
the HIV-uninfected population.  
 
Baltimore and Washington, DC are two geographic regions with high prevalence of HIV and risk of CVD. 
We recently performed a cross-sectional analysis of a retrospective cohort study on 100 patients from 
our Baltimore HIV clinic22. This cohort consists of 95% African American and 38% women with median 
age of 52 years old. The majority of patients had been diagnosed with HIV for over 10 years at study 
entry (86%) and 87% patients were receiving ART with 55% achieving viral suppression. The 
atherosclerotic vascular disease risk score was calculated using the Pooled Cohort Equation by 
calculating the 10-year risk of developing CVD according to 2013 AHA/ACC guideline23. The study 
findings confirm that there is an elevated risk of developing CVD in high risk demographic groups of the 
HIV epidemic at a relatively young age in the current HIV era.   
 
Washington DC has a disproportionally high rate of HIV patients with a rate of 22.324 per 1,000 cases. 
Lifetime risk of HIV acquisition is 1 in 1325, the highest in the United States. Also, in Washington DC, 
heart disease ranks first as the then leading cause of death, with 1,300, or 28%, of all deaths in 2010, 
attributed to CVD. CVD accounts for nearly 1 in 3 deaths in DC26 and is an area in which CVD risk 
reduction methods must be targeted. Therefore, this study will recruit from both the Baltimore and 
Washington, DC areas. 
 
There will be no racial, ethnic, religious, or gender discrimination. Persons in jail or prison are not 
eligible for this study. We will be enrolling participants from ongoing clinical trials with collaborators, as 
well as recruiting referrals.  Adults will be recruited through Institutional Review Board (IRB)-approved 
advertising to HIV providers and screened to confirm eligibility requirements for participation.  
 
 
5.1 
INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. At least 50 years of age or older at screening 
4. LDL-C > 70 mg/dL. 
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5. Has a median ACC/AHA ASCVD risk score ≥ 7.5%.   
6. Available for clinical follow-up through Week 28 after enrollment 
7. Chronic HIV infection based on documentation from a primary care physician that the patient 
has HIV and is on antiretroviral therapy 
8. On a stable regimen of ART for more than 3 months. The subject is expected to continue on an 
accepted ART regimen for the duration of the study (through week 28). 
a. Accepted combinations  
• 
FTC/TAF [Descovy®], FTC/TDF [Truvada®], or ABC/3TC [Epzicom®] 
PLUS 
o Ritonavir © and darunavir (DRV), or 
o Raltegravir (RAL), or 
o Elvitegravir (EVG) ± Cobicistat©, or  
o Dolutegravir (DTG), or 
o Rilpivirine (RPV) 
b. Accepted fixed dose combinations  
• 
FTC/RPV/TAF [Odefsey®] 
• 
FTC/RPV/TDF [Complera®] 
• 
EVG/c/TAF/FTC [Genvoya®] 
• 
EVG/c/TDF/FTC [Stribild®] 
• 
DTG/ABC/3TC [Triumeq®] 
• 
BIC/TAF/FTC [Biktarvy®] 
c. Alternative ART regimens will be considered on an individual basis, based on available 
DDI data at the discretion of the principal investigator 
9. At least 2 years of maintained HIV RNA < 50 copies/mL (or < LLOQ if the local laboratory assay’s 
LLOQ is ≥50 copies/mL) prior to Screening and HIV RNA<50 at screening. 
10. CD4 count ≥ 350 cells/mm3 at Screening 
11. Ability to communicate effectively with the study investigator and other key personnel 
12. Subjects must have a primary care doctor for their medical management 
13. Willing to donate blood for sample storage to be used for future research 
14. Female study participants with childbearing potential (defined below) and male study 
participants with female partners of childbearing potential must be willing to practice either: 
• Complete abstinence from sexual intercourse with a member of the opposite sex  
OR 
• At least one form of effective contraception from the list below, in addition to correct use of 
either a male or female condom throughout dosing and for a defined period following the 
last dose (30 days for women, 14 days for men) of study medication.: 
i. Intrauterine device with a failure rate of <1% per year 
ii. Tubal sterilization 
iii. Bilateral tubal occlusion 
iv. Vasectomy in a male  
v. Female barrier method (diaphragm or cervical cap)  
vi. Hormonal methods 
1. Oral contraceptives 
2. Injectable progesterone 
3. Implants of levonorgestrel or etonorgestrel 
4. Transdermal contraceptive patch 
5. Contraceptive vaginal ring 
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a. Definition of Childbearing Potential: For the purposes of this study, a female subject is 
considered of childbearing potential from menarche until becoming post-menopausal, 
unless permanently sterile or with medically documented ovarian failure.  Women are 
considered to be in a post-menopausal state when they are > 54 years of age with 
cessation of previously occurring menses for > 12 months without an alternative 
cause. Permanent sterilization includes hysterectomy, bilateral oophorectomy, or 
bilateral salpingectomy in a female subject of any age.  
 
15. Agreement to adhere to Lifestyle Considerations (see section 4.3) throughout study duration 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Current or prior history of any of the following:  
 
a. Clinically significant illness (other than HIV) or any other major medical disorder that 
may, in the opinion of the investigator, interfere with the subject treatment, 
assessment of compliance with the protocol; subjects currently under evaluation for a 
clinically-significant illness (other than HIV) are also excluded 
b. Poor venous access interfering with required study blood collection 
c. Solid organ transplantation 
d. Significant pulmonary disease, significant cardiac disease, or porphyria  
e. Uncontrolled chronic hepatitis B infection (surface antigen positive with detectable 
HBV DNA as noted in patient’s medical documentation from a treating physician) 
f. Chronic hepatitis C infection (current active only) 
g. Unstable psychiatric disease. (Subjects with psychiatric illness that is well-controlled 
on a stable treatment regimen or currently not requiring medication may be 
included.)  
h. Any malignancy or its treatment that in the opinion of the PI may cause ongoing 
interference with host immunity; subjects under evaluation for malignancy are not 
eligible.  
2. Abnormal hematological and biochemical parameters at screening, unless the test has been 
repeated and at least one subsequent result is within the acceptable range prior to study drug 
administration, including: 
a. Neutrophil count <750 cells/mm3  
b. Hemoglobin level <10 g/dL  
c. Platelet count ≤50,000 cells/mm3 
d. Estimated glomerular filtration rate, calculated by the chronic kidney disease 
epidemiology collaboration formula: <30 mL/min/1.73 m2 
e. ALT or AST level ≥5 times upper limit of normal (ULN) 
f. Total bilirubin level ≥2.0 times ULN, except in subjects with Gilbert’s syndrome or 
other clinical explanation at the discretion of the PI 
g. Albumin level <3 g/dL 
3. Poorly controlled diabetes as indicated by a screening glycosylated hemoglobin (HbA1c) >10 
4. Need for the use of the following medications from 21 days prior to the start of study drugs 
through the end of treatment:  
a. Hematologic stimulating agents, erythropoiesis stimulating agents (ESAs), granulocyte 
colony stimulating factor (GCSF, thrombopoietin (TPO) mimetics 
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b. Chronic systemic antineoplastic or immunomodulatory treatment including 
supraphysiologic doses of immunosuppressants such as corticosteroids (e.g., 
prednisone equivalent >10 mg/day for >2 weeks), azathioprine or monoclonal 
antibodies (e.g., infliximab) 
c. Investigational agents or devices for any indication 
5. Hyperlipidemia (defined as an LDL≥190 mg/dL), that is not being treated per the 2018 
ACC/AHA Cholesterol Clinical Practice guidelines with medications such as statins, Ezetimibe, 
and PCSK9 inhibitors, since these would be the standard of care for these patients., Patients 
with hyperlipidemia who are deemed ineligible to be on statin therapy by a treating physician 
will not be excluded.  
6. Initiation of statin therapy or change in dose of already-prescribed statin therapy within the 
last 3 months.  
7. Known history of cardiac arrhythmia or baseline ECG with arrhythmia including but not limited 
to atrial fibrillation (with or without rapid ventricular rate), supraventricular tachycardia or 
ventricular tachycardia. 
8. Any medical, psychiatric, social condition, occupational reason or other responsibility that, in 
the judgment of the investigator, is a contraindication to protocol participation or impairs a 
volunteer’s ability to give informed consent. 
Female-specific criteria: 
9. Woman who is breast-feeding or planning to become pregnant during the first 24 weeks after 
study drug administration. 
5.3 
LIFESTYLE CONSIDERATIONS 
During this study, participants are asked to: 
• 
Abstain from alcohol for 24 hours before the start of each dosing session until after collection of 
the final PK and/or pharmacodynamic sample. If participants do not abstain from alcohol use, 
samples will not be collected for PK assessment. This will be pertinent for 6 subjects in the 
study. 
• 
Fasting prior to blood draws for each study visit. 
• 
If having FDG-PET/CT, nothing by mouth for 6 hours prior to the imaging study. This will be 
pertinent for 12 subjects in the study.  Subjects should dress in warm, comfortable clothing with 
no zippers, snaps clips or metal of any kind.  A high fat/low carbohydrate diet should be 
followed for 24 hours prior to the imaging study. 
 
5.4 
SCREEN FAILURES 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography and the 
description of eligibility criteria failure. 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of an 
abnormal hematological or biochemical parameter, poorly controlled diabetes, or use of a restricted 
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medication (for example, exclusion criteria 4) may be rescreened. Rescreened participants should be 
assigned the same participant number as for the initial screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
 
The study will be advertised and posted using flyers and the IHV website. All advertisements will be IRB 
approved before use. We will recruit patients from the University of Maryland Medical Center (UMMC) 
and from Unity Parkside Clinic in Washington DC (patients will only be seen at University of Maryland 
Medical Center). Recruitment of patients will take place largely from outpatient clinics at UMMC and 
Unity Parkside, where HIV patients are seen for primary care. A primary care physician may refer 
patients to the study team, in which case the study team will speak to the patient either in person or by 
phone to schedule a screening appointment at UMMC. Residents of DC will be provided transportation 
to UMMC via mileage reimbursement for Metro, train, Uber or driving as approved by the Sponsor or 
will be scheduled with transportation for the visit as needed. 
 
Study retention will be promoted by visit reminders via phone calls. Participants will receive 
remuneration for their time and any inconvenience due to participating in the study (as outlined below).  
 
An anticipated 110 subjects with HIV will be screened for this study (which includes screening failures 
and those lost to follow-up) in order to enroll 64 subjects.  
 
This study will be limited to adults age 50 and older. This criterion has been included in order to study 
the effects of CD24Fc in a population with inherently higher CVD risk than those aged 18-49 years. 
Children and pregnant women will be excluded since the safety and efficacy of CD24Fc has not been 
studied in the pediatric population or during pregnancy. Any woman of child-bearing potential must 
have a negative serum pregnancy test prior to receiving the first dose of CD24Fc on Day 0 and use 
effective contraception throughout the study.  
 
Subjects will not be excluded based on gender.  This study is designed to target an underrepresented 
demographic of the HIV epidemic in the United States with poor representation in clinical trials, and in 
which current therapy is underutilized and has had poor results.  
 
All remuneration made by the University of Maryland, Baltimore will be provided to participants for 
their time and inconvenience, as outlined below. 
COMPENSATION SCHEDULE 
Screening Visit 
$50 
FDG-PET/CT (#1) if applicable*  
($200 if applicable) 
Fasting Labs & Fibroscan (if needed, not included in totals below) 
($25 if needed) 
Day 0 Study Drug or Placebo Infusion 
$150 (+/- PK $25) 
Week 2 Study Drug or Placebo Infusion 
$150 (+/- PK $25) 
Week 4 Study Drug or Placebo Infusion 
$150 (+/- PK $25) 
Week 6 Follow up 
$50 (+/- PK $25) 
Week 16 Follow Up 
$50 (+/- PK $25) 
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Week 28 Follow Up 
$50 (+/- PK $25) 
FDG-PET/CT (#2) if applicable*  
($200 if applicable) 
TOTAL  
$650 
Additional for PK 
$150 
Additional for FDG-PET/CT x2 at NIH 
$400 
Additional if Fasting Screening labs / FibroScan Visit needed or when 
unexpected visits are required 
$25 
*Compensation due for Optional FDG-PET/CT will be provided to subjects upon next visit to IHV and not at the NIH 
visit. 
 
 
6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
CD24Fc (CD24 Ig) is a fusion protein consisting of the extracellular domain of mature human CD24 linked 
to the human immunoglobulin G1 (IgG1) Fc domain. The complete molecular formula of CD24Fc has not 
been determined at this time.  The mature protein is 261 amino acids long and each CD24Fc molecule 
includes the 30 amino acid CD24 extracellular domain. CD24Fc forms a disulfide-linked homodimer with 
a predicted mass of 57.7 kilodaltons (kDa) based on the homodimer amino acid sequence.  However, the 
apparent molecular weight of the intact dimer is approximately 80 KDa based on non-reduced SDS-
PAGE. The CD24 domain is highly glycosylated with both N-linked and O-linked oligosaccharides, which 
comprise approximately 80% of the mass of the CD24 domain.    
For more information on the description of CD24Fc, please see section 3 of the IB. 
6.1.2 DOSING AND ADMINISTRATION 
 
Dosing of CD24Fc (240mg) will occur intravenously and over the duration of 1 hour (at minimum). A pre-
dose ECG will be completed prior to dosing. The IV rate may be reduced to prolong the duration of 
infusion at the discretion of the investigator and clinical team based upon symptoms suggestive of an 
infusion-related reaction. If an infusion reaction is deemed severe (e.g. severe hypotension, hypoxemia) 
the infusion will be stopped and assessment of AEs will proceed as outlined in section 8. 
 
All enrolled subjects who have received CD24Fc will be evaluated for safety before and after dosing.  
Safety may be assessed by physical examination, vital signs, hematology, and/or chemistries (see section 
8 for detailed study assessments and procedures per visit). Subjects do not have to be fasting to receive 
the infusion (but will be fasting to have lipid panel and leptin drawn, as specified in the SOA). Vital signs 
will include pulse, blood pressure, respiratory rate, and oxygen saturation. The severity of signs, 
symptoms, and AEs will be determined by using DAIDS toxicity table. Subjects will be monitored during 
the infusion and until 2 hours after the infusion has completed, with vital signs every 30 minutes (+/- 5 
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C A LI B E R O n c oI m m u n e C D 2 4 Fc -0 0 3  
Versi o n 5. 0  
Pr ot o c ol H P -0 0 0 8 6 0 2 9  
N o v e m b er 1 2 , 2 0 2 0 
 
 3 2  
mi n ut es  wit h +/ -1 0 mi n ut es at 2 h o urs p ost ) a n d a p ost -i nf usi o n E C G at t w o h o urs p ost d os e ( +/- 1 0 
mi n ut es) . La b or at or y r es ults will b e asc ert ai n e d as n e e d e d b as e d o n r e p ort e d s y m pt o ms. Pl e as e n ot e 
t h at d os e m o dific ati o ns will n ot b e m a d e. 
 
6. 2  
P R E P A R A TI O N/ H A N D LI N G/ S T O R A G E / A C C O U N T A BI LI T Y  
 
6. 2. 1  A C Q UI SI TI O N A N D A C C O U N T A BI LI T Y  
 
T h e sit e will r ec eiv e i n divi d u al vi als of C D 2 4 Fc ( e ac h s hi p m e nt will c o nsist of 8 vi als of i nv esti g ati o n al 
pr o d uct). U p o n r ec ei pt of t h e i nv esti g ati o n al pr o d uct, c o nt e nts will b e ex a mi n e d f or d a m a g e or missi n g 
vi als. T h e pr o d uct will b e i m m e di at ely st or e d i n t h e a p pr o pri at e t e m p er at ur e-c o ntr oll e d c o n diti o ns. 
I ncl u d e d i n t h e s hi p m e nt is a t e m p er at ur e m o nit ori n g d e vic e w hic h will b e us e d t o v erif y t h e mi ni m u m 
a n d m axi m u m t e m p er at ur es  r e ac h e d. T h e I nv esti g ati o n al Pr o d uct R ec ei pt C o nfir m ati o n F or m i ncl u d e d 
wit h t h e s hi p m e nt will b e c o m pl et e d a n d r et ur n e d t o 
 t o ac k n o wl e d g e 
r ec ei pt of t h e s hi p m e nt.  If t h e d evic e s h o ws a n o ut-of -r a n g e v al u e, t h e dr u g will b e q u ar a nti n e d wit hi n 
t h e a p pr o pri at e t e m p er at ur e-c o ntr oll e d e nvir o n m e nt a n d t h e T e m p er at ur e Exc ursi o n R e p ort F or m will 
b e s u b mitt e d f or a p pr o v al.  
 
St u dy a g e nts will b e distri b ut e d acc or di n g t o st a n d ar d p h ar m acy pr oc e d ur es. All dr u g pr o d ucts will b e 
st or e d i n a s ec ur ely l oc k e d ar e a, acc essi bl e o nly t o a ut h oriz e d sit e p ers o n n el. T o e ns ur e t h e st a bility of 
t h e st u dy dr u g a n d t o e ns ur e pr o p er pr o d uct i d e ntific ati o n, t h e dr u g pr o d ucts will n ot b e st or e d i n a 
c o nt ai n er ot h er t h a n t h e c o nt ai n er i n w hic h t h e y ar e s u p pli e d. C o nsi d er ati o n will b e gi v e n t o h a n dli n g, 
pr e p ar ati o n, a n d dis p os al t hr o u g h m e as ur es t h at mi ni miz e dr u g c o nt act wit h t h e b o dy. A p pr o pri at e 
pr ec a uti o ns will b e f oll o w e d t o av oi d dir ect ey e c o nt act or ex p os ur e t hr o u g h i n h al ati o n w h e n h a n dli n g 
st u dy dr u gs. 
 
R ec or ds will b e m ai nt ai n e d i n dic ati n g t h e r ec ei pt , dis p e ns ati o n , a n d d estr ucti o n of all i nv esti g ati o n al 
pr o d uct s hi p m e nts. T h e r es p o nsi bl e P h ar m acist  or d esi g n at e d st aff at t h e i nv esti g ati o n al sit e m ust k e e p 
a n acc ur at e i nv e nt ory of st u dy pr o d uct s hi p m e nts r ec ei v e d, t h e a m o u nt of st u dy pr o d uct a d mi nist er e d, 
a n d all pr o d uct r et ur n e d or d estr o y e d. T his i nf or m ati o n is t o b e r ec or d e d o n t h e M ast er Dr u g 
Acc o u nt a bility L o g, as w ell as o n t h e I nv esti g ati o n al Pr o d uct Ov er all S u bj ect Acc o u nt a bilit y L o g.  
 
6. 2. 2  F O R M U L A TI O N, A P P E A R A N C E, P A C K A GI N G, A N D L A B E LI N G  
 
C D 2 4 Fc is s u p pli e d as a st eril e, cl e ar, c ol orl ess, pr es erv ativ e -fr e e a q u e o us s ol uti o n f or p ar e nt er al 
a d mi nistr ati o n , i n a cl e ar b or osilic at e gl ass vi als wit h c hl or o b utyl r u b b erst o p p ers a n d al u mi n u m fli p off 
s e als. C D 2 4 Fc is f or m ul at e d as si n gl e d os e i nj ecti o n s ol uti o n, at a c o nc e ntr ati o n of 1 0 m g/ mL at p H of 
7. 2. E ac h C D 2 4 Fc vi al c o nt ai ns 1 2 0 m g of t h e f usi o n pr ot ei n i n 12 ± 0. 2 mL i nj ecti o n s ol uti o n. C D 2 4 Fc is 
st or e d at -2 0° C u ntil us e. C D 2 4 Fc s h o ul d b e t h a w e d t o r o o m t e m p er at ur e pri or t o a d mi nistr ati o n. N e w 
C D 2 4 Fc Dr u g Pr o d uct h as b e e n m a n uf act ur e d as “L ot 0 1 1 8 -0 0 2”. St a bilit y st u di es f or L ot 0 1 1 8 -0 0 2  ar e 
o n g oi n g a n d it h as d e m o nstr at e d t o b e st a bl e f or 1 2 m o nt hs at t h e i nt e n d e d st or a g e t e m p er at ur e, -
2 0 oC, f or 6 m o nt hs at 5 oC a n d 1 m o nt h at 2 5° C.  T h e ar e a i n w hic h t h e i nv esti g ati o n al pr o d uct is st or e d 
m ust b e l oc k e d, wit h li mit e d acc ess o nly t o u n bli n d e d st u dy p ers o n n el a n d t h e t e m p er at ur e m ust b e 
m o nit or e d.  
0 6 F 3 4 9
P P D
0 7 X N D S


C A LI B E R O n c oI m m u n e C D 2 4 Fc -0 0 3  
Versi o n 5. 0  
Pr ot o c ol H P -0 0 0 8 6 0 2 9  
N o v e m b er 1 2 , 2 0 2 0 
 
 3 3  
E ac h st u dy vi al will b e l a b el e d acc or di n g t o Titl e 2 1 of t h e U. S. C o d e of F e d er al R e g ul ati o ns.  E ac h vi al 
pr o d uct l a b el will c o nt ai n  t h e f oll o wi n g i nf or m ati o n: 
•  
P r o d uct n a m e ( C D 2 4 Fc) 
•  
L ot n u m b er 
•  
 “ C a uti o n: N e w Dr u g- Li mit e d by F e d er al ( or U nit e d St at es) l a w t o i nv esti g ati o n al us e” 
•  
1 2 0 m g/ vi al, 1 0 m g/ mL i n 1 2. 0 mL  
•  
St or a g e C o n diti o n: -2 0 d e gr e es C elsi us  
•  
“ D O N O T S H A K E O R D R O P T H E VI AL” 
•  
O nc oI m m u n e, I nc.  
 
6. 2. 3  P R O D U C T S T O R A G E A N D S T A BI LI T Y  
 
C D 2 4 Fc m ust b e st or e d b et w e e n -1 5º C a n d -2 5º C.  If a t e m p er at ur e exc ursi o n s h o ul d occ ur, t h e 
i nv esti g ati o n al pr o d uct will b e q u ar a nti n e d  a n d t h e T e m p er at ur e Exc ursi o n R e p ort F or m will  b e 
c o m pl et e d a n d s e nt t o t h e S p o ns or at 
 f or a p pr ov al pri or t o pr oc e e di n g 
wit h us e of t h e i nv esti g ati o n al pr o d uct.  
C D 2 4 Fc is st or e d at -2 0° C u ntil us e. C D 2 4 Fc s h o ul d b e t h a w e d a n d e q uili br at e d t o r o o m t e m p er at ur e 
pri or t o a d mi nistr ati o n. St a bilit y st u di es f or L ot 0 1 1 8 -0 0 2 ar e o n g oi n g a n d it h as d e m o nstr at e d t o b e 
st a bl e f or 1 2 m o nt hs at t h e i nt e n d e d st or a g e t e m p er at ur e, -2 0 oC, f or 6 m o nt hs at 5 oC a n d 1 m o nt h at 
2 5° C.  
 
6. 2. 4  P R E P A R A TI O N  
T h e c o nstit ut e d dr u g i nf usi o n s ol uti o n s h o ul d b e pr e p ar e d by a tr ai n e d m e dic al pr of essi o n al usi n g 
as e ptic t ec h ni q u e by t h e  f oll o wi n g pr oc e d ur e:  
1.    D et er mi n e t h e v ol u m e of C D 2 4 Fc s ol uti o n: 2 4 0 m g p er i nf usi o n wit h a v ol u m e of 2 4 ml fr o m 2 vi als.  
2.    P ar e nt er al dr u g pr o d ucts s h o ul d b e i ns p ect e d vis u all y b ef or e a n d aft er r ec o nstit uti o n f or p artic ul at e 
m att er a n d disc ol or ati o n pri or t o a d mi nistr ati o n, w h e n e v er s ol uti o n a n d c o nt ai n er p er mit. If visi bl y 
o p a q u e p articl es, disc ol or ati o n or ot h er f or ei g n p artic ul at es ar e o bs er v e d, t h e s ol uti o n s h o ul d n ot 
b e us e d.   
3.    C alc ul at e t h e v ol u m e of st eril e 0. 9 % S o di u m C hl ori d e I nj ecti o n, U S P, r e q uir e d: 7 6 ml i n v ol u m e t o 
r e ac h a fi n al v ol u m e of 1 0 0 ml.  
4.    Usi n g a n e m pty I V b a g, a d d t h e a b o v e 7 6 ml v ol u m e of st eril e 0. 9 % S o di u m C hl ori d e f oll o w e d by t h e 
2 4 ml v ol u m e of C D 2 4 Fc s ol uti o n. G e ntly mix.  
5.    T h e C D 2 4 Fc i nf usi o n s h o ul d b e gi n wit hi n 6 h o urs of r ec o nstit uti o n a n d dil uti o n. T h e i nf usi o n m ust b e 
a d mi nist er e d ov er a p eri o d of n ot l ess t h a n 6 0 mi n ut es f or d os e of 2 4 0 m g.   A n i nf usi o n s et wit h a n 
i n-li n e, st eril e, n o n-pyr o g e nic, l o w -pr ot ei n -bi n di n g filt er ( p or e siz e of 1. 2 μ m or l ess) m ust b e us e d.  
6.     At t h e e n d of i nf usi o n, a d d a s m all a m o u nt of  n or m al  s ali n e ( 2 5 ml) t o t h e i nf usi o n b a g t o e ns ur e 
t h e e ntir e v ol u m e of st u dy dr u g is i nf us e d. 
 
F or t h e pl ac e b o, t h e pr e p ar ati o n will b e as f oll o ws.  
1.    C alc ul at e t h e v ol u m e of  st eril e 0. 9 % S o di u m C hl ori d e I nj ecti o n, U S P, r e q uir e d: 1 0 0 ml i n v ol u m e t o 
r e ac h a fi n al v ol u m e of 1 0 0 ml.  
2.    Usi n g a n e m pty I V b a g, a d d t h e a b o v e 1 0 0 ml v ol u m e of st eril e 0. 9 % S o di u m C hl ori d e.  
3.    T h e C D 2 4 Fc or pl ac e b o i nf usi o n s h o ul d b e gi n wit hi n 3 h o urs of r ec o nstit uti o n a n d dil uti o n. T h e 
i nf usi o n m ust b e a d mi nist er e d ov er a p eri o d of n ot l ess t h a n 6 0 mi n ut es f or d os e of 2 4 0 m g.  A n 
i nf usi o n s et wit h a n i n-li n e, st eril e, n o n-pyr o g e nic, l o w -pr ot ei n -bi n di n g filt er ( p or e siz e of 1. 2 μ m or 
l ess) m ust b e us e d.  
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4.   At the end of infusion, add a small amount of normal saline (25 ml) to the infusion bag to ensure the 
entire volume of study drug is infused. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
This is a randomized, double-blinded, placebo-controlled trial. Subjects will be randomized using block 
randomization in a 1:1 ratio of CD24Fc:placebo. They will be block randomized in blocks of six (except 
for the last block of four). The first block of six will all have PK analyses and there will be a safety and 
efficacy review upon completion of dosing by this group of six without halting enrollment.     
 
Every effort will be made to minimize the various known sources of bias. Breaking the blind will be 
considered only when knowledge of the treatment assignment is deemed essential by the subject's 
physician for the subject's care. Any intentional or unintentional breaking of the blind will be reported to 
the sponsor and IRB, and explained at the end of the trial, irrespective of the reason for its occurrence.  
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Since the study drug will be administered intravenously by the clinical staff in an outpatient setting. 
Compliance with drug administration and adherence to the protocol will be documented by clinical staff 
in the study record.   
 
6.5 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported are concomitant prescription 
medications, over-the-counter medications and supplements. 
 
Information about use of concomitant medications will be collected at the screening visit and 
subsequent visits as outlined in section 1.3. Use of these concomitant medications (which may affect 
study endpoints) that exclude a participant from enrolling in the study include those outlined in Section 
4.2.  Additionally, medications for disease conditions excluded from the protocol (e.g., active cancer, 
transplantation) are not allowed in the study.  Should subjects have a need to initiate treatment with 
any disallowed concomitant medication, the medical monitor must be consulted prior to initiation of the 
new medication. 
 
6.5.1 RESCUE MEDICINE 
Not applicable  
 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
 
 If a clinically significant finding is identified (including, but not limited to changes from baseline) after 
enrollment, the investigator or qualified designee will determine if any change in participant 
management is needed. Any new clinically relevant finding will be reported as an adverse event (AE). 
 
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AEs are evaluated according to the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events, version 2.1, July 2017. All adverse events will be reviewed by the Principal 
Investigator (PI) and the study team at team meetings. All Grade 3 events will be evaluated by the PI and 
the designated Medical Monitor. Grade 4 and Grade 5 events will be reported to the Sponsor and the 
Medical Monitor within 24 hours of notification of the event.   
 
CD24Fc infusion will be paused for a single subject for any grade 4 event pending review by the Medical 
Monitor. The MM will include review of this event in a report issued to the DSMB every 12 weeks.  
Administration of medication will be paused for all subjects if 2 or more subjects have the same grade 4 
adverse event deemed related to study drug. The MM will report these events to the DSMB and 
enrollment and dosing will be held for all pending review by the DSMB. 
 
The study may be terminated after consultation with the Medical Monitor, DSMB and Sponsor, in the 
event that one or more of the following adverse reactions are not remediated within 2-4 hours, and in 
the opinion of the PI and Medical Monitor, are clinically relevant and constitute a substantial risk to the 
participants: cytokine release syndrome, hypotension, shortness of breath, disseminated intravascular 
coagulation, mental status changes.  
 
Other criteria for study termination may include: 
• 
the decision of the Medical Monitor or DSMB to stop further study visits  
• 
the recommendation or decision for any reason of the PI that safety may be at risk or 
compromised by continuing the trial 
• 
the decision of the Sponsor to terminate the study for any reason 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Vital signs and physical examination 
• 
Complete metabolic panel, complete blood count with differential, PT/INR 
• 
Other laboratory tests that further evaluate a sign or symptom  
• 
Procedures for further evaluation of lab abnormalities or symptoms  
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request. 
 
An investigator will discontinue or withdraw a participant from the study for the following reasons: 
• 
Pregnancy or breastfeeding 
• 
Significant study intervention non-compliance  
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
which occurs such that continued participation in the study would not be in the best interest of 
the participant (including malignancy) 
• 
New or recurrent Centers for Disease Control and Prevention (CDC) category C AIDS-indicator 
condition. 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive CD24Fc for 2 doses  
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• 
Development of life-threatening infection or clinical reason deemed to be life-threatening by 
the physician 
• 
Request of the primary care provider or Investigator if s/he thinks the study is no longer in the 
best interest of the subject.  
• 
If the subject is judged by the Investigator to be at significant risk 
• 
The following laboratory abnormalities 
o HIV RNA>200 copies/mL (2 readings at least 2 weeks apart) 
o Decrease in eGFR to <30mL/min, confirmed by immediate repeat testing 
o Elevation of ALT >5x OR AST >5x Day 0, confirmed by immediate repeat testing 
o Abnormal elevation of ALT >3 x Day 0 and total bilirubin >2 x ULN, confirmed by 
immediate repeat testing   
o For participants with entry CD4+ T cell count between 350 - 500 cells/mm3, confirmed 
absolute and percent CD4+ decline greater than 25% of baseline. 
o For participants with entry CD4+ T cell count between 501 to 800 cells/ mm3, a 
confirmed absolute and percent CD4+ T cell decline greater than 33% of baseline. 
o For participants with entry CD4+ T cell count greater than 800 cells/ mm3, a confirmed 
absolute and percent CD4+ T cell decline greater than 50% of baseline.  
o Occurrence of Grade 4 anemia/neutropenia or recurrence of Grade 3 
anemia/neutropenia. 
 
The reason for participant discontinuation or withdrawal from the study will be recorded in the study 
record. Subjects who sign the informed consent form and are randomized but do not receive the study 
intervention may be replaced.  Subjects who sign the informed consent form, and are randomized and 
receive the study intervention, and subsequently withdraw, or are withdrawn or discontinued from the 
study, will not be replaced. 
 
Participants who prematurely discontinue the study agent due to toxicity will be followed closely for 
resolution of symptoms, until final outcome is known or until the end of the study follow-up period.  
 
Subjects who discontinue the agent due to toxicity, as well as those who elect to discontinue study 
drugs prior to treatment completion for medical or personal reasons, will continue to follow the general 
study schedule of assessments unless unwilling to do so.  The participant should have an end of 
treatment visit scheduled as soon as possible after all therapy is discontinued, if he/she is willing. Any 
subject continuing in the study will be followed closely for resolution of active laboratory abnormalities 
or adverse events that are considered related to the study agents.  
 
7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to return for 2 scheduled visits and is 
unable to be contacted by the study site staff.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within 2 days for 
any visit through week 4 and within 1 visit for weeks 6,  16 and 28 visits, and counsel the 
participant on the importance of maintaining the assigned visit schedule and ascertain if the 
participant wishes to and/or should continue in the study. 
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• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if necessary, 
a certified letter to the participant’s last known mailing address). These contact attempts will be 
documented in the participant’s medical record or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
STUDY VISITS 
 
Study visits, including screening, will occur at the IHV Clinical Research Unit at UMB. Drug doses may be 
infused +/-4 days to be considered in the study window (Day 0 to Week 4). Residents of DC may be 
provided transportation via Metro, train, or taxi, as needed. 
 
All subjects will have a History and Physical during the screening process as part of final determination 
of protocol eligibility.  Physical exams will be performed with study point visits at screening, Day 0, Week 
6, Week 16 and Week 28. Directed physical exam will be done as needed at other study points. Subjects 
will be asked about their state of health and use of any concomitant medication since the previous study 
visit. They will also be questioned about adverse events and their adherence with study restrictions. 
 
8.1.1.1 SCREENING 
Each subject will provide informed consent of his/her free will prior to commencement of any study 
procedures according to ICH and Code of Federal Regulations (CFR).  Each subject will be provided a 
copy of the signed informed consent form. 
 
After a participant has provided informed consent, the Investigator and other study personnel will 
determine if they are eligible for participation in the study.  Screening may begin up to 8 weeks prior to 
dosing with at least 14 days before Day 0.  
 
Screening will include a review of the inclusion/exclusion criteria and completion of all screening 
procedures. Screening tests within the last 8 weeks prior to screening visit that have been done as part 
of routine medical care or at an outside facility can be used if within the acceptable time frame.  
Screening procedures do not need to be repeated within the 8-week screening window unless clinically 
indicated. Once the screening window has elapsed, subjects may be rescreened at the discretion of the 
PI. 
 
At the screening visit, participants will have an H&P (including vital signs), height, weight and BMI 
assessment, and a medication reconciliation. Laboratory tests including CMP, CBC, HIV VL, CD4, PT/INR, 
hemoglobin A1c, Hepatitis B panel, Hepatitis C antibody and reflex RNA, and Troponin I and T will be 
collected. ECG will be done to assess for abnormalities. Females of child-bearing potential will have a 
serum hCG tested. Immunology labs looking at CD4 and CD8 by flow, sCD14, and inflammatory cytokines 
will also be done. If a subject is fasting, the procedures in section 8.1.1.3 including transient 
elastography may be done at this visit instead of at the “Fasting Lab Visit”.  
 
8.1.1.2 FDG-PET/CT VISIT 
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Twelve subjects will undergo FD -PET/CT to assess aortic inflammation at NIH. These participants will 
have an LDL>125. Subjects will have an FDG-PET/CT after screening, but prior to Day 0 and at week 28. 
Subjects will be provided transportation to and from the NIH if needed.  
 
8.1.1.3 FASTING LAB VISIT, IF NEEDED 
If subjects were not fasting at screening, they may return for fasting serum lipid and leptin levels along 
with transient elastography to assess for hepatic steatosis and fibrosis.  
 
8.1.1.4 DAY 0 (FIRST INFUSION) 
The participant will be started on CD24Fc or placebo on Day 0. For the first 6 subjects, prior to drug 
infusion and 2 hours after, blood samples for PK will be obtained.  A window of +/- 10 minutes will be 
given around each post-infusion draw time point. Blood samples for anti-drug antibody will also be 
drawn before drug dosing for all subjects. For all subjects, an H&P will be performed, as well as a 
medication reconciliation prior to infusion. ECG should be done prior to infusion and two hours post 
infusion (+/- 10 minutes).  Laboratory tests prior to drug infusion include: a CMP, CBC with diff, 
urinalysis, HIV VL, PT/INR, CD4, lipid panel, and point of care urine hCG (for females of child-bearing 
potential), Hs-CRP, along with research immunology and inflammation labs. Subjects participating in the 
FDG-PET/CT will also have GlycA, CEC, and NMR lipoprotein collected. All subjects must be fasting prior 
to blood draw. Adverse events will be documented. 
 
8.1.1.5 WEEK 2 VISIT 
At this visit, a medication reconciliation will be done, as well as documentation and review of adverse 
events. The first 6 subjects who had PK samples done at Day 0 will also have PK blood samples obtained 
before and 2 hours after dosing of study drug. A window of +/- 10 minutes will be given around each 
post-infusion draw time point. ECG should be done prior to infusion and two hours post-infusion (+/- 10 
minutes). The following laboratory tests will be done prior to drug dosing: CMP, CBC, urinalysis, HIV VL, 
CD4, PT/INR, lipid panel, urine hCG (for females of child-bearing potential), and research immunology 
and inflammation labs. A dose of CD24Fc, 240mg vs placebo, will be infused intravenously, pending no 
laboratory abnormalities or adverse events which warrant holding the study drug. He/she must be 
fasting prior to blood draw. 
 
8.1.1.6 WEEK 4 VISIT 
At this visit, there will be a medication reconciliation and documentation and review of adverse events. 
The first 6 subjects who had PK samples done at Day 0 and Week 2 will also have PK blood samples 
obtained before and 2 hours after dosing of study drug. A window of +/- 10 minutes will be given around 
each post-infusion draw time point. ECG should be done prior to infusion and two hours post- infusion 
(+/- 10 minutes). The following laboratory tests will be done prior to drug dosing: CBC, urinalysis, HIV VL, 
CD4, PT/INR, lipid panel, urine hCG (for females of child-bearing potential), and research immunology 
and inflammation labs. A dose of CD24Fc, 240mg vs placebo, will be infused intravenously, pending no 
laboratory abnormalities or adverse events which warrant holding the study drug. He/she must be 
fasting prior to blood draw.  
 
8.1.1.7    WEEK 6 VISIT 
At this visit, there will be vital signs, a medication reconciliation and documentation and review of 
adverse events. The first 6 subjects who had PK samples done at Day 0, Week 2, and Week 4 will also 
have PK blood samples obtained. The following laboratory tests will be done prior to drug dosing: CMP, 
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CBC, urinalysis, HIV VL, CD4, PT/INR, lipid panel, urine hCG (for females of child-bearing potential), 
HbA1c, immunology labs, IL-6, apoB, Lp(a), urine albumin:creatinine ratio, Hs-CRP. Subjects participating 
in the FDG-PET/CT will also have GlycA, CEC, and NMR lipoprotein collected. He/she must be fasting 
prior to blood draw. 
 
8.1.1.8 WEEK 16 VISIT 
At this visit, vital signs, H&P and medication reconciliation will be done, as well as documentation and 
review of adverse events. The first 6 subjects who had PK samples done at Day 0, Week 2, Week 4, 
Week 6 will also have PK blood samples obtained. The following laboratory tests will be done: CMP, CBC, 
urinalysis, HIV VL, CD4, PT/INR, hemoglobin A1c, lipid panel, leptin,  troponin I, urine hCG (for females of 
child-bearing potential), , IL-6, apoB, Lp(a), urine albumin:creatinine ratio, anti-drug antibody, and 
research immunology and inflammation labs.. He/she must be fasting prior to blood draw. 
 
8.1.1.9 WEEK 28 VISIT  
At this visit, vital signs, height, weight and BMI, H&P and medication reconciliation will be done, as well 
as documentation and review of adverse events. The first 6 subjects who had PK samples done at Day 0, 
Week 2, Week 4, Week 6, Week 16 will also have PK blood samples obtained. The following laboratory 
tests will be done: CMP, CBC, urinalysis, HIV VL, CD4, PT/INR, lipid panel, leptin, HbA1c, serum hCG (for 
females of child-bearing potential), Troponin I and T, anti-drug antibody,  immunology labs, IL-6, apoB, 
Lp)a, urine albumin:creatinine ratio. Hs-CRP will also be drawn along with research immunology and 
inflammation labs. Subjects participating in the FDG-PET/CT will also have GlycA, CEC, and NMR 
lipoprotein collected.  He/she must be fasting prior to blood draw. Transient elastography will be 
performed to assess for any change seen in hepatic steatosis post-dosing as immediate change within 
the four-week dosing period would not be expected. 
 
Last, those who had a FDG-PET/CT prior to Day 0 will have a follow-up FDG-PET/CT done at the NIH. 
Again, this timing allows for potential vascular inflammatory changes to occur over the six month follow 
up period. Subjects will be provided transportation to and from the NIH if needed.  
 
8.2 
ASSAYS 
Assays will be performed at one of the following locations: 
1. NIAID (National Institute of Allergy and Infectious Diseases) Immunopathogenesis section, Building 
10 
2. NHLBI (National Heart, Lung and Blood Institute), Cardiovascular and Pulmonary Branch, Building 10 
3. Laboratory Corp of America (LabCorp) 
4. University of Maryland Marlene and Stewart Greenebaum Comprehensive Care Center- Shared 
Services Core Lab 
5. Institute of Human Virology Research Lab 
 
• 
CMP- comprehensive metabolic panel, serum. This assay will be done through LabCorp. The 
CMP includes Alanine aminotransferase (ALT/SGPT); albumin:globulin (A:G) ratio; albumin, 
serum; alkaline phosphatase, serum; aspartate aminotransferase (AST/SGOT); bilirubin, total; 
BUN; BUN:creatinine ratio; calcium, serum; carbon dioxide, total; chloride, serum; creatinine, 
serum; eGFR calculation; globulin, total; glucose, serum; potassium, serum; protein, total, 
serum; sodium, serum. 
 
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• 
CBC- Complete Blood Count with Differential, whole blood. This assay will be done through 
LabCorp. The CBC includes Hematocrit; hemoglobin; mean corpuscular volume (MCV); mean 
corpuscular hemoglobin (MCH); mean corpuscular hemoglobin concentration (MCHC); red cell 
distribution width (RDW); percentage and absolute differential counts; platelet count (RBC); red 
cell count; white blood cell count (WBC). 
 
• 
Urinalysis- complete, with microscopic examination. This test will be done by LabCorp. This 
includes color, appearance, specific gravity, pH, protein, glucose, occult blood, ketones, 
leukocyte esterase, nitrite, biliriubin, urobilinogen, microscopic examination of urine sediment. 
 
• 
HIV VL (viral load)- Human immunodeficiency virus 1 (HIV-1), quantitative, real-time PCR 
(nongraphical), plasma.  
 
• 
CD4- Helper T-lymphocyte marker CD4, whole blood. This assay will be done through LabCorp. 
This test includes percentage of CD4+; absolute CD4+ (helper/inducer); absolute lymphocyte 
count. 
 
• 
PT/INR- Prothromibin Time and Partial Thromboplastin Time, whole blood, plasma. This assay 
will be done through LabCorp. This test includes Activated partial thromboplastin time (aPTT); 
international normalized ratio (INR); prothrombin time (PT) 
 
• 
Hemoglobin A1c- whole blood. This assay will be done through LabCorp.  
 
• 
Lipid Panel- serum (fasting). This assay will be done through LabCorp. This test includes 
Cholesterol, total; high-density lipoprotein (HDL) cholesterol; low-density lipoprotein (LDL) 
cholesterol (calculation); triglycerides; very low-density lipoprotein (VLDL) cholesterol 
(calculation). 
 
• 
Hepatitis B panel- HBV Evaluation Panel, serum or plasma. This assay will be done through 
LabCorp. This test includes Hepatitis B core antibody, total; hepatitis B surface antibody, 
qualitative; hepatitis B surface antigen 
 
• 
Hepatitis C Ab with reflex RNA- Hepatitis C Virus (HCV) Antibody with reflex to quantitative real-
time PCR, serum or plasma. This assay will be done through LabCorp.  
 
• 
Serum hCG- human chorionic gonadotropin, beta-subunit, qualitative, serum. This assay will be 
done through LabCorp. A serum hCG will be done for females of child-bearing potential, at the 
screening visit.  
 
• 
Urine hCG- human chorionic gonadotropin, beta-subunit, qualitative, urine. This will be a point-
of care assay. A urine hCG will be done for females of child-bearing potential before drug dosing, 
using a point-of-care urine hCG assay.  
 
• 
Troponin I and T- In conjunction of cardiovascular inflammation measurement, we will also 
assess myocardial damage using a validated, sensitive cardiac troponin I and T assays (through 
LabCorp) will be used for all subjects run as batched samples.  
 
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• 
Leptin- serum or plasma (fasting). Used as a marker for lipodystrophy.   
 
• 
hsCRP (high-sensitivity CRP), serum or plasma. This assay will be done through LabCorp.  
 
• 
 IL-6 (Interleukin- 6), serum or plasma.  
 
• 
Apo B (apoliprotein B), serum. This assay will be done through LabCorp.  
 
• 
Lp(a) (Lipoprotein a), serum. This assay will be done through LabCorp. 
 
• 
Urine albumin /creatinine ratio, random urine. This assay will be done through LabCorp.  
 
• 
Pharmacokinetic analyses- done for the first 6 subjects receiving CD24Fc.  
For PK analysis, blood samples will be collected prior to drug infusion at weeks 0, 2, 4, 6, 16, 28 
before and 2 hours post dosing of CD24Fc as applicable. A +-/10-minute window around each 
draw point will be allowed. At weeks 6 and 28, a blood sample for PK will also be collected in 
order to demonstrate a decrease in drug concentration after dosing completion on week 4.  
 
Anti-drug antibody: For ADA analysis, blood samples on day 0 (predosing), week 6, and week 28 
visits will be collected. ADA will be measured using a validated assay in a GLP-compliant 
laboratory that performed these analyses for the phase I and phase IIa CD24Fc studies. 
Pharmacokinetic parameters will be calculated using actual collection times. In those with pre-
existing or induced ADA also completing the PK analysis, effects of ADA on the PK of the drug 
will be evaluated, although the results from the phase I study demonstrated that a small 
number of subjects with either pre-existing or induced ADA have similar PK to subjects without 
ADA. 
 
If ADA is positive, the ADA titration will be done and samples will be saved for neutralizing 
antibodies when the assay for neutralizing antibodies is available.  
 
When suspected immune related adverse events occur that are potentially related to CD24Fc, 
the unscheduled samples for ADA analysis will be collected and temporal correlation with a 
positive binding antibody results will be analyzed and recorded.  
 
All patients with treatment-emergent ADA titer greater than 1:64 should be followed until the 
ADA titers drop to 1:64 or lower. A titer of 1:64 is equivalent to 5 µg/ml of reference mouse 
anti-human CD24 monoclonal antibodies.   This threshold is selected based on our phase I data 
that the patient this titer (the highest in our phase I cohort, and happened to be predosing) 
experienced neither adverse events nor aberrant CD24Fc PK. 
 
We will follow the recommendation from the White Paper by Shankar 27. The treatment 
emergent ADA response will be defined as ADA is negative in pre-dosing but have positive ADA 
titers in samples from week 6 or week 28.  Persistent ADA response is defined as the ADA titers 
remain unchanged from Week 6 and Week 28. Transient ADA response is defined the ADA is 
positive in one time point only.    
 
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RNAseq analysis provides an accurate and comprehensive profiling of gene expression. In 
addition to the immunological approaches, we will use RNAseq data to identify biomarkers for 
clinical response and PD-markers of drug efficacy. RNA-seq will be used to create a participant 
profile. RNA sample preparation will have two key steps: (a) RNA will be poly-A selected so that 
only mRNA is obtained for sequencing and (b) sample from CD24Fc and placebo-treated groups 
will be multiplexed across lanes and plates to mitigate batch effects from lane and plate bias. 
Illumina HiSeq sequencer will be used to generate 2x100bp sequencing reads. 3 replicates will 
be generated per sample, and samples will be multiplexed to obtain ~30M reads per sample; 
these specifications are common best practices for accurately quantifying mRNA expression.  
 
A local computing cluster will analyze the RNA-seq data using the well-knownSAT-StringTie-
Ballgown pipeline 28. This pipeline produces (a) FPKM (fragments per kilobase per million reads), 
a measure of mRNA abundance, for each gene in a sample and (b) differentially-expressed genes 
and log-fold change between samples. The performance of this pipeline improves with 
replicates, so it matches well with this experimental design. Statistical analysis of RNA-seq 
pipeline outputs will be performed using log transformed intensities and measurements of 
correlation between the quantified proteome and transcriptome changes in the R software 
environment. To reduce dimensionality and avoid overfitting, correlations will use only 
differentially-expressed genes. DAVID 29 will be used to annotate our results with categorical 
annotation, including Gene Ontology and KEGG pathways for pathway analysis. Enrichment for 
these categories will be evaluated by Fisher exact test.    
 
• 
sCD14 
Preliminary studies demonstrate that CD24Fc suppresses production of multiple inflammatory 
cytokines associated with HIV infections.  To test the impact of CD24Fc on the systemic 
inflammatory responses, soluble factors that have been previously demonstrated with negative 
HIV outcomes (e.g. sCD14) and a larger array of inflammatory factors in the serum (IFNs, TNF 
etc.) will be quantified. The Luminex platform allows evaluation of over 60 soluble factors and 
performs bioinformatics analysis to identify factors/patterns of cytokine expression associated 
with changes in HIV latency. 
 
• 
HIV Reservoirs (Proviral DNA)  
Although CD24Fc is not expected to have anti-viral activity, preliminary studies in humanized 
mice and non-human primate models 30, showed that CD24Fc significantly reduced viral burden 
in vivo, including proviral burden in the PBL of SIV-infected Macaques rhesus, perhaps by 
preventing T cell over-activation and its associated exhaustion immunity30.  This hypothesis will 
be tested in ART-treated HIV infected subjects by longitudinal analysis of proviral titers. 
Established methods for quantification of proviral DNA (droplet digital PCR) will be used as 
described31,32. Droplet digital PCR will be conducted to quantitate the frequency of cells carrying 
HIV proviral DNA and cell-associated HIV RNA with single copy sensitivity. The level of 
replication-competent/infectious HIV in the CD4+ T cell compartment will be determined by 
quantitative coculture assays. 
 
• 
Inflammatory cytokines  
Peripheral blood mononuclear cells will be isolated using Ficoll-Hypaque density gradient 
technique and used for immunophenotyping. Cells will be washed and stained using appropriate 
panels of monoclonal antibodies that distinguish cell type (B, T NK, monocyte etc.), cellular 
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activation states (CD14, CD38, HLA DR, CD25, etc.) and their ability to secrete inflammatory 
cytokines (IFN, TNF) using intracellular cytokine staining using a 12 color flowcytometry analysis 
with FlowJo software, at the University of Maryland.  
 
• 
CD4 and CD8 T cell counts and ratio 
T cell immunophenotyping will be performed as a clinical laboratory test using flow cytometry at 
the University of Maryland.  
  
• 
GlycA, plasma. This is a heterogeneous nuclear magnetic resonance signal originating from 
mobile glycan residues on plasma glycoproteins, used as a novel composite biomarker of 
systemic inflammation. This assay will be done at the NIH for those subjects completing the 
optional FDG-PET/CT. 
 
• 
CEC- cholesterol efflux capacity, plasma. This is an assay assessing HDL function using the 
macrophage J774 efflux system. This assay will be done at the NIH for those subjects completing 
the optional FDG-PET/CT. 
 
• 
NMR lipoproteins, plasma. This is an assay looking at lipoprotein particle size and number using 
NMR spectroscopy. This assay will be done at the NIH for those subjects completing the optional 
FDG-PET/CT. 
 
• 
Endothelin-1, plasma. An ELISA test will be done for subjects at screening and week 28 to look 
for changes in endothelin-1, which may indicate changes in pulmonary arterial pressure.  
 
• 
Vascular inflammation, as measured by FDG-PET/CT 
A major challenge in pilot studies attending to study impact of interventions on CVD risk is the 
requirement of large sample sizes.  Recent studies demonstrated that arterial inflammation may 
be a valuable surrogate marker for CDV risk 33-36. 18F-fluorodeoxyglucose (FDG) uptake is a 
sensitive and reliable marker of atherosclerotic inflammation, and this test will be done at the 
NIH. Measurements will be performed with the ascending aortic root 18F-FDG standardized 
uptake values (SUVs) as the maximal SUVs using regions of interest. At the same time, blood-
pool SUV in the same superior vena cava will also be measured. The maximal SUV will be divided 
by the blood-pool SUV, yielding a target-to-background ratio (TBR). The average value will be 
calculated, and the degree of inflammation will be defined based on the TBR value. For our 
studies, TBR for 12 HIV subjects with LDL levels greater than 125 mg/dL will be imaged before 
day 0.  These subjects will have a repeat FDG PET/CT at week 24 This allows us to compare the 
mean TBR score using unpaired t tests at the end of the trial as well as progression of TBR in the 
two groups using paired t test.  
 
Results of subject’s laboratory values and radiologic assessments will be discussed at the completion of 
study or during the study, in the event of laboratory or imaging abnormalities which require follow-up. 
 
8.3 
SAFETY AND OTHER ASSESSMENTS 
 
Safety oversight will be conducted by collaboration between the Principal Investigator (PI), lead Study 
Coordinator (SC), the DSMB, and the Medical Monitor. A Medical Monitor (MM) has been appointed for 
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oversight of safety in this clinical study. If at any point in the trial halting rules are met, the study team 
(PI and SC) will arrange a (tele)conference so that the event can be reviewed and the discussion 
documented. At the end of each MM review meeting, the MM will be asked to provide a formal 
recommendation as to whether or not the protocol should be halted. A written summary of each MM 
review meeting will be provided to the MM and appropriate individuals.  Participants on the MM 
teleconferences will include the MM, the PI and appropriate study team members. The MM will provide 
a written report to the DSMB as per Appendix A, Data Safety and Monitoring Plan (DSMP). 
 
An independent DSMB has been established for oversight of safety in this clinical study, responsible to 
the NHLBI. This DSMB will be independent of regulatory agencies, IRB/EC, OncoImmune, Inc, and 
investigators. See Appendix A for the Data Safety Monitoring Plan. 
 
Subject safety will be monitored by the PI and study team. Clinical data and safety data will be 
monitored at least every 2 weeks (or less frequently, based on the SOA). An evaluation of safety and 
efficacy data will be obtained when the first 6 subjects complete 4 weeks of therapy by the appointed 
Medical Monitor. The Medical Monitor will not be part of the clinical staff caring for subjects during 
study visits, so blinding will be maintained. If concerns about the safety or efficacy arise, the Medical 
Monitor will refer concerns to the Sponsor and DSMB and review of adverse events will proceed per 
section 8 and the DSMP.  Thereafter, safety and data analysis will be performed every 12 weeks through 
completion of the study. Additionally, the PI will be responsible for submitting the IRB Continuing 
Review package and will provide the necessary safety data for the FDA IND Annual Report. 
 
All enrolled subjects who have received CD24Fc will be evaluated for safety with the laboratory assays 
done at each visit as outlined in section 8.2. Safety will be assessed by physical examination, vital signs, 
hematology, and chemistries. Vital signs will include pulse, blood pressure, respiratory rate, and oxygen 
saturation. The severity of signs, symptoms, and AEs will be determined by using DAIDS toxicity table, 
version 2.1, July 2017. The CD24Fc infusion will be administered over a minimum of 1 hour. Subjects will 
be monitored during and after infusion is completed for 2 hours every 30 minutes and repeat vital signs 
and laboratory results will be ascertained as needed based on reported symptoms.  
 
In the event of abnormal laboratory tests, the tests will be repeated immediately if they are inconsistent 
with the subject’s screening (baseline) laboratory results. If considered abnormal and deviating from 
baseline, they will be repeated and may be referred for physician sub-specialty consultation. These 
laboratory results will be repeated until they have returned to the normal range and/or an adequate 
explanation of the abnormality is found. If a clear explanation is established it should be recorded in the 
subject’s study record. 
 
8.4 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.4.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related. 
 
8.4.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
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An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes: death, a life-threatening adverse 
event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or significant 
incapacity or substantial disruption of the ability to conduct normal life functions, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or convulsions that do 
not result in inpatient hospitalization, or the development of drug dependency or drug abuse. 
 
8.4.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.4.3.1 SEVERITY OF EVENT 
 
The investigator will grade the severity of each AE according to the “Division of AIDS Table For Grading 
The Severity Of Adult and Pediatric Adverse Events”, version 2.1, July 2017. 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
 
For adverse events (AEs) not included in the protocol defined grading system, the following guidelines 
will be used to describe severity.  
 
• 
Grade 1-Mild – Causing no or minimal interference with usual social and functional activities 
with intervention not indicated.  
• 
Grade 2-Moderate – Causing greater than minimal interference with usual social and functional 
activities with intervention indicated. 
• 
Grade 3-Severe – Causing inability to perform usual social and functional activities with 
intervention or hospitalization indicated.  
• 
Grade 4-Potentially Life Threatening – Causing inability to perform basic self-care functions 
with intervention indicated to prevent permanent impairment, persistent disability or death. 
• 
Grade 5-Death 
 
 
8.4.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. 
The degree of certainty about causality will be graded using the categories below.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. The response to withdrawal of the 
study intervention (dechallenge) should be clinically plausible. The event must be 
pharmacologically or phenomenologically definitive, with use of a satisfactory rechallenge 
procedure if necessary. 
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• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within 
a reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides 
plausible explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
8.4.3.3 EXPECTEDNESS  
 
The PI will be responsible for determining whether an adverse event (AE) is expected or unexpected.  An 
AE will be considered unexpected if the nature, severity, or frequency of the event is not consistent with 
the risk information previously described for the study intervention. 
 
8.4.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured in the 
study record. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to study product (assessed only by those with the training and 
authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring while 
on study must be documented appropriately regardless of relationship. All AEs will be followed to 
adequate resolution. AEs and SAEs will be collected between Day 0 and Week 28 (completion of study).  
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity. AEs characterized as intermittent require documentation of onset and duration 
of each episode. 
 
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The PI or study coordinator will record all reportable events with start dates occurring any time after 
informed consent is obtained until the last day of study participation.  At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed for 
outcome information until resolution or stabilization. 
 
All enrolled subjects who have received CD24Fc will be evaluated for safety with the laboratory assays 
done at each visit as outlined in section 8.2. Safety will be assessed by physical examination, vital signs, 
hematology, and chemistries. Vital signs will include pulse, blood pressure, respiratory rate, and oxygen 
saturation. The severity of signs, symptoms, and AEs will be determined by using DAIDS toxicity table, 
version 2.1. The CD24Fc infusion will be administered over a minimum of 1 hour. Subjects will be 
monitored after infusion is completed for 2 hours and repeat vital signs and laboratory results will be 
ascertained as needed based on reported symptoms.  
 
In the event of abnormal laboratory tests, the tests will be repeated immediately if they are inconsistent 
with the screening (baseline) laboratory results. If considered abnormal and deviating from baseline, they 
will be repeated and subjects may be referred for physician sub-specialty consultation. These laboratory 
results will be repeated and followed up until they have returned to the normal range and/or an adequate 
explanation of the abnormality is found.  If a clear explanation is established, it should be recorded in the 
subject’s study record. 
 
8.4.5 ADVERSE EVENT REPORTING  
 
All AEs occurring from the time of ingesting one dose of the medications through the end of study will 
be documented, recorded, and reported.  The Investigator will evaluate all AEs with respect to Severity 
(intensity or grade) and Causality (relationship to study agent and relationship to research). The 
investigator will record nonserious adverse events and report them to the sponsor within 30 days of the 
event occurrence.  
 
Laboratory abnormalities that are gradable per the DAIDS toxicity table (version 2.1, July 2017) will be 
recorded as AEs or SAEs. All other laboratory abnormalities without clinical significance will not be 
recorded as AEs or SAEs. Laboratory abnormalities that require medical or surgical intervention or lead 
to study drug interruption, modification or discontinuation must be recorded as an AE or SAE if 
applicable. Laboratory assessments that are associated with signs and/or symptoms must be recorded 
as an AE or SAE if they meet the definition. If a diagnosis is clinically evident, the diagnosis, rather than 
the individual signs and symptoms or lab abnormalities will be recorded as the AE. 
 
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any new or worsening adverse event that begins on or after the date of 
first dose of study drug up until study completion. Summaries (number and percentage of subjects) of 
treatment-emergent adverse events will be provided at study completion.  
 
At each contact with the subject as outlined above in the study activities table, information regarding 
AEs will be elicited by appropriate questioning and examinations and will be immediately documented in 
the subject’s medical record. Medical records will be reviewed in a timely manner by the research team. 
The onset date, the end date, the severity of each reportable event, and the Investigator’s judgment of 
the AEs relationship to CD24Fc will also be recorded. 
 
 
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8.4.6 FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
Adverse events that occur following initiation of investigational agent on day 0 will be followed at a 
minimum until a final outcome is known (resolution of the AE or a return to baseline laboratory value) 
or until the end of the study follow-up period (Week 28).  
 
SAEs that occur after the study follow-up period that are reported to and are assessed by the 
Investigator to be possibly, probably, or definitely related must be reported to the Medical Monitor. 
 
8.4.7 SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician will immediately report to the Medical Monitor any serious adverse event, whether 
or not considered study intervention related, including those listed in the protocol or investigator 
brochure and must include an assessment of whether there is a reasonable possibility that the study 
intervention caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) 
must be reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the study intervention and the event (e.g., death from anaphylaxis). In that case, 
the investigator must immediately report the event to the Medical Monitor.  The University of Maryland 
Medical Monitor will in turn notify the ClinDatrix Medical Safety Medical Monitor via email. 
 
All serious adverse events (SAEs) will be followed until satisfactory resolution or until the site 
investigator deems the event to be chronic or the participant is stable. Other supporting documentation 
of the event may be requested by the study sponsor and should be provided as soon as possible. 
 
The study sponsor will be responsible for notifying the Food and Drug Administration (FDA) of any 
unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but in no case later 
than 7 calendar days after the sponsor's initial receipt of the information.  In addition, the sponsor must 
notify the FDA and all participating investigators in an Investigational New Drug (IND) safety report of 
potential serious risks, from clinical trials or any other source, as soon as possible, but in no case later 
than 15 calendar days after the sponsor determines that the information qualifies for reporting. 
 
The Medical Monitor will advise the Sponsor regarding the safety of the study participants as well as the 
continuing safety and scientific validity of the trial.  The Medical Monitor may also review the results of 
any planned analysis, if applicable. If the data analysis shows significant findings with regards to safety, 
the Medical Monitor may recommend modification of the protocol, Informed Consent, and/or 
monitoring of the study.  In these cases, the regulatory authorities and local review committees may be 
notified. The Medical Monitor may also stop the study for reasons of safety and/or futility. The Medical 
Monitor will also perform a quarterly review of the safety data.  This review may include the designated 
reviews as described above based on the timing of the reviews. 
 
8.4.8 REPORTING OF PREGNANCY  
 
Pregnancy itself is not an AE. However, complications of pregnancies are AEs and may be SAEs.  
Pertinent obstetrical information of all pregnancies will be reported to the MM via HIPAA-compliant fax 
or email within 3 business days from site awareness of the pregnancy. Study drug must be stopped 
immediately. The participant will be advised to notify her obstetrician of study agent exposure.   
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Pregnancy outcome data (e.g., delivery outcome, spontaneous, or elective termination of the 
pregnancy, presence of absence of birth defects, congenital abnormalities, or other complications) will 
be reported to the MM within 3 business days of the site’s awareness via HIPAA-compliant fax or email. 
 
8.4.9 PAUSING AND HALTING RULES 
 
See Appendix A (Safety Monitoring Plan). 
 
 
8.5 
UNANTICIPATED PROBLEMS 
 
8.5.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
 
8.5.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the lead PI. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the study sponsor 
within 3 days of the investigator becoming aware of the event.  
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• 
Any other UP will be reported to the IRB and to the study sponsor within 15 days of the 
investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 30 days of the IRB’s receipt of the report of the 
problem from the investigator. 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
The objectives of this phase II trial are to (1) determine the safety and tolerability of CD24Fc during the 
4-week dosing period and a 24-week follow-up period in a cohort of HIV subjects and (2) evaluate the 
change in LDL during a 4-week dosing period of CD24Fc and a 24-week follow-up period. The primary 
efficacy endpoint is the reduction of LDL levels when compared with placebo control at week 6. The 
hypothesis of superiority of CD24Fc 240mg compared to Placebo will be tested for the reduction of LDL 
levels.  
 
Primary Efficacy Endpoints:  
1. Incidence and severity of any adverse events (AEs) during the administration of drug and 24 
weeks after completion. Safety will be evaluated by assessment of clinical laboratory tests, 
physical examination at various time points during the study, and by the documentation for 
AEs. 
2. The percentage reduction in LDL level from the baseline (predosing) to 2 weeks after the last 
treatment.  
3.  
Secondary Efficacy Endpoint(s):  
1. Percent change in levels of total cholesterol, HDL, and triglycerides from baseline to Weeks 
6 and 28 between placebo and intervention arms.  
2. Percent change in markers of immune activation (CD4 and CD8 T cells, IFN, TNF, sCD14) 
from baseline to Week 6 and 28 between placebo and intervention arms. 
3. Change in proviral DNA from baseline to Week 6 and 28 between placebo and intervention 
arms. 
4. Percent change from baseline to week 28 in Troponin I and T between placebo and 
intervention arms.  
5. Change in percent of hepatic steatosis (by CAP measurement) and fibrosis (by KPA) as 
determined by transient elastography from baseline to week 28 between placebo and 
intervention arms.  
6. Percent change in leptin from baseline to Week 6 and 28 between placebo and intervention 
arms.  
7. Percent change in hemoglobin A1c from baseline to Week 6 and 28 between placebo and 
intervention arms.  
8. PK and PD assessments (For 6 subjects) 
9. Presence of ADA in all subjects with temporal correlation to any adverse events, and its effect 
on PK (For first 6 subjects). 
10. Changes in IL-6, apoB, Lp(a), urine albumin:creatinine ratio before and after treatment.   
 
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Exploratory Endpoints: 
1. Change in vascular inflammation as evidenced by aortic FDG uptake by FDG-PET/CT will be 
assessed before and after therapy. The arterial uptake of FDG is measured by the standardized 
uptake value (SUV) max divided by the venous SUV mean yielding a target to background ratio 
(TBR).  
2. Changes in hs-CRP and GlycA before and after treatment. 
3. Changes in CEC and NMR lipoproteins before and after treatment.  
4. Changes in endothelin-1 before and after treatment.  
 
9.2 
SAMPLE SIZE DETERMINATION 
We anticipate enrolling 64 subjects with HIV who have achieved viral suppression for 2 years while on 
ART. The primary efficacy endpoint is the reduction of LDL levels when compared with placebo control at 
week 6. We expect a 15% reduction of LDL levels.  For better comparison, we define the predosing LDL 
level of each subject as baseline and compare the LDL levels at 6 weeks (2 weeks after the last treatment) 
to determine percentage reduction.  The mean variations of the placebo groups will be subtracted when 
used to determine whether the 15% endpoints haven been met. From our previous Phase 1 and Phase 2a 
human studies, the estimate of standard deviation is about 20% for both placebo and treatment groups. 
A sample size of 28 completed subjects per treatment group (56 subjects in total) will provide 80% power 
to detect 15% reduction difference between treatment and placebo groups at a 2-sided significance level 
of 0.05. Accounting for 11% attrition, it is expected that a total of 64 subjects will be enrolled.  
 
9.3 
POPULATIONS FOR ANALYSES 
The following analysis sets will be used in this trial: 
• 
Intention-to-Treat (ITT) Analysis Dataset - this includes all randomized subjects 
• 
Modified Intention-to-Treat Analysis Dataset (mITT) - this includes all randomized subjects with 
at least one application of study drug 
• 
Safety Analysis Dataset- this includes all randomized subjects with at least one application of 
study drug 
• 
Per-Protocol Analysis Dataset - this includes a subset of the subjects in the ITT analysis set who 
complied with the protocol sufficiently to ensure that these data would be likely to represent 
the effects of study intervention according to the underlying scientific model (e.g., subjects who 
took at least 80% of study intervention treatment for at least 80% of the initial 4 weeks). 
 
9.4 
STATISTICAL ANALYSES 
 
9.4.1 GENERAL APPROACH 
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject evaluability, 
and appropriateness of the planned statistical methods. 
 
A statistical analysis plan (SAP) will be prepared and finalized prior to unblinding of subject’s 
treatment assignment. This document will provide further details regarding the definition of 
analysis variables and analysis methodology to address all study objectives. 
 
For descriptive statistics categorical data will be presented as frequencies and percentages. 
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Percentages will be based on the number of subjects with non-missing values for the corresponding 
categorical variable. Continuous data will be presented as number of subjects with non-missing 
values, mean standard deviation, median, minimum and maximum, as well as the 25th and 75th 
percentile. 
 
All statistical tests as well as the confidence intervals will be two-sided. The type I error probability 
for the confirmatory analysis is set to 5%. 95% confidence intervals are to be calculated, if feasible. 
Covariates for the primary analyses will be pre-specified. For secondary analyses these will be 
specified later in the SAP. 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY AND SECONDARY ENDPOINTS 
The primary efficacy and secondary analysis will be based on the mITT set. Most of primary and 
secondary variables such as T cell surface markers and plasma cytokine levels, and change and percent 
change from baseline to week 28 on markers of vascular inflammation and myocardial damages will be 
viewed as continuous variables and transformed as necessary. Each of efficacy variables will be analyzed 
using an Analysis of Covariance (ANCOVA) model with treatment as the fixed effect and other potential 
risk factors such as baseline value, clinical measures and demographic information as covariates. 
Differences between treatment groups and 95% confidence intervals will be estimated within the 
framework of ANCOVA. The statistical test for each of those variables will be a two-sided test at a 
significance level of 0.05 and no multiplicity adjustment will be done. 
 
Specific details will be provided in the full statistical analysis plan (SAP) for the study. 
 
9.4.3 SAFETY ANALYSES 
Safety and tolerability will be summarized by treatment arm, including Treatment Emergent Adverse 
events (TEAEs), and laboratory evaluations.  No inferential analysis is planned for safety data.  Adverse 
events will be coded using the most current version of the Medical Dictionary for Regulatory Activities 
(MedDRA). TEAEs are defined as new or worsening AEs after the first dose of study medication, and will 
be summarized by system organ class, and preferred term.  A list of subjects who have Severe Adverse 
Events (SAEs) and who discontinue from the study due to an adverse event will be provided.   
Summary statistics for laboratory values will be provided at baseline, post baseline, and for changes 
from baseline to post baseline.  Vital signs will also be summarized in the same way.  Occurrence of 
significant laboratory abnormalities will be tabulated. Values of potential clinical concern will be pre-
specified in the SAP. All medications administered during the study period must be documented on the 
Concomitant Medication electronic case report form (eCRF).  These medications will be coded using the 
most current version of the World Health Organization Drug Dictionary.  A listing of all medications 
including the reported term, dictionary term, start and stop dates, and other relevant data will be 
provided. The Safety Analysis Set (SAF) will include all subjects who received at least 1 dose of study 
medication and the subjects will be analyzed as treated.  The safety and efficacy analyses will be 
summarized based on the SAF. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
 
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10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.    Subjects will also sign an NIH specific consent form for 
any procedures taking place at the NIH. 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be Institutional 
Review Board (IRB)-approved and the participant will be asked to read and review the document. The 
investigator will explain the research study to the participant and answer any questions that may arise. 
A verbal explanation will be provided in terms suited to the participant’s comprehension of the 
purposes, procedures, and potential risks of the study and of their rights as research participants.  
Participants will have the opportunity to carefully review the written consent form and ask questions 
prior to signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their records. 
The informed consent process will be conducted and documented in the source document (including the 
date), and the form signed, before the participant undergoes any study-specific procedures. The rights 
and welfare of the participants will be protected by emphasizing to them that the quality of their 
medical care will not be adversely affected if they decline to participate in this study. Only participants 
who can consent for themselves will be consented.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to study participants, the principal investigator, funding 
agency (NHLBI), the Investigational New Drug (IND) sponsor and regulatory authorities.  If the study is 
prematurely terminated or suspended, the Principal Investigator (PI) will promptly inform study 
participants, the Institutional Review Board (IRB), and sponsor and will provide the reason(s) for the 
termination or suspension.  Study participants will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
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• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may 
inspect all documents and records required to be maintained by the investigator, including but not 
limited to, medical records (office, clinic, or hospital) and pharmacy records for the participants in this 
study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the Institute of Human Virology and the Department of Epidemiology 
(University of Maryland School of Medicine). This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites and by 
research staff will be secured and password protected. The PI and study team will have access to the 
password-protected database. At the end of the study, all study databases will be de-identified and 
archived at the University of Maryland Medical School of Medicine.  
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored at the Institute of Human Virology (University of 
Maryland). After the study is completed, the de-identified, archived data will be retained at the Institute 
of Human Virology (IHV) for use by other researchers including those outside of the study. Permission to 
retain the data at the IHV will be included in the informed consent.  
 
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-
identified biological samples will be stored at the IHV. These samples could be used to research the 
causes of cardiovascular disease in HIV, its complications and other conditions for which individuals with 
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C A LI B E R O n c oI m m u n e C D 2 4 Fc -0 0 3  
Versi o n 5. 0  
Pr ot o c ol H P -0 0 0 8 6 0 2 9  
N o v e m b er 1 2 , 2 0 2 0 
 
 5 5  
HI V  ar e at i ncr e as e d ris k, a n d t o i m pr ov e tr e at m e nt. I H V r es e arc h ers will b e pr o vi d e d wit h a c o d e -li n k 
t h at will all o w li n ki n g t h e bi ol o gic al s p eci m e ns wit h t h e p h e n ot y pic d at a fr o m e ac h p artici p a nt, 
m ai nt ai ni n g t h e bli n di n g of t h e i d e ntit y of t h e p artici p a nt. G e n etic t esti n g will n ot b e p erf or m e d.  
 
W h e n t h e st u dy is c o m pl et e d, acc ess t o st u dy d at a a n d/ or s a m pl es will b e pr o vi d e d t hr o u g h t h e I H V. 
 
1 0. 1. 5  K E Y R O L E S  A N D S T U D Y G O V E R N A N C E  
 
Pri nci p al I n v esti g at or  
M e dic al M o nit or  
S hy a m as u n d ar a n  K ottilil M D, P h D  
Instit ut e of H u m a n Vir ol o gy, U niv ersity 
of M ar yl a n d  
7 2 5 W. L o m b ar d St.  
B alti m or e, M D 2 1 2 0 1  
 
 
 
T h e N ati o n al I nstit ut es of H e alt h, B et h es d a, M D   
T h e N ati o n al I nstit ut es of H e alt h, B et h es d a, M D c a m p us will pr o vi d e acc ess t o a dv a nc e d c ar di ac i m a gi n g 
a n d ot h er cli nic al r es e arc h r es o urc es n ot av ail a bl e at t h e cli nic al sit es.  H e nr y M as ur, M D a n d N e h al M e ht a, 
M D  ar e  t h e NI H I ntr a m ur al sit e I nv esti g at ors.  Drs. M as ur a n d M e ht a will o v ers e e t h e pr ot oc ol a n d all t h e 
i n divi d u als  w orki n g  o n  it  at  t h e  NI H  Cli nic al  C e nt er  a n d  pr ovi d e  ex p ertis e  o n  st u dy  d esi g n  a n d  
i m pl e m e nt ati o n. T h es e i n divi d u als ar e list e d i n t h e U MB Pr ot oc ol as S u b -I nv esti g at ors a n d  m a y i ncl u d e 
f e d er al e m pl oy e es, s p eci al v ol u nt e ers, a n d/ or c o ntr act ors. Drs. M e ht a, A mit D e y a n d H e nr y M as ur will b e 
a ut h oriz e d t o o bt ai n i nf or m e d c o ns e nt, h a v e acc ess t o i d e ntifi a bl e d at a, a n d p artici p at e i n d at a a n alysis 
a n d m a n uscri pt pr e p ar ati o n/r e vi e w.   Drs. M e ht a a n d D ey ar e ex p erts i n c ar di o m et a b olic ev al u ati o n of 
F D G -P E T/ C T a n d will pr o vi d e i nt er pr et ati o n of t h e r es ults of t h es e i m a gi n g st u di es w hic h will str e n gt h e n 
e v al u ati o ns t o c h ar act eriz e t h e bi ol o gic eff ects of C D 2 4 Fc. T h e l a b of T a e -W o o k C h u n, P h D will  b e 
pr oc essi n g r es e arc h s a m pl es f or t h e st u dy at t h e NI H t hr o u g h a NI AI D f u n d e d l a b or at or y.  
S hy a m  K ottilil,  P o o n a m  M at h ur  a n d  A my  N els o n  ar e  U M B  s u b -i nv esti g at ors  w h o  ar e  als o  s p eci al  
v ol u nt e ers at NI H a n d ar e f ull y cr e d e nti al e d a n d a bl e t o s e e r es e arc h p ati e nts at t h e NI H.  T h e y ar e 
a ut h oriz e d  t o  o bt ai n  i nf or m e d  c o ns e nt,  h a v e  acc ess  t o  i d e ntifi a bl e  d at a,  s e e  p ati e nts  at  NI H  a n d  
p artici p at e i n d at a a n al ysis a n d m a n uscri pt pr e p ar ati o n/r e vi e w.  
 
1 0. 1. 6  S A F E T Y O V E R SI G H T  
 
S af et y ov ersi g ht will b e u n d er t h e d ir ecti o n of t h e M e dic al M o nit or, 
. T h e M e dic al 
M o nit or will b e i n d e p e n d e nt fr o m t h e st u dy c o n d uct a n d fr e e of c o nflict of i nt er est. T h e M e dic al 
M o nit or will m e e t at l e ast q u art erl y wit h t h e PI a n d st u dy t e a m t o ass ess s af et y a n d effic ac y d at a o n 
e ac h ar m of t h e st u dy. T h e M e dic al M o nit or will pr o vi d e its i n p ut t o t h e st u dy s p o ns or q u art erly a n d t h e 
N HL BI as n e e d e d.  
 
A n i n d e p e n d e nt D S M B h as als o b e e n est a blis h e d f or ov ersi g ht of s af ety i n t his cli nic al st u dy, r es p o nsi bl e 
t o t h e N HL BI. T h is D S M B will b e i n d e p e n d e nt of r e g ul at or y a g e nci es, I R B/ E C, O nc oI m m u n e, I nc, a n d 
i nv esti g at ors. T h e D S M P  c a n b e f o u n d i n A p p e n dix A  at  t h e e n d of t his pr ot oc ol . 
0 6 F 3 4 9
P P D
P P D
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10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with International 
Conference on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory 
requirement(s).  
 
• 
Monitoring of the site will be conducted in accordance to the current procedures in place at the 
Institute of Human Virology, University of Maryland School of Medicine. 
• 
Authorized representatives of the Sponsor, a regulatory authority, an Independent Ethics 
Committee or the Institutional Review Board may visit the site to perform audits or inspections, 
including source data verification. The purpose of a Sponsor audit or inspection is to 
systematically and independently examine all study-related activities and documents to 
determine whether these activities were conducted, and data were recorded, analyzed, and 
accurately reported according to the protocol, Good Clinical Practice guidelines of the 
International Conference on Harmonization, and any applicable regulatory requirements.  The 
Investigator should contact the Sponsor immediately if contacted by a regulatory agency about 
an inspection. The Investigator agrees to allow access to the required participant and study 
records during an audit. The Investigator will provide the Sponsor with copies of all 
correspondence with the regulatory authority which may affect the review of the current study 
or their qualification as an Investigator in studies conducted by the Sponsor. The Sponsor 
reserves the right to be present during an inspection by the regulatory agency.  
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Data quality control (QC) checks will be run on the database. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
 
The Medical Monitor and the DSMB will verify that the clinical trial is conducted and data are generated 
and biological specimens are collected, documented (recorded), and reported in compliance with the 
protocol, International Conference on Harmonisation Good Clinical Practice (ICH GCP), and applicable 
regulatory requirements (e.g., Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)). 
To ensure compliance with Good Clinical Practices and all applicable regulatory requirements, the 
Sponsor may conduct a quality assurance audit.   
 
During the study, the Sponsor or designee will conduct periodic monitoring visits to ensure that the 
protocol and ICH GCP guidelines are being followed.  The monitors may review source documents to 
confirm that the data recorded is accurate.  The Investigator and institution will allow the Sponsor 
monitor or designee and appropriate regulatory authorities direct access to source documents to 
perform this verification. 
 
The study site may be participant to review by the IRB, and/or quality assurance audits performed by 
the Sponsor, or companies working with or on behalf of the Sponsor, and/or inspection by appropriate 
regulatory authorities. 
 
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10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Data will be recorded in an electronic case report form (eCRF) using a secure electronic database. The 
data system includes password protection. The data entered will include but not be limited to clinical 
findings and observations, laboratory and test data, hospital medical records, physician or office charts, 
physician or nursing notes, recorded data from automated instruments, x-rays, etc. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harmonization (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP), or Manual of Procedures (MOP) requirements. The 
noncompliance may be either on the part of the participant, the investigator, or the study site staff. As a 
result of deviations, corrective actions are to be developed by the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
Anticipated deviations in the conduct of the protocol will not be reported to the IRB unless they occur at 
a rate greater than anticipated by the study team, in accordance with findings from previous trials as 
outlined in the IB. If the rate of these events exceeds the rate expected by the study team, the events 
will be classified and reported as though they are unanticipated problems. Deaths related to the natural 
history of HIV will be reported at the time of continuing review.  
 
It is the responsibility of the site investigator to use continuous vigilance to identify and report 
unanticipated deviations within 7 working days of identification of the protocol deviation, or within 7 
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working days of the scheduled protocol-required activity.  All unanticipated deviations must be 
addressed in study source documents, reported to the NHLBI Program Official and sponsor.   
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
The PI and study team share de-identified or identified data generated in this study with all collaborators 
and will have access to all data collected from all sites.  The NIH will share cardiac imaging results and 
analysis as well as research lab data with the study team.  All NIH data will be subject to a certificate of 
confidentiality whether it stays at the NIH or is shared with others. 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access to the 
published results of NIH funded research. It requires scientists to submit final peer-reviewed journal 
manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for 
publication. 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.  Data from this study may be requested from other researchers 2 years after the 
completion of the primary endpoint by contacting the study Sponsor. 
At the conclusion of the study, the Sponsor will support the writing and publication of scientific reports, 
journal papers and oral presentations by the study principal investigator and others making scientific 
contribution to the research effort. Any reports, papers, and/or presentations must be reviewed and 
approved by prior to submitting for publication.  All reports generated by this study will be in 
accordance with the ethical standards of the responsible committee on human experimentation and the 
Helsinki Declaration of 1975, as revised in 1983.   
All publications relating to the study will comply with the guidelines set forth by the Uniform 
Requirements for Manuscripts Submitted to Biomedical Journals drawn up by the International 
Committee of Medical Journal Editors.  
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial.  The study 
leadership in conjunction with the NHLBI has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
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reported dualities of interest.  All NIH Investigators have been cleared of actual or perceived influence 
by the Deputy Ethics Counselors of the NIH Clinical Center 
 
10.2 ADDITIONAL CONSIDERATIONS 
Not applicable.  
 
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10.3 ABBREVIATIONS 
 
ABBREVIATION 
TERM 
ADA 
Anti-Drug Antibody  
AE 
Adverse Event  
AIDS 
Acquired Immunodeficiency Syndrome 
ALT 
Alanine Aminotransferase 
ART 
Antiretroviral Therapy  
AST 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
CBC 
Complete Blood Count 
CD4 
Cluster of Differentiation 4 
CD8 
Cluster of Differentiation 8 
CD24 
Cluster of Differentiation 24 
CDC 
Centers for Disease Control 
CEC 
Cholesterol Efflux Capacity 
CFR 
Code of Federal Regulations 
ChRM 
Chinese Rhesus Macaques 
CMP 
Complete Metabolic Panel 
COC 
Certificate of Confidentiality  
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CT 
Computed Tomography  
CVD 
Cardiovascular Disease  
DAMPs 
Danger Associated Molecular Patterns 
DSMB 
Data and Safety Monitoring Board 
DSMP 
Data Safety Monitoring Plan 
ECD 
Extracellular Domain 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Forms 
ESA 
Erythropoietin Stimulating Agent 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act 
of 2007 
FDG 
Fluorodeoxyglucose 
GCP 
Good Clinical Practice 
G-CSF 
Granulocyte Colony Stimulating Factor 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GVHD 
Graft Versus Host Disease  
HDL 
High Density Lipoprotein 
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HIPAA 
Health Insurance Portability and Accountability 
Act  
HIV 
Human Immunodeficiency virus  
HSA 
Heat Stable Antigen 
Hs-CRP 
High Sensitivity CRP 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation  
IFN 
Interferon 
IL-6 
Interleukin 6 
IND 
Investigational New Drug Application 
Institute of Human Virology 
IHV 
IRB 
Institutional Review Board 
ITT 
Intention-to-treat 
LDL  
Low Density Lipoprotein 
MM 
Medical Monitor 
MS 
Multiple Sclerosis  
NCT 
National Clinical Trial 
NHLBI 
National Heart, Lung, and Blood Institute  
NIH  
National Institutes of Health 
NMR 
Nuclear Magnetic Resonance 
PD 
Pharmacodynamics 
PET 
Positron Emission Tomography 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
QA 
Quality Assurance 
QC 
Quality Control 
OHRP 
Office for Human Research Protections 
RA 
Rheumatoid Arthritis  
RNA 
Ribonucleic Acid 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SC 
Study Coordinator 
sCD14 
Soluble Cluster of differentiation 14 
SIV 
Simian Immunodeficiency Virus 
SOA 
Schedule of Activities 
TEAE 
Treatment Emergent Adverse Event 
TG 
Triglycerides 
TNF 
Tumor Necrosis Factor 
TnI 
Troponin I 
TnT 
Troponin T 
TPO 
Thrombopoietin 
ULN 
Upper Limit of Normal 
UP 
Unanticipated Problem 
US 
United States 
 
 
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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
2 
July 2019 
Decrease dosing to 4 weeks, 
addition of further clinical 
laboratory testing and inclusion 
criteria strengthening, change to 
include CT with FDG PET 
In response to FDA 
recommendations, CT added 
at request of NIH collaborator 
3 
February 2020 
Revisions to clarify NIH Lead 
Investigator, roles, compensation 
for visits occurring at NIH, sharing 
of data.  Addition of NIH Protocol 
Addendum to this protocol. 
In response to NIH review to 
allow protocol to occur at 
their site 
4 
June 2020 
Add DSMP appendix to protocol 
and clarify DSMB language in 
protocol 
Per grant requirements, a 
DSMB was required 
5 
November  2020 
Addition of endothelin-1 research 
testing and endpoints, 
clarification of screening window 
in SofA. Clarification of timing 
windows in post-infusion 
monitoring. Clarification of 
payment for unscheduled visits.  
Correction to inclusion criteria for 
drug components of Biktarvy. 
Clarification for discontinuation 
based on CD4 changes to include 
both change in absolute value 
and CD4%.  
SofA changed for consistency, 
researchers desired to follow 
endothelin changes with the 
study. Windows added for 
allowable timepoints for 
monitoring.  Payment 
changes to inform subjects of 
unscheduled visit payment 
and need to collect SS# for 
possible 1099.  Biktarvy 
change as mistake noted.  
Absolute changes in CD4 
undergo daily variation, so 
correlating absolute CD4 with 
CD4% will be more useful to 
determine if there is a clinically 
significant decline. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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21. 
Wang Y-C, Zhu L, McHugh R, Sell KW, Selvaraj P. Expression of heat-stable antigen on tumor cells provides 
co-stimulation for tumor-specific T cell proliferation and cytotoxicity in mice. Eur J Immunol 1995;25:1163-7. 
22. 
Bagchi S, Burrowes SA, Fantry LE, et al. Factors associated with high cardiovascular risk in a primarily 
African American, urban HIV-infected population. SAGE Open Med 2017;5:2050312117725644. 
23. 
Stone NJ, Robinson JG, Lichtenstein AH, et al. 2013 ACC/AHA guideline on the treatment of blood 
cholesterol to reduce atherosclerotic cardiovascular risk in adults: a report of the American College of 
Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2014;63:2889-934. 
24. 
2017. at https://aidsvu.org/.) 
25. 
CDC. Lifetime Risk of HIV Diagnosis: Half of black gay men and a quarter of Latino gay men projected to be 
diagnosed within their lifetime. . 2016. 
26. 
Kret J. The burden of cardiovascular disease in the District of Columbia: Department of Health; 2014. 
27. 
Shankar G, Arkin S, Cocea L, et al. Assessment and reporting of the clinical immunogenicity of therapeutic 
proteins and peptides-harmonized terminology and tactical recommendations. AAPS J 2014;16:658-73. 
28. 
Pertea M, Kim D, Pertea GM, Leek JT, Salzberg SL. Transcript-level expression analysis of RNA-seq 
experiments with HISAT, StringTie and Ballgown. Nature protocols 2016;11:1650-67. 
29. 
Huang da W, Sherman BT, Lempicki RA. Systematic and integrative analysis of large gene lists using DAVID 
bioinformatics resources. Nature protocols 2009;4:44-57. 
30. 
Tian RR, Zhang MX, Zhang LT, et al. CD24 and Fc fusion protein protects SIVmac239-infected Chinese 
rhesus macaque against progression to AIDS. Antiviral Res 2018;157:9-17. 
31. 
Sneller MC, Justement JS, Gittens KR, et al. A randomized controlled safety/efficacy trial of therapeutic 
vaccination in HIV-infected individuals who initiated antiretroviral therapy early in infection. Sci Transl Med 2017;9. 
32. 
Chun TW, Engel D, Mizell SB, et al. Effect of interleukin-2 on the pool of latently infected, resting CD4+ T 
cells in HIV-1-infected patients receiving highly active anti-retroviral therapy. Nat Med 1999;5:651-5. 
33. 
Tawakol A, Lo J, Zanni MV, et al. Increased arterial inflammation relates to high-risk coronary plaque 
morphology in HIV-infected patients. J Acquir Immune Defic Syndr 2014;66:164-71. 
34. 
Knudsen A, Hag AM, Loft A, et al. HIV infection and arterial inflammation assessed by (18)F-
fluorodeoxyglucose (FDG) positron emission tomography (PET): a prospective cross-sectional study. J Nucl Cardiol 
2015;22:372-80. 
35. 
Petersen H, Holdgaard PC, Madsen PH, et al. FDG PET/CT in cancer: comparison of actual use with 
literature-based recommendations. Eur J Nucl Med Mol Imaging 2016;43:695-706. 
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November 12, 2020 
 
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36. 
Sulkowski MS, Eron JJ, Wyles D, et al. Ombitasvir, paritaprevir co-dosed with ritonavir, dasabuvir, and 
ribavirin for hepatitis C in patients co-infected with HIV-1: a randomized trial. JAMA 2015;313:1223-31. 
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NI H A D D E N D U M T O T H E M AI N/ S P O N S O R P R O T O C OL (t his n e e ds t o b e r e a d i n c o nj u ncti o n wit h t h e 
m ai n/s p o n s or pr ot oc ol) 
A b br e vi at e d Titl e:  
C ALI B E R  
V ersi o n D at e:  
0 1/ 1 3/ 2 0 2 0  
 
 6 6  
A b br e vi at e d Titl e:  C ALI B E R  
 
Pr ot oc ol #:  i RIS assi g n e d n u m b er- 2 0 C C 0 0 3 8; U M B H P -0 0 0 8 6 0 2 9; I N D S p o ns or - O nc ol m m u n e I nc. 
C D 2 4 Fc -0 0 3; R a di ati o n S af et y # 2 7 5 7 A p pr o v e d 1 0/ 2 4/ 2 0 1 9  
 
U M B V ersi o n D at e:  Oct o b er 1 6, 2 0 1 9  
 
NI H V ersi o n D at e:   0 1/ 1 3/ 2 0 2 0  
 
Titl e: C D 2 4 Fc  Ad mi nistr ati o n t o D ecr e as e  LDL a n d  Infl a m m ati o n i n HI V P ati e nts,  Bot h as M ark ers 
of  Effic ac y a n d C ar di ov asc ul ar Ris k R e d ucti o n  ( C ALI B E R) 
( P h as e II, r a n d o miz e d, d o u bl e-bli n d, pl ac e b o -c o ntr oll e d cli nic al tri al) 
 
NI H Pri nci p al I n v esti g at or:  
H e nr y M as ur,  M D  
Critic al C ar e M e dici n e Br a nc h  
T h e NI H Cli nic al C e nt er  
B uil di n g 1 0, R m 2 C 1 4 5  
9 0 0 0 R oc k vill e Pi k e  
B et h es d a, M D 2 0 8 9 2  
 
 
I n v esti g ati o n al A g e nts:  N o n e ( n ot at t h e NI H)  
C o m m erci al A g e nts:  Fl u d e ox y gl uc os e F 1 8 I nj ecti o n  
 
Pr ecis:  
T his st u dy is a p h as e 2, r a n d o miz e d, pl ac e b o -c o ntr ol, d o u bl e-bli n d e d cli nic al tri al t o ass ess t h e 
s af et y a n d t ol er a bility of C D 2 4 Fc a m o n g p ati e nts wit h HI V, a n d t h e eff ect of C D 2 4 Fc o n c h a n g e i n l o w-
d e nsit y li p o pr ot ei n (L DL) a m o n g p ati e nts wit h HI V.  W e will als o e v al u at e t h e eff ect of C D 2 4 Fc o n t ot al 
c h ol est er ol a n d tri gl yc eri d es, m ark ers of i m m u n e activ ati o n ( T c ell activ ati o n, s C D 1 4, a n d i nfl a m m at or y 
c yt o ki n es), siz e of HI V r es erv oirs, H b A 1c a n d l e pti n, a n d h e p atic st e at osis, a m o n g ot h er i nfl a m m at or y 
m ar k ers.  
W e hy p ot h esiz e t h at t h er a py wit h C D 2 4 Fc will b e s af e a n d t ol er a bl e i n HI V p ati e nts o n A R T a n d  
r es ult i n si g nific a nt d ecr e as es i n L DL. I n a d diti o n, w e hy p ot h esiz e t h at C D 2 4 Fc will r e d uc e c h ol est er ol, 
l e pti n, H b A 1c, h e p atic st e at osis a n d fi br osis, a n d m ar k ers of i nfl a m m ati o n i n p ati e nts wit h c hr o nic HI V 
w h o ar e vir all y s u p pr ess e d o n A R T.  
I n t his p h as e 2 st u dy, a c o h ort of 6 4 HI V p ati e nts vir ally s u p pr ess e d o n A R T will b e r a n d o miz e d i n 
a 1: 1 f as hi o n t o r ec eiv e a n i ntr av e n o us i nf usi o n of 2 4 0 m g of C D 2 4 Fc vs. pl ac e b o a d mi nist er e d ev ery 2 
w e eks d uri n g a 4 -w e e k tr e at m e nt wi n d o w, f oll o w e d by a 2 4 - w e e k f oll o w -u p p eri o d. P ati e nts will b e 
f oll o w e d f or s af ety a n d a dv ers e e v e nts as w ell as c h a n g es i n li pi d m et a b olis m a n d i nfl a m m at or y m ark ers 
d uri n g a 2 4 -w e ek f oll o w -u p p eri o d. T his i nv esti g ati o n will t a k e pl ac e at t h e U niv ersit y of M ar yl a n d a n d 
N ati o n al I nstit ut es of H e alt h.  
T h e r es e arc h b ei n g c o m pl et e d at t h e N ati o n al I nstit ut es of H e alt h Cli nic al C e nt er  as p art of t h e 
U niv ersity of M ar yl a n d st u dy is t o ass ess t h e eff ect of C D 2 4 Fc o n a ortic v asc ul ar i nfl a m m ati o n as 
m e as ur e d by st a n d ar diz e d u pt a k e v al u e of art eri al F D G by P E T/ C T.  T w el v e s u bj ects wit h a n L DL > 1 2 5 ( a 
hi g h l e v el of l o w -d e nsit y li p o pr ot ei ns (L DL), als o k n o w n as “ b a d c h ol est er ol”) will b e s el ect e d t o h a v e a n 
0 6 F 3 4 9
P P D
P P D
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Abbreviated Title: 
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optional FDG PET/CT scan.  Change in vascular inflammation as evidenced by aortic FDG uptake by FDG-
PET/CT will be assessed before and after therapy.  The arterial uptake of FDG is measured by the 
standardized uptake value (SUV) max divided by the venous SUV mean yielding a target to background 
ratio (TBR).  
This scan is completed twice, once before starting the study drug, and again 24 weeks after 
completing the study drug.  The FDG PET/CT scans will help to determine if there are any changes to the 
levels of inflammation in the blood vessels after taking the study drug, or placebo. 
 
 
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main/sponsor protocol) 
Abbreviated Title: 
CALIBER 
Version Date: 
01/13/2020 
 
 68
12 TABLE OF CONTENTS 
 
1 
NUMBER OF PATIENTS TO BE ENROLLED AT THE NIH .................................................................... 69 
2 
NIH PATIENT REGISTRATION .................................................................................................................... 69 
2.1 
Registration Procedures ................................................................................................................... 69 
2.1.1 
Registration Process at NIH ......................................................................................... 69 
3 
CRITERIA FOR REMOVAL FROM SPONSOR PROTOCOL .................................................................. 69 
4 
SAFETY REPORTING REQUIREMENTS/DATA AND SAFETY MONITORING PLAN (THIS 
REPORTING SECTION OUTLINES THE REPORTING REQUIREMENTS THAT ARE REQUIRED TO 
THE NIH AND ARE IN ADDITION TO THE REPORTING REQUIREMENTS FOR THE UMB IRB.) ......... 70 
4.1 
NIH Definitions ................................................................................................................................... 70 
4.2 
NIH IRB and Clinical Director Reporting ........................................................................................ 70 
4.2.1 
NIH Intramural IRB ......................................................................................................... 70 
4.2.2 
Reporting to NIH Intramural IRB .................................................................................. 70 
4.2.3 
NIH CC Clinical Director Reporting ............................................................................. 70 
4.3 
Data and Safety Monitoring Plan ..................................................................................................... 70 
4.3.1 
Principal Investigator/Research Team ........................................................................ 70 
5 
DATA COLLECTION AND EVALUATION ................................................................................................... 70 
5.1 
Data Collection ................................................................................................................................... 70 
5.2 
Future use of Stored Data/Samples................................................................................................ 71 
6 
HUMAN SUBJECTS PROTECTIONS ......................................................................................................... 71 
6.1 
Rationale For Subject Selection ...................................................................................................... 71 
6.2 
Risk/Benefit Assessment .................................................................................................................. 71 
6.2.1 
Known Potential Risks ................................................................................................... 71 
7 
COLLABORATIVE AGREEMENTS ............................................................................................................. 71 
7.1 
Agreement Type ................................................................................................................................ 71 
8 
CERTIFICATE OF CONFIDENTIALITY ...................................................................................................... 72 
9 
INSURANCE BILLING .................................................................................................................................... 72 
10 
COMPENSATION, REIMBURSEMENT, AND PAYMENT ....................................................................... 72 
 
 
 
STATEMENT OF COMPLIANCE 
The trial will be carried out in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP) and the following:  
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812)  
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are responsible 
for the conduct, management, or oversight of NIH-funded clinical trials have completed Human Subjects 
Protection and ICH GCP Training. 
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Abbreviated Title: 
CALIBER 
Version Date: 
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The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the Institutional Review Board (IRB) for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any amendment to 
the protocol will require review and approval by the IRB before the changes are implemented to the 
study.  In addition, all changes to the consent form will be IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 
 
1 
NUMBER OF PATIENTS TO BE ENROLLED AT THE NIH 
12 subjects will come to the NIH for the optional FDG PET/CT scans. 
2 
NIH PATIENT REGISTRATION  
2.1 
REGISTRATION PROCEDURES 
2.1.1 REGISTRATION PROCESS AT NIH 
Screening and enrollment into this study was performed at the University of Maryland in accordance 
with the sponsor protocol section 7.1 Study Visits and 7.1.1.1 Screening. After the subjects meets the 
eligibility and signs the consent document, 12 subjects will be selected to travel to the NIH CC for the 
optional FDG PET/CT scans.  Authorized member of the research team will make a request in the 
Admission Travel Voucher (ATV) system and have a medical record number assigned. Subject will then 
be registered in NIH Clinical Research Information System (CRIS). Both ATV and CRIS systems are 
password protected with access granted only to authorized personnel.  
3 
CRITERIA FOR REMOVAL FROM SPONSOR PROTOCOL 
Per sponsor protocol section 6.2 Participant Discontinuation/Withdrawal from the Study, study 
participation could be discontinued due to the following reasons: 
• 
Pregnancy or breastfeeding 
• 
Significant study intervention non-compliance  
• 
Any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
which occurs such that continued participation in the study would not be in the best interest of 
the participant (including malignancy) 
• 
New or recurrent Centers for Disease Control and Prevention (CDC) category C AIDS-indicator 
condition. 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive CD24Fc for 2 doses  
• 
Development of life-threatening infection or clinical reason deemed to be life-threatening by 
the physician 
• 
Request of the primary care provider or Investigator if s/he thinks the study is no longer in the 
best interest of the subject.  
• 
If the subject is judged by the Investigator to be at significant risk 
• 
The following laboratory abnormalities 
o HIV RNA>200 copies/mL (2 readings at least 2 weeks apart) 
o Decrease in eGFR to <30mL/min, confirmed by immediate repeat testing 
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NI H A D D E N D U M T O T H E M AI N/ S P O N S O R P R O T O C OL (t his n e e ds t o b e r e a d i n c o nj u ncti o n wit h t h e 
m ai n/s p o n s or pr ot oc ol) 
A b br e vi at e d Titl e:  
C ALI B E R  
V ersi o n D at e:  
0 1/ 1 3/ 2 0 2 0  
 
 7 0  
o  El e v ati o n of AL T > 5x O R A S T > 5x D a y 0, c o nfir m e d by i m m e di at e r e p e at t esti n g  
o  A b n or m al el ev ati o n of AL T > 3 x D ay 0 a n d  t ot al bilir u bi n > 2 x UL N, c o nfir m e d by 
i m m e di at e r e p e at t esti n g   
o  F or p artici p a nts wit h e ntry C D 4 + T c ell c o u nt b et w e e n 3 5 0 - 5 0 0 c ells/ m m 3, c o nfir m e d 
C D 4 + d ecli n e gr e at er t h a n 2 5 % of b as eli n e.  
o  F or p artici p a nts wit h e ntry C D 4 + T c ell c o u nt b et w e e n 5 0 1 t o 8 0 0 c ells/ m m 3, a 
c o nfir m e d C D 4 + T c ell d ecli n e gr e at er t h a n 3 3 % of b as eli n e.  
o  F or p artici p a nts wit h e ntry C D 4 + T c ell c o u nt gr e at er t h a n 8 0 0 c ells/ m m 3, a c o nfir m e d 
C D 4 + T c ell d ecli n e gr e at er t h a n 5 0 % of b as eli n e.  
o  Occ urr e nc e of Gr a d e 4 a n e mi a/ n e utr o p e ni a or r ec urr e nc e of Gr a d e 3 
a n e mi a/ n e utr o p e ni a.  
4  
S A F E T Y R E P O R TI N G R E Q UI R E M E N T S / D A T A A N D S A F E T Y M O NI T O RI N G P L A N ( T HI S 
R E P O R TI N G S E C TI O N O U T LI N E S T H E R E P O R TI N G R E Q UI R E M E N T S T H A T A R E 
R E Q UI R E D T O T H E NI H A N D A R E I N A D DI TI O N T O T H E R E P O R TI N G R E Q UI R E M E N T S 
F O R T H E U M B I R B.)  
4. 1  
NI H D E FI NI TI O N S  
Pl e as e r ef er t o d efi niti o ns pr o vi d e d i n P olic y 8 0 1: R e p orti n g R es e arc h E v e nts f o u n d  h er e . 
4. 2  
NI H I R B A N D C LI NI C A L DI R E C T O R R E P O R T I N G 
4. 2. 1  NI H I N T R A M U R A L I R B  
Pl e as e r ef er t o t h e r e p orti n g r e q uir e m e nts i n P olic y 8 0 1: R e p orti n g R es e arc h Ev e nts  h er e . 
4. 2. 2  R E P O R TI N G T O NI H I N T R A M U R A L I R B  
Pl e as e r ef er t o t h e r e p orti n g r e q uir e m e nts i n P olic y 8 0 1: R e p orti n g R es e arc h Ev e nts  h er e . 
4. 2. 3  NI H C C C LI NI C A L DI R E C T O R R E P O R TI N G  
All s eri o us a dv ers e e v e nts (S A Es) t h at m e et t h e d ef i niti o n p er P olic y 8 0 1: m ust b e r e p ort e d t o NI H C C 
Cli nic al Dir ect or vi a
. 
4. 3  
D A T A A N D S A F E T Y M O NI T O RI N G P L A N  
4. 3. 1  P RI N CI P A L I N V E S TI G A T O R / R E S E A R C H T E A M  
Drs. M as ur a n d M e ht a will o v ers e e t h e NI H p ort i o n of t h e pr ot oc ol (F D G by P E T/ C T)  a n d all t h e 
i n divi d u als w orki n g o n it at t h e NI H Cli nic al C e nt er. 
5  
D A T A C O L L E C TI O N A N D E V A L U A TI O N  
5. 1  
D A T A C O L L E C TI O N  
T h e PI will b e r es p o nsi bl e f or o v ers e ei n g c oll ecti o n a n d m ai nt e n a nc e of s o urc e d oc u m e nts a n d d at a 
e ntr y i nt o e C R Fs i n acc or d a nc e wit h t h e s p o ns or pr ot oc ol s ecti o n 9. 1. 9 D at a H a n dli n g a n d R ec or d 
K e e pi n g.  
E n d of st u d y pr oc e d ur es: D at a will b e st or e d acc or di n g t o a p plic a bl e r e g ul ati o ns, p olici es a n d 
r e q uir e m e nts as w ell as NI H I ntr a m ur al R ec or ds R et e nti o n Sc h e d ul e as a p plic a bl e. 
L oss or d estr ucti o n of d at a: S h o ul d w e b ec o m e a w ar e t h at a m aj or br e ac h i n o ur pl a n t o pr ot ect s u bj ect 
c o nfi d e nti ality a n d tri al d at a h as occ urr e d, t h e I R B will b e n otifi e d as a b ov e.  
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Abbreviated Title: 
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5.2 
FUTURE USE OF STORED DATA/SAMPLES 
FDG PET/CT scans will be kept indefinitely at the NIH and they may be used in the future.  We will also 
receive blood in EDTA tubes from subjects seen at UMB.  The samples will be coded and we will not 
know the identity of the subjects.  We will be conducting measurements of HIV reservoir size (HIV DNA 
PCR, cell-associated RNA PCR) and soluble factors in plasma such as D-dimer, CRP, IL-2, IL-4, IFNg, TNF-a 
and other cytokines.  Any remaining samples will be stored temporarily at NIAID but will be shipped 
back to UMB upon conclusion of our assays. No one else at NIH will have access to specimens coming 
from UMB. 
6 
HUMAN SUBJECTS PROTECTIONS  
6.1 
RATIONALE FOR SUBJECT SELECTION 
Subjects for this study will include all subjects who meet the eligibility criteria outlined in the sponsor 
protocol sections 5.1 Inclusion Criteria and 5.2 Exclusion Criteria.  No gender, racial, or ethnic groups 
will be excluded from participation in this trial.  
6.2 
RISK/BENEFIT ASSESSMENT 
6.2.1 KNOWN POTENTIAL RISKS 
18FDG PET CT:   
The study involves exposure to radiation from the radioactive sugar, but the radiation from 2 FDG 
PET/CT scans will be less than the radiation safety limit for research. There is no medical risk from lying 
in the scanner, although subjects may become uncomfortable or restless. Subjects will also have to fast 
6 hours before the appointment due to the use of radioactive glucose, which may also cause discomfort. 
In addition to any radiation concern, there could be psychological distress caused by an incidental 
finding of asymmetric FDG uptake that would likely necessitate additional investigation to exclude 
cancer. Additional minimal risks include bleeding or bruising at the venous site of FDG administration. 
6.4.2 
Known Potential Benefits 
This research involves no prospect of direct benefit to individual subjects but is likely to yield 
generalizable knowledge about the subject’s disorder or condition. 
7 
COLLABORATIVE AGREEMENTS 
7.1 
AGREEMENT TYPE 
NHLBI is in the process of putting together a Research Collaborative Agreement.  Once the agreement is 
executed, more details will be provided.  
Transfers that are associated with correlative studies conducted under an approved protocol:  Dr. 
Chun will be receiving coded samples from the University of Maryland Baltimore.  He will be conducting 
measurements of HIV reservoir size (HIV DNA PCR, cell-associated RNA PCR) and soluble factors in 
plasma such as D-dimer, CRP, IL-2, IL-4, IFNg, TNF-a and other cytokines. 
Investigators in the NIH intramural program may participate in multi-site clinical trials (either as a site or 
as the coordinating center) under which human materials are transferred from the intramural program 
to another site for correlative studies that are part of the approved protocol. In such a situation, the 
protocol clearly documents the tests conducted under the correlative studies, and each institution 
participating in the clinical study is bound by the terms of their Protocol and their obligations under the 
statutes and regulations. In addition, intramural protocols are cleared by the IC Clinical Director. In such 
situations, use of an HM-MTA is not necessary for these transfers. 
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Abbreviated Title: 
CALIBER 
Version Date: 
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8 
CERTIFICATE OF CONFIDENTIALITY 
To further protect the privacy of study participants, a Certificate of Confidentiality has been issued by 
the National Institutes of Health (NIH).  This certificate protects identifiable research information from 
forced disclosure.  It allows the investigator and others who have access to research records to refuse to 
disclose identifying information on research participation in any civil, criminal, administrative, legislative, 
or other proceedings, whether at the federal, state, or local level.    By protecting researchers and 
institutions from being compelled to disclose information that would identify research participants, 
Certificates of Confidentiality help achieve the research objectives and promote participation in studies 
by helping assure confidentiality and privacy of participants. 
9 
INSURANCE BILLING 
The NIH will not bill any insurance companies or participants for any research or related clinical care as 
the NIH is not a HIPPA-covered entity, 
10 COMPENSATION, REIMBURSEMENT, AND PAYMENT 
If a participant requires it, transportation to the NIH will be arranged by the UMB study staff.  
Participants will receive $200 cash after they have completed each FDG PET/CT from the UMB study 
staff. 
 
If a participant is unable to finish the optional study after they arrive at the NIH for some reason, they 
will receive $100 from the UMB study staff. 
 
All compensation will be given to the participant by a UMB study team member at their next visit to 
UMB. 
 
This study does not offer reimbursement for or payment of travel, lodging or meals.
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Appendix A 
 
 
CALIBER HP-00086029 
Data and Safety Monitoring Plan 
 
May 26, 2020 
 73
APPENDIX A: SAFETY MONITORING BOARD AND PLAN  
 
Full Title: 
CD24Fc Administration to Decrease LDL and Inflammation in HIV 
Patients, Both as Markers of Efficacy and Cardiovascular Risk Reduction 
Short Title: 
 
 
CALIBER 
Clinical Phase: 
II 
IND Sponsor: 
OncoImmune, Inc. 
Principal Investigator:  
Shyam Kottilil, MD PhD 
Sample Size: 
n = 64 
Accrual Ceiling: 
110 
Study Population: 
 
Adults age 50 or older with chronic HIV infection who have achieved 
viral suppression with use of ART for at least 2 years 
 
Accrual Period: 
 
18 months 
Study Design: 
 
This is a double blind, placebo controlled, randomized trial to evaluate 
the safety of CD24Fc in adults with HIV. Patients will be randomized to 
two arms: (1) CD24Fc (IV) for 3 doses over 6 weeks vs (2) Placebo (IV) 
for 3 doses over 6 weeks 
 
Study Duration: 
 
Start Date: January 2020 
 
 
End Date: December 2021 
Study Agent: 
 
CD24Fc 240mg IV Infusion 
Primary Objectives: 
1.  To determine the safety and tolerability of CD24Fc during the 4-week 
dosing period and a 24-week follow-up period in a cohort of HIV 
patients.  
2. To evaluate the change in LDL during a 4-week dosing period of 
CD24Fc and a 24-week follow-up period. 
Secondary Objectives:  
 
1. Levels of total cholesterol, HDL, and triglycerides  
2. Markers of immune activation (CD4 and CD8 T cells, IFN, TNF, 
sCD14) 
3. Size of HIV reservoirs  
4. Myocardial damage (measured by Troponin I and T) 
5. Hepatic steatosis, as determined by transient elastography  
6. Leptin 
7. Hemoglobin A1c 
8. Presence of anti-drug antibody (ADA) and temporal correlation to 
any adverse events, and its effect on PK (For first 6 subjects). 
9. The pharmacokinetics (PK) and pharmacodynamics (PD) of CD24Fc 
in the first 6 randomized subjects. 
10. Changes in IL-6, apoB, Lp(a), urine albumin to creatinine ratio before 
and after treatment.  
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Exploratory Objectives:  
 
1. To assess the effect of CD24Fc on aortic vascular inflammation as 
measured by standardized uptake value of arterial FDG by 
PET/CT. We will select 12 subjects with an LDL>125 to have the 
imaging study.  
2. To assess the effect of CD24Fc on the inflammatory markers hs-
CRP and GlycA. 
3. To assess the effect of CD24Fc on the CEC and NMR lipoproteins. 
4. To assess the effect of CD24 Fc on endothelin-1. 
 
Primary Endpoints: 
 
1. Incidence and severity of any adverse events (AEs) during the 
administration of drug and 24 weeks after completion. Safety will be 
evaluated by assessment of clinical laboratory tests, physical 
examination at various time points during the study, and by the 
documentation for AEs. 
 
 
 
2. The percentage reduction in LDL level from the baseline (predosing) 
to 2 weeks after the last treatment. 
 
Secondary Endpoints: 
 
1. Percent change in levels of total cholesterol, HDL, and 
triglycerides from baseline to Week 6 and 28 between placebo 
and intervention arms. 
2. Percent change in markers of immune activation (CD4 and CD8 
T cells, IFN, TNF, sCD14) from baseline to Week 6 and 28 
between placebo and intervention arms. 
3. Change in proviral DNA from baseline to Week 6 and Week 28 
between placebo and intervention arms. 
4. Percent change from baseline to week 28 in Troponin I and T 
between placebo and intervention arms.  
5. Change in percent of hepatic steatosis (by CAP measurement) 
and fibrosis (by KPA) as determined by transient elastography 
from baseline to week 28 between placebo and intervention 
arms.  
6. Percent change in leptin from baseline to Week 6 and Week 28 
between placebo and intervention arms.  
7. Percent change in hemoglobin A1c from baseline to Week 6 and 
week 28 between placebo and intervention arms.  
8. PK and PD assessments (For 6 subjects; presence of ADA and its 
effect on PK in all subjects 
 
Exploratory Endpoints:    
1. Change in vascular inflammation as evidenced by aortic FDG uptake 
by FDG-PET/CT will be assessed before and after therapy. The arterial 
uptake of FDG is measured by the standardized uptake value (SUV) 
max divided by the venous SUV mean yielding a target to background 
ratio (TBR).  
 
 
2. Changes in hs-CRP and GlycA before and after treatment. 
 
 
3. Changes in CEC and NMR lipoproteins before and after treatment. 
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4. Changes in endothelin-1 before and after treatment.  
 
 
Adverse Events, Serious Adverse Events, and Unanticipated Problems 
The investigator will grade the severity of each adverse event (AE) according to the “Division of AIDS 
Table For Grading The Severity Of Adult And Pediatric Adverse Events”, version 2.1, July 2017. 
https://rsc.niaid.nih.gov/sites/default/files/daidsgradingcorrectedv21.pdf 
 
For AEs not included in the protocol defined grading system, severity will be determined using the 
guidelines outlined in the protocol. All AEs must have their relationship to study intervention assessed 
by the clinician who examines and evaluates the participant based on temporal relationship and his/her 
clinical judgment. The degree of certainty about causality will be graded using the categories outlined in 
the protocol. The investigator will record nonserious adverse events and report them to the sponsor 
within 30 days of the event occurrence.  
 
The PI will be responsible for determining whether an AE is expected or unexpected.  An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study intervention. All AEs will be followed to adequate 
resolution. AEs will be collected between Day 0 and Week 28 (completion of study).  
 
The PI or study coordinator will record all reportable events with start dates occurring any time after 
informed consent is obtained until the last day of study participation.  At each study visit, the 
investigator will inquire about the occurrence of AE/SAEs since the last visit.  Events will be followed for 
outcome information until resolution or stabilization. 
 
Events will be summarized on the basis of the date of onset for the event. A treatment-emergent 
adverse event will be defined as any new or worsening adverse event that begins on or after the date of 
first dose of study drug up until study completion. Summaries (number and percentage of subjects) of 
treatment-emergent adverse events will be provided at study completion.  
 
Serious Adverse Events (SAEs) 
SAEs that occur after the study follow-up period that are reported to and are assessed by the 
Investigator to be possibly, probably, or definitely related must be reported to the Medical Monitor. 
 
The study clinician will immediately report to the sponsor any serious adverse event, whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention 
caused the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be 
reported in accordance with the protocol unless there is evidence suggesting a causal relationship 
between the study intervention and the event (e.g., death from anaphylaxis). In that case, the 
investigator must immediately report the event to the sponsor. 
 
All serious adverse events (SAEs) will be collected between Day 0 and Week 28 and followed until 
satisfactory resolution or until the site investigator deems the event to be chronic or the participant is 
stable.  
 
Unanticipated Problems 
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The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the lead PI. The UP report will include the following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the study sponsor 
within 3 days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the study sponsor within 15 days of the 
investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within 30 days of the IRB’s receipt of the report of the 
problem from the investigator. 
 
Pausing and Halting Rules 
Enrollment and dosing will be paused for an individual subject who has a Grade 4 AE. After review by the 
Medical Monitor (MM) and reporting to the DSMB in the regularly scheduled report every 12 weeks, the 
MM will evaluate whether study participation for the subject should continue. During MM review, 
enrollment and dosing will not be paused for other study subjects. 
 
If two subjects experience the same Grade 4 AE related to the study drug, all enrollment will be paused 
and all doses for enrolled subjects will be held. The MM will report to the DSMB within 24 hours and 
study dosing will halt until DSMB determination regarding continuation of study enrollment and dosing. 
 
If one or more subjects experiences changes in mental status, DIC, dyspnea, cytokine release syndrome 
and/or hypotension related to the study drug, without remediation in 2-4 hours, the MM will report to 
the DSMB within 24 hours and the DSMB will review the report for possible study termination. During 
this review, enrollment and dosing will be halted for all subjects.  
 
Safety and Efficacy Analyses 
The primary safety endpoint will be assessed by Incidence and severity of any adverse events (AEs) 
during the administration of drug and 24 weeks after completion. Safety will be evaluated by 
assessment of clinical laboratory tests, physical examination at various time points during the study, and 
by the documentation for AEs. A statistical analysis plan (SAP) will be prepared and finalized prior to 
unblinding of subject’s treatment assignment. This document will provide further details regarding the 
definition of analysis variables and analysis methodology to address all study objectives.  
 
Safety and tolerability will be summarized by treatment arm, including Treatment Emergent Adverse 
events (TEAEs), and laboratory evaluations.  No inferential analysis is planned for safety data.  Adverse 
events will be coded using the most current version of the Medical Dictionary for Regulatory Activities 
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(MedDRA). TEAEs are defined as new or worsening AEs after the first dose of study medication, and will 
be summarized by system organ class, and preferred term.  A list of subjects who have Severe Adverse 
Events (SAEs) and who discontinue from the study due to an adverse event will be provided.   
 
Summary statistics for laboratory values will be provided at baseline, post baseline, and for changes 
from baseline to post baseline. Vital signs will also be summarized in the same way. Occurrence of 
significant laboratory abnormalities will be tabulated. All medications administered during the study 
period must be documented on the Concomitant Medication electronic case report form (eCRF).  These 
medications will be coded using the most current version of the World Health Organization Drug 
Dictionary.  A listing of all medications including the reported term, dictionary term, start and stop 
dates, and other relevant data will be provided. The Safety Analysis Set (SAF) will include all subjects 
who received at least 1 dose of study medication and the subjects will be analyzed as treated.  The 
safety and efficacy analyses will be summarized based on the SAF. 
 
The following analysis sets will be used in this trial: 
• 
Intention-to-Treat (ITT) Analysis Dataset - this includes all randomized subjects 
• 
Modified Intention-to-Treat Analysis Dataset (mITT) - this includes all randomized subjects with 
at least one application of study drug 
• 
Safety Analysis Dataset- this includes all randomized subjects with at least one application of 
study drug 
• 
Per-Protocol Analysis Dataset - this includes a subset of the subjects in the ITT analysis set who 
complied with the protocol sufficiently to ensure that these data would be likely to represent 
the effects of study intervention according to the underlying scientific model (e.g., subjects who 
took at least 80% of study intervention treatment for at least 80% of the initial 4 weeks). 
 
A blinded data review will be conducted prior to unblinding of subject’s treatment assignment. This 
review will assess the accuracy and completeness of the study database, subject evaluability, and 
appropriateness of the planned statistical methods. For descriptive statistics categorical data will be 
presented as frequencies and percentages. Percentages will be based on the number of subjects with 
non-missing values for the corresponding categorical variable. Continuous data will be presented as 
number of subjects with non-missing values, mean standard deviation, median, minimum and 
maximum, as well as the 25th and 75th percentile. 
 
All statistical tests as well as the confidence intervals will be two-sided. The type I error probability for 
the confirmatory analysis is set to 5%. 95% confidence intervals are to be calculated, if feasible. 
Covariates for the primary analyses will be pre-specified. For secondary analyses these will be specified 
later in the SAP. 
 
The primary efficacy and secondary analysis will be based on the mITT set. Most of primary and 
secondary variables such as T cell surface markers and plasma cytokine levels, and change and percent 
change from baseline to week 36 on markers of vascular inflammation and myocardial damages will be 
viewed as continuous variables and transformed as necessary. Each of efficacy variables will be analyzed 
using an Analysis of Covariance (ANCOVA) model with treatment as the fixed effect and other potential 
risk factors such as baseline value, clinical measures and demographic information as covariates. 
Differences between treatment groups and 95% confidence intervals will be estimated within the 
framework of ANCOVA. The statistical test for each of those variables will be a two-sided test at a 
significance level of 0.05 and no multiplicity adjustment will be done. 
 
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Timing of DSMB Meetings 
 
Timeline  
Type of Data 
Prior to study dosing 
Review charter, Review protocol, Select 
roles of DSMB members 
Every Six Months 
Enrollment summary, adverse events 
listings and tables for primary 
endpoints available. 
Medical Monitor report 
every 12 weeks 
Review for determination of need for 
additional DSMB review prior to next 
meeting 
If two subjects have same 
G4 event related to study 
drug 
AE reviews, response to continue or 
revert enrollment and dosing hold 
If one or more subjects 
have mental status 
changes, DIC, dyspnea, 
cytokine release syndrome 
or hypotension not 
remediated within 2-4 
hours and categorized as 
clinically relevant by PI and 
Medical Monitor with risk 
to participants 
Review of events with determination of 
study termination or continuance 
Unanticipated Problem or 
non-SAE 
Review for determination of need for 
additional DSMB review prior to next 
meeting 
Upon completion or 
termination of study 
Enrollment summary, adverse events 
listings and tables for primary 
endpoints available. 
 
Study Termination 
This study may be terminated under a variety of circumstances including, but not limited to, termination 
for overwhelming effectiveness, futility, or safety issues per protocol or DSMB monitoring guidelines. 
Responsibilities of the DSMB with regard to closeout will be to review the final study report to ensure 
study integrity. The DSMB may recommend continuing action items based upon the final review. 
 
 
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