Conditions: Human Immunodeficiency Virus
Keywords: Immunotherapy Immunologic Non-Responder Immunologic Response Randomized PD-1
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 11
Healthy volunteers: no

Brief summary:
Background:

Human immunodeficiency virus (HIV) attacks the immune system. Some people with HIV have a low CD4+ T-cell count despite taking antiviral medicines that control HIV replication. These cells fight disease, so a low count makes it easier for people to become sick. Researchers want to see if a new drug can improve the immune system, including T cells. The drug is called pembrolizumab

Objective:

To see if pembrolizumab is safe to use in people with HIV who have a low CD4+ T cell count despite taking medicines that control HIV replication, and to see if it strengthens the immune system.

Eligibility:

People age 18 years or older with HIV who are taking antiretroviral drugs as treatment, have blood HIV levels below detection limits of commercial assays, and have a low CD4+ T-cell count (below 350 cells/mm3).

Design:

Participants will be screened with:

* Medical history
* Physical exam
* Heart, blood, and urine tests

Sexually active participants must use 2 kinds of birth control.

Participants will have leukapheresis. Blood will be removed through a needle in one arm. A machine will remove white blood cells. The rest of the blood will be returned into the other arm.

Participants will have a baseline visit. They will have blood tests. They may have a pregnancy test.

A needle will insert a thin plastic tube (IV) into an arm vein. The participants will get the study drug or a placebo through the IV for 30 minutes. They will be watched for a couple hours after.

Participants will have 11 follow-up visits over the next 48 weeks. They will have a physical exam, vital signs, medical review, and blood tests.

Participants may have another leukapheresis.

Participants will be called every 12 weeks after their last follow-up visit to talk about how they feel and their health. Participation ends after the week 96 phone call.

Detailed description:
A subset of HIV-infected patients, those with poor immunologic response to combined antiretroviral therapy (CD4+ T-cell count of less than 300-350 cells/mm\^3) despite control of viremia, are at increased risk for both HIV-related and non-HIV-related complications compared to immunologic responders. Thus, novel approaches for treating HIV infection are needed to facilitate management of this patient population.

One potential drug target for HIV treatment is the T-cell receptor PD-1. Binding of PD-1 to its ligands, PD-L1 and PD-L2, inhibits proliferation of T cells and production of cytokines. This naturally serves to dampen potentially harmful excessive immune responses. Upregulation of PD-1 and/or its ligands can be observed in tumors and people with chronic viral infection, including HIV. This upregulation can inhibit T-cell immune surveillance, which may result in tumor growth or poor control of infection.

Pembrolizumab is an IgG4 kappa monoclonal antibody that binds to PD-1, thus blocking the receptor from binding with its ligands. In cancer indications, inhibition of PD-1 induces an antitumor immune response, which in turn reduces tumor growth. The Food and Drug Administration has approved pembrolizumab for treatment of unresectable or metastatic melanoma, non-small cell lung cancer, head and neck squamous cell carcinoma, and other cancers. Similarly, in animal models of HIV and in vitro studies, PD-1 blockade was associated with a decrease in viral load and an increase in CD8+ T cells. A clinical trial to examine the effects of PD-1 inhibition by pembrolizumab on HIV infection is thus supported by the data.

The purpose of this study is to evaluate, in a randomized, double-blind, placebo-controlled study, the safety and tolerability of a single dose of pembrolizumab in HIV-infected participants who have controlled viremia with a low T-cell count (\> 100 cells/mm3 and less than or equal to 350 cells/mm\^3). Study participants will be followed for 96 weeks after receiving the study drug and will be assessed for adverse events, CD4+ and CD8+ T-cell counts, PD-1 expression, CD8+ T-cell anti-HIV activity, and viral load. If a single dose of pembrolizumab appears to be safe and tolerable, then larger multi-dose and efficacy studies can be planned.

Arms:
arm 1: Participants with HIV and CD4+ of 100-350 cells/mm\^3 received a single dose of Pembrolizumab 200 mg via intravenous (IV) infusion. arm 2: Participants with HIV and CD4+ of 100-350 cells/mm\^3 received a single dose of Placebo via intravenous (IV) infusion.

Interventions: intervention 1: Placebo intervention 2: Pembrolizumab
Intervention descriptions: intervention 1: Single dose of Placebo given via intravenous (IV) infusion. intervention 2: Pembrolizumab is a potent and highly selective humanized monoclonal antibody (immunoglobulin \[Ig\] G4 kappa isotype) that binds to PD-1, thus blocking the receptor from binding with its ligands. Single dose of Pembrolizumab 200 mg given via intravenous (IV) infusion.

Protocol document:
Prot_SAP_000.pdf: 
A Randomized, Double-Blind, Placebo-Controlled Study of a Single 
Dose of Pembrolizumab in HIV-infected Patients
NIAID Protocol Number: 18-CC-0013
Version Number: 8.0
Date: 16 February 2021 
Investigational New Drug (IND) Number: 137163
IND Sponsor: Office of Clinical Research Policy and Regulatory Operations 
(OCRPRO), Division of Clinical Research (DCR), National Institute of Allergy and 
Infectious Diseases (NIAID), National Institutes of Health (NIH)
Sponsor Medical Monitor: Marc J. Teitelbaum, MD, MS
Clinical Monitoring Research Program
Frederick National Laboratory for Cancer Research Leidos Biomedical Research, Inc. 
Support to: Regulatory Compliance & Human Subjects Protection Program/NIAID/NIH
5705 Industry Lane 
Frederick, MD 21704
Phone 301-228-4707
Fax 301-846-6224
Marc.Teitelbaum@fnlcr.nih.gov 
Pharmaceutical Support Provided by: Merck & Co, Inc
2000 Galloping Hill Road
Kenilworth, NJ 07033
Principal Investigator: Joseph A. Kovacs, MD
Critical Care Medicine Department (CCMD), NIH Clinical Center (CC)
Building 10 room 2C145
10 Center Drive
Bethesda, MD 20814
301-496-9907
jkovacs@mail.nih.gov 
Conducted by: CCMD, NIH CC and Laboratory of Immunoregulation (LIR), NIAID, NIH


Study Site:
NIH CC
10 Center Drive
Bethesda, MD 20814
NIH Review Board (IRB): 
Office of IRB Operations
Office of Intramural Research
National Institutes of Health
6700B Rockledge Drive, Suite 4300, 
Bethesda MD 20817


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Table of Contents
Table of Contents .............................................................................................................3
List of Tables ....................................................................................................................5
List of Appendices ............................................................................................................5
List of Abbreviations .........................................................................................................6
Protocol Summary ............................................................................................................8
Précis .............................................................................................................................10
1
Background Information and Scientific Rationale ................................................11
1.1
Background Information ....................................................................................11
1.2
Description of Pembrolizumab...........................................................................13
1.3
Scientific Rationale............................................................................................13
2
Study Objectives..................................................................................................15
2.1
Primary Objective ..............................................................................................15
2.2
Secondary Objective .........................................................................................15
2.3
Exploratory Objective ........................................................................................15
3
Study Design........................................................................................................15
3.1
Description of the Study Design ........................................................................15
3.2
Study Endpoints ................................................................................................16
3.2.1
Primary Endpoint.......................................................................................16
3.2.2
Secondary Endpoint..................................................................................16
4
Study Population..................................................................................................16
4.1
Recruitment Plan...............................................................................................16
4.2
Participant Inclusion Criteria..............................................................................17
4.3
Participant Exclusion Criteria.............................................................................19
4.4
Justification for Exclusion of Special Populations .............................................20
5
Study Agent/Interventions....................................................................................21
5.1
Disposition, Dispensation, and Accountability...................................................21
5.2
Formulation, Packaging, and Labeling ..............................................................21
5.3
Study Agent Storage and Stability.....................................................................21
5.4
Preparation, Administration, and Dosage of Study Agents ...............................21
5.5
Randomization and Blinding..............................................................................22
5.5.1
Emergency Unblinding..............................................................................22
5.6
Concomitant Medications and Procedures........................................................22
5.7
Prohibited Medications and Procedures............................................................23
5.8
Management of Study Drug-related AEs...........................................................23
6
Study Schedule....................................................................................................24
6.1
Screening (week −6 to 0) ..................................................................................24
6.2
Baseline (day 0).................................................................................................25
6.3
Follow-up (weeks 1-96) .....................................................................................25
6.4
Early Termination Visit.......................................................................................26
7
Research Procedures/Evaluations.......................................................................26
8
Potential Risks and Benefits ................................................................................27
8.1
Potential Risks...................................................................................................27
8.2
Potential Benefits...............................................................................................30
9
Research Use of Stored Human Samples, Specimens, or Data .........................30
10
Data Sharing Plan................................................................................................31


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11
Remuneration Plan for Participants .....................................................................32
12
Assessment of Safety ..........................................................................................32
12.1 Documenting, Recording, and Reporting Adverse Events ................................32
12.2 Investigator Assessment of Adverse Events .....................................................33
12.2.1
Severity .....................................................................................................33
12.2.2
Causality ...................................................................................................34
12.3 Investigator Reporting Responsibilities to the Sponsor.....................................35
12.3.1
Adverse Events.........................................................................................35
12.3.2
Reporting to the Sponsor’s Safety Office..................................................35
12.3.2.1
Serious Adverse Events ......................................................................35
12.3.2.2
Unanticipated Problems ......................................................................36
12.3.2.3
Events of Clinical Interest....................................................................36
12.3.2.4
Pregnancy ...........................................................................................37
12.3.3
Investigator Reporting Responsibilities to the NIAID IRB .........................37
12.4 Sponsor’s Reporting Responsibilities................................................................37
12.5 Halting Rules for the Protocol............................................................................38
12.5.1
Reporting a Study Halt..............................................................................38
12.5.2
Resumption of a Halted Study ..................................................................38
12.6 Withdrawal Criteria for an Individual Participant................................................38
12.7 Safety Oversight................................................................................................39
12.7.1
Safety Review and Communications Plan ................................................39
12.7.2
Sponsor Medical Monitor ..........................................................................39
12.7.3
Data and Safety Monitoring Board............................................................39
13
Site Monitoring Plan.............................................................................................40
14
Statistical Considerations.....................................................................................41
15
Ethics/Protection of Human Participants..............................................................42
15.1 Informed Consent Process................................................................................42
15.1.1
Ongoing Informed Consent.......................................................................43
15.2 Participant Confidentiality..................................................................................43
16
Data Handling and Record Keeping ....................................................................43
16.1 Data Capture and Management ........................................................................43
16.2 Record Retention...............................................................................................43
17
Scientific References ...........................................................................................45
Appendix A: Supportive Care Measures for Immune-mediated Adverse events and 
Infusion Reactions ..........................................................................................................47
Appendix B: Schedule of Procedures and Evaluations ..................................................50


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List of Tables
Table 1. Immune-mediated Adverse Reactions .............................................................29
Table 2. CTCAE Infusion Reaction Severity Grading Criteria ........................................34
Table 3. Probability of Observing Adverse Events .........................................................42
Table 4. Infusion Reaction Treatment Guidelines ..........................................................49
List of Appendices
Appendix A: Supportive Care Measures for Immune-mediated Adverse events and 
Infusion Reactions ..........................................................................................................45
Appendix B: Schedule of Procedures and Evaluations ..................................................48


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List of Abbreviations
ACTH
Adrenocorticotropic hormone
AE
Adverse event
ALT
Alanine transaminase
AR
Adverse reaction
ART
Antiretroviral therapy
ARV
Antiretroviral drug
AST
Aspartate transaminase
BTRIS
Biomedical Translational Research Information System
cART
Combined antiretroviral therapy
CBC/diff
Complete blood count with differential
CC
Clinical Center
CCMD
Clinical Care Medicine Department
CFR
United States Code of Federal Regulations
CRADA
Cooperative research and development agreement
CRIMSON
Clinical Research Information Management System of the NIAID
CSO
Clinical Safety Office
DAIDS
Division of AIDS
DCR
Division of Clinical Research
DM
Diabetes mellitus
DSMB
Data and safety monitoring board
ECI
Event of clinical interest
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HBS
Hepatitis B surface antigen
HBV
Hepatitis B
HCV
Hepatitis C
HIV
Human immunodeficiency virus
HRPP
Human Research Protections Program
HSV
Herpes simplex virus
ICH
International Council on Harmonisation
Ig
Immunoglobulin
IND
Investigational new drug
INR
Immunologic nonresponder
IRB
Institutional review board
IV
Intravenous(ly)
LIR
Laboratory of Immunoregulation
NCI
National Cancer Institute
NIAID
National Institute of Allergy and Infectious Diseases 
NIH
National Institutes of Health
NINDS
National Institute of Neurological Disorders and Stroke
OCD
Office of the Clinical Director
OCRPRO
Office of Clinical Research Policy and Regulatory Operations
OHRP
Office for Human Research Protections
OHSRP
Office of Human Subjects Research Protections


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PI
Principal investigator
PML
Progressive multifocal encephalopathy
SAE
Serious adverse event
SAR
Suspected adverse reaction
SERF
Safety expedited report form
SINS
Section of Infections of the Nervous System
SIV
Simian immunodeficiency virus
SRCP
Safety review and communications plan
SUSAR
Serious and unexpected suspected adverse reaction
SVR
Sustained virologic response
T4
Thyroxine
TB
Tuberculosis
Tfh
T follicular helper
TSH
Thyroid-stimulating hormone
ULN
Upper limit of normal
UP
Unanticipated problem
UPnonAE
Unanticipated problem that is not an adverse event
USP
United States Pharmacopeia
VZV
Varicella-zoster virus


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Protocol Summary
Short Title:
Pembrolizumab in HIV+ Patients
Clinical Phase:
I
Sample Size:
N = 20 
Accrual Ceiling:
N = 60
Study Population:
All participants are ≥ 18 years old, have human 
immunodeficiency virus (HIV) infection, are currently on a 
combined antiretroviral therapy (cART) regimen, and are 
immunologic non-responders (INRs), who have suppressed 
viremia (viral load < 40 copies/mL for at least 12 months 
before screening) and have been on a stable cART regimen 
for at least 4 weeks, but have a CD4+ T-cell count >100 
cells/mm3 and ≤ 350 cells/mm3.
Accrual Period:
2 years
Study Duration:
Start Date: January 2018
End Date: January 2022
Total length of individual participation: Up to 102 weeks
Study Design:
Randomized, double-blind, placebo-controlled study. 
Twenty HIV-infected patients with poor immunologic 
response will be randomized 3:1 to receive a single dose of 
either pembrolizumab or placebo and be followed for safety 
for 96 weeks. Blood will be drawn at each visit for research 
evaluations. Participants will undergo leukapheresis at 
screening (after confirmation of eligibility), with optional 
leukapheresis at weeks 3-4 and 12.
Study Agent/
Intervention Description: Pembrolizumab, 200 mg, or placebo via intravenous (IV) 
infusion, single dose.
Primary Objective:
To evaluate safety and tolerability of a single dose of 
pembrolizumab in people with HIV infection and poor 
immunologic response.


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Secondary Objective:
To evaluate the expression of PD-1 on CD4+ and CD8+ 
T cells following a single dose of pembrolizumab.
Primary Endpoint:
Frequency of either Grade 3 or higher adverse events or 
Grade 2 or higher autoimmune events requiring 
corticosteroid therapy that are possibly, probably, or 
definitely related to pembrolizumab. 
Secondary Endpoint:
Magnitude and duration of decreased expression of PD-1 
relative to baseline levels on lymphocytes. 


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Précis
A subset of HIV-infected patients, those with poor immunologic response to combined 
antiretroviral therapy (CD4+ T-cell count of less than 300-350 cells/mm3) despite control 
of viremia, are at increased risk for both HIV-related and non–HIV-related complications 
compared to immunologic responders. Thus, novel approaches for treating HIV infection 
are needed to facilitate management of this patient population.
One potential drug target for HIV treatment is the T-cell receptor PD-1. Binding of PD-1 
to its ligands, PD-L1 and PD-L2, inhibits proliferation of T cells and production of 
cytokines. This naturally serves to dampen potentially harmful excessive immune 
responses. Upregulation of PD-1 and/or its ligands can be observed in tumors and 
people with chronic viral infection, including HIV. This upregulation can inhibit T-cell 
immune surveillance, which may result in tumor growth or poor control of infection.
Pembrolizumab is an IgG4 kappa monoclonal antibody that binds to PD-1, thus blocking 
the receptor from binding with its ligands. In cancer indications, inhibition of PD-1 
induces an antitumor immune response, which in turn reduces tumor growth. The Food 
and Drug Administration has approved pembrolizumab for treatment of unresectable or 
metastatic melanoma, non–small cell lung cancer, head and neck squamous cell 
carcinoma, and other cancers. Similarly, in animal models of HIV and in vitro studies, 
PD-1 blockade was associated with a decrease in viral load and an increase in CD8+ 
T cells. A clinical trial to examine the effects of PD-1 inhibition by pembrolizumab on 
HIV infection is thus supported by the data.
The purpose of this study is to evaluate, in a randomized, double-blind, 
placebo-controlled study, the safety and tolerability of a single dose of pembrolizumab 
in HIV-infected participants who have controlled viremia with a low T-cell count (> 100 
cells/mm3 and ≤ 350 cells/mm3). Study participants will be followed for 96 weeks after 
receiving the study drug and will be assessed for adverse events, CD4+ and CD8+ 
T-cell counts, PD-1 expression, CD8+ T-cell anti-HIV activity, and viral load. If a single 
dose of pembrolizumab appears to be safe and tolerable, then larger multi-dose and 
efficacy studies can be planned.


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1
Background Information and Scientific Rationale
1.1
Background Information
Since 1981, an estimated 78 million people worldwide have become infected with 
human immunodeficiency virus (HIV) and an estimated 35 million people have died from 
HIV-related causes.1 Current estimates indicate that there are 37 million people living 
with HIV worldwide, with approximately 1 million deaths annually. Over the last 
2 decades there have been major advances in prevention, diagnosis, and treatment of 
HIV infection, including the development of well-tolerated antiretroviral drug (ARV) 
regimens, which have led to major improvements in survival and the quality of life in 
HIV-infected patients. Despite these advances, it is estimated that in the United States 
alone, there are approximately 1.2 million people infected with HIV, with approximately 
39,000 new infections diagnosed in 2015.2 Without treatment, the majority of people 
infected with HIV eventually develop AIDS. 
A subset of patients with poor immunologic response to cART are known as 
immunologic non-responders (INRs), who, despite having plasma viral load below 
detection limits of commercial assays for more than 1 year, nevertheless have a CD4+ 
T-cell count of less than 300-350 cells/mm3.3,4 Such patients are at increased risk for 
both HIV-related and non-HIV-related complications compared to immunologic 
responders, though they are at lower risk than patients with uncontrolled viremia.5-7 
Thus, novel approaches for treating HIV infection are needed to facilitate management 
of this patient population. 
Cell-mediated immunity appears critical to controlling HIV infection.8 Both CD4+ and 
CD8+ T cells play important roles in controlling infections by many intracellular 
pathogens, including viruses such as HIV.9 However, HIV avoids immune regulation by 
undermining T-cell control through effects on the function of both CD4+ and CD8+ 
T cells. HIV-specific CD8+ T-cell responses are a component of the immune response 
to HIV and appear to play an important role in the ability of the immune system to 
restrict viral replication. This is true even, as suggested by macaque studies, in the 
setting of effective cART.10 In most patients, however, the anti-HIV activity of CD8+ 
T cells is limited, allowing varying degrees of ongoing viral replication that leads to 
inevitable declines in CD4+ T cells. 
One potential contributor to this limited efficacy is the development of anergy, or 
exhaustion, of HIV-specific CD8+ T cells. This anergy is mediated in part by 
upregulation of surface-expressed co-inhibitory molecules such as PD-1, a member of 
the B7-CD28 family of co-signaling molecules. PD-1 can be expressed on CD4+ and 
CD8+ T cells, natural killer cells, B cells, and monocytes after activation. When PD-1 is 


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engaged by one of its ligand, PD-L1, in conjunction with T-cell receptor activation, it 
down-modulates T-cell proliferation and effector functions. During normal activity, this 
serves to dampen potentially harmful excessive immune responses, including 
autoimmunity. However, as initially demonstrated in animal models, during chronic viral 
infection (e.g., lymphocytic choriomeningitis virus), persistently high levels of PD-1 
expression are associated with poor control of infection, and blockade of the 
PD-1/PD-L1 interaction resulted in improved T-cell function and better viral control.11 
The potential role of PD-1 in HIV infection has been evaluated in vitro and in animal 
models. In a 2006 study, PD-1 was shown to be upregulated on HIV-specific CD8+ 
T cells compared to total or cytomegalovirus-specific CD8+ T cells, and expression 
levels inversely correlated with antigen-specific proliferation.12 Subsequent studies have 
confirmed this upregulation.13-16 In INRs, PD-1 expression has been reported to be 
increased on CD4+ but not CD8+ T cells.13,17 PD-1 also is a marker of T follicular helper 
(Tfh) cells, and Tfh cells appear to be a site of ongoing HIV transcription and a potential 
reservoir for active virus production in patients with controlled viremia who are on 
cART.18
In simian immunodeficiency virus (SIV)-infected macaques, PD-1 blockade using an 
anti-PD-1 antibody was associated with an expansion of SIV-specific CD8+ T cells, with 
improved functionality, decreased viral load, and improved survival.19 In a BLT 
humanized mouse model of HIV infection, PD-1 blockade was associated with a 
decrease in viral load and an increase in the percentage of CD8+ T cells in animals with 
high, but not low, PD-1 expression.20 In vitro PD-L1 blockade resulted in an increase of 
HIV-specific cytokine secretion by CD4+ cells, most prominently in cells from viremic 
individuals.21,22 In a small study of SIV-infected macaques who were taking cART, 
administration of a fully human anti-PD-L1 antibody (n = 3) was associated with a 
non-significant trend (p = 0.15) toward lower viral loads after discontinuation of cART 
compared to a control group that did not receive the antibody (n = 3).23 Administration of 
multiple doses of a primatized anti-PD-1 antibody to SIV-infected macaques during 
initiation of cART resulted in more rapid viral suppression, and administration while on 
cART resulted in up to an 80-fold reduction in SIV viral set point compared to pre-cART 
levels.24
A single study has treated HIV-infected patients with an antibody that interferes with 
PD-1/PD-L1 signaling.25 In ACTG A5326 (ClinicalTrials.gov identifier NCT02028403), 
originally designed as a dose-escalation study, patients on cART with CD4+ T-cell count 
greater than 350 cells/mm3 and HIV levels below detection limits for at least 2 years 
received a single dose of BMS 936559 (an anti-PD-L1 monoclonal antibody) or placebo. 
The study was stopped after the first (lowest dose) of a planned 4 cohorts had enrolled, 
because of the development of retinal toxicity in a 3-month animal study, although no 


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similar findings were seen in ACTG A5326. In 2 of 6 BMS 936559 recipients, an 
increase in gag-specific CD8+ T-cell responses was seen, though there was no 
significant increase in the 6 patients overall. No significant changes in HIV RNA or DNA 
levels were seen. The single dose was overall well tolerated; however, one patient 
developed apparent hypophysitis, manifested as hypoadrenalism and hypogonadism, 
approximately 9 months after dosing, which was determined to be consistent with an 
autoimmune event; this resolved 11 months after the initial diagnosis. 
1.2
Description of Pembrolizumab
Pembrolizumab is a potent and highly selective humanized monoclonal antibody 
(immunoglobulin [Ig] G4 kappa isotype) that binds with high affinity to the T-cell receptor 
PD-1, thus blocking it from interacting with its ligands, PD-L1 and PD-L2.26 In cancer 
indications, inhibition of PD-1 induces an antitumor immune response, which in turn 
reduces tumor growth.
Pembrolizumab is marketed in the United States as Keytruda™ by Merck & Co, Inc 
(Kenilworth, NJ). Keytruda was first approved by the Food and Drug Administration 
(FDA) for treatment of unresectable or metastatic melanoma in 2014.26 Approval for 
non–small cell lung cancer in tumors with high PD-L1 expression was granted in 2015, 
followed by approval in 2016 and 2017 for subsets of patients with head and neck 
squamous cell carcinoma, urothelial carcinoma, and microsatellite instability-high 
cancer. Infusions of pembrolizumab are generally well tolerated. However, in cancer 
patients, pembrolizumab therapy has been associated with the development of 
immune-related adverse reactions, most commonly pneumonitis, colitis, hepatitis, 
hypophysitis, nephritis, and thyroid disease (described in greater detail in Section 8.1).
For further background information on pembrolizumab (MK-3475), and approved 
prescription drug labeling, please refer to the Investigator’s Brochure.
1.3
Scientific Rationale
Upregulation of PD-1 is observed in CD4+ and CD8+ T cells in people with chronic viral 
infections, including HIV infection. This overexpression may contribute to persistent 
immune dysfunction. Inhibition of the interaction of PD-1 with its ligands, PD-L1 and 
PD-L2, can therefore potentially impede or reverse this dysfunction. A clinical trial to 
examine the immunologic and virologic effects of PD-1 inhibition by pembrolizumab is 
supported by available preclinical data. 
There are no published studies evaluating the safety and biologic effects of 
pembrolizumab in HIV-infected patients. Pembrolizumab is currently being studied in 
patients with HIV infection in one other clinical study, “Pembrolizumab in Treating 


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Patients with HIV and Relapsed, Refractory, or Disseminated Malignant Neoplasms” 
(NIH protocol 16-C-0066, ClinicalTrials.gov identifier NCT02595866), which is being 
conducted by intramural National Cancer Institute (NCI) investigators as well as other 
sites. The purpose of this study is to evaluate the safety and tolerability of 
pembrolizumab in people with both HIV infection (on a stable cART regimen with 
controlled viremia) and relapsed, refractory, or disseminated cancer. To date they have 
treated 17 patients with approximately 100 doses of pembrolizumab. Two patients 
developed hypothyroidism that was detected on routine screening. In addition, 2 
patients developed hepatotoxicity and 2 developed pneumonitis that were possibly 
immune-related toxicities and were treated with corticosteroids, though tumor burdens 
at the site of toxicity complicated this assessment. 
Intramural investigators at NINDS have also administered pembrolizumab to 2 patients 
with HIV-associated progressive multifocal leukoencephalopathy. In both patients, the 
infusions were well tolerated. One patient experienced a mild transient increase in 
subjective progressive multifocal encephalopathy (PML) symptoms that were 
associated with magnetic resonance imaging changes suggesting increased immune 
response in the areas of the PML lesions; symptoms resolved after approximately 1 
week. 
Given the demonstrated, presumably immune-based clinical activity of pembrolizumab 
seen in cancer patients, and the potential role of PD-1 in impairing control of HIV 
infection, a clinical trial of pembrolizumab in HIV-infected patients who do not have 
cancer is warranted. The current study will focus on the safety of a single dose of 
pembrolizumab and will enroll patients who have controlled viremia but poor 
immunologic response (CD4+ T cells > 100 cells/mm3 ≤ 350 cells/mm3), since they are 
at greater risk for HIV-related disease progression than well-controlled patients with 
greater numbers of CD4+ T cells. If a single dose of pembrolizumab appears to be safe 
and tolerable for this population, then larger multi-dose and efficacy studies can be 
undertaken either as an amendment to the current protocol or as new protocols. We will 
also examine the duration of downregulation of PD-1 expression on CD4+ and CD8+ T 
cells, to explore if dosing less frequently than every 3 weeks (which is currently utilized 
in cancer studies) may be sufficient to maintain downregulation of PD-1 on these cells.  
2
Study Objectives
2.1
Primary Objective
To evaluate safety and tolerability of a single dose of pembrolizumab in people with HIV 
infection and poor immunologic response.


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2.2
Secondary Objective
To evaluate the expression of PD-1 on CD4+ and CD8+ T cells following a single dose 
of pembrolizumab.
2.3
Exploratory Objective
To evaluate changes in T lymphocyte subsets, HIV plasma viral load, cell-associated 
HIV RNA and DNA levels, plasma cytokine, chemokine, and other biomarker levels, and 
CD8 anti-HIV activity following a single dose of pembrolizumab. 
3
Study Design
3.1
Description of the Study Design
Twenty adults (≥ 18 years) with HIV infection will be enrolled. Eligible participants will be 
INRs, with a recent CD4+ T-cell count >100 cells/mm3 and ≤ 350 cells/mm3, who have 
been on a cART regimen for at least 12 months and on a stable regimen for at least 
4 weeks and have evidence of viral suppression.
Participants will be randomized 3:1 to receive either a single 200-mg dose of 
pembrolizumab or placebo via IV infusion at baseline. The dosage is based on the 
recommendation of Merck investigators and is the dose currently recommended on their 
product label. Inclusion of a placebo group will allow a blinded assessment of adverse 
events (AEs) and provide a control group with which to compare PD-1 expression levels 
over time. Participants will return for follow-up visits at weeks 1, 2, 3, 4, 6, 9, 12, 16, 24, 
36, and 48, and will have phone calls with the study team at weeks 60, 72, 84, and 96. 
Blood will be collected at every visit for clinical and research evaluations. Participants 
will undergo leukapheresis at screening (after confirmation of eligibility) with optional 
leukapheresis at week 3 or 4 and week 12. 
Five participants will be enrolled initially and followed for 90 days for safety 
outcomes. No additional participants will be enrolled until the DSMB has 
reviewed the 90-day safety data and recommended that the protocol can resume 
enrollment. 
3.2
Study Endpoints
3.2.1 Primary Endpoint
Frequency of either Grade 3 or higher AEs or Grade 2 or higher autoimmune events 
requiring corticosteroid therapy that are possibly, probably, or definitely related to 
pembrolizumab.


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3.2.2 Secondary Endpoint
Magnitude and duration of decreased expression of PD-1 relative to baseline levels on 
lymphocytes.
4
Study Population
4.1
Recruitment Plan
Participants will be recruited from existing NIH protocols/cohorts, e.g., protocols 
09-I-0013 “Biomarkers of Inflammation, Coagulation, and Endothelial Function in HIV-
infected Adults “and 09-I-0030 “Clinical and Immunologic Monitoring of Patients with 
Known or Suspected HIV Infection,” as well as locally and nationally from HIV care 
providers and clinics. We will use the OP8 Clinic recruitment strategies that are in place 
and include a full-time patient recruiter and community-based outreach within local area 
clinics specializing in HIV. Additional recruitment may be done using IRB-approved 
internet ad campaigns, social media outlets, print ads, and direct mailings to infectious 
disease physicians and HIV clinics.
Recruitment of NIH employees: NIH employees and members of their immediate 
families may participate in this protocol. We will follow the Guidelines for the Inclusion of 
Employees in NIH Research Studies and will give each employee a copy of the “NIH 
Information Sheet on Employee Research Participation.”
For NIH employees:

NIH staff may be a vulnerable class of participants.

Neither participation nor refusal to participate will have an effect, either beneficial 
or adverse, on the participant’s employment or work situation.

The NIH information sheet regarding NIH employee research participation will be 
distributed to all potential participants who are NIH employees.

The employee participant’s privacy and confidentiality will be preserved in 
accordance with NIH CC and NIAID policies, which define the scope and 
limitations of the protections.

For NIH employee participants, consent will be obtained by an individual 
independent of the employee’s team. Those in a supervisory position to any 
employee and co-workers of the employee will not obtain consent.

The importance of maintaining confidentiality when obtaining potentially sensitive 
and private information from co-workers or subordinates will be reviewed with the 
study staff at least annually and more often if warranted.


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4.2
Participant Inclusion Criteria
Individuals must meet all of the following criteria to be eligible for study participation:
1. ≥ 18 years of age.
2. Documented HIV-1 infection (e.g., positive standard enzyme-linked 
immunosorbent assay or rapid HIV-1/HIV-2 antibody test with a confirmatory test 
such as western blot, or documentation of repeated HIV RNA of 
> 1000 copies/mL). Outside documentation will be acceptable. 
3. Absolute neutrophil count > 1000/µL.
4. Platelet count > 125,000/µL.
5. Hemoglobin > 10 g/dL.
6. Aspartate transaminase (AST) and alanine transaminase (ALT) < 1.1 times the 
upper limit of normal (ULN). Total bilirubin < 1.1 x ULN (unless participant is 
taking atazanavir or has Gilbert syndrome).
7. Calculated creatinine clearance (estimated glomerular filtration 
rate) ≥ 60 mL/min/1.73 m2.
8. Thyroid-stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) 
within normal limits. If TSH is not within normal limits, then the participant may be 
eligible if thyroxine (T4) is within normal limits. Participants will not be excluded if 
they are on a stable dose of replacement thyroid medication; dose may be 
adjusted as needed.
9. No significant underlying pulmonary, cardiac, renal, or hepatic disease, as 
defined by a need for drug treatment or ongoing physician care.
10.Under the care of a primary care physician.
11.Willing to comply with study requirements and procedures including storage of 
biological specimens for future use in medical research.
12.Willing to allow genetic testing.
13.Able to provide informed consent.
14.Participants of reproductive potential must agree to not become pregnant or to 
impregnate a partner beginning 30 days before the dose of pembrolizumab 
through 120 days postdose. Non-reproductive potential is defined as 
azoospermia, postmenopausal, surgical sterilization at least 6 weeks before 
screening, or a congenital or acquired condition that definitively prevents 
conception. Further, postmenopausal is defined as at least 12 consecutive 
months with no menses at age 50 or older, and also a high follicle-stimulating 
hormone level in postmenopausal range at ages 45-50 years, for participants not 
using hormonal contraception or hormone replacement therapy.
Participants of reproductive potential must either practice complete and 
uninterrupted abstinence from heterosexual activity or use two of the following 


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methods of contraception with their partners. The 2 methods must include one 
from each group, both of which must be consistently use:
Barrier methods:
a. Diaphragm with spermicide (cannot be used in conjunction with cervical 
cap/spermicide).
b. Cervical cap with spermicide (only for nulliparous partners).
c. Contraceptive sponge (only for nulliparous partners).
d. Male or female condom (cannot be used together).
Non-barrier methods:
a. Intrauterine device.
b. Hormonal contraception: pill (estrogen/progestin or progestin-only), skin 
patch, vaginal ring, rod implanted in the skin, or subcutaneous injection.
15.Participants must meet criteria for INR, defined as follows: 
a. Has been on a cART regimen for at least 12 months and on a stable 
regimen for at least 4 weeks.
b. Has evidence of viral suppression, defined as viral load < 40 copies/mL, 
and documented suppression for at least 12 months prior to screening. A 
viral load of < 500 copies/mL once in the year preceding screening will be 
allowed if there is documentation of a viral load < 40 copies/mL on 
subsequent testing and at screening.
c. CD4+ T-cell count > 100 cells/mm3 and ≤ 350 cells/mm3.
4.3
Participant Exclusion Criteria
Individuals meeting any of the following criteria will be excluded from study participation:
1. Has used an investigational drug agent or investigational device within 12 weeks 
of baseline. However, ARVs obtained through expanded access programs are 
permitted.
2. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent.
3. Known allergy to any component of the pembrolizumab formulation.
4. Systemic steroid therapy or other immunosuppressive therapy in the 3 months 
prior to enrollment. (Inhaled or topical corticosteroids are permitted.)
5. Has used an immunotherapeutic agent (e.g., cyclosporine, tacrolimus, 
mycophenolate mofetil, azathioprine, sirolimus, therapies targeting tumor 
necrosis factor-α) within 6 months of baseline.
6. Has received any vaccine, live or inactivated, within 30 days of baseline, or plans 
to receive any vaccine within 16 weeks of receiving pembrolizumab. 
7. Has active autoimmune disease or a history of autoimmune disease that has 
required systemic treatment (e.g., with use of disease-modifying agents, 


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corticosteroids, or immunosuppressive drugs). Such autoimmune diseases 
include for example psoriasis, systemic lupus erythematosus, autoimmune 
uveitis, autoimmune hepatitis, inflammatory colitis, rheumatoid arthritis, 
Guillain-Barré syndrome, Stevens-Johnson syndrome, or toxic epidermal 
necrolysis. Replacement therapy (e.g., T4) is not considered a form of systemic 
treatment. 
8. Has known history of, or any evidence of active, non-infectious pneumonitis.
9. Malignancy requiring systemic therapy, or a history of malignancy that required 
systemic therapy within the past 5 years. However, cutaneous basal cell 
carcinoma or cutaneous Kaposi sarcoma not requiring systemic therapy will not 
be exclusionary.
10.Has known active hepatitis B (HBV) or potential for HBV reactivation 
(e.g., hepatitis B surface antigen [HBS] reactive, HBV DNA positive, or isolated 
anti-core antibody positive; individuals who are anti-HBS antibody positive with or 
without anti-core Ab are eligible).
11.Has known active hepatitis C (HCV; e.g., HCV RNA [qualitative] is detected). 
Patients who have sustained virologic response (SVR) to anti-HCV treatment are 
eligible if at least 24 weeks have passed since achieving SVR.
12.Females who are pregnant, planning to become pregnant, or are breastfeeding. 
13.Has known psychiatric or substance abuse disorders that would interfere with 
cooperation with the requirements of the study.
14.History or other clinical evidence of: 
a. Significant or unstable cardiac disease (e.g., angina, congestive heart 
failure, myocardial infarction).
b. Significant pulmonary disease (e.g., chronic obstructive pulmonary 
disease, asthma requiring systemic therapy).
c. Severe illness, chronic liver disease, malignancy, immunodeficiency other 
than HIV, active systemic infection (other than HIV) requiring therapy. 
15.Opportunistic infection requiring maintenance therapy, including toxoplasmosis, 
fungal infections other than candida (e.g., cryptococcosis, histoplasmosis, 
coccidioidomycosis), atypical mycobacterial infection. Secondary Pneumocystis, 
candida, varicella-zoster virus (VZV), and herpes simplex virus (HSV) 
prophylaxis will be permitted.  
16.Active or history of tuberculosis (TB), or positive TB QuantiFERON Gold test. 
17.Known osteoporosis or diabetes mellitus. 
18.Hemoglobin A1c > 6%.
19.Fasting triglyceride > 300 mg/dL.
20.Any condition that, in the opinion of the investigator, would make the participant 
unsuitable for the study.  


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Co-enrollment guidelines: Co-enrollment in other trials is restricted, other than 
enrollment on observational studies or expanded access studies for antiretroviral 
agents, during the first 48 weeks of the study. If NIH blood volume limits are exceeded 
due to the requirements of the combined studies, then co-enrollment will not be 
permitted.
4.4
Justification for Exclusion of Special Populations
Females who are pregnant or of reproductive potential: Dedicated developmental 
and fetal toxicity studies of pembrolizumab have not been conducted in humans or 
animals. However, animal models of the PD-1/PD-L1 pathway suggest that 
perturbations may affect the maternal immune response to fetal tissue. Human IgG4 
antibodies (the IgG subtype of pembrolizumab) are also known to cross the placental 
barrier and be transmitted from mother to fetus. Additionally, pregnancy may affect the 
participant’s immune response. Therefore, pregnant participants are excluded from this 
study. Per recommendations in the pembrolizumab package insert, contraception (for 
this study, two forms, one of which must be a barrier-based method, see Section 4.2) 
will be required from 30 days prior through 120 days after the pembrolizumab dose.
Breastfeeding: It is unknown whether pembrolizumab is excreted in human milk. Since 
many drugs are excreted in human milk, and because of the potential for serious 
adverse reactions (ARs) in the nursing infant, participants who are breast-feeding are 
not eligible for enrollment. 
Exclusion of children: Because there are insufficient data regarding dosing or AEs 
available in adults to judge the potential risk in children, and because this is the first 
safety study in HIV-infected patients without cancer, children are excluded from this 
study.
5
Study Agent/Interventions
5.1
Disposition, Dispensation, and Accountability
Study agent or placebo will be distributed and accounted for by the NIH pharmacy 
according to standard pharmacy procedures.
5.2
Formulation, Packaging, and Labeling
Each pembrolizumab ready-for-injection vial will be further diluted according to the 
manufacturer’s label instructions and administered as an IV infusion to the study 
subject. Each IV infusion bag for both study agent and placebo will be individually 
labeled with the subject ID number, administration instructions, and the Investigational 


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Use Statement (“Caution: New Drug-Limited by Federal [USA] Law to Investigational 
Use’).  
5.3
Study Agent Storage and Stability
Vials of pembrolizumab injection solution should be stored at 2°C-8°C and should not 
be shaken or frozen. Vials should be kept in their cartons and protected from light. 
Diluted study drug may be stored at 2°C-8°C for up to 24 hours, or room temperature 
(approximately 22°C) for up to 6 hours.
5.4
Preparation, Administration, and Dosage of Study Agents
Pembrolizumab is provided as a ready-for-injection solution at 100 mg/4 mL and should 
be further diluted for administration.
Participants will receive a single 200-mg dose of pembrolizumab in 5% dextrose or 
placebo (matching diluent). To maintain the double-blind, pembrolizumab and placebo 
infusions should be prepared in matching diluent solutions and administered in the 
same manner (please see administration instructions below).
Preparation: When preparing pembrolizumab, allow the required number of vials to 
equilibrate to room temperature. For IV infusion, the study drug should be diluted to a 
final concentration between 1 and 10 mg/mL in 5% dextrose solution for injection, USP. 
The placebo will be an equivalent volume of 5% dextrose solution for injection, USP.
In the event of a diluent shortage, 0.9% sodium chloride solution may be used in place 
of 5% dextrose to prepare pembrolizumab and placebo infusions. 
Administration: Pembrolizumab and placebo infusion should be administered over 30 
minutes through an IV line containing a sterile, non-pyrogenic, low-protein-binding 
0.2-5–µm in-line or add-on filter. Pembrolizumab should not be co-administered with 
other drugs in the same infusion line.
5.5
Randomization and Blinding
Eligible participants will be allocated 3:1 to study agent or placebo. A randomization 
scheme will be generated by the study statistician who will provide a randomized list of 
arm assignments to the NIH CC Pharmacy. Block randomization will be designed to 
ensure that some participants among the first 5 enrolled will receive pembrolizumab. 
Study participants and the study team will be blinded through week 16 of the last 
participant treated. 


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5.5.1 Emergency Unblinding 
If a participant experiences an AE whose management (e.g., diagnostic procedures, 
treatment) in the opinion of the principal investigator (PI) or designee would differ 
depending on the study arm, or in the case of pregnancy of a participant’s partner, then 
the PI or designee will contact the NIH CC Pharmacy for release of the randomization 
code. The sponsor and data and safety monitoring board (DSMB) executive secretary 
will be informed within 1 business day of any request for unblinding. The participant will 
remain enrolled in the study and the data will be used for analysis.
5.6
Concomitant Medications and Procedures
All concomitant medications, including those received within 28 days before the 
administration of pembrolizumab, will be recorded in the Clinical Research Information 
Management System of the NIAID (CRIMSON), including all prescription, 
over-the-counter, herbal supplements, and IV medications and fluids. For this protocol, 
a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. If changes occur during the study period, then 
documentation of drug dosage, frequency, route, and date may also be included in 
CRIMSON.
5.7
Prohibited Medications and Procedures
Treatment with systemic corticosteroids, other immunomodulatory drugs, or other drugs 
targeting PD-1, PD-L1, or PD-L2 will not be permitted during the first 48 weeks of the 
study except as summarized below, unless discussed with and approved by the PI or 
designee.
Participants are prohibited from receiving the following therapies during the first 48 
weeks of the study:

Immunotherapy not specified in this protocol (e.g., cyclosporine, tacrolimus, 
mycophenolate mofetil, azathioprine, sirolimus, therapies targeting tumor 
necrosis factor-α).

Investigational agents other than pembrolizumab or expanded access ARVs.

Any vaccine within 30 days pre-dose and through week 16, and live vaccines 
through week 48 in this study. Examples of live vaccines include, but are not 
limited to, the following: measles, mumps, rubella, varicella/zoster, yellow fever, 
rabies, Bacillus Calmette–Guérin, and typhoid. 
Note: Seasonal influenza vaccines for injection are generally inactivated flu 
vaccines and are allowed after week 16; however intranasal influenza vaccines 
(e.g., Flu-Mist®) are live attenuated vaccines, and are not allowed.


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
Systemic corticosteroids for any purpose other than to modulate symptoms from 
an event of clinical interest (ECI) of suspected immunologic etiology. 
Participants who, in the assessment of the investigator, require the use of any of the 
aforementioned treatments for clinical management after receiving the single dose of 
pembrolizumab will continue to be followed in the study. Participants may receive other 
medications that the investigator deems to be medically necessary.
5.8
Management of Study Drug-related AEs
In the event of AEs related to the study drug, participants will receive appropriate 
supportive care measures as deemed necessary by the treating investigator. Given that 
management may depend on knowledge of the underlying treatment arm, as noted 
above, the PI or designee may unblind (see emergency procedure for unblinding) to 
ensure that the diagnostic evaluations and therapeutic interventions are directed 
appropriately. Suggested supportive care measures for the management of 
pembrolizumab-related AEs with potential immunologic etiology are outlined in 
Appendix A. Where appropriate, these guidelines include the use of oral or IV treatment 
with corticosteroids as well as additional anti-inflammatory agents if symptoms do not 
improve with administration of corticosteroids. Note that several courses of steroid 
tapering may be necessary as symptoms may worsen when the steroid dose is 
decreased. For each disorder, attempts should be made to rule out other causes such 
as bacterial or viral infection, which might require additional supportive care. The 
treatment guidelines are intended to be applied when the investigator determines the 
events to be related to pembrolizumab. 
Note: if after the evaluation, the event is determined not to be related, the investigator 
does not need to follow the treatment guidance (as outlined in Appendix A). 
It may be necessary to perform conditional procedures such as bronchoscopy, 
endoscopy, or skin photography as part of standard clinical evaluation of the event. 
6
Study Schedule
NOTE:  Five participants will be enrolled initially and followed for 90 days for 
safety outcomes. No additional participants will be enrolled until the DSMB has 
reviewed the 90-day safety data and recommended that the protocol can resume 
enrollment. 
All study visits will be done at the NIH CC. A table of the study schedule is presented in 
Appendix B. 


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6.1
Screening (week −6 to 0)
The participant will sign the informed consent form for this study before undergoing any 
procedure or evaluation. Screening procedures/evaluations to determine eligibility for 
this study are listed below. These procedures may occur over more than 1 visit.

Physical exam with vital signs.

Review medical and medication history, including past and current ART 
regimens.

For participants of reproductive potential, counseling concerning the importance 
of consistently using two forms of effective birth control in light of the potential 
risk of pembrolizumab to a developing fetus.

Blood draw for clinical lab evaluations: complete blood count with differential 
(CBC/diff), prothrombin/partial thromboplastin time, chemistry panels (acute, 
hepatic, and mineral), lipid panel, TSH and T4, ACTH, cortisol, hemoglobin A1c, 
TB QuantiFERON Gold, HIV serology (if not previously documented at NIH), 
plasma HIV viral load, immune profile including CD4 count, HBV testing (DNA, 
surface antigen, and antibody), and HCV testing (RNA and antibody).

Urinalysis.

Pregnancy test (serum or urine, for participants of childbearing potential only).

Electrocardiogram.

HLA typing (unless previously performed at NIH).

Collection of cells/serum/plasma for research and stored samples.

Leukapheresis to store cells for research studies, after eligibility is confirmed. If 
leukapheresis cannot be performed for technical or other reasons (e.g., poor 
venous access or other contraindication to the procedure), then an additional 
80 mL of blood will be drawn.
6.2
Baseline (day 0)

At baseline, blood for baseline safety and research labs will be drawn. For 
participants of childbearing potential only, pregnancy test (serum or urine) will be 
obtained, 

For participants of reproductive potential, counseling concerning the importance 
of consistently using two forms of effective birth control in light of the potential 
risk of pembrolizumab to a developing fetus.
Participants will be randomized and will receive either a single 200-mg dose of 
pembrolizumab or placebo via IV infusion. The infusion will be administered over at 
least 30 minutes, and the participant will be monitored throughout and for 2 hours after 
for any signs of infusion or allergic reactions. Infusion-related reactions will be managed 


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as summarized in Appendix A. If the infusion is discontinued due to an infusion-related 
reaction, it will not be resumed. 
6.3
Follow-up (weeks 1-96)
Participants will return for follow-up visits at weeks 1, 2, 3, 4, 6, 9, 12, 16, 24, 36, and 
48. All visits through week 6 will have a window of ± 4 days; visits from week 9 onward 
will have a window of ± 7 days. At all visits, participants will have the following:

Review of medical and medication history.

Targeted physical exam, including weight, vital signs, and a symptom-directed 
evaluation.

Assessment of AEs.

For participants of reproductive potential, counseling concerning the importance 
of consistently using two forms of effective birth control in light of the potential 
risk of pembrolizumab to a developing fetus.

Blood draw for clinical and research evaluations (see Section 7).

Pregnancy test (serum or urine, for participants of childbearing potential only).

Optional follow-up leukapheresis at weeks 3 or 4 and 12. Refusal to undergo 
leukapheresis will not otherwise affect participation in the study. 
Follow-up telephone calls at weeks 60, 72, 84, and 96 (± 2 weeks) will be conducted to 
see if any AEs potentially related to pembrolizumab occurred during the prior 12 weeks. 
Participation in this study will end after the week 96 call.  
6.4
Early Termination Visit
Participants who leave the study before week 48 (the final scheduled visit to the NIH), 
voluntarily or otherwise, will be urged to return to the NIH CC for an early termination 
visit. As with the follow-up visits, participants will have a physical exam, have their 
medical and medication history reviewed, be assessed for AEs, and have blood drawn 
for clinical and research evaluations. If a participant decides to leave the study between 
weeks 48 and 96, then the telephone call follow-up will be conducted at that time, with 
the participant’s agreement.  
7
Research Procedures/Evaluations
Medical history and physical exam.
Blood draw: The amount of blood drawn for research purposes will be within the limits 
allowed for adult research participants by the NIH CC (Medical Administrative Policy 


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95-9, Guidelines for Limits of Blood Drawn for Research Purposes in the Clinical 
Center: http://cc-internal.cc.nih.gov/policies/PDF/M95-9.pdf).
Safety labs at each visit will include CBC/diff, chemistry panels (acute, hepatic, and 
mineral), lipid panel, TSH and T4, ACTH, cortisol, plasma HIV viral load, and immune 
profile including CD4 count.
Research evaluations on blood and/or leukapheresis will include the following:

Fluorescence-activated cell sorting analysis, including CD4+ and CD8+ 
populations and subsets, and PD-1 expression on CD4+ and CD8+ T cells.

Assays to measure CD8+ T-cell anti-HIV activity.
Other research evaluations may include but are not limited to the following:

Frequency of CD4+ T cells carrying HIV pro-viral DNA and cell-associated HIV 
RNA.

Frequency of HIV-specific CD4+ and CD8+ T cells.

T-cell activation and soluble markers of inflammation.

Gene expression profiling of T cells.

Antibodies to HIV-specific and other proteins using the luciferase 
immunoprecipitation system assay.

Cell-associated p24 antigen levels (to be performed at Merck).

Plasma levels of pembrolizumab (to be performed at Merck).
Leukapheresis: Leukapheresis will be performed by trained members of the Apheresis 
Unit under supervision of the medical staff of the Department of Transfusion Medicine at 
the NIH CC according to CC standard operating procedures. If leukapheresis cannot be 
performed for technical reasons (eg, poor venous access) or due to scheduling or 
logistical issues, then 80 mL of blood will be drawn instead. Samples collected from this 
procedure will be used for assays to measure CD8+ T-cell anti-HIV activity and may be 
utilized for research evaluations as summarized above.
8
Potential Risks and Benefits
8.1
Potential Risks
Pembrolizumab 26: The clinical safety profile of pembrolizumab is based on studies 
conducted exclusively in patients with a variety of cancers, the majority with melanoma 
and non–small cell lung cancer; many of these patients had received prior 
chemotherapy as well as other immunomodulatory drugs, and most patients received 
multiple doses of pembrolizumab, with dosing every 2 to 3 weeks. Thus, it is currently 


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unknown if, and with what frequency, the AEs seen in these patient populations will 
occur in HIV-infected patients.  
The most commonly reported AEs of pembrolizumab (> 5% of patients) are fatigue, 
fever, pruritus, diarrhea, nausea, vomiting, decreased appetite, rash, dyspnea, 
constipation, asthenia, arthralgia, back pain, cough, headache, peripheral edema, 
anemia, myalgias, and vitiligo. Other AEs include chills, constipation, abdominal pain, 
dizziness, insomnia, upper respiratory tract infection, and laboratory abnormalities 
including increased ALT and AST, hyperglycemia, hyponatremia, hypoalbuminemia, 
and hypertriglyceridemia.
Pembrolizumab inhibits an immune checkpoint, and thus there is the potential for 
development of immune-related complications. Treatment-emergent immune-mediated 
diseases have been observed in cancer trials, and include pneumonitis, colitis, hepatitis, 
hypophysitis, thyroid disorders (hyper- and hypothyroidism, and thyroiditis), type 1 
diabetes mellitus (DM), and nephritis and renal dysfunction (Table 1).27 Rare potentially 
immune-mediated diseases include uveitis (0.5%) and other ocular disorders, myositis 
(0.5%), pancreatitis (0.3%), arthritis (1.5%), and Guillain-Barre syndrome (0.1%). There 
have been rare reports of primary adrenal insufficiency, hypoparathyroidism, 
myasthenia gravis, vasculitis, hemolytic anemia, autoimmune thrombocytopenia, 
hemophagocytic lymphohistiocytosis, systemic inflammatory response syndrome, 
histiocytic necrotizing lymphadenitis, sarcoidosis, gastritis, duodenitis, polymyalgia 
rheumatica, meningitis, myelitis, encephalitis and other neurologic disorders, 
pericarditis, myocarditis, some of which have been fatal, as well as severe skin 
reactions including Stevens-Johnson syndrome, toxic epidermal necrolysis (some cases 
with fatal outcome), exfoliative dermatitis, and bullous pemphigoid. Onset of immune-
mediated complications typically occurred between 1 and 5 months, though onset has 
been reported as early as 1 day and as late as 21 months after initiation of 
pembrolizumab, and can occur after discontinuation of the drug.27 Management 
(Appendix A) includes treating with corticosteroids (e.g., prednisone, 1-2 mg/kg/day 
followed by a taper); hypothyroidism may be treated with levothyroxine. Very rarely, 
immune-mediated pneumonitis has been fatal. 
Of the 2799 patients treated with pembrolizumab in the Merck Reference Safety 
Dataset, there were 10 deaths attributed to the drug: respiratory failure (n = 1), 
cardio-respiratory arrest (n = 1), interstitial lung disease (n = 1), general physical health 
deterioration (n = 1), myocardial infarction (n = 1), pneumonia (n = 2), and pneumonitis 
(n = 3).27


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Table 1. Immune-mediated Adverse Reactions
Adverse Reaction
All Grades 
(%)
Grade 2 
(%)
Grade 3 
(%)
Grade 4 
(%)
Grade 5 
(%)
Hypothyroidism
8.5
6.2
0.1
0
0
Hyperthyroidism
3.4
0.8
0.1
0
0
Pneumonitis
3.4
1.3
0.9
0.3
0.1
Colitis
1.7
0.4
1.1
< 0.1
0
Hepatitis
0.7
0.1
0.4
< 0.1
0
Hypophysitis
0.6
0.2
0.3
< 0.1
0
Nephritis
0.3
0.1
0.1
< 0.1
0
Type 1 diabetes 
mellitus
0.2
< 0.1
0.1
0.1
0
Pembrolizumab dose = 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. 
n = 2799.
Anti-pembrolizumab antibodies can potentially develop with treatment since 
pembrolizumab is a monoclonal antibody. In clinical studies, the incidence of 
development of anti-pembrolizumab antibodies was 2% of 1289 evaluable patients.27 
The clinical significance of these antibodies is uncertain. There is also the risk of allergic 
or anaphylactic reactions. Infusion-related reactions reported in other clinical trials 
include rigors, chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and 
fever, with an overall incidence of 2.5%.27 In this study, all participants will be monitored 
during and for 2 hours after infusion so these potential reactions can be immediately 
cared for.
There may be other risks of pembrolizumab that are currently unknown.
Leukapheresis: The potential risks associated with leukapheresis include 
lightheadedness, dizziness, possible fainting, tingling around the mouth and in the 
fingers and toes, nausea, chills, vomiting, mild muscle cramps, loss of less than 1 pint of 
blood, or pain, bruising, or discomfort at the needle insertion sites. Most procedures are 
performed without an incident. Blood components removed during leukapheresis are 
generally replaced by the body within a few hours or a few days. No infections 


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associated with this procedure have been reported in thousands of cases performed 
over the last 10 years at the NIH.
Temporary or permanent nerve damage may also occur at the needle placement sites. 
This is very rare. There have been no cases of permanent nerve damage with 
apheresis reported at the NIH.
Blood draw and IV catheter: The risks of drawing blood or inserting an IV catheter for 
study drug/placebo infusion include pain, bruising, bleeding, and, rarely, fainting or 
infection.
HLA typing: HLA typing will be performed on samples collected from all enrolled 
participants, unless previously performed at NIH. Results from the HLA typing will 
become part of each participant’s medical record at the NIH. Medical records containing 
this information are maintained in a secure place. Some HLA types have been 
associated with an increased risk of certain diseases like arthritis and other 
rheumatologic disorders, or a faster progression to AIDS. Therefore, results of genetic 
testing may have psychological implications for participants. Genetic counseling and 
advice is available from the NIH to help participants with the implications of findings, 
where appropriate.
8.2
Potential Benefits
Participants will likely not receive direct benefit in this study. It is possible that 
pembrolizumab may result in temporary improvement in anti-HIV host immunity. The 
information collected in this study may enhance the investigators’ understanding of the 
use of pembrolizumab as an immunomodulatory drug for treating HIV infection.
9
Research Use of Stored Human Samples, Specimens, or Data
Intended Use: Samples, specimens, and data collected under this protocol will be used 
to study the potential role of pembrolizumab for treatment of HIV infection and may be 
used to study immune function and immune mechanisms, HIV infection and its 
complications, and HIV immunopathogenesis.  
Storage: All of the stored study research samples are labeled by a code that only the 
investigators can link to the participant. Samples are stored at the NCI at Frederick 
Central Repository, which is a secure facility with limited access. Data will be kept in 
password-protected computers. Only investigators or their designees will have access 
to the samples and data. 


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Tracking: Samples will be tracked using the NCI at Frederick Central Repository. Data 
will be stored and maintained in the CRIMSON database. 
Disposition at the Completion of the Protocol:

In the future, other investigators (both at NIH and outside) may wish to study 
these samples and/or data. Before any sharing of samples, data, or clinical 
information, either IRB approval must be obtained or the NIH Office of Human 
Subjects Research Protections (OHSRP) must determine that the research is 
exempt from IRB oversight. OHSRP can make this determination for some 
research where the samples or data have no personal identifying information 
about the study participant and the researcher is not able to ascertain it.

At the time of protocol termination, samples will either be destroyed, or after IRB 
approval, transferred to another existing protocol. Data will be archived by the 
study team in compliance with requirements for retention of research records; 
alternatively, after IRB and study sponsor approval, the data may be either 
destroyed or transferred to another repository.
Reporting the Loss or Destruction of Samples/Specimens/Data to the IRB:

Any loss or unanticipated destruction of samples (for example, due to freezer 
malfunction) or data (for example, misplacing a printout of data with identifiers) 
that meets the definition of protocol deviation, unanticipated problem (UP), and/or 
compromises the scientific integrity of the data collected for the study will be 
reported to the NIAID IRB. 

Additionally, participants may decide at any point not to have their samples 
stored. In this case, the PI will destroy all known remaining samples and report 
what was done to both the participant and to the IRB. This decision will not affect 
the individual’s participation in this protocol or any other protocols at NIH.
10
Data Sharing Plan
Human data generated in this study will be shared for future research as follows:

Identified data in the Biomedical Translational Research Information System 
(BTRIS; automatic for activities in the CC).

De-identified or identified data with approved outside collaborators under 
appropriate agreements.

Through publication and/or public presentations.

Data sharing may be complicated or limited in certain cases by contractual 
obligations or agreements with outside collaborators, such as a cooperative 


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research and development agreements, clinical trial agreements, other restraints, 
etc.
Data will be shared at the time of publication.
11 Remuneration Plan for Participants
Eligible participants will be compensated for travel according to the NIAID/NIH travel 
policy. Participants will receive financial compensation for time and inconvenience 
according to the NIH CC volunteer guidelines: screening ($50), 2-pass leukapheresis 
($200 for a procedure; $50 for unsuccessful apheresis attempts), research blood draw 
and clinic visits ($75), pembrolizumab/placebo infusion ($150). If a participant does not 
qualify or declines leukapheresis, then an additional 80 mL of research blood will be 
drawn, and the participant may be compensated an additional $25 for inconvenience. If 
a participant completes all visits in the follow up phase of the study, there is a $200 
completion bonus. Actual compensation is based on the number and type of study visits 
participants complete. Therefore, the maximum remuneration for a participant is $1900.
12 Assessment of Safety
AEs and other reportable events are defined in Policy 801:  Reporting Research Events
Adverse Reaction: An AE that is caused by an investigational agent (drug or biologic).
Suspected Adverse Reaction (SAR): An AE for which there is a reasonable possibility 
that the investigational agent caused the AE. “Reasonable possibility” means that there 
is evidence to suggest a causal relationship between the drug and the AE. An SAR 
implies a lesser degree of certainty about causality than AR, which implies a high 
degree of certainty.
12.1 Documenting, Recording, and Reporting Adverse Events
All AEs occurring from the time of the initial leukapheresis through week 48 will be 
documented, recorded, and reported. If no leukapheresis is performed, then all AEs 
occurring from the time of pembrolizumab administration through week 48 will be 
documented, recorded, and reported. Between weeks 48 and 96, reporting will be 
limited to only those SAEs and autoimmune events that are possibly, probably, or 
definitely related to pembrolizumab.
At each contact with the participant, information regarding AEs will be elicited by 
appropriate questioning and examinations and will be:


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
documented in the participant’s medical record/source document,

recorded in CRIMSON, and

reported as outlined below (e.g., IND sponsor and FDA).
If a diagnosis is clinically evident (or subsequently determined), then the diagnosis 
rather than the individual signs and symptoms or lab abnormalities will be recorded as 
the AE.
All abnormal laboratory findings will be reviewed on a routine basis by the PI to identify 
potential safety signals. An abnormal lab not included on the toxicity table should be 
assessed in a similar fashion to the criteria above.
12.2 Investigator Assessment of Adverse Events
The investigator will assess all AEs with respect to severity (intensity or grade), and 
causality (relationship to study agent and relationship to research) according to the 
following guidelines.
12.2.1 Severity
The Investigator will grade the severity of each AE according to the “Division of AIDS 
(DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events” most 
recent Version 2.1, July 2017, which can be found at: https://rsc.tech-
res.com/docs/default-source/safety/division-of-aids-(daids)-table-for-grading-the-
severity-of-adult-and-pediatric-adverse-events-corrected-v-2-1.pdf 
Because the DAIDS toxicity table does not have specific criteria for infusion-related 
reactions, we will use the following criteria, based on the Common Terminology Criteria 
for Adverse Events Version 4.0 (https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-
06-14_QuickReference_8.5x11.pdf). This is very similar to the grading criteria for 
“Cytokine release syndrome” that is part of the DAIDS table.


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Table 2. CTCAE Infusion Reaction Severity Grading Criteria
Adverse 
event
Grade 1
Grade 2
Grade 3
Grade 4
Grade 5
Infusion-
related 
reaction. 
Mild transient 
reaction; 
infusion 
interruption 
not indicated; 
intervention 
not indicated.
Therapy or infusion 
interruption indicated 
but responds promptly 
to symptomatic 
treatment (eg, 
antihistamines, 
NSAIDS, narcotics, IV 
fluids); prophylactic 
medications indicated 
for ≤ 24 hrs.
Prolonged (eg, not 
rapidly responsive to 
symptomatic 
medication and/or 
brief interruption of 
infusion); recurrence 
of symptoms following 
initial improvement; 
hospitalization 
indicated for clinical 
sequelae.
Life-threatening 
consequences; 
urgent 
intervention 
indicated.
Death. 
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous; NSAID = nonsteroidal 
anti-inflammatory drug.
Some Grade 1 lab parameters on the DAIDS Toxicity Table fall within the NIH lab 
reference range for normal values. These normal values will not be reported as Grade 1 
AEs.
12.2.2 Causality
Causality (likelihood that the event is caused by the study agent) will be assessed 
considering the factors listed under the following categories:
Definitely Related

reasonable temporal relationship

follows a known response pattern

clear evidence to suggest a causal relationship

there is no alternative etiology
Probably Related

reasonable temporal relationship

follows a suspected response pattern (based on similar agents)

no evidence of a more likely alternative etiology
Possibly Related

reasonable temporal relationship

little evidence for a more likely alternative etiology


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Unlikely Related

does not have a reasonable temporal relationship
OR

good evidence for a more likely alternative etiology
Not Related

does not have a temporal relationship
OR

definitely due to an alternative etiology
Note: Other factors should also be considered for each causality category when 
appropriate. Causality assessment is based on available information at the time of the 
assessment of the AE. The investigator may revise the causality assessment as 
additional information becomes available.
12.3 Investigator Reporting Responsibilities to the Sponsor
12.3.1 Adverse Events
AE data will be submitted to the IND sponsor when requested for periodic safety 
assessments, review of IND annual reports, review of IND safety reports, and 
preparation of final study reports.
12.3.2 Reporting to the Sponsor’s Safety Office
12.3.2.1
Serious Adverse Events 
All SAEs (regardless of relationship and whether or not they are also UPs) must be 
reported on the safety expedited report form (SERF) and sent to the Clinical Safety 
Office (CSO) by fax or email attachment. Deaths and immediately life-threatening SAEs 
must be reported to the CSO within 1 business day after the site becomes aware of the 
event. All other SAEs must be reported within 3 business days of site awareness.
CSO CONTACT INFORMATION:
Clinical Safety Office
5705 Industry Lane
Frederick, MD 21704
Phone: 301-846-5301
Fax: 301-846-6224
E-mail: rchspsafety@mail.nih.gov 


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SAEs that have not resolved by the end of the follow-up period are followed until final 
outcome is known. If it is not possible to obtain a final outcome for an SAE (e.g., the 
participant is lost to follow-up), then the reason a final outcome could not be obtained 
will be recorded by the investigator in CRIMSON and the SERF.
SAEs that occur after week 96 that are reported to and are assessed by the investigator 
to be possibly, probably, or definitely related to study drug must be reported to the CSO.
12.3.2.2
Unanticipated Problems 
UPs that are also AEs must be reported to the CSO by fax or e-mail attachment using 
the NIH Problem Report Form no later than 7 calendar days of site awareness of the 
event. UPs that are not AEs are not reported to the CSO.
12.3.2.3
Events of Clinical Interest 
The following ECIs must be reported to the CSO on a SERF within 3 business days of 
site awareness:

Immune-mediated AEs other than hypothyroidism (Section 8.1).

Opportunistic infections.

An elevated AST or ALT lab value that is greater than or equal to 3 x ULN and an 
elevated total bilirubin lab value that is greater than or equal to 2 x ULN 
(excluding patients with Gilbert syndrome or those receiving atazanavir) and, at 
the same time, an alkaline phosphatase lab value that is less than 2 x ULN, as 
determined by way of protocol-specified laboratory testing or unscheduled 
laboratory testing. (These criteria are based on available regulatory guidance 
documents. The purpose of the criteria is to specify a threshold of abnormal 
hepatic tests that may require an additional evaluation for an underlying etiology.)

Development of a new cancer.

AEs that occur in reasonable temporal association with an overdose of 
pembrolizumab. (Overdose, in and of itself, without an associated AE, is 
reportable in an expedited fashion to the sponsor and IRB as a UP but is not 
considered an SAE. An overdose is defined as any dose greater than the 
protocol-defined dose of 200 mg.)
12.3.2.4
Pregnancy
Participants who inadvertently impregnate a partner after receiving study agent will be 
instructed to immediately inform the investigator. All pregnancies occurring within 120 
days of pembrolizumab administration will be reported on the Pregnancy 
Notification/Outcome Form to the CSO within 1 business day from site awareness.


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The investigator will make every effort to obtain pregnancy outcome data (e.g., delivery 
outcome, spontaneous or elective termination of the pregnancy). SAEs and the 
outcome of the pregnancy will be reported to the CSO within 3 business days of the 
site’s awareness.
Although pregnancy itself is not an AE, events that meet SAE criteria during pregnancy, 
delivery, or in the neonate (eg, miscarriage, congenital anomaly/birth defect) are 
reportable on the SERF.
In the event of pregnancy, the following steps will be taken:

Report to the CSO, IRB, and DSMB.

Unblind participant.

If participant received pembrolizumab, advise research participant that his 
partner should notify her obstetrician of study participation and study agent 
exposure.

Maintain regular (e.g., monthly) contact with the participant to track the progress 
and outcome of the pregnancy, including any untoward events, AEs, and SAEs.
 
12.3.3 Investigator Reporting Responsibilities to the NIAID IRB
Unanticipated problems, non-compliance, and other resportable events will be reported 
to the NIH IRB as per Policy 801.
12.4 Sponsor’s Reporting Responsibilities
SUSARs, as defined in Title 21 of the United States Code of Federal Regulations (CFR) 
Part 312.32 and determined by the IND sponsor, will be reported to FDA and all 
participating investigators as IND Safety Reports.
The IND sponsor will also submit an IND Annual Report of the progress of the 
investigation to the FDA as defined in 21 CFR 312.33.
12.5 Halting Rules for the Protocol
Halting the study requires immediate discontinuation of study agent administered for all 
participants and suspension of enrollment until a decision is made whether or not to 
continue enrollment and study agent administration.


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The halting rules are:

Any SAE that is unexpected and possibly, probably, or definitely related to the 
study agent;
OR

2 or more of the same or similar AEs in different participants that are Grade 3 or 
above (not including transient, subjective infusion-related symptoms such as 
malaise, fatigue, headache, or chills, or elevated total bilirubin in patients with 
Gilbert syndrome or those receiving atazanavir) and are possibly, probably, or 
definitely related to the study agent;
OR

2 or more Grade 2 or higher autoimmune events requiring corticosteroid therapy 
that are possibly, probably, or definitely related to the study agent; 
OR

Any safety issue that the PI and/or the CSO determines should halt the study.
The PI and/or CSO will determine if the study should be halted. In addition, the FDA 
may halt the study at any time following review of any safety concerns. 
12.5.1 Reporting a Study Halt
If a halting rule is met, then a description of the AE(s) or safety issue must be reported 
by the PI within 1 business day to the CSO, the IRB, and the DSMB by fax or email. The 
FDA will also be notified when a study is halted. 
12.5.2 Resumption of a Halted Study
The IND sponsor, in collaboration with the PI and the DSMB, will determine if it is safe 
to resume the study. The PI will notify the IRB of the decision on resumption of the 
study; the FDA will also be notified of this decision.
12.6 Withdrawal Criteria for an Individual Participant
An individual participant will be withdrawn for any of the following:

An individual participant’s decision. (The investigator should attempt to determine 
the reason for the participant’s decision.)

Non-compliance with study procedures to the extent that it is potentially harmful 
to the participant or to the integrity of the study data.

Co-enrollment in a study with an investigational research agent other than 
expanded access antiretroviral medications.


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
The investigator determines that continued participation in the study would not be 
in the best interest of the participant.
Prior to withdrawal, participants will be offered the opportunity to continue in the 
study for safety follow-up only, unless in the opinion of the investigator such follow-
up would be potentially harmful to the participant. 
Only participants who receive pembrolizumab or placebo will be included in the safety 
assessment. Once a participant has received the pembrolizumab or placebo infusion 
they will be included in the safety assessment regardless of early withdrawal. 
Participants who withdraw prior to receiving the infusion of pembrolizumab or placebo, 
or who receive the infusion but withdraw prior to week 6 for reasons unrelated to safety 
(eg, personal decision) may be replaced with a participant who is assigned to the same 
study arm. 
12.7 Safety Oversight
12.7.1 Safety Review and Communications Plan
A safety review and communications plan (SRCP) has been developed for the protocol. 
The SRCP is an internal communications document between the PI and the CSO, 
which delineates the safety oversight responsibilities of the PI, the CSO, and other 
stakeholders. The SRCP also includes the overall plan for conducting periodic safety 
surveillance assessments.
12.7.2 Sponsor Medical Monitor
A medical monitor, representing the IND sponsor (OCRPRO), has been appointed for 
oversight of safety in this clinical study. The sponsor medical monitor will be responsible 
for performing safety assessments as outlined in the SRCP.
12.7.3 Data and Safety Monitoring Board
The NIAID intramural DSMB includes independent experts that do not have direct 
involvement in the conduct of the study and have no significant conflicts of interests as 
defined by NIAID policy. The DSMB will review the study prior to initiation and twice a 
year thereafter and may convene additional reviews as necessary.
The DSMB will also review the safety data after 5 participants have been enrolled and 
followed for 90 days (this review may be one of the twice-yearly reviews); no additional 
participants will be enrolled until the DSMB recommends that study enrollment can be 
resumed. 


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The board will review the study data to evaluate the safety, efficacy, study progress, 
and conduct of the study. All SAEs, all UPs, and all IND Safety Reports will be reported 
by the PI to the DSMB at the same time they are submitted to the IRB or IND sponsor. 
The PI will notify the DSMB of any cases of intentional or unintentional unblinding as 
soon as possible. The PI will notify the board at the time pausing or halting criteria are 
met and obtain a recommendation concerning continuation, modification, or termination 
of the study. The PI will submit the written DSMB summary reports with 
recommendations to the IRB.
13 Site Monitoring Plan
According to the International Council on Harmonization (ICH) E6(R2) Good Clinical 
Practice (GCP) guidelines, section 5.18, and 21 CFR 312.50, clinical protocols are 
required to be adequately monitored by the study sponsor. This study monitoring will be 
conducted according to the “NIAID Intramural Clinical Monitoring Guidelines.” Monitors 
under contract to the NIAID/OCRPRO will visit the clinical research site to monitor 
aspects of the study in accordance with the appropriate regulations and the approved 
protocol. The objectives of a monitoring visit will be: 1) to verify the existence of signed 
informed consent documents and documentation of the consent process for each 
monitored participant; 2) to verify the prompt and accurate recording of all monitored 
data points in CRIMSON and prompt reporting of all SAEs; 3) to compare abstracted 
information entered into CRIMSON with individual participants’ records and source 
documents (participants’ charts, laboratory analyses and test results, physicians’ 
progress notes, nurses’ notes, and any other relevant original participant information); 
and 4) to help ensure investigators are in compliance with the protocol. The monitors 
also will inspect the clinical site regulatory files to ensure that regulatory requirements 
(Office for Human Research Protections [OHRP]), FDA, and applicable guidelines (ICH 
GCP) are being followed. During the monitoring visits, the investigator (and/or designee) 
and other study personnel will be available to discuss the study progress and monitoring 
visit.
The investigator (and/or designee) will make study documents (eg, consent forms, 
CRIMSON data abstracts) and pertinent hospital or clinical records, including 
CRIMSON, readily available for inspection by the local IRB, the FDA, the site monitors, 
and the NIAID staff for confirmation of the study data. 
A specific protocol monitoring plan will be discussed with the PI and study staff prior to 
enrollment. The plan will outline the frequency of monitoring visits based on such factors 
as study enrollment, data collection status, and regulatory obligations.


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14 Statistical Considerations
The primary safety outcome is the occurrence of Grade 3 or higher AEs or Grade 2 or 
higher autoimmune events requiring corticosteroid therapy. 
Although this is a randomized controlled trial, the placebo arm will be used informally to 
interpret AEs in the pembrolizumab arm. For instance, concern over AEs in the 
pembrolizumab arm would be tempered if one or more people in the placebo arm 
experienced the same type of AE. Formal between-arm comparisons will also be made, 
but it is extremely difficult to show a statistically significant between-arm difference. For 
instance, if there are no AEs of a given type in the placebo arm, 9 or more people out of 
15 in the pembrolizumab arm would have to experience the AE to declare a statistically 
significant difference using Fisher’s exact test and two-tailed type 1 error rate 0.05. For 
this reason, we focus below on estimating the probability of AEs in the pembrolizumab 
arm rather than on power to compare arms. 
An exact 95% confidence interval for the probability of AEs will be computed using the 
Clopper-Pearson method. Changes from baseline in continuous measurements will be 
analyzed using paired t-tests or, if data are skewed, then the Wilcoxon signed rank 
statistic. Secondary analyses will use mixed models to estimate the trajectories over 
time. Linear and quadratic terms will be incorporated, if warranted.
A sample size of 15 pembrolizumab-administered participants provides a 91.3% chance 
of observing at least one AE under the assumption of single participant AE rate of 15%. 
Table 3 shows the chance of observing at least one AE of given probability.
Table 3. Probability of Observing Adverse Events 
Probability of Grade 3 or 
higher AE for a single 
participant 
0.025
0.050
0.075
0.100
0.125
0.150
Probability of observing at 
least one AE with 15 
participants
0.316
0.537
0.689
0.794
0.865
0.913
Time for PD-1 levels to return to baseline will be estimated and plotted using the 
Kaplan-Meier method. In addition, trajectories of PD-1 levels over time for different 
participants will be plotted, and an average trajectory will be estimated using a mixed 
model.


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15 Ethics/Protection of Human Participants
15.1 Informed Consent Process
Informed consent is a process where information is presented to enable persons to 
voluntarily decide whether or not to participate as a research subject. It is an ongoing 
conversation between the human research participant and the researchers which 
begins before consent is given and continues until the end of the participant’s 
involvement in the research. Discussions about the research will provide essential 
information about the study and include: purpose, duration, experimental procedures, 
alternatives, risks, and benefits. Participants will be given the opportunity to ask 
questions and have them answered.
The participants will sign the informed consent document prior to undergoing any 
research procedures. The participants may withdraw consent at any time throughout the 
course of the trial. A copy of the informed consent document will be given to the 
participants for their records. The researcher will document the signing of the consent 
form in the participant’s medical record. 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.
The consent form has been translated into Spanish due to the expected enrollment of 
Spanish-speaking subjects.
15.1.1 Ongoing Informed Consent
People who are unable to provide informed consent are excluded from enrolling in the 
protocol (Section 4.2). If a participant becomes decisionally impaired during the course 
of the study, then they will be removed from the study.
15.2 Participant Confidentiality
All records will be kept confidential to the extent provided by federal, state, and local 
law. The study monitors and other authorized representatives of the sponsor may 
inspect all documents and records required to be maintained by the investigator, 
including but not limited to, medical records. Records will be kept locked and all 
computer entry and networking programs will be done with coded numbers only. Clinical 
information will not be released without written permission of the participant, except as 
necessary for monitoring by IRB, the FDA, NIAID, OHRP, the pharmaceutical supporter, 
or the sponsor’s designee.


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16 Data Handling and Record Keeping
16.1 Data Capture and Management 
Study data will be maintained in CRIMSON and collected directly from participants 
during study visits and telephone calls or will be abstracted from participants’ medical 
records. Source documents include all recordings of observations or notations of clinical 
activities and all reports and records necessary to confirm the data abstracted for this 
study. Data entry into CRIMSON will be performed by authorized individuals. The 
investigator is responsible for assuring that the data collected are complete, accurate, 
and recorded in a timely manner.
16.2 Record Retention
The investigator is responsible for retaining all essential documents listed in the ICH 
GCP guidelines. Study records will be maintained by the PI for a minimum of 5 to 
7 years and in compliance with institutional, IRB, state, and federal medical records 
retention requirements, whichever is longest. All stored records will be kept confidential 
to the extent required by federal, state, and local law.
Should the investigator wish to assign the study records to another party and/or move 
them to another location, the investigator will provide written notification of such intent to 
OCRPRO/NIAID with the name of the person who will accept responsibility for the 
transferred records and/or their new location. NIAID will be notified in writing and written 
OCRPRO/NIAID permission shall be obtained by the site prior to destruction or 
relocation of research records.


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17 Scientific References
1.
UNAIDS. Fact Sheet November 2016. 
http://www.unaids.org/sites/default/files/media_asset/UNAIDS_FactSheet_en.pdf
. Published December 1, 2016. Accessed January 6, 2017.
2.
United States Centers for Disease Control and Prevention. HIV in the United 
States: At a Glance. https://www.cdc.gov/hiv/statistics/overview/ataglance.html. 
Updated December 2, 2016. Accessed January 6, 2017. (7601).
3.
Gazzola L, Tincati C, Bellistri GM, Monforte AD, Marchetti G. The Absence of 
CD4(+) T Cell Count Recovery Despite Receipt of Virologically Suppressive 
Highly Active Antiretroviral Therapy: Clinical Risk, Immunological Gaps, and 
Therapeutic Options. Clin Infect Dis. 2009;48(3):328-337.
4.
Kelley CF, Kitchen CMR, Hunt PW, et al. Incomplete Peripheral CD4(+) Cell 
Count Restoration in HIV-Infected Patients Receiving Long-Term Antiretroviral 
Treatment. Clin Infect Dis. 2009;48(6):787-794.
5.
Baker JV, Peng G, Rapkin J, et al. CD4+ count and risk of non-AIDS diseases 
following initial treatment for HIV infection. AIDS. 2008;22(7):841-848.
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Appendix A: Supportive Care Measures for Immune-mediated Adverse events and 
Infusion Reactions
Note: These recommendations provide guidance, but management should be 
individualized based on clinical evaluation of the patient. 

Pneumonitis: 
o
For Grade 2 events, treat with oral corticosteroids. 
o
For Grade 3-4 events, immediately treat with IV corticosteroids followed by 
high-dose oral corticosteroids. Administer additional anti-inflammatory 
measures as needed.
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.
o
Add prophylactic antibiotics for opportunistic infections in the case of 
prolonged steroid administration.

Diarrhea/Colitis: 
Participants should be carefully monitored for signs and symptoms of 
enterocolitis (such as diarrhea, abdominal pain, blood or mucus in stool, with or 
without fever) and of bowel perforation (such as peritoneal signs and ileus).  
o
All participants who experience diarrhea/colitis should be advised to drink 
liberal quantities of clear fluids. If sufficient oral fluid intake is not feasible, 
then fluid and electrolytes should be substituted via IV infusion. For Grade 2 
or higher diarrhea, consider gastrointestinal consultation and endoscopy to 
confirm or rule out colitis.
o
For Grade 2 diarrhea/colitis, administer oral corticosteroids. 
o
For Grade 3 or 4 diarrhea/colitis, treat with IV corticosteroids followed by 
high-dose oral corticosteroids.  
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks.

Type 1 diabetes mellitus (DM, if new onset, including diabetic ketoacidosis 
[DKA]) or ≥ Grade 3 hyperglycemia, if associated with ketosis (ketonuria) or 
metabolic acidosis (DKA)
o
For type 1 DM or Grade 3-4 hyperglycemia

Insulin replacement therapy is recommended for type I DM and for 
Grade 3-4 hyperglycemia associated with metabolic acidosis or ketonuria. 

Evaluate participants with serum glucose and a metabolic panel, urine 
ketones, glycosylated hemoglobin, and C-peptide. 


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
Hypophysitis:
o
For Grade 2 events, treat with oral corticosteroids. 
o
For Grade 3-4 events, treat with an initial dose of IV corticosteroids followed 
by oral corticosteroids. 
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. Replacement of appropriate 
hormones may be required as the steroid dose is tapered.

Hyperthyroidism or Hypothyroidism: 
Thyroid disorders can occur at any time after the dose. Monitor participants for 
changes in thyroid function (at the start of treatment, periodically during 
treatment, and as indicated based on clinical evaluation) and for clinical signs 
and symptoms of thyroid disorders.
o
Grade 2 hyperthyroidism events and Grade 2-4 hypothyroidism:

In hyperthyroidism, non-selective beta-blockers (eg, propranolol) are 
suggested as initial therapy.

In hypothyroidism, thyroid hormone replacement therapy, with 
levothyroxine or liothyronine, is indicated per standard of care.
o
Grade 3-4 hyperthyroidism 

Treat with an initial dose of IV corticosteroids followed by oral 
corticosteroids. When symptoms improve to Grade 1 or less, steroid taper 
should be started and continued over no less than 4 weeks. Replacement 
of appropriate hormones may be required as the steroid dose is tapered.

Hepatic:
o
For Grade 2 events, monitor liver function tests more frequently until returned 
to baseline values (consider weekly).

Treat with IV or oral corticosteroids
o
For Grade 3-4 events, treat with IV corticosteroids for 24 to 48 hours, 
followed by oral corticosteroids. 
o
When symptoms improve to Grade 1 or less, a steroid taper should be started 
and continued over no less than 4 weeks.

Renal Failure or Nephritis:
o
For Grade 2 events, treat with oral corticosteroids.
o
For Grade 3-4 events, treat with systemic corticosteroids. 
o
When symptoms improve to Grade 1 or less, steroid taper should be started 
and continued over no less than 4 weeks. 


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
Management of Infusion Reactions: Signs and symptoms usually develop 
during or shortly after study drug infusion and generally resolve completely within 
24 hours of completion of infusion. 
Table 4 below shows treatment guidelines for subjects who experience an infusion 
reaction associated with administration of pembrolizumab.
Table 4. Infusion Reaction Treatment Guidelines
NCI CTCAE Grade
Treatment
Grade 1
Mild transient reaction; infusion 
interruption not indicated; 
intervention not indicated.
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
Grade 2
Therapy or infusion interruption 
indicated but responds promptly to 
symptomatic treatment (eg, 
antihistamines, NSAIDS, narcotics, 
IV fluids); prophylactic medications 
indicated for ≤ 24 hrs.
Stop Infusion and monitor symptoms.
Additional appropriate medical therapy may include but is not limited to, IV fluids, 
antihistamines, NSAIDS, acetaminophen, narcotics.
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
Grades 3 or 4
Grade 3:
Prolonged (ie, not rapidly 
responsive to symptomatic 
medication and/or brief interruption 
of infusion); recurrence of 
symptoms following initial 
improvement; hospitalization 
indicated for other clinical sequelae 
(eg, renal impairment, pulmonary 
infiltrates).
Grade 4:
Life-threatening consequences; 
urgent intervention indicated.
Stop Infusion.
Additional appropriate medical therapy may include but is not limited to IV fluids, 
antihistamines, NSAIDS, acetaminophen, narcotics, oxygen, pressors, 
corticosteroids, epinephrine.
Increase monitoring of vital signs as medically indicated until the participant is 
deemed medically stable in the opinion of the investigator.
Hospitalization may be indicated.
CTCAE = Common Terminology Criteria for Adverse Events; IV = intravenous(ly); NCI = National Cancer Institute; 
NSAID = nonsteroidal anti-inflammatory drug.
Appropriate resuscitation equipment should be available in the room and a physician readily available during the period 
of drug administration.


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Appendix B: Schedule of Procedures and Evaluations
Study week (day window)
Evaluation
Screeninga
Week -6 to 0
Baseline
Day 0
1
(± 4)
2
(± 4)
3
(± 4)
4
(± 4)
6
(± 4)
9
(± 7)
12
(± 7)
16
(± 7)
24
(± 7)
36
(± 7)
48
(± 7)
60, 72, 
84, 96
(all ± 14)
Early 
termination 
visit
Informed consent
X
Physical exam with vital 
signs
X
X
X
X
X
X
X
X
X
X
X
X
Xb
Medical 
history/medication 
review
Counseling on use of 
birth control
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
  X
X
X
X
X
X
X
X
X
X
Xc
X
Xd
Xc
Blood draw for 
screening labs
X
Urinalysis
X
Urine Pregnancy 
t(for participants 
of childbearing 
potential only)
X
X
X
X
X
X
X
X
X
X
X
X
X
ECG
X
HLA typing
X
Blood draw for storage
X
Leukapheresis
Xe
Xf.g
Xf,g
Xf


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Study week (day window)
Evaluation
Screeninga
Week -6 to 0
Baseline
Day 0
1
(± 4)
2
(± 4)
3
(± 4)
4
(± 4)
6
(± 4)
9
(± 7)
12
(± 7)
16
(± 7)
24
(± 7)
36
(± 7)
48
(± 7)
60, 72, 
84, 96
(all ± 14)
Early 
termination 
visit
Administration of 
pembrolizumabh or 
placebo
X
AE assessment
X
X
X
X
X
X
X
X
X
X
X
Xc
Xd
Blood draw for 
clinical/research labs, 
storage
X
X
X
X
X
X
X
X
X
X
X
X
Xb
AE = adverse event; ECG = electrocardiogram; X = to be performed.
a
Screening can be scheduled over multiple visits per convenience of the participant and study team.
b
This assessment will only be conducted if the early termination visit is on or before week 48.
c
This assessment will be conducted over the phone.
d
This assessment will be conducted over the phone if the early termination visit is after week 48.
e
Will be performed after confirmation of eligibility. If the participant cannot do this procedure (eg, poor venous access), then an extra 80 mL of blood will be collected 
for storage and research.
f
This procedure is optional. If the participant declines to do it or cannot (eg, poor venous access), then an extra 80 mL of blood will be collected for storage and 
research.
g
Leukapheresis will be done at either week 3 or 4, not both. Scheduling will depend on the convenience of the participant and study team.
h
200 mg via intravenous infusion for 30 minutes.