Evaluating the Safety and Drug Levels of an Antibody Against HIV in Healthy, HIV-Uninfected Adults

The purpose of this study is to evaluate the safety, tolerability, and drug levels of five
different schedules for the intravenous (IV) and subcutaneous (SC) administration of a human
monoclonal antibody (VRC-HIVMAB060-00-AB [VRC01]) against HIV in healthy, HIV-uninfected
adults.

The study will enroll 88 healthy, HIV-uninfected adults aged 18 to 50 years.

This study will enroll participants in 5 groups. Groups 1-3 will enroll simultaneously.
Groups 1 and 2 will be randomized together but not blinded, while Group 3 will be randomized
separately and will be blinded. With the implementation of Version 2.0, Groups 4 and 5 will
be randomized together and will enroll simultaneously. Each group will have a different
schedule of clinic visits and receive different doses of VRC01 or placebo for VRC01.
Participants will attend 8 months of scheduled clinic visits.

Participants in Group 1 will receive an IV infusion of VRC01 on Days 0, 28, 56, 84, 112, and
140. Participants in Group 2 will receive an IV infusion of VRC01 on Days 0, 56, and 112.
Participants in Group 3 will receive an IV infusion of VRC01 or IV placebo for VRC01 on Day
0, followed by SC injections of VRC01 or SC placebo for VRC01 on Days 14, 28, 42, 56, 70,
84, 98, 112, 126, 140, and 154. Participants in Groups 4 and 5 will receive an IV infusion
of VRC01 (each group will receive a different dose) on Days 0, 56, and 112.

Participants will remain in the clinic for about an hour after receiving the infusions and
injections for observation and monitoring. Participants in Group 3 who have no problems with
the first SC injection will have to wait in the clinic for only a half an hour after the
rest of the SC injections.

At study entry, participants will give a medical history; undergo a physical exam, blood
collection, and urine collection; and receive HIV risk reduction counseling. At follow-up
visits, participants will undergo a brief physical exam and blood collection, receive HIV
risk reduction counseling, and be asked questions about their health and their experience
participating in the study. At all visits, participants who were born female will have a
pregnancy test. At select study visits, saliva, rectal, and semen or cervical secretion
samples will be collected from participants who consent to collection of these samples.

Inclusion Criteria:

General and Demographic Criteria

- Weight at least 53 kg and up to 115 kg

- Access to a participating HIV Vaccine Trials Network (HVTN) clinical research site
(CRS) and willingness to be followed for the planned duration of the study

- Ability and willingness to provide informed consent

- Assessment of understanding: participant demonstrates understanding of this study;
completes a questionnaire prior to first infusion, with verbal demonstration of
understanding of all questionnaire items answered incorrectly

- Agrees not to enroll in another study of an investigational research agent until
completion of the last study visit

- Good general health as shown by medical history, physical exam, and screening
laboratory tests

HIV-Related Criteria

- Willingness to receive HIV test results

- Willingness to discuss HIV infection risks, amenable to HIV risk reduction
counseling, and committed to maintaining behavior consistent with low risk of HIV
exposure through the last required protocol clinic visit

- Assessed by the clinic staff as being at "low risk" for HIV infection and committed
to maintaining behavior consistent with low risk of HIV exposure through the last
required protocol clinic visit

Laboratory Inclusion Values

Hemogram/Complete Blood Count (CBC)

- Hemoglobin greater than or equal to 11.0 g/dL for participants who were born female,
greater than or equal to 13.0 g/dL for participants who were born male

- White blood cell count equal to 2,500 to 12,000 cells/mm^3

- Total lymphocyte count greater than or equal to 800 cells/mm^3

- Remaining differential either within institutional normal range or with site
physician approval

- Platelets equal to 125,000 to 550,000/mm^3

Chemistry

- Chemistry panel: alanine aminotransferase (ALT), aspartate aminotransferase (AST),
and alkaline phosphatase less than 1.25 times the institutional upper limit of
normal; creatinine less than or equal to the institutional upper limit of normal

Virology

- Negative HIV-1 and -2 blood test: U.S. participants must have a negative Food and
Drug Administration (FDA)-approved enzyme immunoassay (EIA).

- Negative hepatitis B surface antigen (HBsAg)

- Negative anti-hepatitis C virus (anti-HCV) antibodies, or negative HCV polymerase
chain reaction (PCR) if the anti-HCV is positive

Urine

- Normal urine:

- Negative urine glucose, and

- Negative or trace urine protein, and

- Negative or trace urine hemoglobin (if trace hemoglobin is present on dipstick,
a microscopic urinalysis with red blood cell levels within institutional normal
range).

Reproductive Status

- Participants who were born female: negative serum or urine beta human chorionic
gonadotropin (beta-HCG) pregnancy test performed prior to infusion on the day of
initial infusion. Persons who are not of reproductive potential because of having
undergone total hysterectomy with bilateral oophorectomy (verified by medical
records) are not required to undergo pregnancy testing.

- Reproductive status: A participant who was born female must:

- Agree to consistently use effective contraception (see the protocol for more
information) for sexual activity that could lead to pregnancy from at least 21
days prior to enrollment through the last required protocol clinic visit.
Effective contraception is defined as using any of the following methods:
condoms (male or female) with or without a spermicide; diaphragm or cervical cap
with spermicide; intrauterine device (IUD); hormonal contraception; any other
contraceptive method approved by the HVTN 104 Protocol Safety Review Team
(PSRT); successful vasectomy in the male partner (considered successful if a
participant reports that a male partner has [1] documentation of azoospermia by
microscopy, or [2] a vasectomy more than 2 years ago with no resultant pregnancy
despite sexual activity postvasectomy);

- Or not be of reproductive potential, such as having reached menopause (no menses
for 1 year) or having undergone hysterectomy, bilateral oophorectomy, or tubal
ligation;

- Or be sexually abstinent.

- Participants who were born female must also agree not to seek pregnancy through
alternative methods, such as artificial insemination or in vitro fertilization until
after the last required protocol clinic visit.

Exclusion Criteria:

General

- Blood products received within 120 days before first infusion, unless eligibility for
earlier enrollment is determined by the HVTN 104 PSRT

- Investigational research agents received within 30 days before first infusion

- Intent to participate in another study of an investigational research agent during
the planned duration of the HVTN 104 study

- Pregnant or breastfeeding

Vaccines and Other Injections

- HIV vaccine(s) received in a prior HIV vaccine trial. For participants who have
received control/placebo in an HIV vaccine trial, the HVTN 104 PSRT will determine
eligibility on a case-by-case basis.

- Non-HIV experimental vaccine(s) received within the last 6 months in a prior vaccine
trial. Exceptions may be made for some vaccines and vaccine trials. For participants
who have received an experimental vaccine(s) less than 6 months ago, eligibility for
enrollment will be determined by the HVTN 104 PSRT on a case-by-case basis.

- Live attenuated vaccines other than influenza vaccine received within 10 days before
first infusion and with no evidence of residual inflammation; or scheduled within 10
days after first infusion (e.g., measles, mumps, and rubella [MMR]; oral polio
vaccine [OPV]; varicella; yellow fever).

- Previous receipt of humanized or human monoclonal antibodies (mAbs) whether licensed
or investigational

Immune System

- Immunosuppressive medications received within 30 days before first infusion. (Not
excluded: [1] corticosteroid nasal spray; [2] inhaled corticosteroids; [3] topical
corticosteroids for mild, uncomplicated dermatitis; or [4] a single course of
oral/parenteral corticosteroids at doses less than 2 mg/kg/day and length of therapy
less than 11 days, with completion at least 30 days prior to enrollment.

- Serious adverse reactions to vaccines or to vaccine components, including history of
anaphylaxis and related symptoms such as hives, respiratory difficulty, angioedema,
and/or abdominal pain. (Not excluded: a participant who had a nonanaphylactic adverse
reaction to pertussis vaccine as a child)

- Immunoglobulin received within 90 days before first infusion, unless eligibility for
earlier enrollment is determined by the HVTN 104 PSRT.

- Autoimmune disease (Not excluded: participant with mild, stable, and uncomplicated
autoimmune disease that does not require immunosuppressive medication and that, in
the judgment of the site investigator, is likely not subject to exacerbation and
likely not to complicate reactogenicity and adverse event [AE] assessments)

- Immunodeficiency

Clinically Significant Medical Conditions

- Untreated or incompletely treated syphilis infection

- Clinically significant medical condition, physical examination findings, clinically
significant abnormal laboratory results, or past medical history with clinically
significant implications for current health. A clinically significant condition or
process includes but is not limited to:

- A process that would affect the immune response,

- A process that would require medication that affects the immune response,

- Any contraindication to repeated infusions or blood draws,

- A condition that requires active medical intervention or monitoring to avert
grave danger to the participant's health or well-being during the study period,

- A condition or process for which signs or symptoms could be confused with
reactions to vaccine, or

- Any condition specifically listed among the exclusion criteria below.

- Any medical, psychiatric, occupational, or other condition that, in the judgment of
the investigator, would interfere with, or serve as a contraindication to, protocol
adherence, assessment of safety or reactogenicity, or a participant's ability to give
informed consent

- Psychiatric condition that precludes compliance with the protocol. Specifically
excluded are persons with psychoses within the past 3 years, ongoing risk for
suicide, or history of suicide attempt or gesture within the past 3 years.

- Current anti-tuberculosis (TB) prophylaxis or therapy

- Asthma other than mild, well-controlled asthma (symptoms of asthma severity as
defined in the most recent National Asthma Education and Prevention Program [NAEPP]
Expert Panel report).

- Exclude a participant who uses a short-acting rescue inhaler (typically a beta 2
agonist) daily, or uses moderate/high dose inhaled corticosteroids, or in the past
year has either of the following:

- Greater than one exacerbation of symptoms treated with oral/parenteral
corticosteroids;

- Needed emergency care, urgent care, hospitalization, or intubation for asthma.

- Diabetes mellitus type 1 or type 2, including cases controlled with diet alone. (Not
excluded: history of isolated gestational diabetes)

- Hypertension:

- If a person has been found to have elevated blood pressure or hypertension
during screening or previously, exclude for blood pressure that is not well
controlled. Well controlled blood pressure is defined as consistently less than
or equal to 140 mm Hg systolic and less than or equal to 90 mm Hg diastolic,
with or without medication, with only isolated, brief instances of higher
readings, which must be less than or equal to 150 mm Hg systolic and less than
or equal to 100 mm Hg diastolic. For these participants, blood pressure must be
less than or equal to 140 mm Hg systolic and less than or equal to 90 mm Hg
diastolic at enrollment.

- If a person has NOT been found to have elevated blood pressure or hypertension
during screening or previously, exclude for systolic blood pressure greater than
or equal to 150 mm Hg at enrollment or diastolic blood pressure greater than or
equal to 100 mm Hg at enrollment.

- Bleeding disorder diagnosed by a doctor (e.g., factor deficiency, coagulopathy, or
platelet disorder requiring special precautions)

- Malignancy (Not excluded: participant who has had malignancy excised surgically and
who, in the investigator's estimation, has a reasonable assurance of sustained cure,
or who is unlikely to experience recurrence of malignancy during the period of the
study)

- Seizure disorder: history of seizure(s) within past 3 years. Also exclude if
participant has used medications in order to prevent or treat seizure(s) at any time
within the past 3 years.

- Asplenia: any condition resulting in the absence of a functional spleen

- History of hereditary angioedema, acquired angioedema, or idiopathic angioedema.