Clinical trial NCT02446847
Conditions: HIV-1 Infection
Keywords: HIV 3BNC117 Broadly neutralizing antibody
Sponsor: Rockefeller University
Start date: 2015-03-11; Completion date: 2017-03-25
Enrollment: 16 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the effects of two infusions of 3BNC117 in preventing or delaying rebound of viral load during a brief treatment interruption of standard ART and its safety during a brief analytical interruption of antiretroviral therapy.

Detailed description:
The proposed study is a Phase II, open label study to evaluate the safety and antiretroviral activity of two and four infusions of 3BNC117 in HIV-infected subjects on combination ART during a brief analytical treatment interruption.

After meeting enrollment criteria sixteen subjects with 3BNC117 sensitive virus (\<2μg/ml IC50) will receive two (Group A) or four (Group B) intravenous infusions of 3BNC117, administered at 30 mg/kg.

In both dosing groups, antiretroviral therapy will be discontinued 2 days after the first 3BNC117 infusion (day 2) until week 12. Combination ART will be resumed at week 12. ART will be resumed sooner if plasma HIV-1 RNA level is ≥ 200 copies/ml or if CD4+ count drops \< 350 cells/μl and either result is confirmed upon repeat measurement. Participants will be followed weekly until week 12 for safety assessments and for monitoring plasma HIV-1 RNA levels (viral load). CD4+ T cell counts will be monitored every 2 weeks until week 12.

Participants may remain off antiretroviral therapy after week 12, with weekly viral load monitoring, if viral rebound does not occur by week 12. Participants will be followed for a total of 36 weeks.

Arms: arm 1: Two intravenous infusions of 3BNC117 (30 mg/kg) at day 0 and day 21, with interruption of antiretroviral treatment (ART) at day 2. arm 2: Four intravenous infusions of 3BNC117 (30 mg/kg) at day 0, day 14, day 28, and day 42 with interruption of antiretroviral treatment (ART) at day 2.
Interventions: intervention 1: 3BNC117 intervention 2: ART Interruption
Intervention descriptions: intervention 1: 3BNC117 infusions intervention 2: Antiretroviral therapy will be discontinued 2 days after the first 3BNC117 infusion (day 2) and resumed at week 12.

Protocol documents:
ICF_002.pdf: 
Official title: A phase 2, open label study of the safety, antiretroviral activity and 
pharmacokinetics of 3BNC117 during a short analytical treatment interruption in HIV-
infected subjects 
 
NCT number: NCT02446847 
 
Document date: 09/21/2015 
 


 
Clinical Investigation Consent Form 
Page 1 of 15 
 
Revised 3/17/15 
 
Clinical Investigation Consent Form                                  IRB Rev 2014 
The Rockefeller University Hospital 
1230 York Avenue 
New York, New York 10065 
Principal Investigator: Marina Caskey, MD 
Phone:  212-327-7396 
Fax: 212-327-7234 
E-mail: mcaskey@rockefeller.edu 
 
You are being asked to join a research study, which will take place at The Rockefeller 
University Hospital.  This form tells about the research.  You should ask questions of the 
person who is explaining this form to you.  After you feel that you understand the research, 
if you want to be part of the study, you will be asked to sign the form.  You can always ask 
more questions and can later change your mind about staying in the study. 
 
If you join the research study, you will take part for a total of 38 weeks. The research study 
as a whole will last about 3 years. 
 
About 15 people will take part in the research study.  
 
Title of the research study: 
 
A phase 2, open label study of the safety, antiretroviral activity and pharmacokinetics 
of 3BNC117 during a short analytical treatment interruption in HIV-infected subjects 
 
I. 
What this research study is about, and the reason for doing this research. 
 
The research will test a drug called 3BNC117, which is a monoclonal antibody to HIV, the 
virus that causes AIDS (acquired immune deficiency syndrome). A monoclonal antibody is 
an artificial substance made in the laboratory. An antibody is a substance that the body 
makes in response to an infection. The monoclonal antibody we are testing attaches to HIV, 
and can block HIV from attacking cells in your body and from spreading to other parts of 
the body. 3BNC117 is being developed to treat and potentially prevent HIV infection. In 
this study we will test this monoclonal antibody in HIV-positive people with well- 
controlled HIV infection, and who are on combination antiretroviral therapy (HIV 
medications). The monoclonal antibody, 3BNC117, being tested was designed by scientists 
at The Rockefeller University and was manufactured at Celldex Therapeutics Inc.  
 
One of the reasons to do this study is to find out if it is safe to give this antibody. Another 
reason is to determine how this antibody might affect HIV levels in HIV-infected 
individuals during a brief pause of their HIV medications. 
 
You are being asked to participate in this research because you are HIV-infected and are on 
combination antiretroviral therapy.  
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 2 of 15 
 
Revised 3/17/15 
The antibody will be given directly into your blood stream. This means that the medicine is 
given into a vein or intravenously. How this will be done is explained in Section II, What is 
going to happen in this research study? 
 
 
Requirements to join this research: 
 
- 
Age from 18 to 65 years old; 
- 
HIV-1 infection confirmed by laboratory tests; 
- 
Undetectable HIV viral loads for at least 12 months while on a combination of HIV 
medications; 
- 
Current CD4 cell count > 500 cells/μl and no prior CD4 cell count < 200 cells/μl; 
- 
HIV that is sensitive to 3BNC117. We will know if the HIV in your body is sensitive to 
3BNC117 by testing blood you have already donated for another study (MCA-823).  
- 
You agree to pause your HIV medication (ART) for 12 weeks after you receive the 
antibody, and agree to return to the clinic every week for follow-up visits. 
- 
If you are a sexually active male or female, participating in sexual activity that could 
lead to pregnancy you must agree to use an effective method of contraception 
throughout the study period. You must also agree to use male or female condoms 
during the time of pausing your HIV medication. If you are female, you will have 
pregnancy tests at most study visits. 
- 
If your ART includes a Non-Nucleoside Reverse Transcriptase Inhibitor [NNRTI], i.e. 
Atripla Complera, Itelence, or Sustiva you must be willing to a switch for 4 weeks to 
dolutegravir, which we can provide to you during this time. 
 
 
You cannot join this research if you have: 
 
- 
History of AIDS-defining illness within 1 year prior to enrollment; 
- 
Used systemic corticosteroids, immunosuppressive anticancer, or other medications 
considered significant by the trial physician within the last 6 months; 
- 
Any clinically significant acute or chronic medical condition, other than HIV infection, 
or significant laboratory abnormality, that in the opinion of the investigator would 
preclude participation; 
- 
Any history of significant cardiovascular disease such as coronary artery disease, 
myocardial infarction, percutaneous coronary intervention with placement of cardiac 
stents; 
- 
Uncontrolled hypertension, as defined by a systolic blood pressure > 180 and/or 
diastolic blood pressure > 120, whether or not you are taking anti-hypertensive 
medications; 
- 
Current cigarette use in excess of 1 pack per day; 
- 
History of Diabetes type 1 or 2 and/or currently use insulin or oral hypoglycemic 
medications; 
- 
Chronic Hepatitis B or Hepatitis C infection; 
- 
Current ART regimen includes either Selzentry (maraviroc) or Fuzeon (enfuvirtide); 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 3 of 15 
 
Revised 3/17/15 
- 
History of resistance to two or more antiretroviral drug classes; 
- 
Received any vaccination within 14 days prior to receiving the monoclonal antibody; 
- 
Received monoclonal antibody therapy of any kind in the past; 
- 
Participated in another clinical study of an investigational product currently or within 
past 12 weeks, or expect to participate during this study; 
- 
History of severe reaction to a vaccine or drug infusion or history of severe allergic 
reactions. 
- 
If you are pregnant or breastfeeding. 
 
 
II. 
What is going to happen in this research study? 
 
Consent Process:  Informed consent is a process to help you understand the purpose of the 
research study, what will happen in the study, possible risks and benefits, and your right to 
withdraw from the study at any time. All of this information will be explained to you in 
detail.  You should ask any questions you have until you feel that you understand what is 
asked of you to participate.  You may then want to enroll, or you may decide not to join the 
study.  The decision to participate is entirely up to you.  Even after the study has started, 
you may at any time ask more questions, and decide to withdraw from the study. 
 
Study Procedures: 
 
Experimental Drug Infusion 
In this study you will receive an experimental drug called 3BNC117.  The United States 
Food and Drug Administration (FDA) has not approved this experimental drug for general 
use by the public.  However, we have told the FDA about this study and they have given us 
permission to conduct this study. This study will evaluate how your blood cells respond to 
3BNC117.  
 
The antibody, 3BNC117, will be given directly into your blood stream. This means that the 
medicine is given into a vein or intravenously. This means a small plastic tube will be 
placed into a vein in your arm. Then the medicine will be given through the plastic tube.  
 
You will receive two infusions of 3BNC117 at a dose of 30mg/kg. The amount of 
3BCN117 that you will receive will be calculated based on your body weight. For example, 
if you weigh 70 kg (or 154 lbs), you will receive 2100 mg of 3BNC117 (30 mg of 
3BNC117 for each kg of body weight). 
 
After administration of 3BNC117, blood will be taken to measure 3BNC117 levels in your 
blood and the effect of 3BNC117 on blood cells and on the amount of HIV virus in your 
blood (HIV viral load). You will also be asked questions to determine if you are having any 
side effects. Details of the study procedures are found below. 
 
You will be followed for 36 weeks after your first of two 3BNC117 infusions. 
 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 4 of 15 
 
Revised 3/17/15 
ART Discontinuation 
 
You will take your HIV meds once more on the day after the first 3BNC117 infusion. Your 
HIV meds will then be discontinued.  
 
If your ART includes a Non-Nucleoside Reverse Transcriptase Inhibitor [NNRTI], i.e. 
Atripla Complera, Itelence, or Sustiva, the NNRTI will be switched to a medication called 
Dolutegravir (Tivicay), 4 weeks prior to pausing all HIV meds. You will restart taking HIV 
meds at week 12.  
 
During the 12 weeks you will be off HIV meds, your HIV viral loads will be monitored 
weekly and you will be asked to restart taking your HIV meds if: 
 Your HIV viral load is ≥ 200 copies/ml, and confirmed by a repeat test; 
 Your HIV viral load measurement is ≥ 10,000 copies/ml at any time; 
 You become pregnant; 
 Your CD4+ count drops < 350 cells/l, and confirmed by a repeat test; 
 If you develop symptoms of fever, rash, swollen glands, headache, sore throat, 
nausea or vomiting, you will be asked to come in for an unscheduled visit. ART 
will be resumed if the study team determines that you are experiencing these 
symptoms due to increased HIV levels. 
 
If your meds were not restarted within three weeks after you stopped taking them, you will 
receive a second infusion of 3BNC117 on day 21.  
 
If your viral load remains suppressed by week 12, you will be asked by the study doctor if 
you would like to stay off your HIV medications while in the study, with continued close 
follow up.  
 
If you continue off your HIV meds beyond week 12, your HIV viral load will be monitored 
every week. Your CD4+ counts will be monitored every 2 weeks. You will be asked to 
restart taking your HIV meds for any of the 5 reasons listed above.  
 
Any change in your HIV medication regimen will be done in collaboration with your HIV 
primary care physician. 
 
Pre-Screening 
 
Before screening, you will have had the opportunity to review information about the details 
of the study. You will have the opportunity to talk to the study investigators and ask them 
questions.  
 
 
 
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IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 5 of 15 
 
Revised 3/17/15 
Screening Visit 
 
 Screening will determine whether or not you are eligible for the study.  
 If you agree to be screened, you will sign a copy of the Informed Consent Form 
confirming that you have been informed about the study and voluntarily agree to 
take part. You will be given a signed copy of this consent form and the original 
consent form will be kept in your medical record. 
 You will be asked questions about your general health.  
 If prior results are not available, an HIV test will be performed to confirm HIV-1 
infection. Before having the HIV test, you will be asked to sign a separate informed 
consent form. 
 Up to 30 ml (2 tablespoons) of blood will be drawn to test for Hepatitis B/C, 
syphilis, to evaluate liver and kidney functions, for complete blood count, to see if 
your blood is able to clot (PT/PTT), for a pregnancy test, and to evaluate other 
health conditions.  
 A urine specimen will be collected to check that your kidneys function normally. 
 All sexually active study volunteers will be asked to use a reliable form of 
contraception from 10 days prior to receiving 3BNC117 and for the duration of the 
study, and to use female or male condoms while not taking their HIV medications. 
 Medical history will be obtained and a physical exam will be performed which 
includes measuring your blood pressure, heart rate, respiration, weight, height (at 
screening only) and temperature.   
 You may not be allowed to participate in this study if the tests indicate you have an 
acute or chronic infection, other than HIV, or if you are pregnant or breastfeeding. 
 
If you are a female who can have a baby, a pregnancy test will be required at most study 
visits.  
 
Blood will also be taken to measure the HIV viral load.  We will also measure the CD4 and 
CD8 cell counts. CD4 cells (also called helper T cells) work for the immune system by 
helping other cells in the body fight infections. CD4 cell counts drop during HIV infection. 
Up to 15 ml (1 tablespoon) of blood will be taken for these tests. 
 
Your study doctor will review the results of these tests, your medical history and your 
examination. If your screening test results, medical history and examination are acceptable 
you may participate in the research. 
 
 
Study Participation  
If you want to participate in the research and the research doctor agrees, you will return to 
the clinic for the day 0 visit (visit at which you will receive the study drug).   
 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 6 of 15 
 
Revised 3/17/15 
Some parts of this study are experimental.  Here, the word “experimental” means that the 
test or the investigational agent given is “not part of the usual routine care of patients”. 
Research blood tests will evaluate the amount of HIV in your body after you receive the 
study drug and the function of your blood cells that protect you from infection before and 
after receiving 3BNC117. These tests are experimental. 
 
You will receive two intravenous (IV) doses of 3BNC117 into a vein in your arm. You will 
be followed for a total of 36 weeks after the first 3BNC117 infusion.  
 
Details of the study procedures are found below. 
 
Infusion Visit:  
 
 On day 0 and day 21 you will receive the study drug and you will be monitored for 4 
hours after the study drug is given.  
 In addition you will have the following procedures prior to drug infusion:  
o You will have the opportunity to speak with members of the study team and ask 
any questions; 
o A physical examination will be performed, including your vital signs; 
o You will be asked questions about your health and medications;  
o Up to 10 ml (2 teaspoons) of blood will be drawn to evaluate liver and kidney 
functions, for complete blood count, and for a pregnancy test; 
o Additional blood samples will be collected for research purposes (up to 90 ml or 
6 tablespoons of blood). 
o A urine sample will be collected; 
 
 The study drug will be given directly into your blood stream through a vein in your 
arm. This is called an infusion. The infusion takes approximately 60 minutes. You will 
be closely observed during and for 4 hours after drug infusion. 
 
 On the day following each drug infusion (days 1 and 22) your vital signs will be taken, 
you will receive a repeat physical examination and will be asked about any new 
complaints.  On day 1 you will also receive your HIV medication.  This will be the last 
time you will take your medication for the next 12 weeks.  
 
 
Follow-up visits:  
 
You will be asked to return to the outpatient clinic for a total of 15 visits on weeks 1, 2, 3, 
4, 5, 6, 7, 8, 9, 10, 11, 12, 14, 24, and 36.  
 
If your HIV viral load remains suppressed by week 12 and you choose to remain off your 
HIV medications, you will return to the clinic every week for follow up after week 12. 
During these visits, vital signs will be taken, you will be asked about any changes in your 
medical condition and any new or discontinued medications. Depending on the specific 
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IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 7 of 15 
 
Revised 3/17/15 
study visit, approximately 3-8 tablespoons of blood will be drawn to study any effect of 
3BNC117 on your blood cells, a limited physical examination may be performed, as well 
as a urine pregnancy test. 
 
Blood will also be taken to measure the amount of HIV in your blood at all study visits 
except for Day 1 after receiving the study drug. We will also measure the CD4 and CD8 
cell counts at Weeks 2, 4, 6, 8, 10, 12, 14, and the final study visit. Up to 15 ml (1 
tablespoon) of blood will be taken for these tests at these visits. 
 
Given the close monitoring of safety and extensive research blood draws that will be 
performed over the course of the study, a total blood volume of 550 ml (approximately 34 
tablespoons or 1 pint of blood), but not more than that, will be collected within any 8-week 
period. 
 
Laboratory testing conducted on your blood or tissues during the research study will fall 
into two general categories, 1) New York State-approved tests, and 2) experimental tests 
that have not been certified by New York State.  
 
We will tell you or your doctor about any tests related to the research protocol that are 
performed by a New York State-approved laboratory, if the results may affect your health 
or safety. 
 
In this study, you will not receive routine care for any medical conditions related to this 
protocol or any other medical conditions that you might have. 
 
Your medical information and test results will be written in your Hospital chart.  The 
researchers of the study may also keep separate records with information about you and 
your study tests. 
 
Dr. Caskey and her research team will also keep separate records with information about 
you, including research results. Your name will not appear in these research records. 
 
If we need to get medical information from other doctors or other health care providers 
who have seen you, we will ask you to sign a consent form to get this information. We will 
also ask you to sign a separate form if we need information from other hospitals where you 
have been treated.   
 
 
III. 
What are the risks of taking part in this research study? 
There may be some risks and discomforts in taking part in a research study.  We know that 
these risks and discomforts may happen during this research study: 
 
Investigational Agent: One of the purposes of this study is to determine the side effects of 
3BNC117. This drug, 3BNC117, has been tested in a small group of humans and to date, it 
has been safe and well tolerated. However, side-effects such as those listed below are 
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IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 8 of 15 
 
Revised 3/17/15 
possible with the administration of a monoclonal antibody:  
 
 
 Infusion of monoclonal antibodies may lead to pain or burning at the place where 
the plastic tube enters the skin.  
 
 People can be allergic to many things including antibodies. An allergic reaction 
means that the body is very sensitive to something. If you are allergic to any part of 
the antibody or to the liquid used to mix them, you may develop a rash on your 
skin, fever, chills or trouble breathing. Very rarely, severe allergic reactions may 
result in a severe reaction or even death. The severe reaction is called 
“anaphylaxis”.  
 
 Monoclonal antibodies activate a part of the immune system called complement. 
Activation of complement may cause body aches, sore muscles, fever, chills, 
shakes, pain in the stomach, or pain in the back. 
 
 By joining with other substances in your body, monoclonal antibodies can form 
something called immune complexes. This happens when the antibody and parts of 
the HIV or something like the HIV virus become linked. These complexes can get 
deposited in the kidneys. If this happens you can get blood or protein in the urine. 
Sometimes this can also affect permanently how well your kidneys work. 
 
 3BNC117’s target is the HIV virus, however when it was tested on different human 
tissues outside the body, it was found that 3BNC117 can bind to cells in the 
conjunctival tissue (the lining that covers the inside of the eyelids and the white part 
of the eyes). This binding could lead to inflammation of the eyes, although 
volunteers that have received 3BNC117 to date have not developed symptoms 
suggestive of conjunctival inflammation. 
 
 To avoid these problems your study team will see you very frequently during the 
study and talk to you about how you feel. If you develop eye complaints, you will 
be referred for evaluation by an ophthalmologist. This will be performed at no cost 
to you. Your research team will also examine you and take blood and urine tests. 
You will be told the results of the tests to make sure that you are not having side 
effects from the monoclonal antibody infusion. 
 
 HIV strains (viruses) in your body that are “resistant” to (not blocked by) 3BNC117 
could become detectable in your blood after the infusion of 3BNC117. However, 
3BNC117 does not interfere with approved antiretroviral medications (ART). 
Standard ART should be able to control the growth of these viruses. If resistance 
develops, this may limit your future use of 3BNC117, if it is licensed for clinical 
use by the FDA. 
 With any new medicine or monoclonal antibody, there is a possibility of totally 
unexpected side effects. The Rockefeller University Hospital inpatient unit is 
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IRB APPROVAL DATE: 10/14/2015
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Clinical Investigation Consent Form 
Page 9 of 15 
 
Revised 3/17/15 
equipped for providing emergency medical interventions in the unlikely event of a 
severe allergic or other reaction. In case of an emergency, after you are stabilized 
you will be transferred to the New York Presbyterian Hospital (Cornell) for 
specialized medical care. 
 
 We don’t know how 3BNC117 would affect your baby or your unborn child. If you 
are a woman who can become pregnant, or a male participating in sexual activity 
that could lead to pregnancy, you must agree to practice an effective form of birth 
control before receiving the first 3BNC117 infusion and until the end of the study, 
even after you restart your HIV medication.  If you think that you or your partner is 
pregnant, you should tell your study doctor or nurse at once. If you are a man who 
has sex with men you must use condoms for all sexual activity. 
 
 
Effective forms of birth control for a female include:  
 Abstinence  
 Intrauterine device (IUD) 
 Hormonal [birth control pills, injections, or implants] 
 Tubal ligation 
 
If you are a sexually active male participating in sexual activity that could lead to 
pregnancy and you have not had a vasectomy you must agree to use an effective method of 
contraception from screening until your ‘End of Study’ clinic visit. 
 
 
Pausing your HIV Medication: 
 
 There is the chance that your HIV viral load will increase when you pause your 
HIV medications.  If this happens, your CD4 cell counts might drop. However you 
will be followed very closely and your HIV medications will be restarted if your 
HIV viral load increases to more than 200 copies/ml or if your CD4 count cell drops 
to less than 350 cells/l, two weeks in a row. Should your HIV medications be 
restarted within the first three weeks of the study you will not receive the second 
infusion of 3BNC117.  
 
 Should you become pregnant while pausing your HIV medications the study doctors 
will ask you to restart your medications immediately because there is a chance that you 
could transmit HIV to your unborn child while you are off your medications.  
 
   When your HIV medications are paused, you might experience symptoms similar to 
when you first got HIV, such as fever, rash, swollen glands, headache, sore throat, 
nausea, vomiting. If you develop these symptoms, the study doctors will evaluate 
you and your HIV medications will be resumed if the symptoms are believed to be 
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IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 10 of 15 
 
Revised 3/17/15 
due to increased HIV levels.  
 
   Resistance to your HIV meds might occur, since your HIV pills will be paused for 
about 3 months. In order to decrease that risk, you will be asked to restart your HIV 
pills if your viral load increases to ≥ 200 copies/ml (confirmed by a repeat 
measurement) or ≥ 10,000 copies/ml at any time.  
 
 While you are off your HIV medications, you are at increased risk of transmitting 
HIV to a sexual partner and at increased risk of HIV “superinfection” from an HIV-
infected partner. Therefore you are asked to use male or female condoms during the 
study, particularly while off your HIV medications. If you feel you have been 
exposed to HIV while off your HIV medications, you may restart your medication 
if your HIV primary care physician recommends this.  
 
Blood draw: the risks associated with a blood draw are generally minor.  They are mild 
pain at the needle site (common), local bruising at needle site (rare), infection and fainting 
(extremely rare). 
 
 
Privacy and Confidentiality Risks: There is the risk that there could be computer security 
breaches which could reveal your identity. There may be the risk that data about you may 
become public, and could be used by employers or law enforcement agencies. These 
privacy risks are described in greater detail below. 
 
There may be other risks and discomforts that we do not know about now, but we will tell 
you any new information discovered which might affect your decision to participate or 
remain in the study. 
 
 
IV. 
What are the alternatives to participating in this research study? 
 
You do not have to participate in this research to receive treatment for your HIV infection. 
There are drugs approved for use in the treatment of HIV infection. You may get these 
drugs from your primary care physician. 
 
 
V. 
What are the benefits of taking part in this research study? 
 
You are unlikely to have any direct benefits from participating in this study.  It is possible 
that 3BNC117 will lead to better control of HIV infection, and it may improve the 
treatment of patients with HIV in the future.  
 
VI. 
Who will be able to see the information learned about you in this research 
study? 
 
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Clinical Investigation Consent Form 
Page 11 of 15 
 
Revised 3/17/15 
We will protect your personal information and will do our best to keep this information 
confidential.  We will listen to what you say we may do with this information, and we will 
follow the law.  For example, by New York State law hospitals must inform the New York 
State Department of Health if we find that you have a reportable communicable disease(s), 
such as sexually transmittable diseases like chlamydia, hepatitis, gonorrhea or syphilis. 
Also, the researchers must report to the authorities if they believe that child abuse or 
neglect has happened, or to prevent serious harm to you or others. 
 
Whenever possible, data about you will be unlinked from your name and identified by a 
code.  Sponsors receive your data linked only to a code.  However, auditors and regulators 
from government agencies that oversee research, and people at the Rockefeller University 
Hospital and at Rockefeller University may see your information in the course of their 
duties. 
 
We will share information about you only with the government agency that oversees this 
research, and the people at the Hospital and the Rockefeller University in connection with 
their duties.   
 
During the research study, only the researchers will know that your samples came from 
you, because your stored samples will be identified only by a special code instead of your 
name.  As a result, the others who study your samples will not know that they came from 
you and will not be able to figure out that they came from you.   
 
If the researchers publish the results of this study, they will not mention your name or other 
information that could identify you.  
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as 
required by U.S. Law. This website will not include information that can identify you. At 
most, the website will include a summary of the results. You can search this website at any 
time.'' 
 
 
Genetic Information Nondiscrimination Act 
A Federal law, called the Genetic Information Nondiscrimination Act (GINA), generally 
makes it illegal for health insurance companies, group health plans, and most employers to 
discriminate against you based on your genetic information. Additional information is 
available in the outpatient or inpatient information handbook. 
 
 
 
 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 12 of 15 
 
Revised 3/17/15 
VII. 
What are the payment arrangements? 
 
There is no cost to you for being in this research study. 
 
Payment will be made to participants who fill out a form from The Rockefeller University 
Finance Office and are eligible for and want to receive payment. 
 
There will be no compensation for the screening visit.  Each study volunteer will be paid 
$200 for each 3BNC117 infusion study visit.  You will receive an additional $60 for each 
follow up study visit after the infusion, up to and including week 12.  You will receive 
$100 for the week 14 and 24 visits and the final study visit. If you complete all of the study 
visits, you will be eligible to receive $1,360 in total compensation.   
 
If your HIV viral load remains suppressed by week 12 and you choose to remain off your 
HIV medications, you will return to the clinic every week for follow up after week 12. You 
will be compensated $50 for each of these additional visits. In total, you may receive up to 
$2,260 if you remain off ART until the final study visit at week 36.  
 
If the study doctors ask that you return for an unscheduled visit, you will be compensated 
$25 each time. 
 
Compensation is provided to help cover your travel expenses, as well as child care and time 
lost from gainful employment. If you stop participating in the study before the last study 
visit, you will be paid for the portion of the study you completed.  
 
Dr. Nussenzweig and Dr. Scheid, co-investigators on this study, are inventors of the study 
drug and are named on a patent application for their invention.  Dr. Nussenzweig holds 
equity in Celldex, the manufacturer of the study drug. Dr. Nussenzweig, Dr. Scheid, the 
Rockefeller University, and Celldex may benefit financially if the study drug is licensed to 
a third-party pharmaceutical company. 
 
If research using your samples helps develop a drug or another product that is sold to the 
public, the drug company, the University and the researchers may share in some of the 
profits.  For example, a cell line from your samples could be used to make a product for 
sale.  There are no plans to pay you any money resulting from such discoveries.  However, 
by signing this form, you do not give up any rights you may have. 
 
 
VIII. What happens if you don’t want to stay in this study or your participation is 
ended? 
 
You can choose if you want or do not want to be part of this study.  If you do not join, there 
is no penalty and no one will hold this against you.  If you decide to join this study, you 
may change your mind and stop taking part in this study at any time, and this will not be 
held against you.  Information about you up to that time may stay a part of the study. 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 13 of 15 
 
Revised 3/17/15 
 
During this study, the researchers may learn new information that might make you change 
your mind about whether you want to stay in the study.  You will be given that information 
promptly. 
 
If you decide to join this study but later want to stop, you should let the researchers know. 
The study team would still like to follow all volunteers who received the study drug for 
safety reasons. 
 
The researchers also may stop you from taking part in this study, even if you do not choose 
to stop being in it.  You may be asked to leave the study if: 
 You fail to keep appointments  
 The research study is terminated or canceled by the investigator, the FDA or the 
Rockefeller University Institutional review Board (RU IRB) 
 There is a significant adverse event to you or other participants in the study 
 
 
IX. 
Consent to the use, storage and sharing of your samples or data for separate 
research studies  
 
The scientific value of your samples and the information obtained from them is greatly 
increased if we can share them with other scientists at universities, pharmaceutical and 
technology companies worldwide. May we store, use and share your blood/or tissue 
samples and data with other investigators at the Rockefeller and elsewhere for separate 
studies for many years?  Your samples will either be stripped of information identifying 
them as yours or coded (we will hold the key to the code) so that they cannot be identified 
as having come from you.  Other data related to your sample, but that does not identify you 
may accompany your samples.  
 
Any time in the future, you may withdraw your consent to use any samples that have not 
already been used in research or shared.  If you withdraw your consent, the remaining 
unused samples will be destroyed, unless the samples cannot be identified as having come 
from you. 
 
Would you like us to store, use and share your blood/or tissue samples/associated data as 
described above?   
 
 
 
Yes  
 
 
 
No  
 
  
 
If you say “no” to this question, this will not affect your participation in this study. 
 
 
X. 
Who do you call if a medical problem results from this research study? 
 
If you believe that this study has led to a medical problem, you should call the researcher 
listed below right away.  The investigator will help you to get the appropriate, available 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 14 of 15 
 
Revised 3/17/15 
medical care.   
 
Name: Marina Caskey, MD 
Phone: 212-327-7396 
Fax: 212-327-7234 
E-mail: mcaskey@rockefeller.edu 
 
The Rockefeller University does not plan to pay for medical care that you may have as a 
result of taking part in a research study at The Rockefeller University Hospital.  However, 
you do not give up any rights you may have to seek compensation by signing this form.  
 
 
XI. 
Who do you contact if you have questions about the research study? 
 
Please ask as many questions as you want about this research study and this consent form.  
If you agree to take part in this study and have questions later on, you may contact the 
following researcher:  
 
 
Name: Noreen Buckley, NP 
Phone: 212-327-7394 
Fax: 212-327-7234 
E-mail: nbuckley@rockefeller.edu  
 
If you have any concerns about your experience while taking part in this research study, 
you may contact The Rockefeller University Institutional Review Board (IRB) Office at 
(212) 327-8410, or the Office of Clinical Research at (212) 327-8408.  
 
 
XII. 
May we have permission to contact you about future studies? 
 
May we contact you by phone to find out if you are interested in hearing about new 
research studies?  Contact would be made by the Rockefeller staff of the Clinical 
Research Support Office for Recruitment.  If you decide at any time that you no longer 
want to be contacted, please tell us, and we will stop calling you. 
 
Would you like us to contact you about future research studies?  
 
Yes ____________ 
 
 
No ____________ 
 
If you say “no” to this question, this will not affect your participation in this study. 
 
 
 
 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016


 
Clinical Investigation Consent Form 
Page 15 of 15 
 
Revised 3/17/15 
AGREEMENT TO PARTICIPATE -- SIGNATURES REQUIRED 
 
I have read this consent form, and my questions have been answered. 
 
A copy of this consent form will be given to you.  Please keep a copy of the form as it 
contains important information that you may wish to refer to during the research study and 
thereafter. 
 
I hereby voluntarily consent to take part in this research study.  
 
 
Name of the Study Participant (Print)  
 
 
 
 
 
 
 
Signature of Study Participant 
Date (To Be Filled in by Study Participant) 
 
 
 
 
 
 
Signature of the Person Conducting the Informed Consent Discussion 
 
I have explained the research protocol and this consent form to the participant and have 
answered the participant’s questions about this research study and/or the consent process.  
 
 
Name of Person (Print)  
 
 
 
 
 
 
 
Signature 
of 
Person 
Discussing 
Consent 
 Date (To Be Filled in by Person Discussing   
 Consent) 
 
 
Rockefeller University Institutional Review Board
IRB NUMBER: MCA-0867
IRB APPROVAL DATE: 10/14/2015
IRB EXPIRATION DATE: 10/13/2016

Prot_000.pdf: 
Official title: A phase 2, open label study of the safety, antiretroviral activity and 
pharmacokinetics of 3BNC117 during a short analytical treatment interruption in HIV-
infected subjects 
 
NCT number: NCT02446847 
 
Document date: 09/21/2015 
 


The Rockefeller University 
 
 IND: 118225/0016 
September 21, 2015 
  
PROTOCOL # MCA-0867 
CONFIDENTIAL 
1
 
A phase 2, open label study of the safety, antiretroviral activity and 
pharmacokinetics of 3BNC117 during a short analytical treatment interruption in 
HIV-infected subjects 
 
 
 
 
IND Sponsor:  
The Rockefeller University (Sarah Schlesinger, MD) 
IND # 118225 
 
Principal Investigator/Protocol Chair: 
Marina Caskey MD 
 
Draft or Version Number: 
Version 1.2 
 September 21, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards. The contents of this document shall not be 
disclosed to others without written authorization from The Rockefeller University, unless 
it is necessary to obtain informed consent from potential study participants. 
 
Statement of Compliance 
The clinical trial will be conducted in compliance with the protocol, with the 
International Conference on Harmonization Good Clinical Practice E6 (ICH-GCP), and 
with 45 CFR 46 and 21 CFR 50, 56 and 312. All protocol investigators have completed 
Protection of Human Subjects Training. 
 


The Rockefeller University 
 
 IND: 118225/0016 
September 21, 2015 
  
PROTOCOL # MCA-0867 
CONFIDENTIAL 
2
 
 
Signature Page 1 
 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines. 
 
The Lead Principal Investigator (Protocol Chair) should sign Signature Page 1. A copy of 
this Signature Page 1 should be filed with the holder of the Regulatory documents and a 
copy should be maintained at the site. 
 
 
Principal Investigator: _______________________________________________ 
Print/Type 
 
Signed: ______________________________      Date:  ____________________ 
Name/Title  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


The Rockefeller University 
 
 IND: 118225/0016 
September 21, 2015 
  
PROTOCOL # MCA-0867 
CONFIDENTIAL 
3
 
 
Signature Page 2 
 
 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and 
according to local legal and regulatory requirements and applicable U.S. federal 
regulations and ICH guidelines.  
 
The Investigator(s) of Record (signature(s) on 1572) from each participating clinical site 
should sign the Signature Page 2 as appropriate. This Signature Page 2 should be 
maintained at each site. 
 
 
Investigator(s) of Record: _______________________________________________ 
Print/Type 
Signed: _________________________________  Date: ______________________ 
Name/Title 
 
Additional Investigators: _______________________________________________ 
Print/Type 
Signed: ________________________________   Date: ______________________ 
Name/Title 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


The Rockefeller University 
 
 IND: 118225/0016 
September 21, 2015 
  
PROTOCOL # MCA-0867 
CONFIDENTIAL 
4
 
 
TABLE OF CONTENTS 
1 
KEY ROLES ....................................................................................................................................... 12 
1.1 
INSTITUTIONS ............................................................................................................................................. 12 
1.2 
INDIVIDUALS ............................................................................................................................................... 13 
2 
LAY SUMMARY ................................................................................................................................ 14 
3 
OBJECTIVES AND RATIONALE ................................................................................................... 14 
3.1 
INTRODUCTION .......................................................................................................................................... 14 
3.1.1 
Background ............................................................................................................................................. 14 
3.1.2 
The Investigational Product, 3BNC117 ...................................................................................... 18 
3.1.3 
Preclinical Toxicity Studies with 3BNC117 .............................................................................. 19 
3.1.4 
Clinical Experience with 3BNC117 ............................................................................................... 20 
3.2 
HYPOTHESIS ............................................................................................................................................... 21 
3.3 
AIMS ............................................................................................................................................................. 21 
3.4 
PRIMARY OUTCOME(S)............................................................................................................................. 22 
3.5 
SECONDARY OUTCOME(S) ....................................................................................................................... 22 
4 
STUDY DESIGN ................................................................................................................................ 22 
5 
STUDY POPULATION .................................................................................................................... 24 
5.1 
INCLUSION CRITERIA: ............................................................................................................................... 24 
5.2 
EXCLUSION CRITERIA: .............................................................................................................................. 25 
6 
METHODS AND PROCEDURES ................................................................................................... 25 
6.1 
SCREENING PROCEDURE AND STUDY VISITS ........................................................................................ 25 
6.1.1 
Pre-Screening Questionnaire .......................................................................................................... 26 
6.1.2 
Screening Visit ........................................................................................................................................ 26 
6.1.3 
3BNC117 Infusion Visits .................................................................................................................... 27 
6.1.4 
Post-3BNC117 Administration Visits ........................................................................................... 28 
6.1.5 
ART interruption and reinitiation of combination ART ..................................................... 28 
6.1.6 
Final Visit/Early termination Visit ............................................................................................... 29 
6.1.7 
Discontinuation of 3BNC117 infusion and/or volunteer withdrawal from study .. 29 
6.2 
STUDY PROCEDURES ................................................................................................................................. 31 
6.2.1 
Consent Procedure ............................................................................................................................... 31 
6.2.2 
Study Assignment ................................................................................................................................. 32 
6.2.3 
3BNC117 Administration Procedure ........................................................................................... 32 
6.2.4 
Medical History and Physical Examination .............................................................................. 32 
6.2.5 
Blood Collection and Shipment ...................................................................................................... 33 
6.2.6 
Monitoring for cytokine release associated adverse events and treatment of 
cytokine release syndrome ............................................................................................................................... 33 
6.2.7 
Family Planning Counseling ............................................................................................................ 34 
6.2.8 
Compensation ......................................................................................................................................... 34 
6.2.9 
Safety Assessments ............................................................................................................................... 34 
6.2.10 
Viral Sensitivity, Antiretroviral and Immunogenicity Assessments ........................... 35 
6.2.11 
Pharmacokinetic evaluations ....................................................................................................... 38 
7 
INVESTIGATIONAL PRODUCT ................................................................................................... 38 
7.1 
REGIMEN ..................................................................................................................................................... 38 


The Rockefeller University 
 
 IND: 118225/0016 
September 21, 2015 
  
PROTOCOL # MCA-0867 
CONFIDENTIAL 
5
7.2 
STORAGE AND SHIPMENT OF THE INVESTIGATIONAL PRODUCT ....................................................... 38 
7.3 
DISPENSING AND HANDLING OF INVESTIGATIONAL PRODUCT.......................................................... 38 
7.4 
ACCOUNTABILITY AND DISPOSAL OF USED AND UNUSED INVESTIGATIONAL PRODUCT .............. 39 
8 
DATA ANALYSIS ............................................................................................................................. 39 
8.1 
DESIGN ........................................................................................................................................................ 39 
8.2 
ANALYSIS OF ANTIRETROVIRAL EFFECTS, SAFETY AND PHARMACOKINETICS ............................... 40 
8.3 
SAMPLE SIZE CONSIDERATIONS .............................................................................................................. 42 
9 
DATA AND SAMPLE STORAGE ................................................................................................... 43 
10 
RECRUITMENT PLAN ................................................................................................................. 44 
11 
POTENTIAL BENEFITS TO SUBJECTS ................................................................................... 44 
12 
POTENTIAL RISKS TO THE SUBJECT INCLUDING TO THE FETUS .............................. 44 
13 
PROCEDURES TO MINIMIZE RISK ......................................................................................... 46 
14 
ALTERNATIVE METHODS OR TREATMENTS ..................................................................... 48 
15 
DATA AND SAFETY MONITORING PLAN ............................................................................. 48 
15.1 
SAFETY MONITORING COMMITTEE...................................................................................................... 48 
15.2 
SAFETY REVIEW ...................................................................................................................................... 50 
15.3 
MONITORING ........................................................................................................................................... 50 
15.4 
ADVERSE EVENT CLASSIFICATION ....................................................................................................... 50 
15.5 
REPORTING ADVERSE EVENTS ............................................................................................................. 50 
15.6 
REPORTING UNANTICIPATED AES:...................................................................................................... 50 
15.7 
CLINICAL LABORATORY IMPROVEMENT AMENDMENT/CLINICAL LABORATORY EVALUATION 
PROGRAM (CLIA/CLEP) .................................................................................................................................... 50 
15.8 
TOXICITY MANAGEMENT AND STOPPING RULES .............................................................................. 50 
16 
CLINICAL TRIAL REGISTRATION ........................................................................................... 51 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


The Rockefeller University 
 
 IND: 118225/0016 
September 21, 2015 
  
PROTOCOL # MCA-0867 
CONFIDENTIAL 
6
 
List of Abbreviations 
 
3BNC117 
Anti-HIV-1 bNAb targeting the CD4 binding site of gp120 
Ab 
Antibody 
AE 
Adverse Event/Adverse Experience 
ART 
Antiretroviral Therapy 
ATI 
Analytic Treatment Interruption 
bNAbs 
Broadly Neutralizing Antibodies 
CD4 
T-cell Surface Glycoprotein CD4 
CFR 
Code of Federal Regulations 
cGMP 
Current Good Manufacturing Practices 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF  
Case Report Form 
CRSO  
Clinical Research Support Office 
CTSA  
Clinical and Translational Science Award 
CCTS  
Center for Clinical and Translational Science 
DC  
Dendritic Cell 
DNA 
Deoxyribonucleic Acid 
DSMB  
Data and Safety Monitoring Board 
FDA  
Food and Drug Administration 
FWA  
Federal-Wide Assurance 
GCP  
Good Clinical Practice 
gp120 
HIV-1 Envelope Glycoprotein 120 
HIPAA  
Health Insurance Portability and Accountability Act 
HIV-1  
Human immunodeficiency virus 
hu-mice 
Humanized Mice 
ICF  
Informed Consent Form 
ICH  
International Conference on Harmonization 
I.M.  
Intramuscularly 
IND  
Investigational New Drug 
IRB  
Institutional Review Board 
I.V.  
Intravenously 
N  
Number (typically refers to participants) 
NIAID  
National Institute of Allergy and Infectious Diseases, NIH 
NIH  
National Institutes of Health 
OHRP  
Office for Human Research Protections 
OHSR  
Office for Human Subjects Research 
PBMC 
Peripheral Blood Mononuclear Cell 
PI  
Principal Investigator 
RU  
The Rockefeller University 
RUH  
The Rockefeller University Hospital 
QA  
Quality Assurance 
QC  
Quality Control 
RNA 
Ribonucleic Acid 
SAE  
Serious Adverse Event/Serious Adverse Experience 
S.C.  
Subcutaneously 
SHIV 
Chimeric Simian/Human Immunodeficiency Virus 
SOP  
Standard Operating Procedure 
T cell 
T lymphocyte 
V3 loop 
 
Third Variable Loop of the HIV-1 Virion Envelope Glycoprotein 120 
 
 
 


The Rockefeller University 
 
 IND: 118225/0016 
September 21, 2015 
  
PROTOCOL # MCA-0867 
CONFIDENTIAL 
7
 
Study Schema 
Title 
A phase 2, open label study of the safety, antiretroviral activity and 
pharmacokinetics of 3BNC117 during a short analytical treatment interruption in 
HIV-infected subjects 
Short Title 
3BNC117 mAb in HIV-infected subjects during treatment interruption 
Protocol 
Number 
MCA-0867 
Phase 
Phase 2 
IND Sponsor 
The Rockefeller University (Sarah Schlesinger, MD) 
 
Study 
Center(s) 
The Rockefeller University (RUH), New York, NY 
 
Principal 
Investigator 
Marina Caskey, MD 
 
Study Design 
 
The proposed study is a Phase II, open label study to evaluate the safety and 
antiretroviral activity of two and four infusions of 3BNC117 in HIV-infected 
subjects on combination ART during a brief analytical treatment interruption 
(Figure 1, Study design). PK assessments are also included.  
 
The subject’s viral sensitivity to 3BNC117 will be tested by outgrowing the 
subject’s virus followed by a TZM-bl assay as previously described (Trkola et al., 
2005a) (Mehandru et al., 2007a). After meeting enrollment criteria sixteen 
subjects with 3BNC117 sensitive virus (<2µg/ml IC50) will receive two (Group A) 
or four (Group B) intravenous infusions of 3BNC117, administered at 30 mg/kg as 
shown below (Figure 1)  
 
Enrollment in Group B will start with a mini cohort of three subjects. These 3 
subjects will receive 2 doses of 3BNC117, administered 2 weeks apart.  Following 
the week 3 visit for the third subject, the Safety Monitoring Committee (SMC) 
will review all available safety data.  The SMC will then provide a 
recommendation regarding administration of a third dose.  If the SMC determines 
it is safe to proceed, the third dose will be administered 2 weeks following the 
second dose and the fourth dose will follow two weeks later. Two weeks after the 
third subject in Group B receives the fourth dose, all available safety data will be 
reviewed by the SMC.  If the SMC determines it is safe to proceed, additional 
subjects will be enrolled to receive 4 doses at 2-week intervals.  
 
In both dosing groups, antiretroviral therapy will be discontinued 2 days after the 
first 3BNC117 infusion (day 2) until week 12. ART regimen will be resumed 
sooner if plasma HIV-1 RNA level is ≥ 200 copies/ml or if CD4+ count drops < 
350 cells/µl and either result is confirmed upon repeat measurement during the 
next weekly scheduled visit. If plasma HIV-1 RNA level is ≥ 1,000 copies/ml, the 
participant will be asked to return for a repeat measurement prior to the next 
scheduled visit, and ART will be resumed if results are confirmed. ART will also 
be resumed early if the participant becomes pregnant, or if otherwise clinically 
indicated. If ART regimen is resumed before completion of 3BNC117 infusions, 
further 3BNC117 infusions will not be performed. 
 
All subjects will be followed weekly until week 12 for safety assessments and for 
monitoring plasma HIV-1 RNA levels. CD4+ T cell counts will be monitored 
every 2 weeks until week 12. After week 12 subjects will be followed as outlined 
in the Time of Events Schedule (Appendix A). Subjects will be offered a 
continuation of the treatment interruption through week 36 in conjunction with 
their primary care physician as long as viral rebound does not occur (Extension 


The Rockefeller University 
 
 IND: 118225/0016 
September 21, 2015 
  
PROTOCOL # MCA-0867 
CONFIDENTIAL 
8
Phase). In the extension phase of the study, subjects will return for follow up 
every week, while off ART. ART resumption will follow same criteria as detailed 
above. 
 
Safety and PK assessments will be performed at multiple time points following 
3BNC117 infusions (see Appendix A). Subjects will be followed for 36 weeks 
from enrollment. 
 
Figure 1. Study Design: 
Group A 
 
Group B 
 
Study Duration 
36 weeks 
Objectives 
- 
The primary objectives of the study are to evaluate the effect of two and four 
infusions of 3BNC117 at 30 mg/kg in delaying virologic rebound and 
maintaining viral suppression during a short analytical treatment interruption; 
and to evaluate its safety, tolerability and pharmacokinetic profile in HIV-
infected subjects with suppressed viremia during a short analytical treatment 
interruption. 
- 
The secondary objective is to determine the range of 3BNC117 serum levels 
at which virologic rebound occurs and to compare the effect of two and four 
infusions of 3BNC117 at 30 mg/kg in delaying virologic rebound and 
maintaining viral suppression during a short analytical treatment interruption. 
- 
Exploratory objectives are to phylogenetically compare viruses grown from 
PBMCs collected from subjects while on ART to rebound viruses collected 
after treatment interruption and analyze the induction of escape mutations that 
might arise after administration of 3BNC117. Furthermore, we plan to 
evaluate HIV-1 specific T and B cell immune responses following 
administration of 3BNC117 and the effect of 3BNC117 on cell associated 
HIV DNA and RNA.  
Number 
of 
Subjects 
16 


The Rockefeller University 
 
 IND: 118225/0016 
September 21, 2015 
  
PROTOCOL # MCA-0867 
CONFIDENTIAL 
9
Study 
Population 
Adults, male and female, ages 18-65 with well-controlled HIV-1 infection on 
standard ART. 
Inclusion 
and 
Exclusion 
Criteria 
 
Inclusion Criteria: 
o 
Age 18 to 65 
o 
HIV-1 infection confirmed by ELISA and immunoblot. 
o 
Plasma HIV-1 RNA < 50 copies/ml for at least 12 months while 
on combination ART and < 20 copies/ml at the screening visit. 
[Note: One or two viral blips of < 200 copies/mL prior to 
enrollment are permitted if preceded and followed by test results 
showing VL less than or equal to 50 copies/mL on the same 
ARV regimen.] 
o 
3BNC117 sensitivity (IC50 < 2 µg/ml) of subject derived HIV-1 
virus isolates. These are isolated under protocol MCA-823 by 
co-culture of subject PBMCs with HIV-uninfected donor 
PBMCs followed by in vitro neutralization assays as previously 
described (Mehandru et al., 2007a) (Trkola et al., 2005a). 
o 
Current CD4 cell count > 500 cells/µl and no prior CD4 cell 
count < 200 cells/µl. 
o 
Willing to interrupt antiretroviral treatment for 12 weeks, or 
until viral rebound occurs. 
o 
If sexually active male or female, and participating in sexual 
activity that could lead to pregnancy using an effective method 
of contraception throughout the study period. Subjects should 
also agree to use a male or female condom during the time of 
pausing their HIV medication. 
o 
If on an NNRTI-based regimen willing to switch for 4 weeks to 
dolutegravir. 
 
Exclusion Criteria:  
o 
Have a history of AIDS-defining illness within 1 year prior to enrollment 
o 
History of systemic corticosteroids, immunosuppressive anti-cancer, or 
other medications considered significant by the trial physician within the 
last 6 months; 
o 
Chronic hepatitis B or hepatitis C; 
o 
Patient report, or chart history, of significant coronary artery disease, 
myocardial 
infarction, 
percutaneous 
coronary 
intervention 
with 
placement of cardiac stents; 
o 
Patient report, or chart history, of diabetes type 1 or 2 and/or current use 
of insulin or oral hypoglycemic medications; 
o 
Uncontrolled hypertension, as defined by a systolic blood pressure > 180 
and/or diastolic blood pressure > 120, in the presence or absence of anti-
hypertensive medications; 
o 
Any other clinically significant acute or chronic medical condition, such 
as autoimmune diseases, that in the opinion of the investigator would 
preclude participation; 
o 
Current cigarette use in excess of 1 pack per day; 
o 
Laboratory abnormalities in the parameters listed below:  
o 
Absolute neutrophil count ≤ 1,000 
o 
Hemoglobin ≤ 10 gm/dL 
o 
Platelet count ≤ 125,000 
o 
ALT ≥ 2.0 x ULN 
o 
AST ≥ 2.0 x ULN 
o 
Total bilirubin ≥ 1.5 ULN  
o 
Creatinine ≥ 1.1 x ULN 
o 
Coagulation parameters ≥ 1.5 x ULN; 


The Rockefeller University 
 
 IND: 118225/0016 
September 21, 2015 
  
PROTOCOL # MCA-0867 
CONFIDENTIAL 
10
o 
Current antiretroviral regimen includes either maraviroc or enfuvirtide; 
o 
Pregnancy or lactation; 
o 
Any vaccination within 14 days prior to 3BNC117 administration; 
o 
Receipt of any monoclonal antibody therapy of any kind in the past; 
o 
Participation in another clinical study of an investigational product 
currently or within past 12 weeks, or expected participation during this 
study; 
o 
History of resistance to two or more antiretroviral drug classes; 
 
Study Product, 
Dose, 
Route, 
Regimen 
3BNC117 is a recombinant, fully human monoclonal antibody (mAb) of the 
IgG1κ isotype that specifically binds HIV envgp120. It is composed of 1,318 
amino acids with a calculated molecular weight of 146,280 Dalton.  
 
In Group A, one intravenous infusion of 3BNC117 mAb will be administered on 
day 0 and a second infusion on day 21 via a peripheral vein over 60 minutes. 
 
In Group B, four intravenous infusions of 3BNC117 mAb will be administered on 
day 0, day 14, day 28 and day 42.  
 
Dose level to be tested: 30 mg/kg. 
 
Statistical 
Methodology 
In this study “occurrence of rebound during treatment interruption” and “time 
from treatment interruption until rebound occurs” are response variables.  A one 
sided less Binomial Test with Clopper-Pearson confidence interval at 95% for 
proportion of rebound will allow us to determine the population probability for the 
first variable, “occurrence of rebound”, with 95% of statistical significance level. 
As such, a sample size of 8 HIV-infected individuals will allow us to reject the 
null hypothesis (p(rebound)=1) with at least 80% power for any effect size of 
0.18, which means the null hypothesis will be rejected with desired power, if at 
least 4 out of 8 subjects enrolled in study group B do not rebound by week 8 (2 
weeks after last 3BNC117 infusion). If 5 or more participants in group B 
experience viral rebound prior to study week 6 [2 weeks after the third 3BNC117 
infusion], additional participants will not undergo ATI. 
 
 Kaplan-Meier survival curves will be used to address the second variable, “time 
to rebound”. 
 
The number and percentage of subjects experiencing one or more AEs will be 
summarized by relationship to study drug, and severity. AEs will also be 
summarized by severity grade and by relationship to study drug according to the 
DAIDS AE Grading Table. The CTCAE v4.03 grading scale will be used for 
reporting and grading adverse events related to infusion reactions and cytokine 
release syndromes (Appendix B). Changes will be calculated relative to the values 
collected at baseline.  
 
Pharmacokinetic parameters will be calculated using standard non-compartmental 
analysis methods. The time to rebound and the concentration of 3BNC117 at the 
time of rebound will be determined and summarized using confidence intervals. 
 
A 95% repeated measures ANOVA F-test will be used to compare the following 
variables, before the first infusion and at 8 weeks after the first infusion if viral 
rebound does not occur: 
• 
levels of plasma HIV-1 RNA by single copy assay;  
• 
levels of cell-associated HIV-1 RNA  and DNA;  


The Rockefeller University 
 
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The frequency and levels of anti-3BNC117 antibodies will be calculated and 
displayed in tables. Genotyping of HIV isolates will be performed to 
phylogenetically compare viruses grown from PBMCs collected from subjects 
while on ART to rebound viruses collected after treatment interruption. Amplified 
HIV envelope genes will be cloned and expressed in pseudoviruses in order to test 
for resistance to 3BNC117 in TZM-bl assays. These results will be descriptive.  
 
 
 


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1 
Key Roles 
1.1 
Institutions 
 
Study Sites: 
- The Rockefeller University Hospital, New York NY  
1230 York Ave. 
New York, NY 10065 
Contact Person: Marina Caskey, MD 
Phone Number: (212) 327-7396 
Fax Number: (212) 327-7234 
E-mail: mcaskey@mail.rockefeller.edu 
 
Clinical Laboratories: 
- Memorial Sloan Kettering Cancer Center 
1275 York Avenue 
NY, NY 10065 
 
- LabCorp 
330 W 58th St 
New York, NY, 10019 
 
Funder: The Bill and Melinda Gates Foundation 
 
Data Management:  
EMMES Corporation 
401 N. Washington St. Suite 700 
Rockville, MD 20850 
 
Independent Safety Monitoring:  
International AIDS Vaccine Initiative (IAVI) 
125 Broad Street, 9th Floor 
New York, NY 10004  
 
 


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1.2 
Individuals 
 
 
 
 
 
Principal Investigator: 
Marina Caskey, MD 
Assistant Professor of Clinical Investigation 
The Rockefeller University 
1230 York Avenue, NY, NY 10065 
Phone Number: 212 327-7396 
Fax Number: 212 327-7234 
E-mail: mcaskey@mail.rockefeller.edu 
 
Co-Investigators: 
Johannes Scheid, MD, PhD 
Sarah Schlesinger, MD 
Michel Nussenzweig, MD, PhD 
Florian Klein, MD 
Leah Burke, MD 
Yehuda Cohen, MD 
Allison Settler, ANP 
Sonya Hadrigan, ANP 
Arlene Hurley, ANP 
Irina Shimeliovich, MD, PhD 
Maggi Pack, PhD 
Sivan Ben Avraham Shulman, MPH 
Rebeka Levin, RN, BSN 
 
Collaborators: 
Mike Seaman, PhD  
Frank Maldarelli, MD 
Richard Koup, MD 
Georgia Tomaras, PhD / David Montefiori, PhD 
 
Consultants: 
Roy Gulick, MD, MPH 
 


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2 
Lay Summary 
Despite the major success of combination antiretroviral therapy (ART) in suppressing 
viral replication and preventing disease progression, HIV-1 infection persists. When 
combination ART is discontinued, viral load levels rebound within 2-3 weeks in most 
subjects. 3BNC117 is a potent neutralizing anti-HIV antibody isolated and cloned in Dr. 
Nussenzweig’s laboratory. In preclinical studies carried out in humanized mice and non-
human primates, 3BNC117 alone or in combination with other neutralizing antibodies led 
to protection from HIV or chimeric simian/human immunodeficiency virus (SHIV) 
infection, and also to sustained suppression of HIV plasma viremia. Moreover, 3BNC117 
alone prevented rebound of viral load after ART was discontinued in humanized mice. 
The aims of this protocol are to evaluate the effect of two and four infusions of 3BNC117 
at 30 mg/kg in delaying virologic rebound and maintaining viral suppression during a 
short analytical treatment interruption. In addition, the study will evaluate the safety of 
3BNC117 infusions during a brief analytical ART interruption. 
 
 
3 
Objectives and Rationale 
 
3.1 
Introduction 
 
3.1.1 Background 
Transmission of HIV continues at staggering rates in many areas of the world and AIDS 
is a major source of human morbidity and mortality worldwide. Despite intense research 
for over 30 years, an effective vaccine against HIV-1 remains elusive, and there are no 
vaccine candidates approaching licensure.  
 
Despite the major success of combination antiretroviral therapy (ART) in suppressing 
viral replication and preventing disease progression, HIV-1 infection persists and is not 
eliminated by available antiretroviral drugs. When ART is discontinued, virological 
rebound occurs within 2-3 weeks in most subjects (Davey et al., 1999) (Strategies for 
Management of Antiretroviral Therapy Study et al., 2006). Even in the context of 
suppressive ART, HIV infection is characterized by persistent low level HIV-1 viremia 
and immune activation and cell-associated HIV-1 remain relatively stable (Deeks et al., 
2013). Studies have shown that intensified antiretroviral regimens do not affect low level 
viremia and do not result in lower levels of HIV-1 persistence (Markowitz et al., 2014; 
McMahon et al., 2010). Therefore, additional HIV treatment modalities are required. 
   
A fraction of HIV-infected individuals (10 – 30%) mount a serologic response that can 
neutralize a broad spectrum of HIV-1 isolates(Simek et al., 2009). Although broadly 
neutralizing antibodies that arise during HIV infection fail to resolve established 
infection, the selection of resistant strains indicates that bNAbs exert selective pressure 
on the virus. Importantly, several different groups of investigators have shown that 
macaque chimeric simian/human immunodeficiency virus (SHIV) infection can be 
prevented by passive transfer of broadly neutralizing anti-HIV-1 monoclonal antibodies, 
(Shingai et al., 2013). Broadly neutralizing antibodies might also play a role in the 
treatment of HIV infection. 


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Broadly neutralizing antibodies (bNAbs) differ from other therapeutic modalities for HIV 
in several respects. First, they can neutralize the pathogen directly; second, they have the 
potential to clear the virus and infected cells through engagement of innate effector 
responses; and third, immune complexes produced by the passively transferred antibodies 
may enhance the immune response to HIV. In fact, recent data show that a subset of 
bNAbs may inhibit cell-to-cell transmission of HIV at very low concentrations (Malbec 
et al., 2013). Experiments in humanized mice and non-human primates indicate that 
combinations of bNAbs can lead to rapid virological suppression that is sustained for as 
long as mAb levels are maintained above a certain threshold(Barouch et al., 2013).  
 
In SHIV-infected nonhuman primates 3BNC117 induces rapid viral suppression as 
monotherapy (7). Also, 3BNC117 monotherapy is able to prevent infection in macaques 
challenged with SHIVAD8EO or SHIVDH12-V3AD8 more effectively than the previously 
described antibody VRC01(10). While antibody monotherapy did not control HIV-1 
infection in viremic, untreated hu-mice, a single neutralizing antibody, i.e. 3BNC117, 
was able to sustain undetectable viral loads after initial suppression by antiretroviral 
therapy. Whereas hu-mice that received ART normally rebounded immediately after the 
drugs were terminated, continuing a single antibody was sufficient to maintain control 
after ART interruption in 50-86% of the hu-mice, for as long as antibody concentrations 
remained therapeutic (Horwitz et al., 2013). Mice that escaped 3BNC117 carried 
resistance mutations in the CD4bs at positions YU2(279-281) or YU2(458/459). In contrast, 
viruses that emerged after immunotherapy was terminated did not contain antibody 
resistance mutations and remained sensitive to neutralization by the antibody.  
 
The SMART randomized trial demonstrated that episodic ART, guided by drop in CD4+ 
count (ART reinitiated if CD4+ count < 250 cells/µl), leads to increased risk of 
opportunistic infections or death from any cause, as compared with continuous ART, 
during a median follow-up time of 16 months (Strategies for Management of 
Antiretroviral Therapy Study et al., 2006). While structured treatment interruptions 
(STIs) have traditionally been avoided given safety concerns, it should be noted that, in 
the first 16 weeks following randomization into the SMART study, there were no deaths 
in either treatment group – those that received continuous ART or those that received 
episodic ART guided by CD4 count.  In addition, the differences in risk of opportunistic 
diseases and major cardiovascular, renal, and hepatic diseases between the two groups 
occurred predominantly after 16 weeks, increased over time and were strongly associated 
with low CD4 counts as well as increased viral loads. Recent evidence suggests that short 
analytical treatment interruption (limited to a maximum of 16 weeks), in individuals with 
preserved CD4 count and virologic suppression, is safe and is an accepted tool to 
evaluate new therapeutic modalities(Kutzler and Jacobson, 2008).  
 
Passive administration of less potent, first generation anti-HIV-1 bNAbs has been 
evaluated in ART-interruption settings in humans. In these studies, 13-16 antibody 
infusions were administered intravenously at doses ranging from 0.5 to 2 g and were 
generally found to be safe and well tolerated. Furthermore, one of the antibodies (2G12) 
seemed to delay viral rebound in several participants. This effect was rather limited, as 


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2G12 did not neutralize the donor’s virus isolates with sufficient potency(Trkola et al., 
2005a) (Mehandru et al., 2007a). However, both studies found some correlation between 
the baseline sensitivity of the subject’s virus to the antibody 2G12 and this antibody’s 
ability to delay viral rebound. Therefore, we will test for the sensitivity of the subject’s 
virus to 3BNC117 before the screening visit (under protocol MCA-823). Based on 
previous data (Scheid et al., 2011) sensitivity to 3BNC117 will be defined by an IC50 titer 
< 2µg/ml. The sensitivity testing will be repeated on day 0, after 3BNC117 infusions, and 
after viral rebound. It will be performed as previously described (Trkola et al., 2005a) 
(Mehandru et al., 2007a) (Laird et al., 2013) by outgrowing the subject’s virus at the 
Laboratory of Molecular Immunology, followed by a TZM-bl assay in the laboratory of 
Dr. Michael Seaman.  
 
Since highly potent second generation bNAbs have not been evaluated before in the 
setting of ART-interruption in humans, it is not known which serum antibody levels will 
be required to prevent viral rebound. In humanized mice, levels of 3BNC117 decreased 
to levels as low as 0.5 µg/ml (10 times the IC50 value for the HIV strain used) before viral 
rebound occurred during ART-interruption (Horwitz et al., 2013). In the setting of 
antibody monotherapy in macaques, 3BNC117 serum levels above 1-10µg/ml (10-100 
times the IC50 value for the respective strain) were required to prevent rebound (Shingai 
et al., 2013). Based on the PK data from the first clinical trial with 3BNC117, MCA-835 
(Caskey et al., 2015) we designed the first group of this trial, Group A, to maintain 
3BNC117 serum levels above 50 µg/ml (25 times the IC50 value of the respective patient 
virus) for at least 5 weeks after starting ATI. This allows us to investigate the ability of 
3BNC117 to prevent viral rebound beyond the period of 2-3 weeks, during which 
rebound usually occurs in the setting of ATI (Davey et al., 1999; SMART Study et al., 
2006; Rothenberger et al., 2015).  
 
Eight subjects have enrolled in this protocol to date (Group A). Preliminary results show 
that the administration of 3BNC117 at 30mg/kg in the setting of an ATI is safe. Most 
reported adverse events were transient and considered of grade 1 severity. Participants 
did not report symptoms consistent with acute retroviral syndrome. To date, seven 
subjects have received the second 3BNC117 infusion (MCA867-701, -702, -703, -704, -
706, -707, -708). Viral rebound has occurred in all seven participants; it occurred at week 
9 in participants MCA867-707 and -708, at week 6 in participants MCA867-701 and -
704, at week 5 in participants -702 and -703, and at week 4 in participant -706 (of note, 
this participant’s viral load was 50 copies/ml at day 0). ART reinitiation led to rapid 
decrease in viral loads in all participants with measurements after ART reinitiation. 
Compared to historic controls who did not receive antibody treatment and showed viral 
rebound after 2-3 weeks after ART interruption, two infusions of 3BNC117 appear to 
delay viral rebound (Davey et al., 1999; SMART Study et al., 2006, Rothenberger et al., 
2015).  
 
 
 
 


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Figure 2. Plasma HIV-1 RNA Levels and 3BNC117 serum levels in Participants 
Enrolled in Study Group A*.  
 
* MCA867-705 and -706 viral loads were not fully suppressed at day 0 and are not displayed in this graph.    
 
According to preliminary results in Group A of MCA-867, serum levels of 3BNC117 can 
decrease to levels as low as 66 μg/ml at week 5 (Figure 2). Experiments in mice and 
macaques suggest that antibody levels 10-100 times the IC50 value against infecting viral 
strains are necessary to control viral rebound. 3BNC117 levels achieved with Group A’s 
dosing regimen, therefore, might only be sufficient to suppress viremia up to week 5. 
This might explain why viral rebound occurred at 4 to 9 weeks in the first 7 participants 
enrolled in this protocol.  
 
In order to test if viral suppression can be further prolonged by 3BNC117 alone, we 
propose an amendment to this protocol to modify and optimize the dosing regimen. 
Enrollment in Group A will be closed. Additional participants will enroll in a new study 
group (Group B) and will receive four 3BNC117 infusions at 30mg/kg on day 0, day 14, 
day 28 and day 42. By decreasing the interval between 3BNC117 infusions and adding 2 
infusions, we expect to maintain higher levels of 3BNC117 over a longer time period 
and, therefore, achieve continued viral suppression during the 3BNC117-dosing period 
and maintain viral suppression. Given the safety profile of 3BNC117 to date, we believe 
this modification does not significantly increase the risk to trial participants, while it 
enhances our ability to evaluate if 3BNC117 can maintain viral suppression during a brief 
analytical treatment interruption. However, as 3BNC117 has not been administered four 
times to single individuals to date, enrollment in Group B will be staggered, as described 
in Section 4. Study Design.  
 
One of the aims of this study is to evaluate the effect of two or four 3BNC117 infusions 
on delaying viral rebound in subjects infected with 3BNC117-sensitive virus, when ART 
is discontinued. In addition the study will evaluate if viral suppression can be maintained 
with four infusions of 3BNC117 given at 14-day intervals. Finally, we will determine the 


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range of 3BNC117 serum levels at which viral rebound occurs and which escape 
mutations mediate viral rebound. Lastly, safety and pharmacokinetic evaluations will be 
performed.  
 
3.1.2 The Investigational Product, 3BNC117 
3BNC117 is a broadly neutralizing and highly potent anti-HIV-1 antibody. 3BNC117 
was initially cloned from one B cell isolated from a volunteer infected with HIV-1 clade 
B, who controls his HIV-1 infection without antiretroviral therapy. The initial study was 
conducted under protocol MNU-0628. 3BNC117 targets the CD4 binding site (CD4bs) 
within HIV-1 envelope gp-120. It showed an average IC80 on a combined group of 95 tier 
2 viruses of 1.4 µg/ml when evaluated by in vitro neutralization assays (Scheid et al., 
2011). 3BNC117 also showed in vivo activity in experiments in both humanized mice and 
non-human primates. In chronically infected animals, passive administration of 
3BNC117 alone or in combination with other potent neutralizing antibodies suppressed 
plasma viremia to levels below detection (Shingai et al., 2013) (Barouch et al., 2013). 
Moreover, 3BNC117 administration protected both humanized mice (Gruell et al., 2013) 
and rhesus macaques (Shingai et al., 2013) from challenge with HIV-1 and tier 2 SHIVs, 
respectively.  
 
3BNC117 has been manufactured for clinical use under cGMP by Celldex Therapeutics.   
The manufacture of the recombinant human monoclonal 3BNC117 was carried out by in 
vitro serum-free CHO cell culture. 3BNC117 was manufactured as a sterile solution 
intended for parenteral use, in compliance with Good Manufacturing Practices (GMP). 
No animal-derived raw materials were used during the cell culture, purification, and 
formulation of the drug substance. The drug substance was manufactured in a dedicated 
suite utilizing single-use equipment (e.g., WAVE bioreactor) to minimize potential for 
product cross contamination. A low pH step and a nanofiltration step were used for virus 
inactivation and reduction. Viral clearance studies used the model viruses PPV and A-
MuLV. Testing for adventitious agents was performed in accordance to FDA Points to 
Consider in the Manufacture and Testing of Monoclonal Antibody Products for Human 
Use (1997). An ongoing drug product stability testing program monitors the quality of 
3BNC117 over the duration of the clinical dosing period. Stability is evaluated in real 
time at the recommended storage conditions of 5 ± 3°C as well as at accelerated 
temperature conditions of 25 ± 2°C / 60 ± 5% RH.  
 
Clinical Safety of Other anti-HIV Monoclonal Antibodies. 
Monoclonal antibodies are a growing part of our therapeutic arsenal. While each mAb 
product has unique safety issues related to its mechanism of action, the major safety 
concern related to mAbs in general is infusion/hypersensitivity reactions, which are more 
common for mAbs that contain murine elements. 3BNC117 is a fully human recombinant 
form of a naturally existing human mAb. Passive administration of antibodies is 
successfully used to prevent or treat several viral diseases and several monoclonal 
antibodies are being developed for use in either prevention or treatment of infectious 
diseases. 
 


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Passive administration of anti-HIV-1 antibodies has also been evaluated in humans. HIV 
Immune Globulin (HIVIG) was in clinical use in the 1990s before the advent of highly 
effective ART. HIVIG was also evaluated in HIV-infected pregnant females and their 
newborns in a phase III trial to assess whether HIVIG plus single dose nevirapine given 
to mothers and infants would provide additional benefit over single dose nevirapine alone 
for prevention of peripartum HIV transmission. While there was no demonstrable 
difference in treatment efficacy, the study showed that that there were no significant 
differences in mortality or serious AEs between the two arms of the trial (Onyango-
Makumbi et al., 2011). 
 
Several monoclonal antibodies that target HIV-1 have been evaluated in clinical studies. 
For example, 2F5 and 4E10 are IgG1 (kappa) monoclonal antibodies that target the 
membrane-proximal ectodomain of gp41, while 2G12 binds to a carbohydrate moiety on 
the silent face of gp120. These neutralizing antibodies were evaluated in combination in 
HIV-infected individuals(Armbruster et al., 2004). The antibodies were administered 
intravenously at 0.5 to 1 g doses; 4 to 8 weekly infusions were given. The antibodies 
were safe and well tolerated and no clinical or laboratory abnormalities were observed 
throughout the studies. A low-level antibody response against 2G12 was found in two 
subjects.  
 
Two other studies included HIV-infected subjects on combination ART and plasma viral 
levels < 50 copies/ml (Trkola et al., 2005a)n = 14); (Mehandru et al., 2007a)n =10). The 
antibodies were administered intravenously at doses ranging from 1 to 2 g for each 
antibody; 13-16 weekly antibody infusions were given. ART was interrupted following 1 
or 4 antibody infusions. Antibody infusions were well tolerated in most subjects; mild 
and transient side effects were reported only occasionally. No serious adverse events 
(SAEs) were recorded. In both studies, the use of mAbs was safe and generally delayed, 
but did not prevent viral rebound. The emergence of resistance to 2G12, however, 
demonstrated that the antibody exerted selective pressure on the circulating viral strains. 
Also, the delay of viral rebound correlated positively with the baseline sensitivity of the 
participants’ virus isolate. It is important to note that the antibodies used in these studies 
have far lower potency and breadth than the more recently isolated neutralizing 
antibodies, such as 3BNC117. Moreover, in contrast to 3BNC117, these antibodies had 
very limited effect in the treatment of HIV in humanized mice(Poignard et al., 1999). 
 
3.1.3 Preclinical Toxicity Studies with 3BNC117  
A tissue cross-reactivity study, performed on a full panel of tissues from humans and rats, 
showed good concordance of binding between the two species. While 3BNC117 showed 
widespread cytoplasmic binding, it is generally understood that cytoplasmic binding is 
considered of little to no toxicologic significance.  Membrane binding of 3BNC117 was 
restricted to two limited/rare cell types in conjunctival recesses and in the urinary bladder 
(neither of which correlated with findings in the repeat dose toxicology study). 
 
The antibody 3BNC117 was evaluated for safety in a multidose study in rats. Despite 
some animals producing anti-drug antibodies, the rats appeared to have maintained 
adequate drug exposure in the study, with twice per week dosing for four weeks. Aside 


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from injection site findings, there were no 3BNC117 related effects, in the Main and 
Recovery group animals, on clinical observations, body weight, food consumption, body 
temperature, clinical pathology parameters, organ weights or macroscopic and 
microscopic observations, and the NOEL (no observable effect level) was determined to 
be the high dose of 60 mg/kg twice a week for four weeks.  
 
3.1.4 Clinical Experience with 3BNC117 
3BNC117 is currently being evaluated in a phase 1 study in both HIV-uninfected and 
HIV-infected subjects (protocol MCA-835). Study subjects are administered one or two 
intravenous infusions of 3BNC117 at increasing dose levels (1 mg/kg, 3 mg/kg, 10 mg/kg 
or 30 mg/kg), and are followed for 24 weeks after last infusion. As of 13 September 
2015, 55 subjects (22 HIV-uninfected, 19 viremic HIV-infected and 14 ART-treated 
HIV-infected individuals) have enrolled in the study. Five HIV-uninfected individuals 
have received two infusions of 3BNC117 at 30mg/kg, 12 weeks apart. Twenty-three 
subjects (3 HIV-uninfected and 19 HIV-infected) have been administered one dose of 30 
mg/kg. 
 
Overall, 3BNC117 has been generally safe and well-tolerated, mild transient myalgia, 
fatigue and headache have occurred. Some participants reported ophthalmic complaints, 
but a causal relationship with 3BNC117 was not established. No SAEs or grade 3/4 AEs 
deemed related to 3BNC117 have occurred. A safety data summary is included in the 
Investigator’s Brochure (IB). 
 
Preliminary PK data show that 3BNC117’s half-life is 17.6 days in HIV-uninfected and 
9.6 days in viremic HIV-infected individuals. Peak serum concentration of 3BNC117 is 
reached at the end of infusion with a mean concentration of 563.6 µg/ml (range 410.2 – 
976.4 µg/ml) after a single 30 mg/kg infusion in HIV-infected individuals. In these 
individuals, 3BNC117 serum levels range from 13 to 65 µg/ml (mean 41.6 +/- 12.5 
µg/ml) three weeks after infusion.  In addition, 3BNC117 decay rates following first and 
second 10 mg/kg infusions in HIV-uninfected individuals are similar.  
 
A transient decline in HIV-1 viremia, of approximately 0.5 log, occurred following the 
administration of 3mg/kg of 3BNC117 to three HIV-infected subjects with detectable 
viremia. Of the 3 individuals receiving the 10mg/kg dose of antibody, only 2 responded 
with a decrease in viremia of 0.69 and 1.36 log10. The individual that did not respond was 
infected with 3BNC117-resistant virus that (2C4; IC50 > 20µg/ml at baseline). All ten 
viremic individuals that received the 30mg/kg dose of 3BNC117 showed rapid decreases 
in their viral loads that varied between individuals from 0.8 to 2.5 log10. The median time 
to reach the nadir in viremia was 7 days, but could be as long as 21 days. Interestingly, 
emergence of resistant viral strains was variable, with some individuals remaining 
sensitive to 3BNC117 for a period of 28 days after infusion (Caskey et al., 2015). 
Virologic data will continue to be analyzed under protocol MCA-835, as additional HIV-
infected subjects are enrolled.  
 
In addition, seven of the eight subjects enrolled in this study (protocol MCA-867) have 
received two 3BNC117 infusions at 30mg/kg at days 0 and 21. One subject’s baseline 


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(day 0) HIV-1 viral load was found to be 8,730 copies/ml (subject -705).  The subject 
was withdrawn from active study (second 3BNC117 dose was not administered), 
however he continues to be followed for safety as he received the first 3BNC117 dose. 
Most reported adverse events were transient and considered of grade 1 severity. 
Participants did not report symptoms consistent with acute retroviral syndrome. 
3BNC117’s peak mean serum concentration was 578.6 µg/ml (range 383.6 – 823.8 
µg/ml) after first infusion and 613.4 µg/ml (range 456 – 757.6 µg/ml) after second 
infusion. The decay rate appears similar after first and second infusions, although follow 
up data is still being generated. 3BNC117 levels decreased to levels as low as 66 μg/ml at 
week 5 (66 – 123 µg/ml), two weeks after the second infusion.  Seven participants 
enrolled (-701, -702, -703, -704, -706, -707, -708) experienced viral rebound at week 4 to 
9 (Figure 2). ART was reinitiated in all subjects and has led to rapid decrease in viral 
loads in all cases.  
 
3.2 
Hypothesis  
 
The administration of two or four infusions of 3BNC117 (30 mg/kg) will be safe, well 
tolerated, and will delay the return of HIV-1 viremia during a brief analytical treatment 
interruption.  
 
3.3 
Aims  
Primary Objectives: 
- 
Evaluate the effect of two and four infusions of 3BNC117 at 30 mg/kg in delaying 
virologic rebound and maintaining viral suppression during a short analytical 
treatment interruption. 
- 
Evaluate the safety, tolerability and pharmacokinetic profile of two and four 
intravenous infusions of 3BNC117 at 30 mg/kg in HIV-infected subjects with 
suppressed viremia during a short analytical treatment interruption. 
 
Secondary Objectives: 
- 
Determine the range of 3BNC117 serum levels at which virologic rebound occurs. 
- 
Compare the effect of two and four infusions of 3BNC117 at 30 mg/kg in delaying 
virologic rebound and maintaining viral suppression during a short analytical 
treatment interruption. 
 
Exploratory Objectives: 
- 
Phylogenetically compare viruses grown from PBMCs collected from subjects while 
on ART to rebound viruses collected after treatment interruption. 
- 
Determine the viral escape mutations that might arise after administration of 
3BNC117.  
- 
Evaluate HIV-1 specific T and B cell immune responses following administration of 
3BNC117. 
- 
Evaluate the effects of 3BNC117 on serum levels of inflammation markers. 
- 
Evaluate the effect of 3BNC117 on cell associated HIV DNA and RNA levels.  
 


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3.4 
Primary Outcome(s)  
- 
The rate of virologic rebound at 8 weeks post ART interruption (plasma HIV-1 RNA 
≥ 200 copies/ml on two separate occasions). 
- 
Time to rebound following ART interruption.  
- 
The rate of signs, symptoms and laboratory abnormalities, in addition to systemic 
reactogenicity events following two 3BNC117 infusions at 30 mg/kg. 
- 
3BNC117 serum levels and anti-drug (3BNC117) antibody responses in serum or 
plasma at multiple time points following 3BNC117 intravenous administrations. 
 
3.5 
Secondary Outcome(s) 
- 
The plasma level of 3BNC117 at the time of viral rebound. 
 
Other evaluations: 
- 
Phylogenetic comparison of viruses grown from PBMCs collected from subjects 
while on ART to rebound viruses collected after treatment interruption. 
- 
Analysis of 3BNC117-induced escape mutations 
- 
Evaluate the effects of 3BNC117 on serum levels of inflammation markers, such as 
C-reactive protein, D-dimers, IL-6 and soluble CD14. 
- 
Evaluate HIV-1 specific T and B cell immune responses following administration of 
3BNC117, including CD8 T cell expression of immune activation markers, such as 
HLA-DR, CD38 and PD-1. 
- 
Evaluate the effect of 3BNC117 on cell associated HIV DNA and RNA levels 
 
4 
Study Design 
The proposed study is a Phase II, open label study to evaluate the safety and antiretroviral 
activity of two and four infusions of 3BNC117 in HIV-infected subjects on combination 
ART during a brief analytical treatment interruption (Figure 3, Study design). PK 
assessments are also included.  
 
The subject’s viral sensitivity to 3BNC117 will be tested by outgrowing the subject’s 
virus at the Laboratory of Molecular Immunology, followed by a TZM-bl assay in the 
laboratory of Dr. Michael Seaman as previously described (Trkola et al., 2005a) 
(Mehandru et al., 2007a) (Laird et al., 2013). The initial testing will be performed under 
the protocol MCA-823. Based on previous data (Scheid et al., 2011) sensitivity to 
3BNC117 will be defined by an IC50 titer < 2µg/ml.  
 
After meeting enrollment criteria, eight subjects with 3BNC117 sensitive virus (< 2µg/ml 
IC50) enrolled in Group A to receive two intravenous infusions of 3BNC117, 
administered at 30 mg/kg on day 0 and day 21. Eight additional subjects with 3BNC117 
sensitive virus (< 2µg/ml IC50) will receive four intravenous infusions of 3BNC117, 
administered at 30 mg/kg on day 0, day 14, day 28 and day 42 (Group B).  
 
As 3BNC117 has not been administered four times to single individuals to date, Group B 
will be started with a mini cohort (n=3). The SMC will review all available safety data up 
to day 21 (1 week after second infusion) of the first 3 subjects enrolled in group B. The 
SMC will then provide a recommendation regarding administration of a third dose.  If the 


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SMC determines it is safe to proceed, the third dose will be administered 2 weeks 
following the second dose (day 28) and the fourth dose will follow two weeks later (day 
42). Two weeks after the third subject in Group B receives the fourth dose, all available 
safety data will be reviewed by the SMC.  If the SMC determines it is safe to proceed, 
additional subjects (n = 5) will be enrolled to receive 4 doses at 2-week intervals.  
 
On day 0 the sensitivity assay will be repeated in order to confirm the baseline sensitivity 
at the time of first infusion. Based on previous PK data from study MCA-835 and 
preliminary data from MCA-867 we expect that 3BNC117 serum levels will be 
maintained above 70 µg/ml for at least 8 weeks in Group B (Caskey et al., 2015). This 
significantly exceeds the typical period of viral rebound after ATI, which ranges from 2-3 
weeks. 
 
Antiretroviral therapy will be discontinued 2 days after the first 3BNC117 infusion (day 
2). Non-nucleoside reverse transcriptase inhibitors have longer elimination half-lives than 
other antiretroviral classes. They are typically cleared in 2-4 weeks. Therefore, in order to 
avoid the risk of inadvertent monotherapy, which can select NNRTI resistant strains, if 
the subject’s ART regimen includes an NNRTI, the NNRTI will be switched to 
dolutegravir (an integrase inhibitor) 4 weeks prior discontinuing all antiretroviral drugs. 
Dolutegravir will be provided to the subjects for that time period. 
 
The original ART regimen will be resumed at week 12. The ART regimen will be 
resumed sooner if plasma HIV-1 RNA level is ≥ 200 copies/ml or if CD4+ count drops < 
350 cells/µl and either result is confirmed upon repeat measurement during the next 
weekly scheduled visit. If plasma HIV-1 RNA level is ≥ 1,000 copies/ml, the participant 
will be asked to return for a repeat measurement prior to the next scheduled visit, and 
ART will be resumed if results are confirmed. ART will also be resumed early if the 
participant becomes pregnant, or if otherwise clinically indicated. If ART regimen is 
resumed before completion of all 3BNC117 infusions, further 3BNC117 infusions will 
not be performed. 
 
All subjects will be followed weekly until week 12 for safety assessments and for 
monitoring plasma HIV-1 RNA levels. CD4+ T cell counts will be monitored every 2 
weeks until week 12. After week 12 subjects will be followed as outlined in the Time of 
Events Schedule (Appendix A). 
 
Subjects will be offered a continuation of the treatment interruption through week 36, 
coordinated with their primary care physician as long as viral rebound does not occur. In 
the extension phase of the study subjects will return for follow up every week, while off 
ART. ART resumption will follow same criteria as detailed above. After ART is 
resumed, study subjects will return for follow up according to the Main Schedule (i.e. wk 
14, 24 and 36) (Appendix A). 
 
Safety and PK assessments will be performed at multiple time points following 3BNC117 
infusions (see Appendix A). Subjects will be followed for 36 weeks from enrollment. 
 


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Figure 3. Study Design 
  
Group A 
 
Group B 
 
5 
Study Population 
Adults, male and female, ages 18-65 with well-controlled HIV-1 infection on standard 
ART. 
 
5.1 
Inclusion Criteria: 
o Age 18 to 65 
o HIV-1 infection confirmed by ELISA and immunoblot. 
o Plasma HIV-1 RNA < 50 copies/ml for at least 12 months while on combination 
ART and < 20 copies/ml at the screening visit. [Note: One or two viral blips of < 
200 copies/mL prior to enrollment are permitted if preceded and followed by test 
results showing VL less than or equal to 50 copies/mL on the same ARV 
regimen.] 
o 3BNC117 sensitivity (IC50 < 2 µg/ml) of subject derived HIV-1 virus isolates. 
These are isolated under protocol MCA-823 by co-culture of subject PBMCs with 
HIV-uninfected donor PBMCs followed by in vitro neutralization assays as 
previously described (Mehandru et al., 2007a) (Trkola et al., 2005a).  
o Current CD4 cell count > 500 cells/µl and no prior CD4 cell count < 200 cells/µl. 
o Willing to interrupt antiretroviral treatment for 12 weeks, or until viral rebound 
occurs. 


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o If sexually active male or female, and participating in sexual activity that could 
lead to pregnancy using an effective method of contraception throughout the 
study period. Subjects should also agree to use a male or female condom during 
the time of pausing their HIV medication. 
o If on an NNRTI-based regimen willing to switch for 4 weeks to dolutegravir. 
 
 
5.2 
Exclusion Criteria: 
o Have a history of AIDS-defining illness within 1 year prior to enrollment 
o History of systemic corticosteroids, immunosuppressive anti-cancer, or other 
medications considered significant by the trial physician within the last 6 months; 
o Chronic hepatitis B or hepatitis C; 
o Patient report, or chart history, of significant coronary artery disease, myocardial 
infarction, percutaneous coronary intervention with placement of cardiac stents; 
o Patient report, or chart history, of diabetes type 1 or 2 and/or current use of insulin 
or oral hypoglycemic medications; 
o Uncontrolled hypertension, as defined by a systolic blood pressure > 180 and/or 
diastolic blood pressure > 120, in the presence or absence of anti-hypertensive 
medications; 
o Any other clinically significant acute or chronic medical condition, such as 
autoimmune diseases, that in the opinion of the investigator would preclude 
participation; 
o Current cigarette use in excess of 1 pack per day; 
o Laboratory abnormalities in the parameters listed below:  
• Absolute neutrophil count ≤ 1,000 
• Hemoglobin ≤ 10 gm/dL 
• Platelet count ≤ 125,000 
• ALT ≥ 2.0 x ULN 
• AST ≥ 2.0 x ULN 
• Total bilirubin ≥ 1.5 ULN  
• Creatinine ≥ 1.1 x ULN 
• Coagulation parameters ≥ 1.5 x ULN; 
o Current antiretroviral regimen includes either maraviroc or enfuvirtide; 
o Pregnancy or lactation; 
o Any vaccination within 14 days prior to 3BNC117 administration; 
o Receipt of any monoclonal antibody therapy of any kind in the past; 
o Participation in another clinical study of an investigational product currently or 
within past 12 weeks, or expected participation during this study. 
o History of resistance to two or more antiretroviral drug classes 
 
6 
Methods and Procedures 
 
6.1 
Screening Procedure and Study Visits 
The Time of Events Schedule summarizes the frequency and timing of various study 
assessments. See Appendix A. Recruitment, screening and post-3BNC117 visits are 


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performed at The Rockefeller University Hospital (RUH) outpatient clinic. 3BNC117 
infusion visits will be performed at RUH.  
 
6.1.1 Pre-Screening Questionnaire 
Subjects eligible for enrollment might be recruited at the RUH outpatient clinic. Potential 
participants will first undergo pre-screening by telephone to assess medical history, 
preliminary HIV risk assessment, and qualification for the study. Potential volunteers will 
have the opportunity to discuss the study and ask questions of the study recruiter at this 
time. Those who are eligible and interested in participating will attend a screening visit at 
the RUH Outpatient Clinic.  
 
The sensitivity of subject’s viral isolates to 3BNC117 will be evaluated under protocol 
MCA-823. This will be performed with a viral outgrowth assay followed by a validated 
in vitro TZM-bl neutralization assay as previously described (Mehandru et al., 2007a) 
(Trkola et al., 2005a) (Laird et al., 2013). Based on previous data (Scheid et al., 2011) 
sensitivity to 3BNC117 will be defined by an IC50 titer < 2µg/ml. The viral outgrowth 
assay will be performed in the Laboratory of Molecular Immunology, the in vitro 
neutralization assay will be performed in Dr. Michael Seaman’s laboratory. 
 
 
6.1.2 Screening Visit 
Screening Visit: 
Study personnel will answer any questions about the study. Written informed consent 
will be obtained prior to conducting any study procedures. To insure informed consent, 
the principal investigator or designee will discuss the following processes individually 
with each volunteer: 
1. Pregnancy avoidance counseling. Sexually active males and females, participating 
in sexual activity that could lead to pregnancy, should use a reliable form of 
contraception for the duration of the trial. 
2. Risk reduction counseling. Sexually active males and females will be asked to use 
condoms during the short analytical treatment interruption due to the risk of 
intermittent viremia. 
3. One must assume that no protection or improvement in control of HIV infection 
will occur given the exploratory nature of this study. 
4. Subjects agree to stopping their antiretroviral medications as planned in the 
protocol and agree to return for weekly follow up visits for monitoring of plasma 
virus levels. 
 
If the volunteer consents to participate, site personnel will: 
• Obtain a complete medical history (including concomitant medications and 
cardiovascular history); 
• Review subject’s previous HIV-1 viral load and CD4/CD8 measurements (records 
should be available for at least 1 year prior to screening) 
• Perform a general physical examination including height, weight, vital signs 
(pulse, respiratory rate, blood pressure and temperature), examination of skin, 


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respiratory, cardiovascular and abdominal systems, and an assessment of cervical 
and axillary lymph nodes; 
• Collect blood and urine specimens for all tests as indicated in the Time of Events 
Schedule, including plasma HIV-1 RNA levels and CD4/CD8 counts. 
• Perform a pregnancy test for all female volunteers. 
 
If the screening visit occurs more than 49 days prior to the date of the first 3BNC117 
mAb infusion, then study procedures for the screening visit must be repeated. The most 
recent set of procedures will be used if there is a discrepancy. 
 
6.1.3 3BNC117 Infusion Visits 
3BNC117 infusions and assessments on the day after the infusions will occur at the 
Rockefeller University Hospital (RUH).  
Prior to drug infusion, site personnel will: 
 Answer any questions about the study; 
 Review interim medical history (including concomitant medications); 
 Review safety laboratory data; 
 Review with the volunteer the informed consent form administered at screening 
visit; 
 Perform a physical examination including weight, vital signs (pulse, respiratory 
rate, blood pressure and temperature) and any further examination indicated by 
history or observation; 
 Collect blood and urine specimens for all tests as indicated in the Time of Events 
Schedule (Appendix A); 
 Perform pregnancy and safe sex counseling; 
 Perform a pregnancy test for all pre-menopausal female volunteers (blood will be 
sent STAT) and obtain results prior to drug infusion; 
 Perform baseline assessment and record any systemic symptoms; 
 3BNC117 will be prepared for administration according to the Rockefeller 
University Pharmacy Standard Operating Procedures; 
 3BNC117 mAb will be administered via a peripheral vein by slow intravenous 
infusion. 
 The infusion will take approximately 60 minutes. Subjects will be closely 
observed for 1.5 hour after drug infusion in the inpatient unit of the RUH. Vital 
signs (pulse, respiratory rate, blood pressure and temperature) will be monitored 
at the end of infusion, 30 (+/- 5 min) minutes, 1 (+/- 10 min), and 1.5 hrs (+/- 10 
min) post infusion. Presence or absence of reactogenicity events, as well as any 
other event that occurs, will be recorded at 30 – 45 minutes and at 1.5 hrs. The 
study staff will record reactogenicity events during clinic visits as shown on Time 
of Events Schedule (Appendix A).  
 If volunteers develop acute infusion reaction during 3BNC117 administration, the 
infusion will be held. Rescue medications, including acetaminophen, 
diphenhydramine and glucocorticoids will be available in the RUH inpatient unit 
for use if clinically indicated. Infusion may be reinitiated after symptoms 
improve, and the remaining dose will be administered over 3 hours. 
 


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Specific procedures to be performed at each clinic visit are illustrated in the Time of 
Events Schedule (Appendix A).   
 
6.1.4 Post-3BNC117 Administration Visits 
Study subjects will be followed through week 36.  
 
During ART interruption follow up visits will be performed on a weekly basis for 12 
weeks (Appendix A, Time of Events Schedule).  
 Review of interim medical history and use of concomitant medications; 
 If symptoms are present, perform a symptom-directed physical examination; 
 Systemic reactogenicity, as well as other adverse events, will be assessed; 
 Pregnancy counseling and pregnancy testing; 
 Safe sex counseling; 
 Vital Signs; 
 Collect blood and urine specimens for all tests as indicated in the Time of Events 
Schedule (Appendix A); 
 At post-infusion study visits, subjects will be asked about symptoms of ocular 
disease (such as blurry vision, increased lacrimation, redness, dryness, pain) and 
the study investigators will perform a directed exam of the eyes. If subjects 
develop symptoms or signs of ocular disease, they will be referred to an 
ophthalmologist for diagnosis and management; expenses resulting from the 
evaluation will be covered by the study.  
 In case of adverse event(s), the volunteer will be assessed and followed up by the 
clinical team. Supplemental visit(s) for further investigation can be planned at the 
discretion of the principal investigator or designee. Supplemental visit(s) may be 
recommended if clinically indicated or to clarify observations. 
 
Specific procedures to be performed at each follow up visit are illustrated in the Time of 
Events Schedules (Appendix A).  
Any abnormalities (adverse events) attributed to study drug, including laboratory 
abnormalities, should be subsequently followed until the event or its sequelae resolve or 
stabilize.  
 
6.1.5 ART interruption and reinitiation of combination ART 
ART regimen will be discontinued for 12 weeks after the first 3BNC117 infusion.  
 
NNRTIs have longer elimination half-lives (> 20 hours) compared with most nucleoside 
reverse transcriptase inhibitors (NRTIs). In order to avoid a period of NNRTI 
monotherapy, which can lead to the development of resistance, if the subject’s ART 
regimen includes an NNRTI, the NNRTI will be switched to dolutegravir (an integrase 
inhibitor) 4 weeks before all other antiretroviral drugs are discontinued. Dolutegravir will 
be provided to the subjects for that time period. 
 
The original ART regimen will be resumed at week 12. ART regimen will be resumed 
sooner if plasma HIV-1 RNA level is ≥ 200 copies/ml or if CD4+ count drops < 350 


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cells/µl and either result is confirmed upon repeat measurement during the next weekly 
scheduled visit. If plasma HIV-1 RNA level is ≥ 1,000 copies/ml, the participant will be 
asked to return for a repeat measurement prior to the next scheduled visit, and ART will 
be resumed if results are confirmed. ART will also be resumed early if the participant 
becomes pregnant, or if otherwise clinically indicated. If ART regimen is resumed before 
completion of 3BNC117 infusions, further 3BNC117 infusions will not be performed.  
 
All subjects will be followed weekly until week 12 for safety assessments and for 
monitoring plasma HIV-1 RNA levels. CD4+ T cell counts will be monitored every 2 
weeks until week 12. After week 12 subjects will be followed as outlined in the Time of 
Events Schedule (Appendix A). 
 
Subjects will be offered a continuation of the treatment interruption through week 36, 
coordinated with their primary care physician as long as viral rebound does not occur. In 
the extension phase of the study subjects will return for follow up every week, while off 
ART. ART resumption will follow same criteria as detailed above. After ART is 
resumed, study subjects will return for follow up according to the Main Schedule (i.e. wk 
14, 24 and 36) (Appendix A). 
 
Safety and PK assessments will be performed at multiple time points following 3BNC117 
infusions (see Appendix A). Subjects will be followed for 36 weeks from enrollment. 
 
The subjects’ primary care physician will be consulted on any changes in antiretroviral 
treatment. In addition, non-research results will be communicated to the subjects’ 
primary care physician after each study visit during all phases of the study. 
 
During the ART-interruption phase of the study subjects may be at increased risk of 
transmitting HIV to their partners, if they become viremic, and of HIV-1 superinfection 
from an HIV-infected partner. Therefore, subjects will be asked to use male or female 
condoms for the duration of ART interruption. In the event of a high-risk exposure to an 
HIV-infected partner, a subject may re-initiate ART as clinically indicated by his/her 
HIV primary care physician. 
 
6.1.6 Final Visit/Early termination Visit 
Assessments will be undertaken according to the Time of Events Schedule (Appendix A). 
 
6.1.7 Discontinuation of 3BNC117 infusion and/or volunteer withdrawal from 
study 
6.1.7.1 Discontinuation of 3BNC117 infusion 
The 3BNC117 infusion will be discontinued for any of the following reasons: 
1. Any immediate hypersensitivity reaction (such as urticarial rash; bronchospasm; 
laryngeal edema; anaphylaxis; syncope). 
2. Life threatening medical event during 3BNC117 infusion. 
 


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6.1.7.2 Discontinuation from subsequent 3BNC117 infusions 
Volunteers will be discontinued from subsequent 3BNC117 infusions for any of the 
following reasons: 
1. A disease or condition or an adverse event that may develop, regardless of 
relationship to 3BNC117, if the principal investigator or designee is of the 
opinion that another 3BNC117 infusion will jeopardize the safety of the 
volunteer. 
2. If ART regimen is resumed before completion of 3BNC117 infusions due to viral 
rebound. ART regimen is resumed if plasma HIV-1 RNA level is ≥ 200 copies/ml 
or if CD4+ count drops < 350 cells/µl and either result is confirmed upon repeat 
measurement. 
3. An abnormal laboratory event based on the following criteria: 
- 
For a moderate laboratory event, the laboratory test must be repeated and the 
event determined to be resolved or improved in the opinion of the principal 
investigator or designee prior to 3BNC117 infusion; 
- 
For a severe or very severe laboratory abnormality, even if resolved, the SMC 
must be consulted before making a decision to administer 3BNC117. 
4. Any immediate hypersensitivity reaction (such as urticarial rash; bronchospasm; 
laryngeal edema; anaphylaxis; syncope). 
5. Life threatening medical event following 3BNC117 unless not related to the 
investigational product. 
6. Intercurrent use of immunosuppressive medication considered significant by the 
trial physician (e.g., systemic corticosteroids). 
7. Pregnancy. 
8. Subject’s request to discontinue further 3BNC117 infusions. 
 
6.1.7.3 Withdrawal from the study (Early Termination) 
     Volunteers may be withdrawn from the study permanently for the following reasons: 
1. Volunteers may withdraw from the study at any time if they wish to do so, for any 
reason. 
2. Following an adverse event at the discretion of the investigator (or designee). 
3. Request of the primary care provider if s/he thinks the study is no longer in the 
best interest of the subject. 
4. Subject judged by the investigator to be at significant risk of failing to comply 
with the protocol in a manner that might lead to harm to self or seriously interfere 
with the validity of the study results. 
5. At the discretion of the FDA or investigator. 
 
6.1.7.4 Follow up after withdrawal from the study (Early Termination) 
Any adverse event resulting in withdrawal of a volunteer will be followed up until 
resolution or until the adverse event is judged by the principal investigator or designee to 
have stabilized where possible. 
 


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At the time of withdrawal, provided the volunteer is willing, all the requested termination 
visit procedures will be performed according to the Time of Events Schedule (Appendix 
A). 
 
The date and reason for withdrawal from the study (early termination) should be 
collected and reported to the SMC, the Clinical Research Office and the IRB. Volunteers 
who are withdrawn from the study (early termination) and received any 3BNC117 
infusion will not be replaced, but, wherever possible, will return for safety assessments 
every 4-6 weeks until the time of their final planned visit. 
 
A pregnant volunteer will not receive a 3BNC117 infusion. If pregnancy occurs after any 
3BNC117 infusion, the volunteer will be asked to return for follow up every 4-6 weeks 
until delivery. Approximately 2-4 weeks after delivery, the baby will be examined by a 
pediatrician to assess the health status of the baby. The health status of the baby will be 
reported to the local IRBs, Clinical Research Office at the Rockefeller University 
Hospital and the SMC. 
 
6.2 
Study Procedures 
 
6.2.1 Consent Procedure 
 
Prior to the initiation of any study related procedures, the potential subjects will be given 
a copy of the most recent IRB stamped and approved informed consent to read. 
Additionally, the PI or study staff member who has been designated to consent will 
discuss the specifics of the study including but not limited to the purpose of the research, 
procedures, time commitment, required tasks, test article or device, alternative 
treatments, benefits, risks, confidentiality etc. in a comprehensible (non-scientific) 
manner, using language readily understandable by the subject. Subjects will be told that 
participation is voluntary and that, if they do not consent, they will not be penalized. The 
person consenting will assure the voluntariness of the subject. 
 
 A private, confidential setting will be provided for the potential subject to read and 
discuss the informed consent free from coercion, undue influence or constraints of time. 
All subjects will be given a chance to ask questions and express concerns. They will be 
given the option to take the consent home and discuss it with family, friends, and /or 
health care providers. After a subject and the person conducting the consenting signs and 
dates the consent, the subject will be given a copy of the signed informed consent form.  
 
An enrollment note will be written in the source document as to who obtained consent, 
how, when were questions asked and answered, and that a copy of the informed consent 
was given to the subject. 
  
The "Teach Back" method will be used in the clinical research setting to ask research 
participants to repeat or “teach back” the information, concepts and directions that the 
staff member has attempted to convey to the subject. This method is used to assess 


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comprehension and retention of protocol requirements, adverse event information, risks 
and benefits, and the subject's rights described in the Informed Consent process. 
  
Subjects for whom English is not a primary language will not be included in this study.  
The study investigators do not wish to discriminate against non-English speakers.  
However, investigators cannot risk having to depend on a translator service in the case of 
an emergency. 
 
6.2.2 Study Assignment 
This is an open-label study. Subjects will be enrolled sequentially as they meet 
enrollment criteria. Enrollment in Group A is closed. The target enrollment in Group B is 
of 8 participants. Enrollment will be staggered, 3 participants will be enrolled first, and 
further enrollment will be contingent upon review of safety data by the SMC.. The RUH 
pharmacist will dispense 3BNC117 in a piggy-back, diluted in sterile normal saline, 
ready for use. This study is open-label, both study investigators and volunteers will know 
the study allocation. 
 
6.2.3 3BNC117 Administration Procedure 
3BNC117 will be provided in single-use vials containing 5 ml of the product at a 
concentration of 20 mg/ml. The volume of 3BNC117 to be administered will be 
calculated by the RUH research pharmacist. 3BNC117 will be administered as a slow 
intravenous infusion over 60 minutes in the RUH inpatient unit. The calculated dose of 
3BNC117 will be diluted in sterile normal saline to a volume of 250 ml. A maximum of 
two participants will receive a 3BNC117 infusion per day. Infusions will not be given 
simultaneously. 
 
3BNC117 will be administered intravenously, via a peripheral vein in one of the upper 
extremities. The administration site should be free of potentially complicating 
dermatologic conditions. At the end of infusion, the IV line will be flushed with 20ml of 
Normal Saline to ensure all the medication has been delivered. 
 
Volunteers will be closely observed for 1.5 hour after drug infusion.  If volunteers 
develop acute infusion reaction during 3BNC117 administration, the infusion will be 
held. 
Rescue 
medications, 
including 
acetaminophen, 
diphenhydramine 
and 
glucocorticoids will be available in the RUH inpatient unit for use if clinically indicated. 
Infusion may be reinitiated after symptoms improve, and the remaining dose will be 
administered over 3 hours. 
 
6.2.4 Medical History and Physical Examination 
At the time of screening, a past medical history will be collected that will include details 
of any previous reaction to vaccination, and contraceptive practices. Interim medical 
histories will be collected at time-points according to the Time of Events Schedule 
(Appendix A).  
 


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A general physical examination will be conducted including weight, height, vital signs, 
and examination of skin, respiratory, cardiovascular, central nervous and abdominal 
systems. At the time of 3BNC117 infusions and at selected time-points thereafter, general 
and/or directed physical examinations will be performed according to the Time of Events 
Schedule (Appendix A). A directed physical examination will include weight, vital signs, 
examination of injection site, and any further examination indicated by history or 
observation. 
 
6.2.5 Blood Collection and Shipment 
Venous blood will be collected at every study visit, usually from the antecubital fossa, 
according to the Time of Events Schedule (Appendix A). Total volume collected at each 
study visit will range from 50-150 ml. Given the close follow up with weekly visits 
during the first 12 weeks of the study, the total blood volume collected may reach up to 
575 ml in an 8-week period during the ATI phase of the study. 
 
All specimens will be handled according to SOPs that were developed in the GLP-like-
Processing Lab within the Laboratory of Molecular Immunology. 
 
Frozen PBMCs, plasma and serum will be processed and stored at the Laboratory of 
Molecular Immunology. 
 
6.2.6 Monitoring for cytokine release associated adverse events and treatment of 
cytokine release syndrome 
Based on previous clinical experience with similar monoclonal antibodies and with 
3BNC117 (protocol MCA-835), it is unlikely that administration of 3BNC117 will lead 
to cytokine release syndrome. To date, 63 individuals have been administered 3BNC117 
without complications. However, a potential side effect of a monoclonal antibody can be 
the stimulation of a massive release of cellular cytokines, which can have profound 
effects on blood pressure, vascular integrity, and myocardial, lung, liver, and kidney 
functions. If cytokine release syndrome occurs, the volunteer may need to be treated with 
intravenous fluids, vasopressors, and high-dose corticosteroids and may require 
ventilatory support.  
 
Study participants will be closely monitored for 1.5 hours post infusion in the RUH 
inpatient unit. Access to a twenty-four hour on-call physician is available. The 
Rockefeller University Hospital outpatient and inpatient units  
are equipped with crash carts for immediate medical care. Supportive medications, 
including acetaminophen, diphenhydramine and glucocorticoids, will be available at both 
clinical sites for use if clinically indicated. In case of an emergency, after stabilization of 
the volunteer, he/she will be transferred to the neighboring tertiary care center, New York 
Presbyterian Hospital (Cornell) for specialized medical care.  
 


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6.2.7 Family Planning Counseling 
During screening and subsequent study visits, study personnel will counsel volunteers 
about the importance of prevention of pregnancies and the use of condoms, as well as 
other effective family planning methods. Condoms will be provided. 
 
Pregnancy tests will be conducted at each clinic visit as outlined in the Time of Events 
Schedule (Appendix A). Should pregnancy be detected before administration of 
3BNC117, the volunteer will not receive the 3BNC117 infusion. Should pregnancy be 
detected after any 3BNC117 infusion, a pregnant volunteer will be asked to return for 
follow up every 4-6 weeks until delivery Approximately 2-4 weeks after delivery, a 
pediatrician to assess the health status of the baby will examine the baby. The health 
status of the baby will be reported to the local IRBs, Clinical Research Office at the 
Rockefeller University Hospital and the SMC. 
 
6.2.8 Compensation 
Group A: There will be no compensation for the screening visit.  Each study volunteer 
will be compensated $200 for each 3BNC117 infusion visit. They will be compensated 
$60 dollars for weekly visits during ART interruption phase. For each of the three follow 
up visits after week 12 they will be compensated $100. In total, these subjects will be 
compensated up to $ 1,360 if all study visits are completed. Subjects that agree to remain 
off ART after week 12 will return every week for follow up, up to 12 visits (week 36). 
These subjects will be compensated up to $1200 for the additional visits. In total, these 
subjects will be compensated up to $2,260 for study participation. Subjects will be 
compensated $25 for each unscheduled visit.  
 
Group B: There will be no compensation for the screening visit.  Each study volunteer 
will be compensated $200 for each 3BNC117 infusion visit. They will be compensated 
$60  for the visits during the ART interruption phase, up to and including week 12. For 
each of the three follow up visits after week 12 they will be compensated $100. In total, 
these subjects will be compensated up to $1,880 if all study visits are completed. Subjects 
that agree to remain off ART after week 12 will return every week for follow up, up to 12 
visits (week 36). These subjects will be compensated $50 per visit, up to $1200 for the 
additional visits. In total, these subjects will be compensated up to $2,780 for study 
participation. Subjects will be compensated $25 for each unscheduled visit.  
 
Compensation is provided to help cover their travel expenses, as well as child care and 
time lost from gainful employment. Volunteers will be compensated only for the visits 
they complete. 
 
 
6.2.9 Safety Assessments 
6.2.9.1 Reactogenicity Events 
Reactogenicity events will be collected prospectively by structured interviews on the 
3BNC117 infusion and post-infusion follow up visits; recorded and graded according to 
pre-established criteria (see Appendix B). The DAIDS AE Grading Table will be used to 


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grade adverse events. In addition, the CTCAE v4.03 grading scale will be used for 
reporting and grading adverse events related to infusion reactions and cytokine release 
syndromes.  
Vital signs (pulse, respiratory rate, blood pressure and temperature) will be measured 
prior to 3BNC117 administration at 30 - 45 minutes and 1.5 hour after the infusion is 
completed, graded according to Appendix B and recorded. Similarly, feverishness, chills, 
headache, nausea, vomiting, malaise and myalgia, arthralgia and rash will be assessed 
and graded. All medications required for treatment of adverse events will be recorded. 
6.2.9.2 Other Adverse Events 
Other adverse events will be recorded following an open question to volunteers, with the 
dates of commencement and resolution and any medication required. All adverse events 
will be followed to resolution. Serious adverse events will be collected during the entire 
study period. They will be graded as indicated in Appendix B.  
 
6.2.9.3 Routine Laboratory Parameters 
As outlined in the Time of Events Schedule, laboratory parameters will include CD4 and 
VL, hematology (WBC and differential, RBC, hemoglobin/hematocrit, platelets), clinical 
chemistry (Na, K, Cl, Ca, CO2, Creatinine, Glucose, Total and Direct bilirubin, Alkaline 
phosphatase, AST and ALT), and urinalysis. ANA will be performed at day 0, at week 
36, and as clinically indicated. Immediately prior to each 3BNC117 infusion, pre-
menopausal female volunteers will have serum beta-HCG assessed and at follow up visits 
they will have urine beta-HCG checked. The laboratory samples for these tests will be 
collected at the time points indicated in the Time of Events Schedule (Appendix A). In 
the event of an abnormal laboratory value, volunteers may be asked to have an additional 
sample collected at the discretion of the principal investigator or designee.  
 
Volunteers will be screened for syphilis and viral hepatitis (HBsAg and HCV-RNA) at 
the Screening Visit.  
 
6.2.10 Viral Sensitivity, Antiretroviral and Immunogenicity Assessments 
 
Sensitivity of the subject’s virus to 3BNC117 will be assayed by: 
 
1. Viral outgrowth assay, performed at the Laboratory of Molecular Immunology as 
previously described (Laird et al., 2013), followed by a TZM-bl neutralization 
assay, performed in the laboratory of Dr. Michael Seaman of the Beth Israel 
Deaconess Hospital in Boston (a Core Laboratory sponsored by the Collaboration 
for AIDS Vaccine Discovery, CAVD). 
 
HIV-1 levels will be assessed by: 
 
2. Standard HIV-1 viral load assay (CLEP-certified) will be performed at a 
contracted laboratory, LabCorp. The detection range of the assay is 20-


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10x106 copies/ml. HIV-1 viral load will be determined at multiple time points 
before and after 3BNC117 administration. 
 
The HIV-1 levels will be further evaluated by the following assays: 
 
3. Single copy HIV-1 viral load assay. This is a more sensitive assay with a limit of 
detection of 1 copy of HIV-1 RNA/ml of plasma. This assay will be performed in 
the laboratory of Dr. Frank Maldarelli (NCI/NIH). 
 
4. HIV-1 cell associated DNA and RNA levels in PBMCs will be determined in the 
Laboratory of Molecular Immunology, before and after administration of 
3BNC117.  
 
In addition, the effects of 3BNC117 on host immune responses and on circulating HIV-1 
strains will be evaluated by the following assays: 
 
5. TZM-bl neutralization assay will performed in the laboratory of Dr. Michael 
Seaman of the Beth Israel Deaconess Hospital in Boston (a Core Laboratory 
sponsored by the Collaboration for AIDS Vaccine Discovery, CAVD). In vitro 
neutralization assays will be performed with serum from study subjects before 
and after administration of 3BNC117.  
 
6. T cell assays - HIV-1 Env and Gag specific responses will be evaluated in 
PBMC’s by IFNγ-ELISpot and/or by multiparametric cytokine flow cytometry. 
Phenotypic analysis, specifically the expression of immune activation/exhaustion 
markers on CD8+ T cells will also be evaluated. These assays will be performed 
at the Laboratory of Molecular Immunology and the laboratory of Dr. Richard 
Koup at the Vaccine Research Center (VRC) at NIH, a core lab of the 
Collaboration for AIDS Vaccine Development (CAVD). 
 
7. B cell assays – HIV-1 Env and Gag specific binding antibody responses will be 
evaluated in serum or plasma samples in the laboratory of Dr. Georgia Tomaras 
(Duke University, a core laboratory of the CAVD. 
 
8. Levels of inflammation markers, such as C-reactive protein, D-dimers, IL-6, and 
soluble CD14 will be performed in plasma or serum samples, prior to and after 
3BNC117 infusions. These will be performed at the Laboratory of Molecular 
Immunology, or by clinical assays at MSKCC or LabCorp. 
 
9. Genotyping – If circulating viral strains can be isolated/cultured ex-vivo, 
sequencing and phylogenetic analysis of HIV-1 env will be performed in samples 
collected before and after the administration of 3BNC117, at the time of virologic 
rebound. This will allow us to compare viruses grown from PBMCs collected 
from subjects while on ART to rebound viruses collected after treatment 
interruption and analyze the induction of escape mutations. Genotyping of HIV 
isolates will be performed in the Laboratory of Molecular Immunology by reverse 


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transcription followed by PCR amplification and sequencing of HIV envelope 
genes. Results will be descriptive. 
 
Genotypic analysis for antiretroviral resistance will be performed by a clinical 
assay (LabCorp) if viral rebound occurs.  
 
10. Resistance testing of amplified HIV envelope genes will be performed as 
previously described (Klein et al., 2012). Amplified HIV envelope genes will be 
cloned and expressed as pseudovirus followed by evaluation of resistance to 
3BNC117 in TZM-bl neutralization assays. Envelope gene amplification and 
cloning will be performed in the Laboratory of Molecular Immunology, TZM-bl 
neutralization assays in the laboratory of Dr. Michael Seaman. Results will be 
descriptive. 
 
11. Evaluation of HIV-1 integration sites by deep sequencing will be performed in the 
Laboratory of Molecular Immunology, before and after administration of 
3BNC117. 
 
 
 
The pharmacokinetics and immunogenicity of 3BNC117 will be evaluated by the 
following assays: 
 
12. Measurement of 3BNC117 levels by validated sandwich ELISA will be 
performed at Celldex Therapeutics. 3BNC117 levels will be measured in serum or 
plasma. 
 
13. Anti-drug (3BNC117) antibody responses in serum or plasma. Validated Assays 
will be performed at Celldex Therapeutics Inc. 
 
The adherence to the treatment interruption will be confirmed at week 8 by the 
following assay:  
 
14. Levels of antiretroviral medications (i.e. protease inhibitors and NNRTI’s) will be 
measured by CLEP-certified assays performed at a contract laboratory (LabCorp).  
 
15. Additionally, antiretroviral activity of serum against HIV pseudotyped with 
murine leukemia virus, performed in the laboratory of Dr. Michael Seaman of the 
Beth Israel Deaconess Hospital in Boston (a Core Laboratory sponsored by the 
Collaboration for AIDS Vaccine Discovery, CAVD). This is not a standardized 
assay. However, negative controls and positive controls with sera from patients 
treated with representative drug classes will be used.   
 
Research samples collected at the RUH will be processed and stored at the Laboratory of 
Molecular Immunology. Optimal sample collection, processing, cryopreservation, 
archiving and storage will be maintained. Additional studies will be performed as 
warranted at the discretion of the investigators. 
 


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6.2.11 Pharmacokinetic evaluations 
Pharmacokinetic parameters will be calculated using standard non-compartmental 
analysis methods. Descriptive results will be presented for the pharmacokinetic 
parameters.  
 
PK assessments will be performed on plasma or serum samples before 3BNC117 
administration, at the end of 3BNC117 infusions, 1 day and 1 week after the infusions, 
and at later time points, as outlined in the Time of Events Schedule (Appendix A). 
Pharmacokinetic parameters to be assessed will include maximum concentration (Cmax) 
elimination half-life (t1/2), clearance (CL/F), volume of distribution (Vz/F), AUC and 
decay curve.  
 
3BNC117 serum or plasma levels will be measured by a validated sandwich ELISA using 
a murine anti-idiotype antibody to 3BNC117. The assays will performed at Celldex 
Therapeutics.   
 
7 
Investigational Product  
 
- Investigational Drug Name:  
3BNC117 
 
3BNC117 is a recombinant, fully human monoclonal antibody (mAb) of the IgG1κ 
isotype that specifically binds HIV envgp120.  
 
- Manufacturer of study drug:  
Celldex Therapeutics, Inc. 
- FDA Approved: 
 
 
No 
- IND Number: 
 
 
118,225 
- IND Sponsor: 
 
 
Sarah Schlesinger, MD 
 
7.1 
Regimen 
3BNC117 will be administered intravenously at 30 mg/kg dose level on day 0 and day 21 
in Group A, and on day 0, 14, 28 and 42 in Group B.  
 
7.2 
Storage and Shipment of the Investigational Product 
3BNC117 will be shipped from Celldex Therapeutics and will be stored in the RU 
Pharmacy at 2- 8°C. 
 
7.3 
Dispensing and Handling of Investigational Product 
3BNC117 will be dispensed by the RU Hospital Pharmacy. Trial personnel will ensure 
that the study ID number on the piggy-back matches the study ID assigned to the 
volunteer prior to administration.  
 
3BNC117 will be provided in single-use vials containing 5 ml of 3BNC117 at a 20 
mg/ml concentration. The appropriate dose will be calculated by the RU pharmacist 
according to subject’s weight. 3BNC117 will be dispensed in a piggy-back, and diluted in 
normal saline (NaCl 0.9%), to a volume of 250 ml. It will be dispensed ready for 
administration by the study investigators. 


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7.4 
Accountability and Disposal of Used and Unused Investigational Product 
The date, allocation number and location of storage of the vials will be recorded in a 
log.  During the trial, the product accountability form, and the dispensing log will be 
monitored. At the end of the trial, unused vials will be returned to Celldex Therapeutics 
or destroyed. 
 
 
8 
Data Analysis 
 
8.1 
Design 
The proposed study is a Phase II, open label study to evaluate the antiretroviral activity 
and safety of two and four 3BNC117 infusions in HIV-infected subjects on combination 
antiretroviral therapy, during a brief analytical treatment interruption. The study will also 
obtain additional data on its pharmacokinetic profile.  
 
After meeting enrollment criteria eight subjects with 3BNC117 sensitive virus (< 2µg/ml 
IC50) enrolled in Group A to receive two intravenous infusions of 3BNC117, 
administered at 30 mg/kg on day 0 and day 21 (Group A). Eight additional subjects with 
3BNC117 sensitive virus (< 2µg/ml IC50) will be enrolled to receive four intravenous 
infusions of 3BNC117, administered at 30 mg/kg on day 0, day 14, day 28 and day 42 
(Group B). As 3BNC117 has not been administered four times to single individuals to 
date, Group B will be started with a mini cohort (n=3). Safety will be assessed by the 
SMC 1 week after the second dose, as well as 2 weeks after the fourth dose in the mini 
cohort, before proceeding with further infusions and enrollment.   
 
Antiretroviral therapy will be discontinued on day 2 for 12 weeks after the first 3BNC117 
infusion (week 12). We project screening 50 subjects in order to achieve 16 evaluable 
subjects. In case of drop-outs an over-enrollment of 10% will be allowed. 
 
The same ART regimen will be resumed at week 12. ART regimen will be resumed 
sooner if plasma HIV-1 RNA level is ≥ 200 copies/ml or if CD4+ count drops < 350 
cells/µl and either result is confirmed upon repeat measurement during the next weekly 
scheduled visit. If plasma HIV-1 RNA level is ≥ 1,000 copies/ml, the participant will be 
asked to return for a repeat measurement prior to the next scheduled visit, and ART will 
be resumed if results are confirmed. ART will also be resumed early if the participant 
becomes pregnant, or if otherwise clinically indicated. If ART regimen is resumed before 
completion of 3BNC117 infusions, further 3BNC117 infusions will not be performed. All 
subjects will be followed weekly until week 12 for safety assessments and for monitoring 
plasma HIV-1 RNA levels. CD4+ T cell counts will be monitored every 2 weeks until 
week 12. After week 12 subjects will be followed as outlined in the Time of Events 
Schedule (Appendix A). 
 
Subjects will be offered a continuation of the treatment interruption through week 36, 
coordinated with their primary care physician as long as viral rebound does not occur. In 


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the extension phase of the study subjects will return for follow up every week, while off 
ART. ART resumption will follow same criteria as detailed above. 
 
The subjects’ primary care physician will be consulted on any changes in antiretroviral 
treatment. In addition, non-research results will be communicated to the subjects’ 
primary care physician after each study visit during all phases of the study. Safety and PK 
assessments will be performed at multiple time points following 3BNC117 infusions (see 
Appendix A). Subjects will be followed for 36 weeks from enrollment. 
 
8.2 
Analysis of Antiretroviral effects, Safety and Pharmacokinetics 
 
Primary Objectives: 
 
1. 3BNC117’s effect on virologic rebound: 
 
A one sided less Binomial Test with Clopper-Pearson confidence interval at 95% for rate 
of rebound will allow us to determine the population probability for the “occurrence of 
rebound”, with 95% of statistical significance level (Clopper, C.; Pearson, E. S. (1934)).   
 
Kaplan-Meier estimator will be used to address the second variable, “time to rebound” 
(Kaplan, E. L.; Meier, P. (1958). 
 
2. 3BNC117’s safety and tolerability profile in HIV-infected subjects with suppressed 
viremia during an analytical treatment interruption: 
 
The number and percentage of subjects experiencing one or more AEs will be 
summarized by relationship to study drug, and severity. AEs will be summarized by the 
number and percentage of subjects who experienced the event, according to system organ 
class (SOC) and preferred term. AEs will also be summarized by severity grade and by 
relationship to study drug according to the DAIDS AE Grading Table (see Appendix B). 
The CTCAE v4.03 grading scale will be used for reporting and grading adverse events 
related to infusion reactions and cytokine release syndromes in all groups.  
 
The changes in hematology, chemistry, and other laboratory values will be summarized 
descriptively. Changes will be calculated relative to the values collected at baseline. 
 
3. 3BNC117’s pharmacokinetic profile in HIV-infected subjects with suppressed 
viremia during an analytical treatment interruption: 
 
Pharmacokinetic parameters will be calculated using standard non-compartmental 
analysis methods. Pharmacokinetic parameters, including AUC, Cmax, T½, Tmax and 
others will be summarized. A 95% two tails matched pairs T-test will be used to compare 
3BNC117 serum levels before and after each antibody infusion. Pharmacokinetic 
parameters will be examined to correlate exposure with safety and pharmacodynamic 
parameters. Variance based on population intrinsic factors such as weight and gender will 
be explored.  


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Secondary and Exploratory Objectives: 
 
1. 
The range of 3BNC117 serum levels at which virologic rebound occurs: 
 
For each participant the time to rebound and the concentration of 3BNC117 at the time of 
rebound will be determined and summarized using confidence intervals.  
 
2.  
Compare the rate and time to rebound between groups:  
 
A Fisher exact test will allow us to contrast the rate of rebound between groups and 
Kruskal–Wallis one-way analysis of variance will be used to compare the mean time to 
rebound. For both tests a 95% significance level will be assumed. 
 
3. 
Host immune responses: 
A 95% repeated measures ANOVA F-test will be used to compare the following 
variables, at baseline, 2 weeks after the last infusion, at weeks 12 and 36: 
• serum levels of inflammation markers, such as: C-reactive protein, D-dimers, 
IL-6 and soluble CD-14. 
• CD8+ T cell expression of activation markers such as: HLA-DR, CD38 and 
PD-1. 
• HIV gag and env-specific T and B cell immune responses will be evaluated by 
intracellular cytokine staining and ELISA. 
 
4. 
Antiretroviral effects: 
A 95% repeated measures ANOVA F-test will be used to compare the following 
variables, before as well as 8 weeks after the first infusion if viral rebound does not 
occur: 
• levels of plasma HIV-1 RNA by single copy assay;  
• levels of cell-associated HIV-1 RNA  and DNA;  
 
 
5. 
 Other measurements: 
 
The frequency and levels of anti-3BNC117 antibodies after each 3BNC117 infusion will 
be calculated and displayed in tables.  
 
Genotyping of HIV isolates will be performed in the Laboratory of Molecular 
Immunology by reverse transcription followed by PCR amplification and sequencing of 
HIV envelope genes. This will allow us to phylogenetically compare viruses grown from 
PBMCs collected from subjects while on ART to rebound viruses collected after 
treatment interruption and analyze the induction of escape mutations. In addition, 
amplified HIV envelope genes will be cloned and produced in pseudoviruses in order to 
test for resistance to 3BNC117 by TZM-bl neutralization assay. Results will be 
descriptive.  
 


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Continuous data will be summarized by descriptive statistics, including the sample size, 
mean, standard deviation, median and range. Categorical data will be summarized by the 
number and percentage of subjects. If necessary Log2 of variables will be used. 
 
8.3 
Sample Size Considerations 
The confidence interval calculation is based on one of the primary objectives of this study 
“Evaluate the effect of two or four infusions of 3BNC117 at 30 mg/kg in delaying 
virologic rebound and maintaining viral suppression during a short analytical treatment 
interruption”. As such, the primary outcome is the occurrence of rebound during 
treatment interruption.  
 
In study group A, 5 out 7 participants who received 2 infusions of 3BNC117 have 
experienced viral rebound to date. Eight participants will be enrolled in the new study 
group B and will be administered four 3BNC117 infusions at days 0, 14, 28 and 42. 
 
A one-sided upper confidence interval will be constructed for the probability of rebound 
in study group B using the Clopper-Pearson method. As such, a sample size of 8 HIV-
infected individuals will allow the rejection of the null hypothesis (rate = 1) with 80% 
power for an effect size equal or higher than 0.18, if at least 4 out of 8 participants 
enrolled in study group B do not experience viral rebound by week 8. The one-sided 95% 
Clopper-Pearson confidence intervals calculated for a varying number of observed 
rebounds are presented in Table 1. If 5 or more participants in group B experience viral 
rebound prior to study week 6 [2 weeks after the third 3BNC117 infusion], additional 
participants will not undergo ATI. 
 
Table 1. Upper bound Confidence Interval  
for a sample size of n=8 (Study Group B) 
 
We will compare days from date of ART 
interruption to viral rebound in group A to group 
B. Given a standard deviation (SD) of 10 (days), 
enrolling 7 or 8 patients in each of the two arms, 
will have 80% power to detect ≥ 15 days 
difference in time to viral rebound at a 5% 
significance 
level 
(Davey 
et 
al., 
1999, 
Rothenberger et al., 2015).  
 
The safety population will include all subjects 
who receive a 3BNC117 infusion. A baseline 
measurement and at least one laboratory, vital 
sign, or other safety-related measurement obtained 
after at least one dose of study treatment may be required for inclusion in the analysis of 
a specific safety parameter.  
 
All adverse events will be reported, grouped as to whether or not they qualify as SAEs, 
their severity grading, and their relationship to the antibody, as judged by the study 
Number of Rebounds 
UCI 
0 
0.3694 
1 
0.5265 
2 
0.6509 
3 
0.7551 
4 
0.843 
5 
0.9148 
6 
0.9682 
7 
0.9968 
8 
1 


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investigators. If none of the subjects experiences a moderate adverse event related to 
3BNC117 (n=16), the 95% upper confidence bound for the rate of adverse events in the 
population is 20.6%. 
 
Two tail matched pairs T- test will be used to compare 3BNC117 serum levels before and 
after each antibody infusion. For two tail matched pairs T- Test, a sample size of 16 
subjects in the group allows to detect an effect size of 0.75, with 80% power and 95% 
confidence.  
 
For repeated measures ANOVA F-test, a sample size of 16 subjects in the group allows to 
detect an effect size of 0.46, with 80% power and 95% confidence. (to compare variables 
of antiretroviral effects and immune responses, before first infusion, at 2 weeks after last 
infusion, at week 12 and week 36. 
 
9 
Data and Sample Storage 
 
The Principal Investigator will oversee how the data are collected, entered, and protected. 
All study data will be collected by the clinical study staff using designated source 
documents and entered onto the appropriate electronic case report forms (eCRFs). Data 
collection forms (DCFs) will be provided by EMMESTM for use as source documents as 
appropriate.  All study data must be verifiable to the source documentation. All source 
documents will be kept in a locked facility at the clinical site and remain separate from 
volunteer identification information (name, address, etc.) to ensure confidentiality. All 
medical records (when not being reviewed by the research team) will be kept under lock 
and key in the Medical Record Department of the hospital with access limited to the 
appropriate RUH personnel. Source documentation will be available for review to ensure 
that the collected data are consistent with the eCRFs.  
 
All eCRFs and laboratory reports will be reviewed by the clinical team, who will ensure 
that they are accurate and complete. 
 
All research samples will have a unique identifier.  The site PI will be responsible for 
ensuring project compliance, data analysis and entry, regulatory monitoring, and 
coordination of the activities of the entire study team.  Standard GCP practices will be 
followed to ensure accurate, reliable and consistent data collection. 
 
Source documents include, but are not limited to: 
- 
Signed Informed Consent Documents 
- 
Dates of visits including date of 3BNC117 infusions 
- 
Documentation of any existing conditions or past conditions relevant to eligibility  
- 
Reported laboratory results 
- 
All adverse events  
- 
Concomitant medications 
 
 


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10 
Recruitment Plan 
 
Both men and women ages 18 through 65 will be recruited for the study from the 
community at large and will be referred by physicians in the community.   We will make 
every effort to recruit minorities and women. We project screening 50 subjects in order to 
achieve 16 evaluable subjects. In case of drop-outs an over-enrollment of 10% will be 
allowed. 
 
- Protocol MCA-823 - Subjects that already participated in protocol MCA-823, were 
found to have 3BNC117-susceptible strains, and agreed to be contacted for future studies 
will be contacted by study investigators. 
 
- Advertisements – The Clinical Research Support Office at the Rockefeller University 
Hospital (CRSO) will utilize the Volunteer Repository. Advertisements will also be 
placed: online (e.g. Craiglist, CenterWatch, etc.), in newspapers (Metro, AMNY) and on 
campus. 
  
Subjects may also be referred by physicians in the community. 
  
 
11 
Potential Benefits to Subjects 
It is unlikely that study subjects will benefit from participating in this study. 
 
12 
Potential risks to the subject including to the fetus 
• This study entails moderate risk to subjects since 3BNC117 is an investigational new 
drug with limited human safety data. The study also includes a period of ART 
interruption.  It has been shown that episodic ART guided by CD4+ count decline 
leads to increased risk of opportunistic infections as compared with continuous ART 
(El-Sadr W et al. NEJM 2006, SMART trial). However, different groups have now 
shown that short analytical treatment interruption is safe (Routy et al., 2012). ART 
will be resumed if plasma HIV-1 RNA levels increase to ≥ 200 copies/ml and are 
confirmed upon repeated measurement (performed within 1 week of first 
measurement). 
 
• If the HIV-1 viremia rebounds after ART is discontinued, absolute CD4+ counts 
might drop. However subjects will be followed very closely and ART will be 
resumed if the CD4+ cell count drops < 350 cells/µl and this is confirmed upon repeat 
measurement.  
 
• During ART interruption, subjects might experience symptoms of acute retroviral 
syndrome, such as fever, rash, swollen glands, headache, sore throat, nausea, 
vomiting. ART will be resumed if acute retroviral syndrome is suspected by study 
investigators. 
 
• Resistant viral strains to previous ART medications might arise during the analytical 
treatment interruption.  


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• During the ART-interruption phase of the study subjects may be at increased risk of 
transmitting HIV to their partners, if they become viremic, and of HIV-1 
superinfection from an HIV-infected partner. Therefore, subjects will be asked to use 
male or female condoms for the duration of ART interruption. In the event of a high-
risk exposure to an HIV-infected partner, a subject may re-initiate ART as clinically 
indicated by his/her primary care physician. 
  
• 3BNC117 has now been administered to 63 volunteers (55 under protocol MCA-835 
and 8 under this protocol – study group A) and it was generally safe and well 
tolerated in all doses tested. Sixteen volunteers have been administered 2 doses of 
3BNC117 and 7 of these received the doses 3 weeks apart. This study will for the first 
time evaluate the safety of four infusions of 3BNC117 administered 2 weeks apart. 
The risk of repeated 3BNC117 infusions is not yet known.  
 
• While each mAb product has unique safety issues related to its mechanism of action, 
the major safety concern related to mAbs in general is an infusion/hypersensitivity 
reaction. These types of reactions are more common for mAbs that contain murine 
elements compared to human mAbs, such as 3BNC117. Passive administration of 
anti-HIV-1 antibodies has been evaluated in humans in the past. As observed with 
other monoclonal antibodies, anti-HIV-1 antibodies were generally safe and well 
tolerated and most adverse events observed were infusion-related events. Grade I 
partial thromboplastin time (PTT) prolongations were also noted in one study that 
tested a combination of three anti-HIV monoclonal antibodies (Mehandru et al., 
2007b; Trkola et al., 2005b).  
 
• Immunologic symptoms such as listed below are possible with administration of a 
monoclonal antibody and will be considered adverse events of interest.  Potential 
allergic-type reactions during and immediately following the administration of 
3BNC117 will be carefully monitored.   
o Constitutional symptoms, such as fever, rigors/chills; 
o Injection site reaction/extravasation changes, pruritus, urticaria; 
o Serum sickness like syndromes as evidenced by fever, rash, arthralgia, 
arthritis,  nephritis; 
o Deposition of immune complexes in the kidneys leading to renal 
insufficiency;  
o Adult Respiratory Distress Syndrome, bronchospasm/wheezing, anaphylaxis; 
o Cytokine release syndrome/ acute infusion reaction.  
 
• 3BNC117-resistant viral strains might arise following administration of 3BNC117. 
Development of 3BNC117 resistance might limit the future use of 3BNC117 by the 
study subject, if this monoclonal antibody is licensed for clinical use by the FDA.  
 
• In the cross-reactivity study in human tissues, 3BNC117 was found to bind to cells in 
the conjunctival recesses. It is possible that this binding could lead to conjunctival 
toxicity. However, when rats and non-human primates were administered 3BNC117, 


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conjunctival toxicity was not observed. Fifty-five participants have received 
3BNC117 in protocol MCA-835. 12 participants reported mild ophthalmic complaints 
(such as pruritus, conjunctival erythema, increased lacrimation) during study follow 
up. In all instances symptoms resolved without specific treatment and ophthalmologic 
evaluations 5 months after 3BNC117 administration did not show changes from 
baseline. To date, ophthalmic complaints have not been reported under this protocol.  
 
• Blood drawing and phlebotomy can be associated with pain, bruising, anemia or 
infection at the site of venipuncture. Rarely, fainting may follow phlebotomy. 
 
• The adverse effects 3BNC117 administration would have in a fetus or unborn child 
are unknown.  
 
13 
Procedures to minimize risk 
• As outlined above, this study will be an exploratory phase II trial of 3BNC117 in 
humans. Potential trial volunteers will be informed about the possible risks of the 
monoclonal antibody administration and that there may be unknown risks.  
 
• Medical records and routine laboratory data will be handled with HIPAA compliance 
and protected by the rules and regulations of the RUH, JCAHO approved institutions. 
 
• With any new medicine or monoclonal antibody, there is a possibility of totally 
unexpected side effects. Subjects will be closely monitored for 1.5 hours post infusion 
in the RUH inpatient unit. The Rockefeller University Hospital inpatient unit is 
equipped for providing emergency medical interventions in the unlikely event of 
acute allergic or other reactions. In case of an emergency, after stabilization of the 
subject, he/she will be transferred to the neighboring tertiary care center, New York 
Presbyterian Hospital (Cornell) for specialized medical care. So far, 3BNC117 has 
been administered to 55 individuals in protocol MCA-835 and 8 in this protocol 
(MCA-867) without any acute unexpected events. A maximum of two participants 
will receive a 3BNC117 infusion per day. Infusions will not be given simultaneously. 
 
• Subjects will be closely monitored for the development of symptoms of ocular 
disease (such as blurry vision, increased lacrimation, redness, dryness, pain) and the 
study investigators will perform a directed exam of the eyes. If subjects develop 
symptoms or signs of ocular disease, they will be referred to an ophthalmologist for 
diagnosis and management. These evaluations will be performed at no cost to the 
subject. 
 
• During the treatment interruption phase of the study, plasma HIV-1 RNA levels will 
be monitored weekly and CD4+ T cell counts will be monitored every other week. 
ART regimen will be resumed if plasma HIV-1 RNA level is  ≥ 200 copies/ml, CD4+ 
T cell count drops < 350 cells/µl, and either result is confirmed upon repeat 
measurement, during the next weekly scheduled visit. If plasma HIV-1 RNA level is 
≥ 1,000 copies/ml, the participant will be asked to return for a repeat measurement 
prior to the next scheduled visit, and ART will be resumed if results are confirmed. 


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ART will also be resumed early if the participant becomes pregnant, or if otherwise 
clinically indicated. If ART regimen is resumed before completion of 3BNC117 
infusions, further 3BNC117 infusions will not be performed. 
 
• In order to minimize the risk of resistance to the previous ART regimen, all 
antiretroviral drugs will be stopped simultaneously and ART will be resumed 
according to the above criteria. Non-nucleoside reverse transcriptase inhibitors have 
longer elimination half-lives than other antiretroviral classes. Therefore, in order to 
avoid the risk of inadvertent monotherapy, which can select NNRTI resistant strains, 
if the subject’s ART regimen includes an NNRTI, the NNRTI will be switched to 
dolutegravir (an integrase inhibitor) 4 weeks prior discontinuing all antiretroviral 
drugs. Dolutegravir will be provided to the subjects for that time period. 
 
•  In order to minimize the risk of transmitting HIV to their partners, if they become 
viremic, and of HIV-1 superinfection from an HIV-infected partner, subjects will be 
asked to use male or female condoms for the duration of ART interruption. In the 
event of a high-risk exposure to an HIV-infected partner, a subject may re-initiate 
ART as clinically indicated by his/her primary care physician. 
 
• To minimize risks associated with phlebotomy, blood drawing will be performed by 
experienced phlebotomists. Should discomfort occur, they will provide appropriate 
treatment. 
 
• To minimize risks associated with blood drawing, volunteers will be closely 
monitored for signs and symptoms of anemia. 
 
• Females of childbearing potential and who participate in sexual activity that might 
lead to pregnancy will be advised to use a reliable form of contraception for the 
duration of the study. In addition, a pregnancy test will be performed at screening, on 
the days of drug infusion, and throughout the course of the study.  Males who are not 
anatomically sterile and who participate in sexual activity that might lead to 
pregnancy will be advised to use condoms from screening throughout the duration of 
the study to avoid pregnancy in a spouse or partner. Condoms will be provided.  
 
• Subjects will have regularly scheduled visits to the outpatient clinic and routine safety 
laboratories [CBC, clinical chemistries, liver function tests, and urinalysis] will be 
checked according to the Time of Events Schedule (Appendix A). HIV-infected 
individuals will have close monitoring of HIV-1 viral load and CD4/CD8 counts 
according to the Time of Events Schedule (Appendix A).  
 
• Adverse events will be monitored and graded using the DAIDS AE Grading Table. 
The CTCAE v4.03 grading scale will be used for reporting and grading adverse 
events related to infusion reactions and cytokine release syndromes in all groups 
(Appendix B). 
 


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• Adverse events will be managed by the clinical trial team who will assess and treat 
the event as appropriate, including referral to an independent physician and/or 
department.  
 
• Safety monitoring at both clinical sites will be conducted both by the International 
AIDS Vaccine Initiative (IAVI) and by an external Study Monitoring Committee 
(SMC). The RUH IRB will conduct the initial review of the proposed study and will 
follow progress through annual reports and by immediate notification of serious and 
unanticipated adverse events. Any serious adverse events will be reviewed by the 
study investigators immediately. Site investigators will notify the local IRB and the 
sponsor at the Rockefeller University within 2 working days from the investigators 
being made aware of the event. The RU sponsor will notify the FDA, per 21 CFR 
312.The SMC will be available to the investigators for consultation and review of 
severe adverse events if needed.  
 
14 
Alternative methods or treatments 
This does not apply to this study. 
 
15 
Data and Safety Monitoring Plan 
This is an exploratory Phase II study which exposes the subjects to “moderate risk”. A 
Study Monitoring Committee (SMC) will be established to monitor the study. 
 
15.1 
Safety Monitoring Committee 
The charter of the SMC is to provide an ongoing assessment of volunteer safety during 
the conduct of the study.  The SMC will consist of three independent individuals who 
have no relationship to the Principal Investigators and Co-Investigators involved in the 
trial. No member of the SMC will have any direct responsibility for the clinical care of 
trial volunteers.  No representative of Celldex Therapeutics, the Rockefeller University, 
or their designees may be a member of the SMC. However, the SMC may invite the 
principal investigators (PI) or designee and a Celldex Therapeutics, and/or Rockefeller 
University representative to an open session of a SMC meeting to provide information on 
study conduct, present data, or to respond to the members’ questions.  
 
The names, university affiliation and title, area of expertise, and contact information of 
each of the SMC members are provided below: 
Michael Keefer, MD 
Professor of Medicine 
University of Rochester Medical Center School of Medicine and Dentistry 
Phone: (585) 275-5871  
Michael_Keefer@urmc.rochester.edu 
Clinical expertise: infectious diseases, vaccines, HIV vaccines. 
 
Karolina Palucka, MD 
Professor of Medicine 
Baylor Institute for Immunology Research 


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Phone:(214) 820-7451 
karolinp@BaylorHealth.edu 
Clinical expertise: immunotherapy, cancer vaccines 
 
 
Eric Daar, MD 
Chief, Division of HIV Medicine 
Harbor-UCLA Medical Center 
Professor of Medicine 
David Geffen School of Medicine at UCLA 
1124 W. Carson St., CDCRC 205 
Torrance, CA 90502 
(424) 201-3000 x7317 
EDaar@LABioMed.org 
Clinical expertise: clinical management of HIV infection 
 
The SMC will be asked to review safety data as needed: 
-        Severe clinical adverse/reactogenicity events judged by the principal investigator 
or designee to be possibly, probably or definitely related to 3BNC117. 
-        Severe laboratory adverse events confirmed on retest and judged by the principal 
investigator or designee to be possibly, probably or definitely related to 3BNC117. 
-      
SAEs and unanticipated adverse events will be reported to the SMC within 2 
working days of the site becoming aware of the event. 
 
If there is one SAE graded as severe and judged as possibly, probably or definitely 
related to the administration of 3BNC117 by the principal investigator or designee, no 
additional enrollment will take place pending a review by at least two members of 
the SMC. Following this review, the SMC member(s) will make a recommendation to the 
principal investigator regarding the continuation of the trial. 
 
In addition, the SMC will review all available safety data up to day 21 (1 week after 
second infusion) of the first 3 subjects enrolled in group B. The SMC will then provide a 
recommendation regarding administration of a third dose.  If the SMC determines it is 
safe to proceed, the third dose will be administered 2 weeks following the second dose 
(day 28) and the fourth dose will follow two weeks later (day 42). Two weeks after the 
third subject in group B receives the fourth dose, all available safety data will be 
reviewed by the SMC.  If the SMC determines it is safe to proceed, additional subjects (n 
= 5) will be enrolled to receive 4 doses at 2-week intervals.  
 
All updated versions of the protocol will be provided to the SMC members. The review 
of trial data by the SMC will take place at least annually. The study team will provide the 
SMC with updated records of all adverse events (AEs) of a grade 2 or higher at least 
annually. 
    
The SMC will provide a written report to the PIs after each evaluation and the PIs in turn 
will distribute these reports to the study team, the local IRBs and the FDA. 


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15.2 
Safety Review  
Subjects will be closely monitored for 1.5 hours post infusion in the RUH inpatient unit. 
The Rockefeller University Hospital inpatient unit is equipped for providing emergency 
medical interventions in the unlikely event of acute allergic or other reactions. RU 
Hospital outpatient and inpatient units are equipped with crash carts for immediate 
medical care, should the need arise. In case of an emergency, after stabilization of the 
volunteer, he/she will be transferred to the neighboring tertiary care center, New York 
Presbyterian Hospital (Cornell) for specialized medical care.  
 
15.3 
Monitoring 
Safety monitoring will be conducted by the study investigators and by the IAVI. An 
external SMC will review SAE’s and Unanticipated AEs and will be available to the 
study investigators for consultation. The RU IRB will conduct the initial review of the 
proposed study and will follow progress through annual reports and by immediate 
notification of SAEs and UAEs.  External monitoring will occur at least quarterly.  
 
15.4 
Adverse Event Classification 
• Scales to be used: the DAIDS AE Grading Table, the CTCAE v4.03 grading scale 
will be used for reporting and grading adverse events related to infusion reactions and 
cytokine release syndromes (Appendix B). 
  
15.5 
Reporting Adverse Events 
All adverse events will be reported to the local IRBs at least annually.  Serious Adverse 
Events, (SAEs) will be reported to the local IRBs and to the sponsor at the Rockefeller 
University according to policy, within two working days of identification of the SAE.  
The RU sponsor will report SAEs directly to the FDA, per 21 CFR 312. 
 
15.6 
Reporting Unanticipated AEs: 
Unanticipated Adverse Events (UAEs) will be reported to the local IRBs.  UAEs that are 
related and greater than moderate severity must be reported to the local IRBs and to the 
sponsor at the Rockefeller University according to policy, within two working days of 
identification of the UAE. The RU sponsor will report UAEs to the FDA, per 21 CRF 
312.  
 
15.7 
Clinical Laboratory Improvement Amendment/Clinical Laboratory 
Evaluation Program (CLIA/CLEP) 
This study includes tests that are not CLIA/CLEP certified. The results of such tests will 
not be used in clinical decision-making or shared with subjects or their health care 
providers. 
 
15.8 
Toxicity Management and Stopping Rules 
A dose limiting toxicity (DLT) will be defined as any adverse event of ≥ Grade 3 
toxicity, if the study investigators recognize a probable or definite attribution to 
3BNC117. In case of DLTs, further enrollment will not occur until investigators and 
SMC review the event. The investigators and SMC will mutually assess the information, 


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along with safety from other subjects, to determine whether a change in study conduct is 
warranted. Enrollment will stop but volunteers will continue to be monitored by the study 
investigators. 
 
Volunteers will be withdrawn from the study if: a) the study team feels that continued 
participation in the study would be harmful to the health of a subject; b) if the study 
volunteer fails to comply with the study procedures and/or fails to keep study visit 
appointments; c) The RU IRB decided to stop or cancel the study for any reason. 
 
16 
Clinical Trial Registration 
The proposed study involves testing of FDA regulated drugs or biologics and is 
registered at www.ClinicalTrials.gov, identifier NCT02446847. 
 
 


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22.0 Bibliography 
Armbruster, C., Stiegler, G.M., Vcelar, B.A., Jager, W., Koller, U., Jilch, R., Ammann, 
C.G., Pruenster, M., Stoiber, H., and Katinger, H.W. (2004). Passive immunization with 
the anti-HIV-1 human monoclonal antibody (hMAb) 4E10 and the hMAb combination 
4E10/2F5/2G12. The Journal of antimicrobial chemotherapy 54, 915-920. 
Barouch, D.H., Whitney, J.B., Moldt, B., Klein, F., Oliveira, T.Y., Liu, J., Stephenson, 
K.E., Chang, H.W., Shekhar, K., Gupta, S., et al. (2013). Therapeutic efficacy of potent 
neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. 
Nature 503, 224-228. 
Davey, R.T., Jr., Bhat, N., Yoder, C., Chun, T.W., Metcalf, J.A., Dewar, R., Natarajan, 
V., Lempicki, R.A., Adelsberger, J.W., Miller, K.D., et al. (1999). HIV-1 and T cell 
dynamics after interruption of highly active antiretroviral therapy (HAART) in patients 
with a history of sustained viral suppression. Proceedings of the National Academy of 
Sciences of the United States of America 96, 15109-15114. 
Deeks, S.G., Tracy, R., and Douek, D.C. (2013). Systemic effects of inflammation on 
health during chronic HIV infection. Immunity 39, 633-645. 
Gruell, H., Bournazos, S., Ravetch, J.V., Ploss, A., Nussenzweig, M.C., and Pietzsch, J. 
(2013). Antibody and antiretroviral preexposure prophylaxis prevent cervicovaginal HIV-
1 infection in a transgenic mouse model. Journal of virology 87, 8535-8544. 
Horwitz, J.A., Halper-Stromberg, A., Mouquet, H., Gitlin, A.D., Tretiakova, A., 
Eisenreich, T.R., Malbec, M., Gravemann, S., Billerbeck, E., Dorner, M., et al. (2013). 
HIV-1 suppression and durable control by combining single broadly neutralizing 
antibodies and antiretroviral drugs in humanized mice. Proceedings of the National 
Academy of Sciences of the United States of America 110, 16538-16543. 
Kutzler, M.A., and Jacobson, J.M. (2008). Treatment interruption as a tool to measure 
changes in immunologic response to HIV-1. Current opinion in HIV and AIDS 3, 131-
135. 
Laird, G.M., Eisele, E.E., Rabi, S.A., Lai, J., Chioma, S., Blankson, J.N., Siliciano, J.D., 
and Siliciano, R.F. (2013). Rapid quantification of the latent reservoir for HIV-1 using a 
viral outgrowth assay. PLoS pathogens 9, e1003398. 
Malbec, M., Porrot, F., Rua, R., Horwitz, J., Klein, F., Halper-Stromberg, A., Scheid, 
J.F., Eden, C., Mouquet, H., Nussenzweig, M.C., et al. (2013). Broadly neutralizing 
antibodies that inhibit HIV-1 cell to cell transmission. The Journal of experimental 
medicine 210, 2813-2821. 
Markowitz, M., Evering, T.H., Garmon, D., Caskey, M., La Mar, M., Rodriguez, K., 
Sahi, V., Palmer, S., Prada, N., and Mohri, H. (2014). A randomized open-label study of 
3- versus 5-drug combination antiretroviral therapy in newly HIV-1-infected individuals. 
Journal of acquired immune deficiency syndromes 66, 140-147. 
McMahon, D., Jones, J., Wiegand, A., Gange, S.J., Kearney, M., Palmer, S., McNulty, S., 
Metcalf, J.A., Acosta, E., Rehm, C., et al. (2010). Short-course raltegravir intensification 
does not reduce persistent low-level viremia in patients with HIV-1 suppression during 
receipt of combination antiretroviral therapy. Clinical infectious diseases : an official 
publication of the Infectious Diseases Society of America 50, 912-919. 
Mehandru, S., Vcelar, B., Wrin, T., Stiegler, G., Joos, B., Mohri, H., Boden, D., 
Galovich, J., Tenner-Racz, K., Racz, P., et al. (2007a). Adjunctive passive 
immunotherapy in human immunodeficiency virus type 1-infected individuals treated 


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with antiviral therapy during acute and early infection. Journal of virology 81, 11016-
11031. 
Mehandru, S., Vcelar, B., Wrin, T., Stiegler, G., Joos, B., Mohri, H., Boden, D., 
Galovich, J., Tenner-Racz, K., Racz, P., et al. (2007b). Adjunctive passive 
immunotherapy in human immunodeficiency virus type 1-infected individuals treated 
with antiviral therapy during acute and early infection. J Virol 81, 11016-11031. 
Onyango-Makumbi, C., Omer, S.B., Mubiru, M., Moulton, L.H., Nakabiito, C., Musoke, 
P., Mmiro, F., Zwerski, S., Wigzell, H., Falksveden, L., et al. (2011). Safety and efficacy 
of HIV hyperimmune globulin for prevention of mother-to-child HIV transmission in 
HIV-1-infected 
pregnant 
women 
and 
their 
infants 
in 
Kampala, 
Uganda 
(HIVIGLOB/NVP STUDY). J Acquir Immune Defic Syndr 58, 399-407. 
Poignard, P., Sabbe, R., Picchio, G.R., Wang, M., Gulizia, R.J., Katinger, H., Parren, 
P.W., Mosier, D.E., and Burton, D.R. (1999). Neutralizing antibodies have limited effects 
on the control of established HIV-1 infection in vivo. Immunity 10, 431-438. 
Routy, J.P., Boulassel, M.R., Nicolette, C.A., and Jacobson, J.M. (2012). Assessing risk 
of a short-term antiretroviral therapy discontinuation as a read-out of viral control in 
immune-based therapy. Journal of medical virology 84, 885-889. 
Scheid, J.F., Mouquet, H., Ueberheide, B., Diskin, R., Klein, F., Oliveira, T.Y., Pietzsch, 
J., Fenyo, D., Abadir, A., Velinzon, K., et al. (2011). Sequence and structural 
convergence of broad and potent HIV antibodies that mimic CD4 binding. Science 333, 
1633-1637. 
Shingai, M., Nishimura, Y., Klein, F., Mouquet, H., Donau, O.K., Plishka, R., Buckler-
White, A., Seaman, M., Piatak, M., Jr., Lifson, J.D., et al. (2013). Antibody-mediated 
immunotherapy of macaques chronically infected with SHIV suppresses viraemia. Nature 
503, 277-280. 
Simek, M.D., Rida, W., Priddy, F.H., Pung, P., Carrow, E., Laufer, D.S., Lehrman, J.K., 
Boaz, M., Tarragona-Fiol, T., Miiro, G., et al. (2009). Human immunodeficiency virus 
type 1 elite neutralizers: individuals with broad and potent neutralizing activity identified 
by using a high-throughput neutralization assay together with an analytical selection 
algorithm. Journal of virology 83, 7337-7348. 
Strategies for Management of Antiretroviral Therapy Study, G., El-Sadr, W.M., 
Lundgren, J., Neaton, J.D., Gordin, F., Abrams, D., Arduino, R.C., Babiker, A., Burman, 
W., Clumeck, N., et al. (2006). CD4+ count-guided interruption of antiretroviral 
treatment. The New England journal of medicine 355, 2283-2296. 
Trkola, A., Kuster, H., Rusert, P., Joos, B., Fischer, M., Leemann, C., Manrique, A., 
Huber, M., Rehr, M., Oxenius, A., et al. (2005a). Delay of HIV-1 rebound after cessation 
of antiretroviral therapy through passive transfer of human neutralizing antibodies. 
Nature medicine 11, 615-622. 
Trkola, A., Kuster, H., Rusert, P., Joos, B., Fischer, M., Leemann, C., Manrique, A., 
Huber, M., Rehr, M., Oxenius, A., et al. (2005b). Delay of HIV-1 rebound after cessation 
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Med 11, 615-622. 
 

SAP_001.pdf: 
Official title: A phase 2, open label study of the safety, antiretroviral activity and 
pharmacokinetics of 3BNC117 during a short analytical treatment interruption in HIV-
infected subjects 
 
NCT number: NCT02446847 
 
Document date: 09/21/2015 
 


The Rockefeller University 
 
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September 21, 2015 
  
STATISTICAL PLAN # MCA-0867 
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1 
 
A phase 2, open label study of the safety, antiretroviral activity and 
pharmacokinetics of 3BNC117 during a short analytical treatment interruption in 
HIV-infected subjects 
 
 
 
 
IND Sponsor:  
The Rockefeller University (Sarah Schlesinger, MD) 
IND # 118225 
 
Principal Investigator/Protocol Chair: 
Marina Caskey MD 
 
Draft or Version Number: 
Version 1.2 
 September 21, 2015 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This document is confidential and is to be distributed for review only to investigators, 
potential investigators, consultants, study staff, and applicable independent ethics 
committees or institutional review boards. The contents of this document shall not be 
disclosed to others without written authorization from The Rockefeller University, unless 
it is necessary to obtain informed consent from potential study participants. 
 
Statement of Compliance 
The clinical trial will be conducted in compliance with the protocol, with the 
International Conference on Harmonization Good Clinical Practice E6 (ICH-GCP), and 
with 45 CFR 46 and 21 CFR 50, 56 and 312. All protocol investigators have completed 
Protection of Human Subjects Training. 
 


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1.1 
Design 
The proposed study is a Phase II, open label study to evaluate the antiretroviral activity 
and safety of two and four 3BNC117 infusions in HIV-infected subjects on combination 
antiretroviral therapy, during a brief analytical treatment interruption. The study will also 
obtain additional data on its pharmacokinetic profile.  
 
After meeting enrollment criteria eight subjects with 3BNC117 sensitive virus (< 2µg/ml 
IC50) enrolled in Group A to receive two intravenous infusions of 3BNC117, 
administered at 30 mg/kg on day 0 and day 21 (Group A). Eight additional subjects with 
3BNC117 sensitive virus (< 2µg/ml IC50) will be enrolled to receive four intravenous 
infusions of 3BNC117, administered at 30 mg/kg on day 0, day 14, day 28 and day 42 
(Group B). As 3BNC117 has not been administered four times to single individuals to 
date, Group B will be started with a mini cohort (n=3). Safety will be assessed by the 
SMC 1 week after the second dose, as well as 2 weeks after the fourth dose in the mini 
cohort, before proceeding with further infusions and enrollment.   
 
Antiretroviral therapy will be discontinued on day 2 for 12 weeks after the first 3BNC117 
infusion (week 12). We project screening 50 subjects in order to achieve 16 evaluable 
subjects. In case of drop-outs an over-enrollment of 10% will be allowed. 
 
The same ART regimen will be resumed at week 12. ART regimen will be resumed 
sooner if plasma HIV-1 RNA level is ≥ 200 copies/ml or if CD4+ count drops < 350 
cells/µl and either result is confirmed upon repeat measurement during the next weekly 
scheduled visit. If plasma HIV-1 RNA level is ≥ 1,000 copies/ml, the participant will be 
asked to return for a repeat measurement prior to the next scheduled visit, and ART will 
be resumed if results are confirmed. ART will also be resumed early if the participant 
becomes pregnant, or if otherwise clinically indicated. If ART regimen is resumed before 
completion of 3BNC117 infusions, further 3BNC117 infusions will not be performed. All 
subjects will be followed weekly until week 12 for safety assessments and for monitoring 
plasma HIV-1 RNA levels. CD4+ T cell counts will be monitored every 2 weeks until 
week 12. After week 12 subjects will be followed as outlined in the Time of Events 
Schedule (Appendix A). 
 
Subjects will be offered a continuation of the treatment interruption through week 36, 
coordinated with their primary care physician as long as viral rebound does not occur. In 
the extension phase of the study subjects will return for follow up every week, while off 
ART. ART resumption will follow same criteria as detailed above. 
 
The subjects’ primary care physician will be consulted on any changes in antiretroviral 
treatment. In addition, non-research results will be communicated to the subjects’ 
primary care physician after each study visit during all phases of the study. Safety and PK 
assessments will be performed at multiple time points following 3BNC117 infusions (see 
Appendix A). Subjects will be followed for 36 weeks from enrollment. 
 


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1.2 
Analysis of Antiretroviral effects, Safety and Pharmacokinetics 
 
Primary Objectives: 
 
1. 3BNC117’s effect on virologic rebound: 
 
A one sided less Binomial Test with Clopper-Pearson confidence interval at 95% for rate 
of rebound will allow us to determine the population probability for the “occurrence of 
rebound”, with 95% of statistical significance level (Clopper, C.; Pearson, E. S. (1934)).   
 
Kaplan-Meier estimator will be used to address the second variable, “time to rebound” 
(Kaplan, E. L.; Meier, P. (1958). 
 
2. 3BNC117’s safety and tolerability profile in HIV-infected subjects with suppressed 
viremia during an analytical treatment interruption: 
 
The number and percentage of subjects experiencing one or more AEs will be 
summarized by relationship to study drug, and severity. AEs will be summarized by the 
number and percentage of subjects who experienced the event, according to system organ 
class (SOC) and preferred term. AEs will also be summarized by severity grade and by 
relationship to study drug according to the DAIDS AE Grading Table (see Appendix B). 
The CTCAE v4.03 grading scale will be used for reporting and grading adverse events 
related to infusion reactions and cytokine release syndromes in all groups.  
 
The changes in hematology, chemistry, and other laboratory values will be summarized 
descriptively. Changes will be calculated relative to the values collected at baseline. 
 
3. 3BNC117’s pharmacokinetic profile in HIV-infected subjects with suppressed 
viremia during an analytical treatment interruption: 
 
Pharmacokinetic parameters will be calculated using standard non-compartmental 
analysis methods. Pharmacokinetic parameters, including AUC, Cmax, T½, Tmax and 
others will be summarized. A 95% two tails matched pairs T-test will be used to compare 
3BNC117 serum levels before and after each antibody infusion. Pharmacokinetic 
parameters will be examined to correlate exposure with safety and pharmacodynamic 
parameters. Variance based on population intrinsic factors such as weight and gender will 
be explored.  
 
Secondary and Exploratory Objectives: 
 
1. 
The range of 3BNC117 serum levels at which virologic rebound occurs: 
 
For each participant the time to rebound and the concentration of 3BNC117 at the time of 
rebound will be determined and summarized using confidence intervals.  
 
2.  
Compare the rate and time to rebound between groups:  


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A Fisher exact test will allow us to contrast the rate of rebound between groups and 
Kruskal–Wallis one-way analysis of variance will be used to compare the mean time to 
rebound. For both tests a 95% significance level will be assumed. 
 
3. 
Host immune responses: 
A 95% repeated measures ANOVA F-test will be used to compare the following 
variables, at baseline, 2 weeks after the last infusion, at weeks 12 and 36: 
• serum levels of inflammation markers, such as: C-reactive protein, D-dimers, 
IL-6 and soluble CD-14. 
• CD8+ T cell expression of activation markers such as: HLA-DR, CD38 and 
PD-1. 
• HIV gag and env-specific T and B cell immune responses will be evaluated by 
intracellular cytokine staining and ELISA. 
 
4. 
Antiretroviral effects: 
A 95% repeated measures ANOVA F-test will be used to compare the following 
variables, before as well as 8 weeks after the first infusion if viral rebound does not 
occur: 
• levels of plasma HIV-1 RNA by single copy assay;  
• levels of cell-associated HIV-1 RNA  and DNA;  
 
 
5. 
 Other measurements: 
 
The frequency and levels of anti-3BNC117 antibodies after each 3BNC117 infusion will 
be calculated and displayed in tables.  
 
Genotyping of HIV isolates will be performed in the Laboratory of Molecular 
Immunology by reverse transcription followed by PCR amplification and sequencing of 
HIV envelope genes. This will allow us to phylogenetically compare viruses grown from 
PBMCs collected from subjects while on ART to rebound viruses collected after 
treatment interruption and analyze the induction of escape mutations. In addition, 
amplified HIV envelope genes will be cloned and produced in pseudoviruses in order to 
test for resistance to 3BNC117 by TZM-bl neutralization assay. Results will be 
descriptive.  
 
Continuous data will be summarized by descriptive statistics, including the sample size, 
mean, standard deviation, median and range. Categorical data will be summarized by the 
number and percentage of subjects. If necessary Log2 of variables will be used. 
 
1.3 
Sample Size Considerations 
The confidence interval calculation is based on one of the primary objectives of this study 
“Evaluate the effect of two or four infusions of 3BNC117 at 30 mg/kg in delaying 
virologic rebound and maintaining viral suppression during a short analytical treatment 


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5 
interruption”. As such, the primary outcome is the occurrence of rebound during 
treatment interruption.  
 
In study group A, 5 out 7 participants who received 2 infusions of 3BNC117 have 
experienced viral rebound to date. Eight participants will be enrolled in the new study 
group B and will be administered four 3BNC117 infusions at days 0, 14, 28 and 42. 
 
A one-sided upper confidence interval will be constructed for the probability of rebound 
in study group B using the Clopper-Pearson method. As such, a sample size of 8 HIV-
infected individuals will allow the rejection of the null hypothesis (rate = 1) with 80% 
power for an effect size equal or higher than 0.18, if at least 4 out of 8 participants 
enrolled in study group B do not experience viral rebound by week 8. The one-sided 95% 
Clopper-Pearson confidence intervals calculated for a varying number of observed 
rebounds are presented in Table 1. If 5 or more participants in group B experience viral 
rebound prior to study week 6 [2 weeks after the third 3BNC117 infusion], additional 
participants will not undergo ATI. 
 
Table 1. Upper bound Confidence Interval  
for a sample size of n=8 (Study Group B) 
 
We will compare days from date of ART 
interruption to viral rebound in group A to group 
B. Given a standard deviation (SD) of 10 (days), 
enrolling 7 or 8 patients in each of the two arms, 
will have 80% power to detect ≥ 15 days 
difference in time to viral rebound at a 5% 
significance 
level 
(Davey 
et 
al., 
1999, 
Rothenberger et al., 2015).  
 
The safety population will include all subjects 
who receive a 3BNC117 infusion. A baseline 
measurement and at least one laboratory, vital 
sign, or other safety-related measurement obtained 
after at least one dose of study treatment may be required for inclusion in the analysis of 
a specific safety parameter.  
 
All adverse events will be reported, grouped as to whether or not they qualify as SAEs, 
their severity grading, and their relationship to the antibody, as judged by the study 
investigators. If none of the subjects experiences a moderate adverse event related to 
3BNC117 (n=16), the 95% upper confidence bound for the rate of adverse events in the 
population is 20.6%. 
 
Two tail matched pairs T- test will be used to compare 3BNC117 serum levels before and 
after each antibody infusion. For two tail matched pairs T- Test, a sample size of 16 
subjects in the group allows to detect an effect size of 0.75, with 80% power and 95% 
confidence.  
Number of Rebounds 
UCI 
0 
0.3694 
1 
0.5265 
2 
0.6509 
3 
0.7551 
4 
0.843 
5 
0.9148 
6 
0.9682 
7 
0.9968 
8 
1 


The Rockefeller University 
 
 IND: 118225/0016 
September 21, 2015 
  
STATISTICAL PLAN # MCA-0867 
CONFIDENTIAL 
6 
 
For repeated measures ANOVA F-test, a sample size of 16 subjects in the group allows to 
detect an effect size of 0.46, with 80% power and 95% confidence. (to compare variables 
of antiretroviral effects and immune responses, before first infusion, at 2 weeks after last 
infusion, at week 12 and week 36. 
 
2 
Data and Sample Storage 
 
The Principal Investigator will oversee how the data are collected, entered, and protected. 
All study data will be collected by the clinical study staff using designated source 
documents and entered onto the appropriate electronic case report forms (eCRFs). Data 
collection forms (DCFs) will be provided by EMMESTM for use as source documents as 
appropriate.  All study data must be verifiable to the source documentation. All source 
documents will be kept in a locked facility at the clinical site and remain separate from 
volunteer identification information (name, address, etc.) to ensure confidentiality. All 
medical records (when not being reviewed by the research team) will be kept under lock 
and key in the Medical Record Department of the hospital with access limited to the 
appropriate RUH personnel. Source documentation will be available for review to ensure 
that the collected data are consistent with the eCRFs.  
 
All eCRFs and laboratory reports will be reviewed by the clinical team, who will ensure 
that they are accurate and complete. 
 
All research samples will have a unique identifier.  The site PI will be responsible for 
ensuring project compliance, data analysis and entry, regulatory monitoring, and 
coordination of the activities of the entire study team.  Standard GCP practices will be 
followed to ensure accurate, reliable and consistent data collection. 
 
Source documents include, but are not limited to: 
- 
Signed Informed Consent Documents 
- 
Dates of visits including date of 3BNC117 infusions 
- 
Documentation of any existing conditions or past conditions relevant to eligibility  
- 
Reported laboratory results 
- 
All adverse events  
- 
Concomitant medications