An Exploratory, Open-Label Study of Vedolizumab (Anti-alpha4beta7 Antibody) in Subjects With HIV Infection Undergoing Analytical Treatment Interruption
Phase: PHASE1
Conditions: HIV
Sponsor: National Institute of Allergy and Infectious Diseases (NIAID)

 
An Exploratory, Open-Label Study of Vedolizumab (anti-47 Monoclonal 
Antibody) in Subjects with HIV Infection Undergoing Analytical Treatment 
Interruption 
 
NIAID Protocol Number: 16-I-0118 
 
Sponsored by:  
National Institute of Allergy and Infectious Diseases (NIAID) 
 
 
 
IND Sponsor: NIAID/OCRPRO 
 
IND # 130343 
 
Medical Monitor: Marc J. Teitelbaum, MD 
 
Principal Investigator: Michael C. Sneller, M.D. 
 
Draft or Version Number: 5.0 
 
22 March 2017 
 
 
 
 
 
 

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Study Staff Roster 
 
 
 
Principal Investigator: 
  
Michael C. Sneller, MD 
 
 
 
 
 
Laboratory of Immunoregulation  
LIR/NIAID 
 
 
 
 
 
Phone: 301-496-0491 
 
 
 
 
 
E-mail: msneller@niaid.nih.gov 
 
Associate Investigators: 
 
Anthony Fauci, MD 
 
 
 
 
 
LIR/NIAID 
 
 
 
 
 
Phone: 301-496-2263 
 
 
 
 
 
E-mail: afauci@niaid.nih.gov 
 
Tae-Wook Chun, PhD 
 
 
 
 
 
LIR/NIAID 
 
 
 
 
 
Phone: 301-496-0890 
 
 
 
 
 
E-mail: twchun@niaid.nih.gov 
 
 
 
 
 
 
Susan Moir, PhD 
LIR/NIAID 
Phone: 301-402-4559 
E-mail: smoir@niaid.nih.gov 
 
Katherine Clarridge, MD 
LIR/NIAID 
Phone: 301-496-0890 
 
 
 
 
 
E-mail: katherine.clarridge@niaid.nih.gov 
 
 
 
 
 
 
Avi Nath, MD 
 
 
 
 
 
NINDS 
 
 
 
 
 
Phone:  301-496-1561 
 
 
 
 
 
E-mail: natha@mail.nih.gov 
 
 
 
 
 
 
Bryan Smith, MD 
 
 
 
 
 
NINDS 
 
 
 
 
 
Phone: 301-451-4585 
 
 
 
 
 
E-mail: bryan.smith2@nih.gov 
 
 
 
 
 
 

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Research Contact 
 
 
Catherine Seamon, RN CCRP 
 
 
 
 
 
Clinical Center/Critical Care Medicine Department 
 
 
 
 
 
Phone: 301-402-3481 
 
 
 
 
 
Email: cseamon@cc.nih.gov 
 
Statistician:  
Michael Proschan, PhD 
Biostatistics Research Branch/DCR 
Phone: 301-451-5129 
E-mail: proscham@niaid.nih.gov 
 
 
 

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Table of Contents 
STUDY STAFF ROSTER........................................................................................................................ 2 
TABLE OF CONTENTS ......................................................................................................................... 4 
LIST OF TABLES ................................................................................................................................. 6 
LIST OF FIGURES................................................................................................................................ 6 
LIST OF ABBREVIATIONS .................................................................................................................... 7 
PROTOCOL SUMMARY ...................................................................................................................... 8 
PRÉCIS ............................................................................................................................................ 10 
1 BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ........................................................... 11 
1.1 
BACKGROUND INFORMATION ................................................................................................................ 11 
 
Description of the Study Agent ............................................................................................... 12 
 
Summary of Pre-Clinical Nonhuman Primate Studies ............................................................ 13 
 
Summary of Relevant Clinical Studies ..................................................................................... 16 
1.2 
RATIONALE ........................................................................................................................................ 19 
2 
STUDY OBJECTIVES ................................................................................................................... 19 
2.1 
PRIMARY OBJECTIVE ............................................................................................................................ 19 
2.2 
SECONDARY OBJECTIVE ........................................................................................................................ 19 
2.3 
EXPLORATORY OBJECTIVES ................................................................................................................... 19 
3 
STUDY DESIGN ......................................................................................................................... 19 
3.1 
DESCRIPTION OF THE STUDY DESIGN ...................................................................................................... 19 
3.2 
STUDY ENDPOINTS .............................................................................................................................. 20 
 
Primary Endpoint .................................................................................................................... 20 
 
Secondary Endpoints............................................................................................................... 20 
4 
STUDY POPULATION ................................................................................................................. 21 
4.1 
RECRUITMENT PLAN ............................................................................................................................ 21 
4.2 
SUBJECT INCLUSION CRITERIA ............................................................................................................... 21 
4.3 
SUBJECT EXCLUSION CRITERIA ............................................................................................................... 22 
4.4 
JUSTIFICATION FOR EXCLUSION OF WOMEN, MINORITIES, AND CHILDREN (SPECIAL POPULATIONS) ................... 23 
5 
STUDY AGENT/INTERVENTIONS ................................................................................................ 23 
5.1 
DISPOSITION AND DISPENSATION ........................................................................................................... 23 
 
Formulation, Packaging and Labeling .................................................................................... 23 
5.2 
STUDY AGENT STORAGE AND STABILITY .................................................................................................. 23 
5.3 
PREPARATION, ADMINISTRATION, AND DOSAGE OF STUDY AGENT............................................................... 23 
 
Dose Adjustments and Modifications ..................................................................................... 25 
 
Duration of Therapy ................................................................................................................ 25 
5.4 
CONCOMITANT MEDICATIONS AND PROCEDURES ..................................................................................... 25 
5.5 
PROHIBITED MEDICATIONS AND PROCEDURES.......................................................................................... 25 
6 
STUDY SCHEDULE ..................................................................................................................... 25 
6.1 
SCREENING ........................................................................................................................................ 25 
6.2 
ENROLLMENT/BASELINE ...................................................................................................................... 26 

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6.3 
STUDY PHASE (FIGURE 1.1.2-1) ........................................................................................................... 27 
6.4 
FOLLOW-UP ....................................................................................................................................... 28 
7 
STUDY EVALUATIONS ............................................................................................................... 29 
7.1 
CLINICAL EVALUATIONS........................................................................................................................ 29 
7.2 
LABORATORY EVALUATIONS .................................................................................................................. 29 
 
Clinical and Research Laboratory Evaluations and Specimen Collection ............................... 29 
8 
POTENTIAL RISKS AND BENEFITS ............................................................................................... 30 
8.1 
POTENTIAL RISKS ................................................................................................................................ 30 
8.2 
POTENTIAL BENEFITS ........................................................................................................................... 31 
9 
RESEARCH USE OF STORED HUMAN SAMPLES, SPECIMENS, OR DATA ........................................ 32 
10 
REMUNERATION PLAN FOR SUBJECTS ..................................................................................... 32 
11 
ASSESSMENT OF SAFETY ......................................................................................................... 33 
11.1 
DOCUMENTING, RECORDING, AND REPORTING ADVERSE EVENTS .............................................................. 33 
11.2 
DEFINITIONS .................................................................................................................................... 33 
11.3 
INVESTIGATOR ASSESSMENT OF ADVERSE EVENTS .................................................................................. 35 
 
Severity ................................................................................................................................. 35 
 
Causality ............................................................................................................................... 35 
11.4 
INVESTIGATOR REPORTING RESPONSIBILITIES TO THE SPONSOR ................................................................. 36 
 
Adverse Events ...................................................................................................................... 36 
 
Serious Adverse Events ......................................................................................................... 36 
 
Unanticipated Problems ....................................................................................................... 36 
 
Protocol Specified Events ...................................................................................................... 36 
 
Pregnancy ............................................................................................................................. 37 
11.5 
INVESTIGATOR REPORTING RESPONSIBILITIES TO THE NIAID IRB............................................................... 37 
 
Expedited Reporting to the NIAID IRB .................................................................................. 37 
 
Annual Reporting to the NIAID IRB ....................................................................................... 37 
11.6 
FOLLOW-UP OF ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ............................................................. 38 
11.7 
SPONSOR’S REPORTING RESPONSIBILITIES ............................................................................................. 38 
11.8 
HALTING CRITERIA FOR THE PROTOCOL ................................................................................................. 38 
 
Reporting of Study Halting ................................................................................................... 39 
 
Resumption of a Halted Study .............................................................................................. 39 
11.9 
PAUSING CRITERIA FOR A SUBJECT ....................................................................................................... 39 
 
Reporting of Pause ............................................................................................................... 39 
 
Resumption of Pausing for a Subject or Group..................................................................... 39 
11.10 
WITHDRAWAL CRITERIA FOR AN INDIVIDUAL SUBJECT ........................................................................... 40 
11.11 
REPLACEMENT FOR WITHDRAWN SUBJECTS ........................................................................................ 40 
11.12 
SAFETY OVERSIGHT ......................................................................................................................... 40 
 
Safety Review and Communications Plan (SRCP) ............................................................... 40 
 
Sponsor Medical Monitor ................................................................................................... 41 
12 
CLINICAL MONITORING STRUCTURE........................................................................................ 41 
12.1 
SITE MONITORING PLAN .................................................................................................................... 41 
13 
STATISTICAL CONSIDERATIONS ............................................................................................... 41 
14 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................................ 43 
14.1 
INFORMED CONSENT PROCESS ............................................................................................................ 43 
 
Non-English–Speaking Participants ...................................................................................... 43 
14.2 
SUBJECT CONFIDENTIALITY ................................................................................................................. 44 

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15 
DATA HANDLING AND RECORD KEEPING ................................................................................. 44 
15.1 
DATA CAPTURE AND MANAGEMENT .................................................................................................... 44 
15.2 
RECORD RETENTION.......................................................................................................................... 45 
APPENDIX A: SCIENTIFIC REFERENCES .............................................................................................. 46 
APPENDIX B: SCHEDULE OF PROCEDURES/EVALUATIONS ................................................................. 49 
APPENDIX C: PML CHECKLIST ........................................................................................................... 51 
 
 
 
 
List of Tables 
Table 1.1.3-1. Adverse Reactions in ≥ 3% of Vedolizumab-treated Patients and ≥ 1% 
Higher than in Placebo ............................................................................................ 17 
Table 13-1. The second row is the probability of observing at least one adverse event of 
probability given in the first row. .............................................................................. 42 
Table 13-2. The second row gives exact 95% confidence intervals for rebound 
probability given the observed number of rebounders in row 1 among the 20 
patients. ................................................................................................................... 42 
Table 13-3.  Futility is declared if the number of patients rebounding by week 30, among 
the number tested in row 1, is at least as large as the figure in row 2……............43 
Table 13-4.  Row 2 shows the probability of crossing the futility threshold if the true 30-
week rebound probability is as shown in row 1. ..................................................... 43 
 
List of Figures 
Figure 1.1.2-1. Nonhuman Primate Trial Design ............................................................ 14 
Figure 1.1.2-2. SIV Plasma Viremia in 47 mAb Treated Animals-Trial 1................... 14 
Figure 1.1.3-3. SIV Plasma Viremia in 47 mAb Treated Animals-Trial 2................... 15 
Figure 3.1-1. Study Design ............................................................................................. 20 
 
 

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List of Abbreviations 
ADR 
 
Adverse Drug Reaction 
AE 
 
Adverse Event/Adverse Experience 
cART  
Combination Antiretroviral Therapy 
CC 
 
Clinical Center 
CD 
 
Crohn’s Disease 
CFR 
 
Code of Federal Regulations 
CIB 
 
Clinical Investigator’s Brochure 
CLIA  
Clinical Laboratory Improvement Amendment of 1988 
COI 
 
Conflict of Interest 
CRADA 
Cooperative Research and Development Agreement 
CRF 
 
Case Report Form 
CRIMSON 
Clinical Research Information Management System of the NIAID 
DCR 
 
Division of Clinical Research 
DSMB  
Data and Safety Monitoring Board 
DSMC  
Data and Safety Monitoring Committee 
FDA 
 
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
GALT  
Gut Associated Lymphoid Tissue 
IB 
 
Investigator’s Brochure 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference on Harmonization 
IND 
 
Investigational New Drug 
IRB 
 
Institutional Review Board 
ISM 
 
Independent Safety Monitor 
IV 
 
Intravenous 
MAb 
 
Monoclonal Antibody 
MRI 
 
Magnetic Resonance Imaging 
N 
 
Number (typically refers to number of subjects/sample size) 
NDA 
 
New Drug Application 
NIAID  
National Institute of Allergy and Infectious Diseases  
NIH 
 
National Institutes of Health 
NNRTI  
Non-Nucleoside Reverse Transcriptase Inhibitors  
OHRP  
Office for Human Research Protections 
OHSRP 
Office of Human Subjects Research Protections 
PBMC  
Peripheral Blood Mononuclear Cells 
PHI 
 
Protected Health Information 
PI 
 
Principal Investigator 
PK 
 
Pharmacokinetics 
PML     
Progressive Multifocal Leukoencephalopathy 
QA 
 
Quality Assurance 
QC 
 
Quality Control 
SAE 
 
Serious Adverse Event/Serious Adverse Experience 
SC 
 
SubCutaneous 
SIV 
 
Simian Immunodeficiency Virus 
SMC  
Safety Monitoring Committee 
UC 
 
Ulcerative Colitis 
UP 
 
Unanticipated Problem 
UPnonAE 
Unanticipated Problem that is not an Adverse Event 

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Protocol Summary 
 
Full Title: 
An Exploratory, Open-Label Study of Vedolizumab (anti-
 antibody) in Subjects with HIV Infection Undergoing 
Analytical Treatment Interruption 
 
Short Title: 
Therapeutic Vedolizumab 
 
Clinical Phase: 
1 
 
IND Sponsor:  
 
OCRPRO 
 
Conducted by: 
 
NIAID/LIR 
 
Principal Investigator: 
Michael C. Sneller, MD 
 
Sample Size: 
N= up to 20  
 
Accrual Ceiling: 
40 
 
Study Population: 
 
HIV-infected Adults (age 18-65 years) on cART with 
suppressed viremia 
 
Accrual Period: 
 
18 months 
 
Study Design: 
 
An exploratory, open-Label, single arm study of 
vedolizumab in subjects with HIV Infection undergoing 
analytical treatment interruption  
 
Study Duration: 
 
Start Date: April 2016   
 
 
End Date: July 2018 
 
Study Agent:   
 
Vedolizumab 300 mg 
 
 
Primary Objective:  
To evaluate the safety and tolerability of vedolizumab in 
HIV-infected individuals prior to and following analytical 
treatment interruption (ATI). 
 

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Secondary Objective: 
To evaluate the effect of vedolizumab administration on 
plasma viral rebound in HIV-infected individuals following 
ATI 
 
 
Endpoints: 
 
1. The rate of occurrence of grade 2 or higher AEs, including SAEs, which are 
probably or definitely related to vedolizumab. 
2. The number of subjects who experience rebound of plasma viremia following 
ATI and meet criteria to restart cART before week 48 
 

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Précis 
 
While combination antiretroviral therapy (cART) has improved the clinical outcome for 
HIV-infected individuals, persistence of viral reservoirs in the peripheral blood and 
lymphoid tissues remains a hurdle to complete eradication of virus and cure of the 
infection. The concept that HIV preferentially infects discrete subsets of CD4+ T cells 
underscores the need to develop therapeutics that exploit specific cell-virus 
interactions. T cells expressing integrin 47 not only regulate migration into the gut-
associated lymphoid tissue (GALT), but also concomitantly bind HIV, placing them in a 
prime position to disseminate HIV throughout the tissue. Previously, it has been shown 
that the HIV envelope protein gp120 binds to 47 on CD4+ T cells in vitro, 47high 
CD4+ T cells are highly susceptible to productive HIV infection in vitro, and the 
administration of anti-47 monoclonal antibody (mAb) prevents and/or delays 
transmission of SIV upon repeated challenges and preserves CD4+ T cells in rhesus 
macaques. Furthermore, it has been demonstrated that administration of anti-47 
mAb in SIV-infected rhesus macaques receiving cART suppresses plasma viremia for 
extended periods following discontinuation of cART, collectively suggesting that 
sustained virologic remission in the absence of cART may be achieved via direct 
targeting of 47 integrin. It is well established that the vast majority of HIV-infected 
individuals treated with cART experience plasma viral rebound within weeks of 
cessation of therapy. Considering that current research on the treatment of HIV-infected 
individuals has been heavily focused on developing strategies aimed at achieving 
sustained virologic remission in the absence of cART, it is of great interest to 
investigate whether administration of anti-47 mAb can prevent plasma viral rebound 
and allow durable suppression of viral replication in HIV-infected individuals after 
discontinuation of cART. We propose to examine the effect of vedolizumab, an FDA-
approved anti-47 mAb for the treatment of ulcerative colitis and Crohn’s disease, on 
plasma viral rebound in HIV-infected individuals following analytical treatment 
interruption (ATI). 

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1 Background Information and Scientific Rationale 
1.1 Background Information 
Prolonged suppression of plasma viremia is now achievable in the majority of HIV-
infected individuals receiving cART1. Complete eradication of virus, however, has not 
been possible with cART alone due to the persistence of viral reservoirs in a variety of 
tissues 2-5. Previous studies have demonstrated that HIV persists in latently infected, 
CD4+ T cells in the peripheral blood of virtually all infected individuals receiving clinically 
effective cART 6-8. In addition, recent studies suggest that low levels of HIV replication 
may persist even in the absence of detectable viremia5,9,10. As plasma viremia appears 
to rebound in nearly all HIV-infected individuals upon cessation of cART regardless of 
duration and timing of therapy11-13, alternative therapeutic strategies aimed at 
destroying or permanently suppressing persistently infected cells are needed to 
potentially eradicate HIV 14. 
 
Despite the success of cART in suppressing plasma viremia and HIV replication, the 
burden of taking daily medication for life, long-term toxicity of cART regimens, and 
potential resistance to antiretroviral drugs, necessitates a continued search for effective 
alternatives for the control of HIV infection. Consequently, a major thrust of HIV 
research over the past several years has been to develop therapeutic strategies that 
target the persistent HIV reservoir and could induce a sustained virologic remission in 
infected individuals in the absence of cART. To this end, numerous attempts have been 
made to purge the persistent HIV reservoir in infected individuals receiving cART. 
These include the use of non-specific immune-activating agents, such as IL-2 15 and an 
anti-CD3 antibody 16, as well as histone deacetylase inhibitors, such as valproic acid 
and vorinostat 17,18. However, these reagents neither prevented plasma viral rebound 
following cessation of cART nor decreased the size of the persistent viral reservoir in 
HIV-infected individuals. 
 
Other therapeutic strategies aimed at achieving eradication are under investigation. 
These include genetic manipulation of CD4+ T cells 19 and stem-cell transplantation 20. 
While it appears that eradication of HIV was achieved in one individual who underwent 
multiple rounds of chemotherapy and stem cell transplantation 20, this approach is 
currently impractical and unlikely to be safely applied to a substantial proportion of the 
HIV-infected population.  
 
In recent years, research directed at the development of an effective HIV vaccine has 
provided insights into the nature of the immune response to HIV infection21,22. Antibody 
cloning technologies and B cell biology have led to the discovery of several highly 
potent and broadly neutralizing mAbs against HIV produced by B cells of some HIV-
infected individuals 23-25. Several studies have demonstrated that certain broadly 
neutralizing HIV-specific mAbs can prevent acquisition of the virus, suppress viral 
replication, prevent plasma viral rebound following treatment interruption in infected 
animals 26-28, and block cell-to-cell transmission of laboratory-adapted HIV in vitro 29. 
However, durable suppression of virus has yet to be achieved via these modalities.  
 
As mechanisms for viral entry are discovered, alternative methods of viral suppression 
may emerge. Recent investigations have revealed a potential access point via 

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engagement of the cell surface integrin 47 by HIV gp120 on CD4+ T cells30,31. The 
47 integrin is expressed on the surface of a discrete subset of T-lymphocytes that 
facilitates preferential migration into the gastrointestinal tract. Integrin 47 mediates 
homing of T lymphocytes to the gut by binding to mucosal addressin cell adhesion 
molecule-1 (MAdCAM-1), an adhesion molecule preferentially expressed on venules in 
gut associated lymphoid tissue (GALT). 
 
In addition to preferentially migrating to GALT, α4β7high CD4+ T are highly susceptible to 
productive HIV infection in vitro.  Furthermore, it has been shown that α4β7 integrin on 
CD4+ T cells binds HIV gp120 leading to rapid activation of LFA-1, the integrin involved 
in the establishment of virologic synapses 30,31. Thus, α4β7high CD4+ T cells are in a 
prime position to disseminate HIV between GALT and the periphery. Based on these 
observations, the efficacy of 47-mAb therapy in preventing transmission was 
evaluated in a nonhuman primate model 32. Initial results revealed that administration 
anti-47 mAb prior to and during acute infection protected rhesus macaques from 
transmission after repeated low-dose intravaginal challenges with SIVmac251. In the 
treated animals that became infected, GALT was protected from infection and CD4+ T 
cells were maintained in both the periphery and GALT32. These results suggest that 
antibodies directed against 47 might have potential as an immune-based therapy for 
HIV.  
 
Description of the Study Agent  
Vedolizumab is a humanized monoclonal antibody that specifically binds to the α4β7 
integrin and blocks the interaction of α4β7 integrin with MAdCAM-1, which in turn 
inhibits the migration of T-lymphocytes across the endothelium into GALT. Vedolizumab 
does not bind to or inhibit function of the α4β1 and αEβ7 integrins and does not 
antagonize the interaction of α4 integrins with vascular cell adhesion molecule-1 
(VCAM-1). 
 
Consistent with its specificity for α4β7, IV administration of vedolizumab did not elevate 
neutrophils, basophils, eosinophils, B helper and cytotoxic T lymphocytes, total memory 
T helper lymphocytes, monocytes or NK cells in the peripheral blood of healthy subjects 
or subjects with UC or CD (Vedolizumab Investigators Brochure, Dec. 2015). 
Vedolizumab did not affect immune surveillance and inflammation of the central 
nervous system (CNS) in experimental autoimmune encephalitis in nonhuman 
primates, a model of multiple sclerosis33. Consistent with these results, vedolizumab IV 
did not alter the ratio of CD4+/CD8+ T cells or the number of T cells in the CSF of 
healthy subjects34. Vedolizumab IV did not inhibit the adaptive immune response to 
intramuscular antigen challenge with hepatitis B vaccine in healthy subjects, but did 
inhibit an adaptive immune response to oral antigen challenge with killed cholera toxin 
vaccine35. These results support the conclusion that, unlike natalizumab (a duel α4β7 
and α4β1 antagonist), vedolizumab selectively inhibits migration of T lymphocytes to 
the gut and does not inhibit central nervous system or systemic immune responses in 
humans. 
 
Clinical Pharmacology 
The single and multiple dose pharmacokinetics (PK) of vedolizumab IV have been 
investigated in completed studies in healthy subjects and in subjects with moderately to 
severely active UC or CD. Similar PK was observed in healthy subjects, as well as in 
subjects with UC or CD. Vedolizumab clearance depends on both linear and nonlinear 

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pathways; with linear PK observed at serum concentrations >1 μg/mL to 10 μg/mL. 
Population PK analyses indicate that the linear clearance was approximately 0.157 
L/day, the serum terminal elimination half-life was approximately 25 days at the 300 mg 
dosage, and the volume of distribution at steady state was approximately 5 L. 
Vedolizumab was not detected in the CSF of 14 healthy subjects at 5 weeks after a 
single intravenous (IV) administration of 450 mg vedolizumab (1.5 times the 
recommended dosage). 
 
Clinical Pharmacodynamics 
 
Two pharmacodynamic markers (Act-1 and MAdCAM-1-Fc) were independently 
evaluated to assess the presence of 47 integrin binding sites on cell surfaces and to 
determine the number of free 47 receptor sites by vedolizumab. Vedolizumab 
inhibition of Act-1 and MAdCAM-1-Fc binding to the 47 receptor indicated the extent 
of 47 receptor saturation by vedolizumab36. 
Dose-dependent duration of 47 receptor saturation was consistently observed 
following both single and multiple dosing in phase 1 studies. Rapid and near complete 
47 receptor saturation was achieved following dosing and the time to loss of 47 
receptor saturation was dose dependent. The serum concentrations of vedolizumab 
following 300 mg dosing every 4-8 weeks are expected to maintain >90% α4 7 
receptor binding saturation over the dosing interval in >90% of subjects36,37.  
 
Summary of Pre-Clinical Nonhuman Primate Studies  
 
Based on the results of the nonhuman primate studies demonstrating efficacy of anti-
47 mAb in preventing SIV infection (see Section 1.1), a follow-up study was designed 
to investigate the potential therapeutic effects of anti-47 mAb in SIV infected 
macaques (A. Ansari unpublished data). The anti-47 mAb used in these studies 
contains the same antigen binding region as vedolizumab fused to a rhesus IgG1 Fc 
region38.  In this study, 10 rhesus macaques were infected with SIVmac239 
intravenously. When the animals reached steady state viremia, they were initiated on 
cART. Once viral levels were suppressed on cART, the monkeys were divided into two 
groups; the control group received 50 mg/kg IV of normal rhesus IgG, while group 2 
received 50 mg/kg IV of anti-47 mAb. Infusions were administered every three weeks 
for a total of 8 infusions. After four infusions, cART was stopped in order to determine 
the effect of anti-47 mAb alone on the expected rebound of plasma viremia  
(Figure 1.1.2-1).  
 
As expected, all five animals in the IgG control group experienced a rebound of viremia 
within 2 weeks of stopping cART. In contrast, 4/5 monkeys in the anti-47 mAb group 
exhibited intermittent or continued suppression of plasma viremia (Figure 1.1.2-1). In 
these animals, suppression of plasma viremia persisted, in the absence of cART 
through week 45 (12 weeks after the last anti-47 mAb).  The single animal in the anti-
47 mAb group (RNo13) that exhibited rebound viremia was shown to have 
developed antibodies against the 47 mAb that became detectable after the third 
infusion.  
 

Pr ot o c ol V er si o n 5. 0 
2 2 - M ar c h-2 0 1 7  
 
P a g e 1 4  of 5 3  
 
A s e c o n d st u d y w a s d e si g n e d i n t h e s a m e m a n n er wit h t h e a d diti o n of 8 a ni m al s, 2 of 
w hi c h w er e a d d e d t o t h e I g G c o ntr ol gr o u p a n d 6 of w hi c h r e c ei v e d a nti -4 7 m A b.  
 
 
Fi g ur e 1. 1. 2 - 1. N o n h u m a n Pri m at e Tri al D e si g n  
 
 
 
B ot h  of t h e c o ntr ol m o n k e y s e x p eri e n c e d vir al r e b o u n d  wit hi n 2 w e e k s of st o p pi n g 
c A R T. T w o  of  t h e m o n k e y s i n t h e tr e at m e nt gr o u p d e v el o p e d a nti b o di e s  a g ai n st t h e 
4 7 m A b  a n d  e x hi bit e d r e b o u n d vir e mi a si mil ar t o t h e c o ntr ol a ni m al s  (Fi g ur e 1. 1. 2 - 3). 
Of t h e r e m ai ni n g 5 a ni m al s i n t h e tr e at m e nt gr o u p, 2 s h o w e d s u st ai n e d s u p pr e s si o n of 
pl a s m a vir e mi a o ut t o st u d y w e e k 4 0 ( 8 w e e k s aft er t h e l a st a nti -4 7 m A b i nf u si o n). 
T h e ot h er 3  a ni m al s s h o w e d i nt er mitt e nt l e v el s of pl a s m a vir e mi a.   
 
 
 
 
 
 
Fi g ur e 1. 1. 2 - 2. SI V Pl a s m a Vir e mi a i n 4 7 m A b Tr e at e d A ni m al s -Tri al 1  
SI V m a c 2 3 9
I nf ect i o n
( 20 0 T CI D 2 0 0 )
0
2 5
1 2
9
1 5
5
1 8 
2 2
c A R T
i niti at e d
c A R T
t er min at e d
3 6 
4 0 
5 0
a 4 ß 7 o r 
I g G 
a d mi ni st r ati o n
A R T
A n ti- a 4 ß 7 
a n tib o d y
W e e k

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Figure 1.1.2-3. SIV Plasma Viremia in 47 mAb Treated Animals-Trial 2  
 
 

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Summary of Relevant Clinical Studies 
 
Vedolizumab (ENTYVIO) is approved by the FDA for treatment of adult patients with 
moderately to severely active ulcerative colitis (UC) or Crohn’s disease (CD) who have 
had an inadequate response to, or were intolerant to a tumor necrosis factor (TNF) 
blocker or immunomodulator; or had an inadequate response with, were intolerant to, or 
demonstrated dependence on corticosteroids. The FDA approval was based largely on 
the results of 2 two integrated randomized controlled studies in UC39 and 2 integrated 
randomized controlled studies in CD40.  In these studies, the dose of vedolizumab was 
300 mg IV.  
 
Ulcerative Colitis (UC) 
In a randomized, multicenter trial, 374 patients with active UC were assigned to 
vedolizumab or placebo for the induction of remission39. A significantly greater 
proportion of vedolizumab-treated patients achieved clinical response, remission, and 
mucosal healing at six weeks compared with placebo. In a trial of vedolizumab for the 
maintenance of remission, 373 patients with a clinical response to vedolizumab at six 
weeks, in either the induction trial or following open label treatment, were assigned to 
continue to receive vedolizumab every eight weeks, four weeks, or switch to placebo for 
up to 52 weeks. At week 52, remission rates were significantly higher in patients who 
received vedolizumab compared with placebo.  
 
Crohn’s Disease (CD) 
A randomized trial enrolling 368 patients with moderately to severely active CD who 
had failed at least one conventional therapy were assigned to vedolizumab or placebo 
for induction therapy40. At week 6, rates of clinical remission were significantly higher in 
patients treated with vedolizumab as compared with placebo (14 versus 7 percent). 
This same trial also looked at the ability of vedolizumab to maintain remission. A total 
461 patients who had had a prior clinical response to vedolizumab were randomly 
assigned to receive placebo or vedolizumab every 8 or 4 weeks until week 52. Subjects 
randomized to vedolizumab for maintenance therapy were more likely to be in 
remission at week 52. 
 
Summary of Adverse Events in Inflammatory Bowel disease Trials 
The data described in Table 1.1.3-1 reflect exposure to vedolizumab in patients 
participating in the four Phase 3 trials39,40. In these trials, 1,434 patients received 
vedolizumab 300 mg for up to 52 weeks, and 297 patients received placebo for up to 52 
weeks. Of these, 769 patients had UC and 962 patients had CD. Patients were exposed 
for a mean duration of 259 days (UC) and 247 days (CD). In these studies, concomitant 
treatment with stable doses of prednisone and/or immunosuppressive agents were 
allowed. Adverse reactions were reported in 52% of patients treated with vedolizumab 
and 45% of patients treated with placebo. Serious adverse reactions were reported in 
7% of patients treated with vedolizumab compared to 4% of patients treated with 
placebo.   
 
The most common adverse reactions were nasopharyngitis, headache, arthralgia, 
nausea, pyrexia, upper respiratory tract infection, fatigue, cough, bronchitis, influenza, 
back pain, rash, pruritus, sinusitis, oropharyngeal pain and pain in extremities (Table 
1.1.3-1). 
 
 

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Table 1.1.3-1. Adverse Reactions in ≥ 3% of Vedolizumab-treated Patients and 
≥ 1% Higher than in Placebo 
 
 
 
 
 
 
      Vedolizumab* 
 
Placebo** 
 
* Patients who received vedolizumab for up to 52 weeks 
** Patients who received placebo for up to 52 weeks 
 
 
Laboratory Abnormalities 
No clinically important treatment group differences in patients with markedly abnormal 
values in laboratory tests (hematology, chemistry, or coagulation) were observed in any 
of the phase 3 studies. 
 
Infusion-Related Reactions 
Serious infusion-related reactions following vedolizumab administration have been 
reported in clinical trials. In the UC and CD phase III trials described above, a single 
case of anaphylaxis (1/1434 subjects-0.07%) was reported in a patient with CD 
following the second infusion of vedolizumab. In these same trials, other infusion-
related reactions were reported in 4% of patients treated with vedolizumab and 3% of 
patients treated with placebo. The most common reactions were nausea, headache, 
pruritus, dizziness, fatigue, pyrexia, urticaria, and vomiting. These reactions generally 
occurred during the infusion, and resolved either with no treatment or following 
administration of antihistamine and/or hydrocortisone. Less than 1% of patients treated 
with vedolizumab developed infusion reactions assessed by the investigator as being 
severe.  

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Infections 
In the Phase III UC and CD Trials, the rate of infections was 0.85 per patient-year in the 
patients treated with vedolizumab and 0.7 per patient-year in the patients treated with 
placebo. The infections consisted primarily of nasopharyngitis, upper respiratory tract 
infection, sinusitis, and urinary tract infection. Two percent of patients discontinued 
vedolizumab due to infections. 
 
The rate of serious infections was 0.07 per patient-year in patients treated with 
vedolizumab and 0.06 per patient-year in patients treated with placebo. Serious 
infections were more common in CD patients than UC patients, and anal abscesses 
were the most frequently reported serious infection in CD patients. Over 48 months, 
there was no increase in the rate of serious infections. Sepsis was reported in 4 of 1434 
(0.3%) of patients treated with vedolizumab compared with 2 of 297 (0.7%). patients 
treated with placebo. 
 
In controlled- and open-label long-term extension trials in adults treated with 
vedolizumab, serious infections have been reported, including anal abscess, sepsis 
(some fatal), tuberculosis, salmonella sepsis, Listeria meningitis, giardiasis, and 
cytomegalovirus colitis. No cases of PML were reported. 
 
Liver Injury 
In the UC and CD phase III trials there were reports of elevations in hepatic 
transaminases and/or bilirubin. Three patients in the UC and CD trials reported SAE 
related to hepatitis. Based on case report information, it is unclear if these SAE were 
related to concomitant medications (e.g. 6-mercaptopurine) or autoimmune processes 
(sclerosing cholangitis). All patients recovered. In controlled trials, ALT/AST elevations 
≥3 X upper limit of normal were seen in <2% of patients in both the placebo and 
vedolizumab groups.  
 
Immunogenicity 
In the completed 52-week controlled studies in subjects with UC or CD, vedolizumab IV 
showed an immunogenicity rate of 4%; 56 of 1434 subjects who received continuous 
treatment with vedolizumab IV tested positive for anti-vedolizumab antibodies at any 
time during treatment. Nine of these 56 subjects were persistently positive (positive at 
≥2 study visits) and 33 subjects developed neutralizing antibodies. As with all 
therapeutic proteins, there is potential for immunogenicity. In UC Trials I and II and CD 
Trials I and III, in patients who received vedolizumab, the frequency of antibodies 
detected in patients was 13% at 24 weeks after the last dose of study drug (greater 
than five half-lives after last dose). 
 
Overall, there was no apparent correlation of anti-vedolizumab antibodies, clinical 
response, or treatment related AE. However, the number of subjects who developed 
antibodies was too limited to make a definitive assessment. 
 
Post Marketing Experience 
Based on drug shipment data as of 19 May 2015, the post marketing patient exposure 
to vedolizumab IV globally is estimated to be approximately 11,943 patient-years. 
The post marketing safety profile of vedolizumab IV is consistent with what was seen in 
the clinical studies and no new safety signals have been identified (vedolizumab 
Investigators Brochure, Dec. 2015). 

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1.2 
Rationale 
Vedolizumab as a Potential Treatment for HIV Infection 
The results in the nonhuman primate SIV study described in Section 1.1.2, suggest that 
blockade of 47 with vedolizumab in virologically suppressed patients with HIV 
infection has the potential to induce sustained suppression of viremia after 
discontinuation of cART and anti-47 mAb administration.  The purpose of this study 
is to test this hypothesis and evaluate the safety of vedolizumab in an exploratory open 
label study. 
 
Use of Analytical Treatment Interruption (ATI) 
Various assays measuring HIV-specific immune responses and the frequency of CD4+ 
T cells carrying infectious HIV have been used to assess efficacy of immune-based 
therapies. To date, none of the assays are clinically validated to predict actual antiviral 
efficacy. Thus, ATI has been used to evaluate the anti-viral efficacy of immune-based 
therapies by testing the ability of these interventions to blunt or prevent the viral 
rebound that occurs following interruption of cART. The use of ATI in the design of this 
study is the only way to determine if administration of vedolizumab results in clinically 
significant antiviral activity, as evidenced by a blunted or absent plasma viral rebound 
following ATI.  
2 Study Objectives 
2.1 
Primary Objective 
• 
To evaluate the safety and tolerability of vedolizumab in HIV-
infected individuals prior to and following analytical treatment 
interruption (ATI) 
 
2.2 
Secondary Objective  
• 
To evaluate the effect of vedolizumab administration on plasma 
viral rebound in HIV-infected individuals following ATI 
2.3 
Exploratory Objectives 
• 
To determine the effect of vedolizumab on the size of persistent 
HIV reservoirs 
 
• 
To examine the impact of vedolizumab on continuing/residual 
HIV replication prior to discontinuation of cART 
3 Study Design 
3.1 
Description of the Study Design 
The proposed trial will be a single arm, open label study to examine the effect of 
vedolizumab on plasma viral rebound in HIV-infected individuals following an 
analytical treatment interruption (ATI). Fifteen HIV-infected individuals with 
suppressed viremia on cART will be studied. All study participants will receive a 
total of 9 IV infusions of vedolizumab 300 mg (Figure 1.1.3-1).   

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Figure 1.1.3-1. Study Design 
 
 
 
At study week 22, all subjects will discontinue cART and enter the ATI phase of the 
study. Individuals taking non-nucleoside reverse transcriptase inhibitors (NNRTIs) 
will switch to a protease inhibitor or an integrase inhibitor-based regimen at least 2 
weeks prior to week 22 to ensure that the washout period of antiretroviral agents is 
roughly equal. HIV plasma viral levels and CD4+ T cell counts will be monitored 
every 2 weeks during the ATI phase. If a subject meets any of the following criteria 
between study weeks 22-30, they will discontinue vedolizumab infusions, re-start 
ART, and enter the follow-up phase. Subjects who meet any of the criteria for 
restarting cART after week 30, will restart cART and enter the follow-up phase.  
 
 
Criteria to Restart cART 
 
• 
A confirmed >30% decline in baseline CD4+ T cell count or an absolute 
CD4+ T cell count <350 cells/mm3 in the setting of detectable (>40 
copies/ml) HIV viremia. 
• 
A sustained (>4 weeks) HIV RNA level of >1,000 copies/mL  
• 
Any HIV-related symptoms (e.g. acute retroviral syndrome, opportunistic 
infection) or pregnancy 
3.2 
Study Endpoints 
 
Primary Endpoint 
The rate of occurrence of grade 2 or higher AEs, including SAEs, 
which, are probably or definitely related (as defined in Section 11.3.2) 
to vedolizumab. 
 
Secondary Endpoints 
Number of subjects who experience rebound of plasma viremia 
following ATI and meet criteria to restart cART before week 48. 
ART Phase (22 weeks) 
Infusions of  
vedolizumab 
0 
48 
22 
26 
6 
ATI-Follow-up Phase 
2 
10 
14 
30 
Cessation  
of ART 
18 

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4 Study Population 
4.1 Recruitment Plan 
Subjects will be recruited from existing cohorts of individuals participating in 
NIAID protocols 09-I-0030 and 02-I-0202 who meet the Inclusion/Exclusion 
Criteria. Additional local and regional recruitment will be done using direct mailing 
to infectious disease physicians, internet ad campaigns, social media outlets, 
print ads, and from local clinics via the NIAID patient recruitment contract with 
Matthews Media Group.  
4.2 Subject Inclusion Criteria 
 
1. Age, 18-65 years 
2. Documented HIV-1 infection and clinically stable 
3. In general good health, with an identified primary health care provider 
for medical management of HIV infection and willing to maintain a 
relationship with a primary health care provider for medical 
management of HIV infection while participating in the study 
4. CD4+ T cell count >450 cells/mm3 at screening 
5. Documentation of continuous cART treatment with suppression of 
plasma viral level below the limit of detection for ≥2 years. Subjects 
with “blips” (i.e., detectable viral levels on cART) prior to screening 
may be included provided they satisfy the following criteria:  
a. The “blips” are <400 copies/mL, and  
b. Succeeding viral levels return to levels below the limit of 
detection on subsequent testing 
6. Willingness to undergo ATI 
7. Laboratory values within pre-defined limits at screening:  
• 
Absolute neutrophil count >1,000/mm3 
• 
Hemoglobin (Hgb) levels >10.0 g/dL for men and >9.0 g/dL for 
women 
• 
Platelet count >100,000/mm3 
• 
Prothrombin time (PT) and partial thromboplastin time (PTT) <1.5 
upper limit of normal (ULN) 
• 
Estimated glomerular filtration rate (eGFR) of ≥50 mL/min as 
determined by the NIH Clinical Center laboratory 
• 
Aspartate aminotransferase (AST) and alanine aminotransferase 
(ALT) levels of <1.1 x ULN. Total bilirubin <1.1 x ULN (unless 
subject is taking atazanavir or has Gilbert’s Syndrome) 
8. Willingness to have samples stored for future research 
 

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Participation of Women:  
Contraception: The effects of vedolizumab on the developing human fetus 
are unknown.  For this reason, men and women of childbearing potential 
must agree to use adequate contraception (hormonal or barrier method of 
birth control; abstinence) prior to study entry and for the duration of study 
participation.   
4.3 
Subject Exclusion Criteria 
 
1. Chronic hepatitis B, as evidenced by a positive test for hepatitis B surface 
antigen (HBsAg), or chronic hepatitis C virus (HCV) infection, as evidenced 
by a positive test for HCV RNA. Subjects with a positive test for HCV 
antibody and a negative test for HCV RNA are eligible. 
2. Documented nadir CD4+ T cell count <200 cells /mm3 
3. Documented multiclass antiretroviral drug resistance that, in the judgment of 
the investigator, would pose a risk of virologic failure should additional 
mutations develop during the study 
4. HIV immunotherapy or vaccine(s) received within 1 year prior to screening 
5. Any licensed or experimental non-HIV vaccination (e.g., hepatitis B, 
influenza, pneumococcal polysaccharide) received within 2 weeks prior to 
study enrollment  
6. Receipt of other investigational study agent within 28 days of enrollment 
7. Any active malignancy that may require systemic chemotherapy or radiation 
therapy 
8. Systemic immunosuppressive medications received within 3 months prior to 
enrollment. The following are not excluded: [1] corticosteroid nasal spray or 
inhaler; [2] topical corticosteroids for mild, uncomplicated dermatitis; and [3] 
oral/parenteral corticosteroids administered for non-chronic conditions not 
expected to recur (length of therapy ≤10 days, with completion in ≥30 days 
prior to enrollment) 
9. History or other clinical evidence of:  
• 
Significant or unstable cardiac disease (e.g., angina, congestive heart 
failure, recent myocardial infarction) 
• 
Severe illness, chronic liver disease, malignancy, immunodeficiency 
other than HIV, active systemic infection other than HIV, or any other 
condition that, in the opinion of the investigator, would make the subject 
unsuitable for the study 
• 
Active or latent tuberculosis, regardless of treatment history 
10. Neurologic or neuropsychiatric disorder, the symptoms of which mimic PML 
and could interfere with the assessment of safety (e.g. history of encephalitis 
with motor sequela, stroke with sequela, severe major depressive disorder, 
severe bipolar disorder, seizure disorder) 

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11. Active drug or alcohol abuse or any other pattern of behavior that, in the 
opinion of the investigator, would interfere with adherence to study 
requirements 
12. Pregnancy or breast-feeding 
 
Routine Vaccination Assessment: During screening, subjects’ vaccination history will 
be assessed. If subjects are not up to date on routine vaccinations (as recommended in 
DHHS Guidelines for the Prevention and Treatment of Opportunistic Infections in HIV-
Infected Adults and Adolescents), they will be offered vaccination prior to initiating 
treatment with vedolizumab.  
 
Co-enrollment Guidelines: Co-enrollment in other trials is restricted, other than 
enrollment on observational studies. Study staff should be notified of co-enrollment as it 
will require the approval of the Principal Investigator. 
4.4 
Justification for Exclusion of Women, Minorities, and Children 
(Special Populations)  
 
Exclusion of Children:   
 
Because there are insufficient data regarding dosing or adverse events available in 
adults to judge the potential risk in children, children are excluded from this study. 
 
5 Study Agent/Interventions  
5.1 
Disposition and Dispensation  
Study agent will be distributed via the NIH Central Pharmacy according to standard 
pharmacy procedures. 
 
Formulation, Packaging and Labeling  
Vedolizumab is supplied in sterile 20 mL single-use glass vials, containing 300 mg of 
vedolizumab as a white to off-white cake. Refrigerate each unopened 300mg single 
dose vial in an individual carton at 2° to 8 C (36º to 46ºF). Retain in original package to 
protect from light. 
5.2 
Study Agent Storage and Stability  
The site pharmacist must promptly report any storage temperature excursions outside 
of the normal allowance for the storage device to the PI and the IND Sponsor. The 
product must be quarantined in a separate area.  The IND Sponsor’s authorized 
representative will notify the site pharmacist if continued clinical use of the product is 
acceptable. 
5.3 
Preparation, Administration, and Dosage of Study Agent 
Reconstitution Instructions 

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Reconstitute vedolizumab at room temperature. Vedolizumab will be reconstituted and 
prepared by the NIH Pharmacy using aseptic technique by the following procedure: 
 
1. Remove the flip-off cap from the single-dose vial and wipe with alcohol swab. 
Reconstitute vedolizumab vial containing lyophilized powder with 4.8 mL of sterile water 
for injection, using a syringe with a 21 to 25 gauge needle. 
 
2. Insert the syringe needle into the vial through the center of the stopper and direct the 
stream of sterile water for injection to the glass wall of the vial to avoid excessive 
foaming. 
 
3. Gently swirl the vial for at least 15 seconds to dissolve the lyophilized powder. Do not  
vigorously shake or invert. 
 
4. Allow the solution to sit for up to 20 minutes at room temperature to allow for 
reconstitution and for any foam to settle; the vial can be swirled and inspected for 
dissolution during this time. If not fully dissolved after 20 minutes, allow another 
10 minutes for dissolution. Do not use the vial if the drug product is not dissolved within 
30 minutes. 
 
5. Visually inspect the reconstituted vedolizumab solution for particulate matter and 
discoloration prior to administration. Solution should be clear or opalescent, colorless to 
light brownish yellow, and free of visible particulates. Do not administer reconstituted 
solution showing uncharacteristic color or containing particulates. 
 
6. Prior to withdrawing the reconstituted vedolizumab solution from the vial, gently invert 
vial 3 times. 
 
7. Withdraw 5 mL (300 mg) of reconstituted vedolizumab solution using a syringe using 
a 21 to 25 gauge needle. Discard any remaining portion of the reconstituted solution in 
the vial. 
 
Dilution Instructions 
Add the 5 mL (300 mg) of reconstituted vedolizumab solution to 250 mL of sterile 0.9% 
sodium chloride and gently mix the infusion bag. Do not add other medicinal products to 
the prepared infusion solution or intravenous infusion set. Once reconstituted and 
diluted, use the infusion solution as soon as possible. 
 
Storage 
If necessary, the infusion solution may be stored for up to four hours at 2° to 8°C (36º to 
46ºF). Do not freeze. Discard any unused portion of the infusion solution. 
 
The dose of vedolizumab for this study is 300 mg in 250 mL normal saline.  
  
The investigational study product solution will be administered by IV infusion over at 
least 30 minutes using a volumetric pump. The total time needed to administer the dose 
may be longer than 30 minutes based on factors such as subject tolerance. After the 
infusion is complete, the IV line will be flushed with 30 ml of normal saline. 
 

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For women of childbearing potential, study agent administration may not proceed 
unless a negative pregnancy test has been obtained within the previous 24 hours. Prior 
to each administration, temperature, blood pressure, heart rate (pulse) and weight will 
be recorded. Vital signs (temperature, blood pressure, heart rate) will be measured 15 
minutes into the infusion and at the end of the infusion. Following completion of the first 
infusion, the subject will be monitored for 2 hours before leaving the clinic. For 
subsequent infusions, the subject will be monitored for 1 hour after completion of the 
infusion. 
 
Dose Adjustments and Modifications  
Should mild-moderate infusion-related symptoms (Grade I-II) develop, they will be 
managed by temporarily stopping the infusion until symptoms have resolved. For 
symptoms such as fever, myalgia, or urticaria, symptomatic treatment with standard 
doses of acetaminophen or antihistamines may be given. Once symptoms have 
resolved, the infusion will be restarted at half the initial rate. If symptoms recur following 
a reduced infusion rate and symptomatic treatment, the infusion will again be stopped 
until symptoms resolved and restarted at a lower rate. If the infusion cannot be 
completed within a 3-hour time frame because of recurrent symptoms, the infusion will 
be discontinued for that visit. 
 
Duration of Therapy 
The planned total duration of vedolizumab therapy is 30 weeks. 
5.4 
Concomitant Medications and Procedures 
All concomitant prescription medications taken during study participation will be 
recorded in CRIMSON. For this protocol, a prescription medication is defined as a 
medication that can be prescribed only by a properly authorized/licensed clinician.  
Medications to be reported in CRIMSON are concomitant prescription medications, 
over-the-counter medications and non-prescription medications taken at the time of 
adverse events (all grades). 
5.5 
Prohibited Medications and Procedures  
Treatment with immunosuppressive medications during the study is prohibited. 
Prohibited immunosuppressive medications do not include [1] corticosteroid nasal 
spray or inhaler; [2] topical corticosteroids for mild, uncomplicated dermatitis; or [3] 
oral/parenteral corticosteroids given for non-chronic conditions not expected to 
recur. 
6 Study Schedule 
For all the study visits, unless otherwise specified, subjects will come to the NIH 
Clinical Center to undergo the procedures. Unless otherwise specified, the visit 
window for the post-entry study visits is ± 5 days. 
6.1 
Screening  

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Screening may occur over the course of several contacts/visits. All inclusion and 
exclusion criteria must be assessed within 8 weeks before enrollment, unless 
otherwise specified in the eligibility criteria.  
After signing informed consent, subjects will undergo the following procedures: 
• 
Medical history and a physical examination, including weight, vital signs, and a 
symptom-directed evaluation based on symptoms or complaints reported by 
each participant. 
• 
Assessment of concomitant medications. 
• 
Blood collection for:  
o Hepatitis B Surface Antibody, HBsAg, Anti-HAV, and Hepatitis C 
antibody serology 
o QuantiFERON® TB test 
o Complete blood count (CBC) with differential, PT, activated PTT 
o Chemistry panel to include: ALT, AST, alkaline phosphatase, creatinine, 
total and direct bilirubin, and serum albumin levels 
o Flow cytometry panel (includes CD4+ T cell count) 
o Plasma HIV and HCV viral RNA levels 
o Serum and plasma for storage 
• 
Urinalysis 
• 
Serum or urine pregnancy test (for women of child-bearing potential)  
• 
Electrocardiogram (ECG) 
6.2 
Enrollment/Baseline 
The enrollment visit may take place over 2 visits to accommodate the baseline 
pretreatment apheresis procedure. The first dose of vedolizumab will be 
administered at this visit, and enrollment is defined as the day and time of receipt of 
the first dose of vedolizumab.  
Subjects will undergo the following procedures (prior to the first dose of study drug): 
• 
Medical history and a targeted physical examination, including weight, vital 
signs, and a symptom-directed evaluation based on symptoms or complaints 
reported by each participant 
• 
PML checklist (Appendix C) 
• 
Baseline neurologic evaluation by a neurologist –screen for signs and symptoms 
of PML 
• 
Assessment of concomitant medications 
• 
HIV transmission risk behavior assessment and counseling 
• 
Leukapheresis for research studies 
• 
Blood collection for: 

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o Flow cytometry panel (includes CD4+ T cell count) 
o Plasma HIV viral RNA level 
o HLA typing (if not already on file) 
o Storage of plasma, serum and peripheral blood mononuclear cells 
(PBMCs).  Optional collection of PAXgene® Blood RNA Tube for 
storage. 
o CBC with differential 
o Chemistry panels, to include: ALT, AST, alkaline phosphatase, 
creatinine, total and direct bilirubin, and serum albumin levels 
• 
Serum or urine pregnancy test (for women of child-bearing potential-obtained 
within 24 hours prior to infusion) 
6.3 
Study Phase (Figure 1.1.2-1) 
 
Vedolizumab will be administered on study day 0. Subsequent infusions of 
vedolizumab (300 mg) will be given at weeks 2, 6, 10, 14, 18, 22, 26, and 30; for a 
total of 9 infusions. After the final infusion at week 30, all subjects will continue to 
be seen every 4 weeks until they restart cART. At infusion visits and the monthly 
visits following week 30, the following will be performed: 
• 
Medical history and a targeted physical examination, including weight, vital 
signs, and a symptom-directed evaluation 
• 
Assessment of concomitant medications  
• 
Assessment of any new or unresolved AEs/intercurrent illnesses 
• 
PML checklist (done prior to infusion at infusion visits only) 
• 
Neurologic examination- screen for signs and symptoms of PML. Any subjects 
that develop signs or symptoms suggestive of PML will be evaluated by a 
neurologist. No further vedolizumab doses will be administered until 
appropriate workup (e.g. MRI) has been done to exclude a diagnosis of PML.  
• 
Blood collection: 
o CBC with differential. 
o Chemistry panels, to include: ALT, AST, alkaline phosphatase, 
creatinine, total and direct bilirubin, and serum albumin levels. 
o Flow cytometry panel (includes CD4+ T cell count). 
o Plasma HIV viral RNA level 
• 
Serum or urine pregnancy test (for women of child-bearing potential); results 
must be reviewed prior to infusion   
• 
Storage of plasma, PBMCs, and serum. Optional collection of plasma, serum, 
and PAXgene® Blood RNA Tube for storage on day 3 (+/- 2 days) and week 1 
visits (+/- 3 days).   Optional collection of PAXgene® Blood RNA Tube for 
storage on week 2 and week 6 visits.   

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• 
Leukapheresis for research studies will be done within 14 days after the study 
week 10 and 22 visits (prior to beginning ATI)  
• 
HIV transmission risk behavior assessment and counseling 
 
Analytical Treatment Interruption 
Following the study week 22 visit, all subjects will discontinue cART.  During the ATI, 
additional CD4+ T cell count, storage of plasma, and plasma HIV RNA levels will be 
obtained such that subjects will have these parameters monitored every 2 weeks during 
the ATI. Genotypic analysis for drug resistance mutations will be performed on all 
plasma samples with HIV viral levels >1,000 copies/ml. For select subjects residing 
outside the local (Bethesda, MD) area, blood samples for CD4+ T cell counts, and HIV 
viral levels, may be collected at their local clinics or Quest Diagnostics and sent to the 
NIH Clinical Center for testing.  Samples collected at clinics or at Quest may be labeled 
with a coded identifier, gender, and date of birth, as required by the local facility. 
 
If a subject develops one or more criteria for ending ATI (see section 3.1) he/she will be 
asked to return for assessment and confirmation of the laboratory/clinical abnormality. If 
the criteria for ending ATI are met, no further vedolizumab infusions will be given, and 
the subject will be instructed to restart cART. He/she will then undergo the schedule of 
procedures described in Section 6.4.  At week 48, any subject who has not met criteria 
to end the ATI but has detectable viremia (>40 copies/ml) will be instructed to restart 
cART. All subjects will be followed for 6 months after restarting cART. If a subject does 
not have detectable (>40 copies/ml) viremia at week 48, they may elect to remain off 
cART and will be followed until viremia becomes detectable. For such subjects, 
laboratory studies will be continued per the schedule outlined in Section 6.3 (except for 
the collection of serum for storage) until viremia is detected; at which time they will be 
instructed to restart cART and be followed as outlined in Section 6.4. 
6.4 
Follow-up  
Upon restarting cART, subject will enter the follow-up phase of the study. After 
restarting cART, subjects will be seen every 4 weeks for 24 weeks. At these visits, 
subjects will undergo the following procedures: 
• 
Medical history and a targeted physical examination, including weight, vital 
signs, and a symptom-directed evaluation based on symptoms or complaints 
reported by each participant 
• 
Assessment of concomitant medications 
• 
Assessment of any new or unresolved AEs or intercurrent illnesses 
• 
Neurological evaluation screen for signs and symptoms of PML. Any subjects 
that develop signs or symptoms suggestive of PML will be evaluated by a 
neurologist and undergo brain MRI and other workup as clinically indicated. 
• 
Blood collection for: 
o CBC with differential 

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o Chemistry panels, to include: ALT, AST, alkaline phosphatase, 
creatinine, total and direct bilirubin, and serum albumin levels 
o Flow cytometry panel (includes CD4+ T cell count) 
o Plasma HIV viral load 
o HIV genotype (performed on all samples with viral levels ≥1,000 
copies/ml) 
o Storage of plasma and PBMCs  
Management of cART during the follow-up period will be according to standard 
guidelines (http://aidsinfo.nih.gov/guidelines) 
 
7 Study Evaluations 
7.1 
Clinical Evaluations 
 
• 
Medical history and physical examination 
• 
Phlebotomy: Blood will be collected for routine serologic, hematologic, and 
clinical chemistry evaluations as described in Section 6 
7.2 
Laboratory Evaluations 
 Clinical and Research Laboratory Evaluations and Specimen 
Collection 
 
• 
HIV viral RNA levels 
• 
Flow cytometry with CD4+ T cell count 
• 
Serum for levels of vedolizumab and antibody to vedolizumab 
 
Leukapheresis: Leukapheresis will be performed for research studies including, 
but not limited to, measurements of the frequency of CD4+ T cells carrying 
replication-competent HIV by quantitative co-culture assays. These studies will 
address the exploratory endpoints. If leukapheresis cannot be performed for 
technical reasons (e.g. poor venous access), 80 ml of blood will be drawn 
instead. 
Other research evaluations measuring the effect of vedolizumab on the HIV 
pathogenesis may include: 
 
• 
Frequency of CD4+ T cells carrying HIV pro-viral DNA and cell-
associated HIV RNA 
• 
Frequency of HIV-specific CD4+ and CD8+ T cells 
• 
T-cell activation and soluble markers of inflammation 

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• 
Residual (1-40 copies/mL) plasma viremia 
• 
Gene expression profiling of T cells 
• 
Immunophenotypic profiling of PBMCs 
 
8 Potential Risks and Benefits 
8.1 
Potential Risks 
 
 
Vedolizumab 
The identified and potential risks of vedolizumab IV treatment listed in this section have 
been assessed during the course of controlled and open label clinical studies. 
 
Identified Risks 
 
Infusion-Related Reactions 
In the completed 52-week controlled studies in subjects with UC or CD, 4% of 
vedolizumab treated subjects and 3% of placebo-treated subjects experienced infusion-
related reactions as defined by the investigator39,40. The majority of reactions were mild 
or moderate in intensity and <1% resulted in discontinuation of study treatment. 
Observed infusion-related reactions generally resolved with no or minimal intervention 
following the infusion.  Most reactions were not serious and occurred during the infusion 
or within the first hour after infusion was completed. 
 
 
Upper Respiratory Tract Infections 
Nasopharyngitis and upper respiratory tract infections are some of the most common 
infectious treatment emergent AE seen across the clinical studies of vedolizumab. In 
the Phase III studies39,40, there was an overall rate of upper respiratory tract infection of 
24% in vedolizumab-treated subjects compared with 17% in the placebo-treated 
subjects (see Section 1.1.3). The most commonly reported diagnosis included 
nasopharyngitis, upper respiratory tract infection, pharyngitis, and sinusitis. 
 
 
Potential Risks of Vedolizumab Treatment 
 
Serious Infections, Including Opportunistic Infections 
In the completed 52-week controlled studies in subjects with UC or CD, the rate of 
infections was 0.85 per patient-year in vedolizumab-treated subjects and 0.70 per 
patient-year in placebo treated subjects. The infections consisted primarily of 
nasopharyngitis, upper respiratory tract infection, sinusitis, and urinary tract infections. 
Most subjects continued on vedolizumab after the infection resolved. In the completed 
52-week controlled studies39,40, the rate of serious infections was 0.07 per patient year 
in vedolizumab-treated subjects and 0.06 per patient-year in placebo-treated subjects. 
Over time, there was no significant increase in the rate of serious infections. 
 
In controlled and open-label studies in adults treated with vedolizumab, serious 

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infections have been reported, which include tuberculosis, sepsis, salmonella sepsis, 
Listeria meningitis, and cytomegaloviral colitis. 
 
Natalizumab, another integrin receptor antagonist, has been associated with PML, a 
rare and often fatal opportunistic infection of the CNS41. PML is caused by the John 
Cunningham virus (JCV) and typically only occurs in patients who are 
immunocompromised. Natalizumab is a pan-4 integrin antagonist that binds to both 
the α4β1 and α4β7 integrins and inhibits cellular adhesion to VCAM-1 and MAdCAM-
142. In contrast, vedolizumab binds to the α4β7 integrin only and inhibits adhesion to 
MAdCAM-1, but not VCAM-143. Although no cases of PML have been reported in 
clinical studies or post-marketing experience with vedolizumab to date (over 11,943 
patient-years), a risk of PML cannot be ruled out. 
 
 
Analytical treatment interruption  
The risks from an ATI, performed under close virologic and immunological monitoring 
are minimal in this subject population. There is a theoretical risk that ATI could lead to 
the development of HIV drug resistance. This may be a particular concern for 
individuals taking NNRTIs. However, this potential risk with NNRTIs is essentially 
eliminated by undertaking the procedures described in Section 3.144. Given the study 
population, the frequency of immunological and virologic monitoring, and strict criteria 
for restarting cART, it is extremely unlikely that the ATI will lead to the development of 
any opportunistic infections or AIDS-defining conditions. 
 
During the ATI phase, subjects may transmit HIV infection if they do not adhere to safe 
sex practices. 
 
Phlebotomy/Insertion of IV Catheter  
This may be associated with discomfort, bruising, local hematoma formation and, on 
rare occasions, infections, lightheadedness, and fainting.  
 
The amount of blood drawn for research purposes will be within the limits allowed for 
adult subjects by the NIH Clinical Center (CC) (Medical Administrative Policy 95-9: 
Guidelines for Limits of Blood Drawn for Research Purposes in the Clinical Center: 
http://cc-internal.cc.nih.gov/policies/PDF/M95-9.pdf). 
 
 
HLA typing 
Some HLA types have been associated with an increased risk of certain diseases like 
arthritis and other rheumatologic disorders, or a faster progression to AIDS. HLA 
typing will be performed on samples collected from all the enrolled subjects. Results 
from the HLA typing will become part of each subject’s medical record at the NIH. 
Medical records containing this information are maintained in a secure place.  
8.2 
Potential Benefits 
The possibility of vedolizumab-induced sustained control of HIV viremia in the 
absence of daily cART is a potential benefit from study participation. In addition, 

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others may benefit from knowledge gained in this study that may aid in the 
development better HIV treatments. 
 
9 Research Use of Stored Human Samples, Specimens, or 
Data 
 
• 
Intended Use: Stored blood samples and data collected under this protocol may 
be used to study the effect of vedolizumab on the virologic and immunologic 
parameters listed in Section 7.2.1. Samples may be used to study other aspects 
of the immunopathogenesis of HIV infection or measure serum levels of 
vedolizumab and antiretroviral agents. Coded samples and demographic data 
will be sent to Takeda-Millennium Pharmaceuticals and its vendor, QPS for PK 
and immunogenicity studies. 
• 
Storage:  Access to stored samples will be limited using a locked room or a 
locked freezer. Samples and data will be stored using codes assigned by the 
investigators. Data will be kept in password-protected computers. Only 
investigators will have access to the samples and data. 
 
• 
Tracking: Samples will be tracked utilizing the NCI at Frederick Central 
Repository. Data will be stored and maintained in the NIAID CRIMSON 
database. 
 
• 
Disposition at the Completion of the Protocol: At the completion of the 
protocol (termination), samples and data will either be destroyed, or after IRB 
approval, transferred to another existing protocol.  
 
• 
Reporting the Loss or Destruction of Samples/Specimens/Data to the IRB: 
o Any loss or unanticipated destruction of samples or data (for example, 
due to freezer malfunction) that meets the definition of Protocol 
Deviation and/or compromises the scientific integrity of the data 
collected for the study, will be reported to the NIAID IRB.  
o Subjects may decide at any point not to have their samples stored.  In 
this case, the principal investigator will destroy all known remaining 
samples and report what was done to both the subject and to the IRB.  
This decision will not affect the subject’s participation in this protocol or 
any other protocols at NIH (If applicable). 
10 Remuneration Plan for Subjects  
Eligible subjects will be compensated for travel according to the NIAID/NIH travel 
policy. Subjects will receive financial compensation for time and inconvenience 
according to the NIH CC volunteer guidelines: screening ($50), 2-pass 
leukapheresis ($200 for a procedure; $50 for unsuccessful apheresis attempts), 
research blood draw ($40), clinic visits ($30), vedolizumab infusion ($80).  If 
subject does not qualify or declines leukapheresis, an additional 80 mL research 
blood will be drawn and subject may be compensated an additional $25 for 
inconvenience. 
 

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11 Assessment of Safety 
11.1 Documenting, Recording, and Reporting Adverse Events  
At designated visits with the subject, information regarding AEs will be elicited 
by appropriate questioning and examinations, and it will be:  
• Immediately documented in the electronic database and medical record. 
• Reported as outlined below (e.g., IND sponsor, IRB, Food and Drug 
Administration [FDA]). 
11.2 Definitions  
Adverse event (AE) 
An AE is any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (e.g., abnormal physical exam or laboratory 
finding), symptom, or disease temporally associated with the subject’s 
participation in the research, whether or not considered related to the 
research. 
 
Adverse reaction (AR) 
An adverse reaction (AR) is an AE that is caused by an investigational agent 
(drug or biologic). 
 
Suspected adverse reaction (SAR) 
A suspected AR (SAR) is an AE for which there is a reasonable possibility that 
the investigational agent caused the AE. ‘Reasonable possibility’ means that 
there is evidence to suggest a causal relationship between the drug and the 
AE. A SAR implies a lesser degree of certainty about the causality than an 
AR, which implies a high degree of certainty. 
 
Serious adverse event (SAE)  
An SAE is an AE that results in one or more of the following outcomes: 
• Death 
• A life-threatening (i.e., an immediate threat to life) event 
• An inpatient hospitalization or prolongation of an existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• A congenital anomaly/birth defect 
• A medically important event* 
*Medical and scientific judgment should be exercised in deciding whether 
expedited reporting is appropriate in other situations, such as important medical 
events that may not be immediately life threatening or result in death or 
hospitalization, but they may jeopardize the subject or may require 
intervention to prevent one of the other outcomes listed above.  
 
Unexpected adverse event 
An AE is unexpected if it is not listed in the investigator’s brochure or package  
insert (for marketed products), or it is not listed at the specificity or severity 
that has been observed. It is the responsibility of the IND sponsor to make this 
determination. 
 

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Serious and unexpected suspected adverse reaction  
A serious and unexpected suspected AR (SUSAR) is a SAR that is both 
serious and unexpected.   
 
Unanticipated problem  
An unanticipated problem (UP) is an event, incident, experience, or outcome 
that is—  
1. Unexpected in terms of nature, severity, or frequency in relation to— 
a. The research risks that are described in the IRB-approved research 
protocol and informed consent document; investigator’s brochure, or 
other study documents; and 
b. The characteristics of the subject population being studied; and 
2. Related or possibly to participation in the research; and 
3. Suggests the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was 
previously known or recognized (per the IND sponsor, an AE with a 
serious outcome will be considered increased risk). 
 
Unanticipated problem that is not an adverse event  
An unanticipated problem that is not an AE is an incident, experience, or 
outcome that is not associated with an AE, which meets the 3 criteria of a UP. 
Examples include breaches of confidentiality, accidental destruction of study 
records, and unaccounted-for study drug. 
 
Protocol Deviation 
Any change, divergence, or departure from the IRB approved study 
procedures in a research protocol. Protocol deviations are designated as 
serious or non-serious and further characterized as: 
 
• 
Those that occur because a member of the research team deviates from the 
protocol 
• 
Those that are identified before they occur, but cannot be prevented 
• 
Those that are discovered after they occur 
 
 
Serious Protocol Deviation: A deviation that meets the definition of a 
Serious Adverse Event or compromises the safety, welfare or rights of 
subjects or others. 
 
Non-compliance: The failure to comply with applicable NIH HRPP policies, 
IRB requirements, or regulatory requirements for the protection of human 
subjects. Non-compliance is further characterized as: 
1. Serious: Non-compliance that 
a. Increases risks, or causes harm, to participants 
b. Decreases potential benefits to participants 
c. Compromises the integrity of the NIH-HRPP 
d. Invalidates the study data 
2. Continuing: Non-compliance that is recurring 
3. Minor: Non-compliance that, is neither serious nor continuing. 

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Protocol specified events 
Protocol specified events are AEs specified in the protocol that the principal 
investigator, IND sponsor, or medical monitor would like to review in real time 
rather than weeks or months later, when they would otherwise appear in 
various line listings. These events may or may not also be SAEs.  
11.3 Investigator Assessment of Adverse Events 
If a diagnosis is clinically evident (or subsequently determined), the diagnosis 
rather than the individual signs and symptoms or lab abnormalities will be 
recorded as the AE. 
 
All AEs occurring from the time when the first infusion is administered through 
the specified study follow-up period will be documented, recorded, and 
reported. The principal investigator will evaluate all AEs with respect to 
Seriousness (criteria listed above), Severity (intensity or grade), and 
Causality (relationship to study agent and relationship to research) according 
to the following guidelines.  
 Severity 
The principal investigator will grade the severity of each AE according to 
the Division of Aids Table for Grading the Severity of Adult and Pediatric 
Adverse Events Version 2.0, November, 2014, which can be found at   
http://rsc.tech-
res.com/Document/safetyandpharmacovigilance/DAIDS_AE_GRADING_T
ABLE_v2_NOV2014.pdf 
 Causality    
Causality (likelihood that the event is related to the study agent) will be 
assessed considering the factors listed under the following categories:  
 
Definitely related 
   
• 
Reasonable temporal relationship 
• 
Follows a known response pattern 
• 
Clear evidence to suggest a causal relationship 
• 
There is no alternative etiology 
 
Probably related 
 
• 
Reasonable temporal relationship 
• 
Follows a suspected response pattern (based on similar agents) 
• 
No evidence of a more likely alternative etiology 
 
Possibly related  
• 
Reasonable temporal relationship 
• 
Little evidence for a more likely alternative etiology 
 
Unlikely related  
• 
Does not have a reasonable temporal relationship  
OR 
• 
Good evidence for a more likely alternative etiology 

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Not related 
 
• 
Does not have a temporal relationship 
         
OR 
• 
Definitely due to an alternative etiology 
 
Note:    
Other factors (e.g., dechallenge, rechallenge) should also be considered for 
each causality category when appropriate. Causality assessment is based 
on available information at the time of the assessment of the AE. The 
investigator may revise the causality assessment as additional information 
becomes available. 
11.4 Investigator Reporting Responsibilities to the Sponsor  
  Adverse Events 
Line listings, frequency tables, and other summary AE data will be 
submitted to the IND sponsor per the Safety Review and Communications 
Plan (SRCP – see below), or as needed for periodic safety assessments, 
review of IND annual reports, review of IND safety reports, and preparation 
of final study reports. 
  Serious Adverse Events 
SAEs (whether or not they are also UPs) must be reported on the SAE/UP 
report form and sent to the sponsor Clinical Safety Office (CSO) by fax or e-
mail attachment. Deaths and immediately life-threatening SAEs must be 
reported within 1 business day after the site becomes aware of the event. 
All other SAEs must be reported within 3 business days of site awareness.  
 
Sponsor clinical safety office contact information:  
OCRPRO Clinical Safety Office 
5705 Industry Lane 
Frederick, MD 21704 
 
Phone 301-846-5301 
Fax 301-846-6224 
E-mail: rchspsafety@mail.nih.gov  
  Unanticipated Problems 
Non-serious AEs that are UPs must also be reported on the SAE/UP report 
form and sent to the CSO by fax or e-mail attachment no later than 7 
calendar days of site awareness of the event. UPs that are not AEs are not 
reported to the sponsor CSO.  
  Protocol Specified Events  
Opportunistic infections are AEs of special interest. These protocol 
specified events must be reported to the CSO on a SAE/UP report form 
within 3 business days of site awareness.   

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  Pregnancy 
Pregnancy itself is not an AE. However, complications of pregnancies are 
AEs and may be SAEs. Pertinent obstetrical information for all pregnancies, 
including pregnancies disclosed by the subject as occurring in a partner of 
a male subject, will be reported to the CSO via fax or e-mail within 3 
business days from the site awareness of the pregnancy.   
 
Pregnancy outcome data (e.g., delivery outcome, spontaneous or elective 
termination of the pregnancy) will be reported to the CSO within 3 business 
days of the site awareness on a protocol-specified form. In the event of 
pregnancy, the following steps will be taken: 
• Discontinuation of the study agents 
• Withdraw from the study but continue following for safety 
• Report to Medical Monitor and the IRB 
• Advise research subject to notify the obstetrician of study agent 
exposure 
11.5 Investigator Reporting Responsibilities to the NIAID IRB   
  Expedited Reporting to the NIAID IRB 
 
Serious and non-serious Unanticipated Problems, deaths, serious 
deviations, and serious or continuing non-compliance will be reported 
within 7 calendar days of investigator awareness. SAEs that are possibly, 
probably, or definitely related to the research will be reported to the NIAID 
IRB within 7 calendar days of investigator awareness, regardless of 
expectedness. 
 
12.5.1.1.  Waiver of Reporting Anticipated Protocol Deviations, 
Expected UP nonAEs and Deaths to the NIAID IRB 
 
Anticipated deviations in the conduct of the protocol will not be 
subject to expedited reporting to the IRB unless they occur at a rate 
greater than anticipated by the study team. Expected adverse 
events will not be reported to the IRB unless they occur at a rate 
greater than that known to occur in HIV(+) population. If the rate of 
these events exceeds the rate expected by the study team, the 
events will be classified and reported as though they are 
unanticipated problems. 
  Annual Reporting to the NIAID IRB  
The following items will be reported to the NIAID IRB in summary at the 
time of continuing review: 
• 
Serious and non-serious unanticipated problems 
• 
Expected serious adverse events that are possibly, probably, or 
definitely related to the research 
• 
Serious adverse events that are not related to the research 
• 
All adverse events, except expected AEs and deaths granted a 
waiver of reporting  

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• 
Serious and Non-Serious Protocol deviations. Anticipated 
deviations in the conduct of the protocol will not be reported to the 
IRB unless they occur at a rate greater than anticipated by the 
study team 
• 
Serious, continuing, and minor non-compliance 
▪ 
Any trends or events which in the opinion of the investigator should 
be reported 
11.6  Follow-up of Adverse Events and Serious Adverse Events 
AEs that occur following enrollment of subjects (i.e., after the first dose of 
vedolizumab) are followed until the final outcome is known or until the end of 
the study follow-up period.  
 
SAEs that that are assessed by the investigator to be possibly, probably, or 
definitely related to vedolizumab and that have not resolved by the end of the 
follow-up period will be followed until the final outcome is known. If it is not 
possible to obtain a final outcome for an SAE (e.g. the subject is lost to follow 
up), the reason a final outcome could not be obtained will be recorded by the 
investigator on the SAE/UP report form.  
 
SAEs that occur after study completion that are reported to and are assessed 
by the investigator to be possibly, probably, or definitely related must be 
reported to the CSO, as described above. 
11.7 Sponsor’s Reporting Responsibilities 
SUSARs as defined in 21 Code of Federal Regulations (CFR) 312.32 and 
determined by the IND sponsor will be reported to the FDA and all 
participating investigators as IND safety reports.  
 
The IND sponsor will also submit an IND annual report of the progress of the 
investigation to the FDA as defined in 21 CFR 312.33.  
11.8  Halting Criteria for the Protocol  
Halting the study requires immediate discontinuation of the study agents 
administered for all subjects and suspension of enrollment until a decision is 
made about whether or not to continue study agent administration.   
 
 
The halting criteria (as determined by the study PI and IND sponsor secondary 
to aggregate data review) for this study include: 
• 
Any SAE or grade 4 AE that is possibly, probably, definitely related to the 
study agent; OR 
• 
Any safety issue that the study principal investigator or IND sponsor 
determines should halt the study.  
• 
Pre-defined futility criteria for virologic failure are met (see Section 13). 
 
Any related AE that is ≥ grade 3 (not including transient, subjective infusion-
related symptoms such as malaise, fatigue, headache, chills) will be reviewed 
within 48 hours of site awareness, by the PI and IND sponsor medical monitor, 

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to consider the need for halting the protocol. 
 
The PI and/or CSO will determine if the study should be halted. In addition, 
the FDA may halt the study at any time following review of any safety 
concerns.  
  Reporting of Study Halting 
If a halting rule is met, a description of the adverse event(s) or safety issue must 
be reported by the PI, within one business day, to the CSO and to the IRB by fax 
or email. The sponsor will notify the FDA as soon as possible that the study has 
been halted. 
 
  Resumption of a Halted Study 
The IND Sponsor, in collaboration with the PI will determine if it is safe to resume the 
study. The PI will notify the IRB of the decision on resumption of the study. The 
sponsor will notify the FDA as soon as possible that the study has been resumed after 
a halt. 
11.9  Pausing Criteria for a Subject   
The decision to suspend administration of the study agent for a single subject requires 
discontinuation of the study agent administrated for the study subject until a decision is 
made whether or not to continue study agent administration.   
 
The pausing criteria for a single subject in this study include:  
 
• A subject experiences an SAE or grade 3 or greater AE (not including 
transient, subjective infusion-related symptoms such as malaise, fatigue, 
headache, chills, or total bilirubin in subjects taking atazanavir) that is (as 
determined by the IND sponsor) possibly, probably, or definitely related to 
the study agent;  
OR 
 
• Any safety issue that the PI determines should pause administration of the 
study agent to a single subject. 
 
The CSO, in collaboration with the PI, may also pause for an individual subject 
or the entire group if a safety concern is identified during routine aggregate 
data analysis. 
  Reporting of Pause 
If a pausing requirement is met, a description of the AE(s) or safety issue 
must be reported by the PI by fax or e-mail within 1 business day to the 
sponsor CSO, principal investigator, IRB, and the Medical Monitor.  The 
sponsor will notify the FDA as soon as possible that the study agent has 
been halted for an individual subject. 
  Resumption of Pausing for a Subject or Group 

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The CSO in collaboration with the PI  will determine whether or not it is safe 
to resume administration of the study agent to the subject. The principal 
investigator will notify the IRB of the decision to resume administration of 
the study agent prior to resumption. The sponsor will notify the FDA as 
soon as possible that the study agent has been resumed for an individual 
subject. 
 
 
A subject who does not resume study agent will continue to be followed for 
safety. 
 
11.10  Withdrawal Criteria for an Individual Subject 
An individual subject will be withdrawn for any of the following:  
• An individual subject’s decision. (The PI will attempt to determine the 
reason for the subject’s decision, and will strongly suggest a follow-up plan 
to help ensure the subject safely returns to baseline or better, if possible). 
• Co-enrollment in a study with an investigational research agent (rare 
exception granted by the PI).  
• Any SAE or grade 4 systemic infusion related symptom(s) or AE that is 
considered to be related to the study agent. 
• Clinically significant type 1 hypersensitivity reaction associated with the 
study agent. In the event of a type 1 hypersensitivity reaction that is NOT 
considered to be clinically significant, (e.g., brief, mild, and self-limited skin 
reaction without other symptoms), the PI may consider possible additional 
infusions of the study agent with appropriate precautions. 
• Any clinical AE, laboratory abnormality, or other medical condition or 
situation such that continued participation in the study would not be in the 
best interest of the subject. Subjects will be followed for the duration of the 
study for indicated safety assessments. 
• Non-compliance with study procedures to the extent that it is potentially 
harmful to the subject or to the integrity of the study data. 
• Pregnancy. 
• Participant misses more than 2 study infusions. 
 
If possible, all subjects who discontinue the study treatment prematurely will 
be followed for 6 months for all the study evaluations. 
11.11  Replacement for Withdrawn Subjects 
Any subject who withdraws from the study, or who discontinues the study 
agent, prematurely, and whose reasons for withdrawing from the study or 
discontinuing study agent administration are unrelated to any real or perceived 
effect of the study agent or their administration, will be replaced.  
11.12  Safety Oversight 
  Safety Review and Communications Plan (SRCP) 

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A Safety Review and Communications Plan (SRCP) has been developed 
for the protocol. The SRCP is an internal communications document 
between the principal investigator and the IND sponsor CSO, which 
delineates the safety oversight responsibilities of the principal investigator, 
the CSO, and other stakeholders. The SRCP also includes the overall plan 
for conducting periodic safety surveillance assessments.  
   Sponsor Medical Monitor  
A medical monitor, representing the IND sponsor (OCRPRO), has been 
appointed for the safety oversight in this clinical study. The sponsor medical 
monitor will be responsible for performing safety assessments as outlined in 
the SRCP.  
12 Clinical Monitoring Structure 
12.1 
Site Monitoring Plan  
As per ICH-GCP 5.18 and FDA 21 CFR 312.50 clinical protocols are required 
to be adequately monitored by the study sponsor. This study monitoring will be 
conducted according to the “NIAID Intramural Clinical Monitoring Guidelines”. 
Monitors under contract to the NIAID/ OCRPRO will visit the clinical research 
site to monitor aspects of the study in accordance with the appropriate 
regulations and the approved protocol. The objectives of a monitoring visit will 
be: 1) to verify the existence of signed informed consent documents and 
documentation of the ICF process for each monitored subject; 2) to verify the 
prompt and accurate recording of all monitored data points, and prompt 
reporting of all SAEs; 3) to compare CRIMSON data abstracts with individual 
subjects’ records and source documents (subjects’ charts, laboratory analyses 
and test results, physicians’ progress notes, nurses’ notes, and any other 
relevant original subject information); and 4) to help ensure investigators’ are 
in compliance with the protocol. The monitors also will inspect the clinical site 
regulatory files to ensure that regulatory requirements (Office for Human 
Research Protections-OHRP, FDA), and applicable guidelines (ICH-GCP) are 
being followed. During the monitoring visits, the investigator (and/or designee) 
and other study personnel will be available to discuss the study progress and 
monitoring visit. 
 
The investigator (and/or designee) will make study documents (e.g., consent 
forms, CRIMSON data abstracts, and pertinent hospital or clinical records 
readily available for inspection by the local IRB, the FDA, the site monitors, 
and the NIAID staff for confirmation of the study data.  
 
A specific protocol monitoring plan will be discussed with the Principal 
Investigator and study staff prior to enrollment. The plan will outline the 
frequency of monitoring visits based on such factors as study enrollment, data 
collection status and regulatory obligations.  
 
13 Statistical Considerations 

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The primary safety outcome is the occurrence of grade 2 or higher adverse events.  An 
exact 95% confidence interval for the probability of adverse events will be computed 
using the Clopper-Pearson method.  The primary efficacy outcome is rebound of 
plasma viremia requiring a restart of cART.  An exact 95% confidence interval will be 
computed for the rebound probability using the Clopper-Pearson method.  Changes 
from baseline in continuous measurements will be analyzed using paired t-tests or, if 
data are skewed, the Wilcoxon signed rank statistic.      
 
In terms of safety, a sample size of 20 patients provides a 96.1% chance of observing 
an adverse event of probability 15% or greater.  Table 1.1.3-1 shows the chance of 
observing at least one adverse event of given probability. 
 
Table 13-1. The second row is the probability of observing at least one 
adverse event of probability given in the first row.  
0.025 
0.050 
0.075 
0.100 
0.125 
0.150 
.397 
.642 
.790 
.878 
.931 
.961 
 
 
The sample size for this study is 20 subjects with suppressed HIV viremia on cART. In 
the absence of a therapeutic intervention, it is expected that 100% of such subjects 
would experience a rebound in plasma HIV viremia; with a median time to rebound of 2-
4 weeks11-13. Based on the pre-clinical primate studies described above, we would 
expect treatment with vedolizumab to significantly reduce the rate of viral rebound after 
discontinuation of cART. Table 13-2 shows the confidence interval for the probability of 
rebound for a sample size of 15 subjects.  Row 1 is the number of rebounds out of 15, 
and row 2 is the confidence interval.  
  
Table 13-2. The second row gives exact 95% confidence intervals for 
rebound probability given the observed number of rebounders in row 1 
among the 20 patients.   
0 
2 
4 
6 
8 
10 
12 
14 
16 
18 
20 
.000-
.168 
.012-
.317 
.057-
.437 
.119-
.543 
.191-
.640 
.272-
.728 
.360-
809 
.457-
.881 
.563-
.943 
.683-
.988 
.832-
1.00 
 
For example, if there are 6 rebounds, we can be quite confident that the true rebound 
probability is between .119 and .543.  
 
Futility guidelines are based on the numbers of patients meeting virologic criteria to 
restart cART prior to study week 30.  We use Bayesian methodology whereby we 
quantify our prior opinion about the 42 day probability with monoclonal antibodies as 
roughly equivalent to having observed 4 people, 2 of whom meet virologic criteria to 
restart cART by 30 weeks.  This translates to a beta (2,2) prior distribution for p, the 
probability of meeting virologic criteria of failure by 30 weeks.  Futility is declared if the 
posterior probability that p exceeds 0.70, given the observed results, is 90% or greater.  
The futility boundary is shown in Table 13-3.  For example, the boundary is crossed if 
the first 9 patients rebound by 30 weeks.  Likewise, futility can be declared if 12 of the 
first 13 rebound by 30 weeks, etc. 
 
 

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Table 13-3 Futility is declared if the number of patients rebounding by 
week 30, among the number tested in row 1, is at least as large as the 
figure in row 2 
9 
10 
11 
12 
13 
14 
15 
16 
17 
18 
19 
20 
9 
10 
11 
12 
12 
13 
14 
15 
16 
16 
17 
18 
 
The probabilities of crossing this futility boundary are shown in Table 13-4 for different 
true probabilities. 
 
 
Table 13-4.  Row 2 shows the probability of crossing the futility threshold 
if the true 30-week rebound probability is as shown in row 1.  
.50 
.60 
.70 
.80 
.90 
.95 
.003 
.021 
.099 
.339 
.775 
.953 
 
 
For instance, if the true 30-week probability of having plasma viral level >1,000 is 0.50, 
the probability of crossing the futility boundary is only 0.003.  On the other hand, if the 
true 30-week rebound probability is 0.95, the probability of crossing the futility boundary 
is 0.953. 
 
14 Ethics/Protection of Human Subjects 
14.1 
Informed Consent Process 
Informed consent is a process where information is presented to enable 
persons to voluntarily decide whether or not to participate as a research 
subject. It is an on-going conversation between the human research subject 
and the researchers which begins before consent is given and continues until 
the end of the subject's involvement in the research. Discussions about the 
research will provide essential information about the study and include 
purpose, duration, experimental procedures, alternatives, risks, and benefits.  
Subjects will be given the opportunity to ask questions and have them 
answered.  
The subjects will sign the informed consent document prior to undergoing any 
research procedures. The subjects may withdraw consent at any time 
throughout the course of the trial.  A copy of the informed consent document 
will be given to the subjects for their records. The researcher will document the 
signing of the consent form in the subject’s medical record. The rights and 
welfare of the subjects will be protected by emphasizing to them that the quality 
of their medical care will not be adversely affected if they decline to participate 
in this study.  
 
Non-English–Speaking Participants 
If a non-English speaking participant is unexpectedly eligible for enrollment, 
the participant will be provided with the CC Short Written Consent Form for 

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Non-English Speaking Research Participants in the participant’s native 
language and a verbal explanation of the purpose, procedures and risks of 
the study as described in MAS Policy M77-2, NIH HRPP SOP 12 and 45 
CFR 46.117(b)(2). The IRB-approved English consent form will serve as 
basis for the verbal explanation of the study. The investigator will obtain an 
interpreter unless the investigator is fluent in the prospective participant’s 
language. Preferably, the interpreter will be someone who is independent of 
the participant (i.e., not a family member). Interpreters provided by the CC 
will be used whenever possible. The interpreters will translate the IRB-
approved English consent form verbatim and facilitate discussion between 
the participant and investigator. 
The IRB-approved English consent form will be signed by the investigator 
obtaining consent and a witness to the oral presentation. The CC Short 
Written Consent Form will be signed by the participant and a witness who 
observed the presentation of information. The interpreter may sign the 
consent document as the witness and, in this case, will note “Interpreter” 
under the signature line. A copy of both signed forms will be provided to the 
participant to take home. 
The investigator obtaining consent will document the consent process in the 
participant’s medical record (CRIMSON), including the name of the 
interpreter. Further, all instances of use of the CC Short Written Consent 
Form will be reported to the IRB at the time of annual review. If the CC 
Short Written Consent Form is used three times or more for the same 
language, this will be reported to the IRB immediately. 
 Illiterate English Speaking Participants 
As the majority of the patient populations from which the study participants 
are drawn are literate, written consent will typically be provided.  However, 
this population does have a significant rate of illiteracy, and oral consent will 
be obtained for illiterate participants as consistent with NIH Medical 
Administrative Services (MAS) Policy M77-2 without separate IRB approval 
for each specific use. At Continuing Reviews, the NIAID IRB will be 
informed of the number of illiterate participants who provided consent 
verbally. 
14.2 
Subject Confidentiality 
All records will be kept confidential to the extent provided by federal, state, and 
local law. The study monitors and other authorized representatives of the 
Sponsor may inspect all documents and records required to be maintained by 
the Investigator, including but not limited to, medical records.  Records will be 
stored in a locked area, and all computer entry and networking programs will 
use coded numbers only.  Clinical information will not be released without 
written permission of the subject, except as necessary for monitoring by IRB, 
FDA, NIAID, OHRP, Takeda, or the sponsor’s designee. 
15 Data Handling and Record Keeping 
15.1 
Data Capture and Management  

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Study data will be maintained in CRIMSON and collected directly from subjects 
during study visits and telephone calls, or will be abstracted from subjects’ 
medical records. Source documents include all recordings of observations or 
notations of clinical activities and all reports and records necessary to confirm 
the data abstracted for this study. Data entry into CRIMSON will be performed 
by authorized individuals. The Investigator is responsible for assuring that the 
data collected are complete, accurate, and recorded in a timely manner. 
 
15.2 
Record Retention 
 
The investigator is responsible for retaining all essential documents listed in the 
ICH Good Clinical Practice Guideline.  Study records will be maintained by the 
PI for a minimum of 3 years and in compliance with institutional, IRB, state, and 
federal medical records retention requirements, whichever is longest. All stored 
records will be kept confidential to the extent required by federal, state, and 
local law. 
 
Should the investigator wish to assign the study records to another party and/or 
move them to another location, the investigator will provide written notification 
of such intent to OCRPRO/NIAID with the name of the person who will accept 
responsibility for the transferred records and/or their new location. Destruction 
or relocation of research records will not proceed without written permission 
from NIAID/RCHSPB. 

Protocol Version 5.0 
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Appendix A: Scientific References 
 
1. 
Volberding PA, Deeks SG. Antiretroviral therapy and management of HIV 
infection. Lancet 2010;376:49-62. 
2. 
Chun TW, Davey RT, Jr., Engel D, Lane HC, Fauci AS. Re-emergence of HIV 
after stopping therapy. Nature 1999;401:874-5. 
3. 
Chun TW, Fauci AS. HIV reservoirs: pathogenesis and obstacles to viral 
eradication and cure. AIDS 2012;26:1261-8. 
4. 
Chun TW, Justement JS, Moir S, et al. Decay of the HIV reservoir in patients 
receiving antiretroviral therapy for extended periods: implications for eradication of virus. 
J Infect Dis 2007;195:1762-4. 
5. 
Chun TW, Nickle DC, Justement JS, et al. HIV-infected individuals receiving 
effective antiviral therapy for extended periods of time continually replenish their viral 
reservoir. J Clin Invest 2005;115:3250-5. 
6. 
Chun TW, Stuyver L, Mizell SB, et al. Presence of an inducible HIV-1 latent 
reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A 
1997;94:13193-7. 
7. 
Finzi D, Hermankova M, Pierson T, et al. Identification of a reservoir for HIV-1 in 
patients on highly active antiretroviral therapy. Science 1997;278:1295-300. 
8. 
Wong JK, Hezareh M, Gunthard HF, et al. Recovery of replication-competent HIV 
despite prolonged suppression of plasma viremia. Science 1997;278:1291-5. 
9. 
Buzon MJ, Massanella M, Llibre JM, et al. HIV-1 replication and immune 
dynamics are affected by raltegravir intensification of HAART-suppressed subjects. Nat 
Med 2010;16:460-5. 
10. 
Yukl SA, Shergill AK, McQuaid K, et al. Effect of raltegravir-containing 
intensification on HIV burden and T-cell activation in multiple gut sites of HIV-positive 
adults on suppressive antiretroviral therapy. AIDS 2010;24:2451-60. 
11. 
Davey RT, Jr., Bhat N, Yoder C, et al. HIV-1 and T cell dynamics after 
interruption of highly active antiretroviral therapy (HAART) in patients with a history of 
sustained viral suppression. Proc Natl Acad Sci U S A 1999;96:15109-14. 
12. 
Rothenberger MK, Keele BF, Wietgrefe SW, et al. Large number of 
rebounding/founder HIV variants emerge from multifocal infection in lymphatic tissues 
after treatment interruption. Proc Natl Acad Sci U S A 2015;112:E1126-34. 
13. 
Steingrover R, Pogany K, Fernandez Garcia E, et al. HIV-1 viral rebound 
dynamics after a single treatment interruption depends on time of initiation of highly 
active antiretroviral therapy. AIDS 2008;22:1583-8. 
14. 
Deeks SG, Autran B, Berkhout B, et al. Towards an HIV cure: a global scientific 
strategy. Nat Rev Immunol 2012;12:607-14. 
15. 
Chun TW, Engel D, Mizell SB, et al. Effect of interleukin-2 on the pool of latently 
infected, resting CD4+ T cells in HIV-1-infected patients receiving highly active anti-
retroviral therapy. Nat Med 1999;5:651-5. 
16. 
Prins JM, Jurriaans S, van Praag RM, et al. Immuno-activation with anti-CD3 and 
recombinant human IL-2 in HIV-1-infected patients on potent antiretroviral therapy. AIDS 
1999;13:2405-10. 
17. 
Lehrman G, Hogue IB, Palmer S, et al. Depletion of latent HIV-1 infection in vivo: 
a proof-of-concept study. Lancet 2005;366:549-55. 
18. 
Archin NM, Liberty AL, Kashuba AD, et al. Administration of vorinostat disrupts 
HIV-1 latency in patients on antiretroviral therapy. Nature 2012;487:482-5. 
19. 
Tebas P, Stein D, Tang WW, et al. Gene editing of CCR5 in autologous CD4 T 
cells of persons infected with HIV. N Engl J Med 2014;370:901-10. 

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20. 
Hutter G, Nowak D, Mossner M, et al. Long-term control of HIV by CCR5 
Delta32/Delta32 stem-cell transplantation. N Engl J Med 2009;360:692-8. 
21. 
Burton DR, Ahmed R, Barouch DH, et al. A Blueprint for HIV Vaccine Discovery. 
Cell Host Microbe 2012;12:396-407. 
22. 
Fauci AS, Marston HD. Ending AIDS--is an HIV vaccine necessary? N Engl J 
Med 2014;370:495-8. 
23. 
Moir S, Malaspina A, Fauci AS. Prospects for an HIV vaccine: leading B cells 
down the right path. Nat Struct Mol Biol 2011;18:1317-21. 
24. 
Walker LM, Huber M, Doores KJ, et al. Broad neutralization coverage of HIV by 
multiple highly potent antibodies. Nature 2011;477:466-70. 
25. 
Zhou T, Georgiev I, Wu X, et al. Structural basis for broad and potent 
neutralization of HIV-1 by antibody VRC01. Science 2010;329:811-7. 
26. 
Barouch DH, Whitney JB, Moldt B, et al. Therapeutic efficacy of potent 
neutralizing HIV-1-specific monoclonal antibodies in SHIV-infected rhesus monkeys. 
Nature 2013;503:224-8. 
27. 
Klein F, Halper-Stromberg A, Horwitz JA, et al. HIV therapy by a combination of 
broadly neutralizing antibodies in humanized mice. Nature 2012;492:118-22. 
28. 
Shingai M, Nishimura Y, Klein F, et al. Antibody-mediated immunotherapy of 
macaques chronically infected with SHIV suppresses viraemia. Nature 2013;503:277-80. 
29. 
Malbec M, Porrot F, Rua R, et al. Broadly neutralizing antibodies that inhibit HIV-
1 cell to cell transmission. J Exp Med 2013;210:2813-21. 
30. 
Arthos J, Cicala C, Martinelli E, et al. HIV-1 envelope protein binds to and signals 
through integrin alpha4beta7, the gut mucosal homing receptor for peripheral T cells. 
Nat Immunol 2008;9:301-9. 
31. 
Cicala C, Martinelli E, McNally JP, et al. The integrin alpha4beta7 forms a 
complex with cell-surface CD4 and defines a T-cell subset that is highly susceptible to 
infection by HIV-1. Proc Natl Acad Sci U S A 2009;106:20877-82. 
32. 
Byrareddy SN, Kallam B, Arthos J, et al. Targeting alpha4beta7 integrin reduces 
mucosal transmission of simian immunodeficiency virus and protects gut-associated 
lymphoid tissue from infection. Nat Med 2014;20:1397-400. 
33. 
Haanstra KG, Hofman SO, Lopes Estevao DM, et al. Antagonizing the 
alpha4beta1 integrin, but not alpha4beta7, inhibits leukocytic infiltration of the central 
nervous system in rhesus monkey experimental autoimmune encephalomyelitis. J 
Immunol 2013;190:1961-73. 
34. 
Milch C, Wyant T, Xu J, et al. Vedolizumab, a monoclonal antibody to the gut 
homing alpha4beta7 integrin, does not affect cerebrospinal fluid T-lymphocyte 
immunophenotype. J Neuroimmunol 2013;264:123-6. 
35. 
Wyant T, Leach T, Sankoh S, et al. Vedolizumab affects antibody responses to 
immunisation selectively in the gastrointestinal tract: randomised controlled trial results. 
Gut 2015;64:77-83. 
36. 
Wyant T, Estevam J, Yang L, Rosario M. Development and validation of receptor 
occupancy pharmacodynamic assays used in the clinical development of the monoclonal 
antibody vedolizumab. Cytometry B Clin Cytom 2015. 
37. 
Parikh A, Leach T, Wyant T, et al. Vedolizumab for the treatment of active 
ulcerative colitis: a randomized controlled phase 2 dose-ranging study. Inflamm Bowel 
Dis 2012;18:1470-9. 
38. 
Pereira LE, Onlamoon N, Wang X, et al. Preliminary in vivo efficacy studies of a 
recombinant rhesus anti-alpha(4)beta(7) monoclonal antibody. Cell Immunol 
2009;259:165-76. 
39. 
Feagan BG, Rutgeerts P, Sands BE, et al. Vedolizumab as induction and 
maintenance therapy for ulcerative colitis. N Engl J Med 2013;369:699-710. 

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40. 
Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and 
maintenance therapy for Crohn's disease. N Engl J Med 2013;369:711-21. 
41. 
Yousry TA, Major EO, Ryschkewitsch C, et al. Evaluation of patients treated with 
natalizumab for progressive multifocal leukoencephalopathy. N Engl J Med 
2006;354:924-33. 
42. 
Miller DH, Khan OA, Sheremata WA, et al. A controlled trial of natalizumab for 
relapsing multiple sclerosis. N Engl J Med 2003;348:15-23. 
43. 
Soler D, Chapman T, Yang LL, Wyant T, Egan R, Fedyk ER. The binding 
specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin 
therapeutic antibody in development for inflammatory bowel diseases. J Pharmacol Exp 
Ther 2009;330:864-75. 
44. 
Spartac Investigators. Short-course antiretroviral therapy in primary HIV infection. 
N Engl J Med 2013;368:207-17. 

Protocol Version 5.0 
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Appendix B: Schedule of Procedures/Evaluations 
 
Screening and Baseline 
ART Phase 
Study Time Point 
Screen 
Apher 
esis 
Base 
line 
Opt. 
Day 
3 
Opt. 
Week 
1 
Week 
2 
Week 
6 
Week 
10 
Apher 
esis 
Week 
14 
Week 
18 
Apher 
esis 
Week 
22 
Week 
24 
Week 
26 
Week 
28 
Week 
30 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Consent  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital Signs  
X 
 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
H & P 
X 
 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
HIV Counseling  
 
 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
PML Checklist 
 
 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Neurologic Exam 
 
 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
MEDICATIONS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Last Dose of 
cART 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
vedolizumab 
Infusion 
 
 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Restart cART 
 
 
 
 
 
 
 
 
 
 
 
 
 
PRN 
PRN 
PRN 
PRN 
PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
EKG 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis 
 
X 
 
 
 
 
 
 
X 
 
 
X 
 
 
 
 
 
CLINICAL LABS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC/Diff 
X 
 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
aPTT/PT 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Acute/Hepatic/ 
/Mineral 
X 
 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy* 
X 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
X 
Anti-HBs, Anti-
HAV, HBsAg, 
Anti-HCV, HCV 
RNA, 
QuantiFERON 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HLA Typing** 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH 
LABS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA 
X 
 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Flow 
Cytometry*** 
X 
 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
Serum storage 
X 
 
X 
X 
X 
 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
Plasma storage 
X 
 
X 
X 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
X 
X 
X 
PBMCs storage 
 
 
 
X 
 
 
X 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
PAXgene RNA 
TWC (Opt.) 
 
 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
Estimated 
Volume per Visit 
61 
 
126 
31 
31 
108 
116 
113 
 
113 
113 
 
113 
30 
113 
30 
113 
 

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Appendix B continued 
 
ATI Phase 
Follow-up Phase 
Study Time Point 
Week 
32 
Week 
34 
Week 
36 
Weeks 
38-48 
Repeat- 
End ATI 
cART 
Start 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24 
ASSESSMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
Consent  
 
 
 
Continue Schedule of Procedures 
 
 
 
 
 
 
 
 
Vital Signs  
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
H & P 
 
X 
 
PRN 
 
X 
X 
X 
X 
X 
X 
HIV Counseling  
 
X 
 
 
 
 
 
 
 
 
 
PML Checklist 
 
 
 
 
 
 
 
 
 
 
 
Neurological 
Evaluation 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
MEDICATIONS 
 
 
 
 
 
 
 
 
 
 
 
Last Dose of 
cART 
 
 
 
 
 
 
 
 
 
 
 
Vedolizumab 
Infusion 
 
 
 
 
 
 
 
 
 
 
 
Restart cART 
PRN 
PRN 
PRN 
PRN 
X 
 
 
 
 
 
 
PROCEDURES 
 
 
 
 
 
 
 
 
 
 
 
EKG 
 
 
 
 
 
 
 
 
 
 
 
Leukapheresis 
 
 
 
 
 
 
 
 
 
 
 
CLINICAL LABS 
 
 
 
 
 
 
 
 
 
 
 
CBC/Diff 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
aPTT/PT 
 
 
 
 
 
 
 
 
 
 
 
Acute/Hepatic/Mi
neral 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
Urinalysis 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy* 
 
X 
 
 
 
 
 
 
 
 
 
Anti-HBs, Anti-
HAV, HBsAg, 
Anti-HCV, HCV 
RNA 
 
 
 
 
 
 
 
 
 
 
 
RESEARCH 
LABS 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA 
X 
X 
X 
PRN 
 
X 
X 
X 
X 
X 
X 
Flow 
Cytometry** 
X 
X 
X 
PRN 
 
X 
X 
X 
X 
X 
X 
Serum storage 
(Opt) 
 
 
X 
 
 
 
 
 
 
 
 
Plasma storage 
X 
X 
X 
PRN 
 
X 
X 
X 
X 
X 
X 
PBMCs storage 
 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
Estimated 
Volume Per Visit 
30 
113 
38 
10-PRN 
 
97 
97 
97 
97 
97 
97 
* for women of childbearing potential   
PRN: as needed depending on when subject meets criteria to restart cART 
 ** if not already on file              
***includes CD4+ T cell count 

Protocol Version 5.0 
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Appendix C: PML Checklist 
▪ 
This checklist will be administered at specified visits as outlined in the schedule of 
events in the protocol and ad hoc for patient reported symptoms. 
▪ 
The purpose of this checklist is to identify a definite change in the patient’s 
neurological status from the previous evaluation. 
▪ 
For all positive subjective findings that are identified, the corresponding objective test 
must be performed. All positive subjective findings will be recorded as an adverse 
event. 
▪ 
Subjects with a definite change in neurological status will be referred to a neurologist 
for evaluation. Where possible, the proposed objective tests will be used to confirm a 
change that warrants referral. 
 

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Subjective PML Checklist 
Symptoms 
“Compared to how 
you usually feel, 
have you had a 
significant change 
in any of the 
following?” 
If the answer is 
"Yes", obtain a 
description of the 
symptom(s) with 
examples. 
Applicable 
Objective Test(s): 
Document results on PML 
Objective Checklist 
 
Yes 
No 
 
 
1. Have you been 
experiencing any persistent 
difficulty with your vision 
such as loss of vision or 
double vision?  Have you 
been having trouble with 
reading?   
 
 
 
Test visual fields and ocular 
motility. 
 
2. Have you been 
experiencing any persistent 
difficulty speaking or having 
your speech understood by 
others? 
 
 
 
Casual observation of speech 
output for dysarthria or 
aphasia.  Ask subject to name 
a few objects and repeat a 
multipart phrase. 
3. Have you been 
experiencing any persistent 
weakness in an arm or a 
leg? 
 
 
 
Test for pronator drift (Barré 
maneuver) and/or fixation on 
arm roll.  Assess the ability to 
hop on either foot and foot and 
finger tapping. Test symmetric 
muscle strength. 
4. Have you noticed yourself 
regularly bumping into things 
or having difficulty writing? 
 
 
 
Ask for spontaneous writing 
sample. Observe finger to 
nose, heel to shin, and tandem 
gait. 
5. Have you regularly been 
experiencing difficulty 
understanding others? 
 
 
 
Test subject’s ability to follow 
serial commands (Close your 
eyes; stick out your tongue, 
and touch your left finger to 
your left ear). 
6.  Have you had persistent 
problems with your memory 
or thinking? 
 
 
 
Test subject’s ability to recall 3 
objects over 1 minute with 
distraction and ability to follow 
commands. 
7.  Have you been 
experiencing any persistent 
numbness or other loss of 
sensation? 
 
 
 
Test sensation side to side 
with pinprick. 
 
      

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Objective PML Checklist 
To be completed for subjects with positive subjective finding 
Perform the objective test(s) that correspond to the subjective checklist finding 
 
 
 
 
 
 
 
 
 
Positive 
Symptom(s) 
Applicable Objective Test(s) 
Test Result(s) 
If test result is abnormal, 
briefly describe result 
 
 
Normal  Abnormal  
 
1. Difficulty 
with vision or 
reading 
Test visual fields and ocular 
motility  
 
 
 
2. Difficulty 
with speaking  
Casual observation of speech 
output for dysarthria or aphasia.   
Ask patient to name a few 
objects and repeat a multipart 
phrase. 
 
 
 
3. Weakness in 
an arm or a leg  
Test for pronator drift and/or 
fixation on arm roll.  Assess the 
ability to hop on either foot; foot 
and finger tapping.  Test muscle 
strength. 
 
 
 
4. Bumping 
into things or 
difficulty writing 
Ask for spontaneous written 
sample and observe finger to 
nose, heel to shin, and tandem 
gait 
 
 
 
5. Difficulty 
understanding 
others 
Ability to follow serial commands 
(Close your eyes, stick out your 
tongue, and touch your left finger 
to your left ear) 
 
 
 
6.  Problems 
with memory or 
thinking 
Recall of 3 objects over 1 minute 
with distraction; ability to follow 
commands. 
 
 
 
7. Problems 
with numbness 
Test sensation side to side with 
pinprick.