The Impact of CCR5 Inhibitor Treatment Intensification on CD4+ T-cell Recovery and Gene Expression Profiles in HIV-Infected Patients With Viral Suppression
Phase: PHASE4
Conditions: HIV Infections
Sponsor: University of California, San Diego

 
 
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CCTG 590 & 590s 
 
 
The Impact of CCR5 Inhibitor Treatment Intensification on CD4+ T-cell Recovery 
and Gene Expression Profiles in HIV-Infected Patients with Viral Suppression 
(Main Study) 
 
Maraviroc Pharmacokinetics and Immunomodulatory Effects within the Central 
Nervous System 
(CSF Sub-Study) 
 
Sponsored by: 
 
The California HIV / AIDS Research Program (CHRP)  
 
University of California Center for AIDS Research (CFAR) 
 
 
 
Pharmaceutical Support Provided by: 
 
 
Pfizer Pharmaceuticals  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol Chair: 
 
 
 
Miguel Goicoechea, M.D. 
 
 
 
 
 
 
  
 

 
 
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TABLE OF CONTENTS 
PROTOCOL TEAM ROSTER ........................................................................................... 4 
SCHEMA ............................................................................................................................ 6 
1.0 
STUDY OBJECTIVES ........................................................................................... 7 
1.1 
Primary Objectives.............................................................................................. 7 
1.2 
Secondary Objectives.......................................................................................... 7 
2.0 
INTRODUCTION .................................................................................................. 8 
2.1 
Background (Main study) ................................................................................... 8 
2.2 
Background (CSF Sub-Study) ............................................................................ 9 
2.3 
Rationale (Main Study) ..................................................................................... 12 
2.4  
Rationale (CSF – Sub-Study)............................................................................ 16 
3.0 
STUDY DESIGN.................................................................................................. 17 
3.1 
Study Design (Main Study) .............................................................................. 17 
3.2 
Study Design (CSF Sub-Study) ........................................................................ 18 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS ......................................... 20 
4.1 
Inclusion Criteria (Main Study) ........................................................................ 20 
4.2 
Inclusion Criteria (CSF Sub-Study) .................................................................. 21 
4.3 
Exclusion Criteria (Main Study) ....................................................................... 21 
4.4 
Exclusion Criteria (CSF Sub-Study) ................................................................. 22 
4.5 
Study Enrollment Procedures ........................................................................... 22 
4.6 
Co-enrollment Guidelines ................................................................................. 23 
5.0 
STUDY TREATMENT ........................................................................................ 23 
5.1 
Dosing, Administration, and Duration .............................................................. 23 
5.2 
Product Formulation and Preparation ............................................................... 24 
5.3 
Product Supply, Distribution, and Pharmacy .................................................... 24 
5.4 
Concomitant Medications ................................................................................. 24 
5.5 
Adherence Assessment ..................................................................................... 28 
6.0 
CLINICAL AND LABORATORY EVALUATIONS ......................................... 28 
6.1 
Schedule of Events – Clinical Evaluations ....................................................... 29 
6.2 
Definitions for Schedule of Events – Timing of Evaluations ........................... 31 
6.3 
Special Instructions and Definitions of Evaluations ......................................... 33 
6.4 
Off-Drug Requirements .................................................................................... 39 
7 
TOXICITY MANAGEMENT .............................................................................. 40 
7.1 
Commonly occurring adverse events ................................................................ 40 
8 
CRITERIA FOR TREATMENT DISCONTINUATION .................................... 43 
8.1 
Criteria for Treatment Discontinuation ............................................................. 43 
8.2 
Criteria for Discontinuation from the Study ..................................................... 43 
9.0 
STATISTICAL CONSIDERATIONS.................................................................. 44 
9.1 
General Design Issues ....................................................................................... 44 
9.2 
Endpoints .......................................................................................................... 44 
9.3 
Sample Size and Accrual .................................................................................. 44 
9.4 
Methods of Analysis ......................................................................................... 45 
9.5 
Monitoring ........................................................................................................ 48 
10.0 
DATA COLLECTION AND MONITORING AND ADVERSE EXPERIENCE 
REPORTING .................................................................................................................... 48 

 
 
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10.1 
Records to Be Kept ........................................................................................... 49 
10.2 
Role of Data Management ................................................................................ 49 
10.3 
Clinical Site Monitoring and Record Availability ............................................ 49 
10.4 
Serious Adverse Experience (SAE) Reporting ................................................. 49 
11.0 
HUMAN SUBJECTS ........................................................................................... 49 
11.1 
Institutional Review Board (IRB) Review and Informed Consent ................... 50 
11.2 
Subject Confidentiality ..................................................................................... 50 
11.3 
Study Discontinuation ....................................................................................... 50 
12.0 
PUBLICATION OF RESEARCH FINDINGS .................................................... 50 
13.0 
BIOHAZARD CONTAINMENT ......................................................................... 50 
14.0 
REFERENCES ..................................................................................................... 50 
 

 
 
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PROTOCOL TEAM ROSTER 
 
Chair 
 
Miguel Goicoechea, M.D. 
Assistant Professor of Medicine 
University of California, San Diego 
150 West Washington Street, 100 
San Diego, CA 92103 
Phone: (619) 543-8080 
Fax:   (619) 298-0177 
E-mail: mgoicoechea@ucsd.edu  
 
Co-Vice Chairs 
 
Richard Haubrich, M.D. 
Professor of Medicine 
University of California, San Diego 
150 West Washington Street, 100 
San Diego, CA  92103 
Phone:  (619) 543-8080 
Fax:   (619) 298-0177 
E-mail: rhaubrich@ucsd.edu 
 
Christopher Woelk, Ph.D. 
Assistant Research Scientist 
Associate Professor of Medicine 
University of California, San Diego 
Veterans Administration San Diego 
Healthcare System 
San Diego, CA 
Phone: (858) 552-8585 x7193 
E-mail: cwoelk@ucsd.edu 
 
Co-Investigators 
 
Davey Smith, M.D., M.A.S. 
Assistant Professor of Medicine 
University of California, San Diego 
150 West Washington Street, 100 
San Diego, CA  92103 
Phone:  (619) 543-8080 
Fax:   (619) 298-0177 
E-mail: davey@ucsd.edu 
 
 
Celsa Spina, Ph.D. 
Associate Professor of Medicine 
University of California, San Diego 
Veterans Administration San Diego 
Healthcare System 
San Diego, CA 
Phone: (858) 552-8585 x7189 
E-mail: cspina@ucsd.edu 
 
Eric Daar, M.D. 
Chief, Division of HIV Medicine 
Harbor-UCLA Medical Center 
Professor of Medicine 
David Geffen School of Medicine at 
UCLA 
1124 W. Carson St., N-24 
Torrance, CA 90502 
Phone: (310) 222-2467 
Fax: 
(310) 533-0447 
E-mail:EDaar@LABioMed.org 
 
CSF Sub-Study Co-Chair 
 
Scott Letendre, M.D. 
Associate Professor of Medicine 
University of California, San Diego 
150 West Washington Street, 100 
San Diego, CA  92103 
Phone:  (619) 543-8080 
Fax:   (619) 298-0177 
E-mail: sletendre@ucsd.edu 
 
Statistician  
 
Sonia Jain, Ph.D. 
Assistant Professor 
Division of Biostatistics & 
Bioinformatics 
University of California, San Diego 
9500 Gilman Drive, MC 0717 
La Jolla, CA 92093-0717 
Phone: (858) 822-2388 

 
 
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Fax: (858) 822-0617 
E-mail:  sojain@ucsd.edu 
 
Ronald G. Thomas, Ph.D. 
Professor and Chief Division of 
Biostatistics and Bioinformatics  
Director of the Biostatistics and 
Bioinformatics Laboratory 
University of California, San Diego 
9500 Gilman Drive, MC 0645 
La Jolla, CA 92093-0645 
Phone: (858) 822-3508 
Fax: (858) 822-5290 
E-mail:  rgthomas@ucsd.edu 
 
Industry Representatives 
 
John Andrews, M.D. 
Director, Regional Medical and 
Research Specialist  
HIV Medical Team 
Pfizer Inc.  
1223 Via Barranca  
La Jolla,CA 92037  
Phone: 858-775-1976 
E-mail: John.S.Andrews@pfizer.com 
 
Protocol Data Center 
 
Fang Wan 
CCTG Data and Biostatistical Unit 
150 West Washington, Suite 100 
San Diego, CA 92103-8208 
(619) 543-8080 
(619) 298-1379 FAX 
 
TBA  
Protocol Coordinator/Monitor 
CCTG Data and Biostatistical Unit  
150 West Washington, Suite 100  
San Diego, CA 92103-8208 
Phone: (619) 543-8080   
Fax: (619) 298-1379  

 
 
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SCHEMA 
 
The Impact of CCR5 Inhibitor Treatment Intensification on CD4+ T-cell Recovery 
and Gene Expression Profiles in HIV-Infected Patients with Viral Suppression  
(Main Study) 
 
Maraviroc Pharmacokinetics and Immunomodulatory Effects within the Central 
Nervous System 
(CSF Sub-Study) 
 
Design: 
 
 
CCTG 590 is a single-arm, open-label study to evaluate the impact of therapy 
intensification of Maraviroc (MVC) (a CCR5 inhibitor) to a stable suppressive 
HIV antiretroviral regimen on the rate of CD4+ T-cell recovery and gene 
expression profiles. Subjects on a stable first-line HIV regimen with continued 
viral suppression and sub-optimal CD4+ T-cell counts will be eligible for this 
study. Those who are found to be eligible will have MVC (dose-adjusted to 
background HIV regimen) added to their current HIV regimen for 24 weeks. 
After the 24 week intensification, the MVC will be discontinued, the original 
antiretroviral regimen will be continued and the subjects will be followed for an 
additional 12 weeks. 
 
CCTG 590s is a central nervous system (CNS) sub-study that will evaluate MVC 
cerebral spinal fluid (CSF) pharmacokinetics and immunomodulatory effects 
within the CNS. The primary eligibility criteria will be enrollment into the MVC 
parent study, ability to give informed consent to lumbar puncture (LPs). Pre-
treatment LPs will be performed, followed by a LP at week 4 of MVC treatment 
intensification (i.e., “steady state”). For subjects willing to undergo more than one 
LP, an additional LP will be performed at week 24 of MVC treatment 
intensification.  
 
Duration: 
 
 
Total study duration is 36 weeks: 24 weeks of MVC treatment intensification, 
followed by an additional 12 weeks of continued monitoring on baseline antiviral 
therapy without MVC.    
 
Sample Size: 30 subjects (17 subjects for the CSF Sub-Study) 
 
Study Population: 
 
HIV-infected patients receiving an initial stable antiretroviral regimen with 12 
months or more of viral suppression (defined by HIV RNA below detection 
limits) will be offered enrollment into this study. Eligible patients must have 

 
 
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documented dates of initiation of first HIV regimen and have been on continuous 
treatment for at least 15 months. In addition, available laboratory data must 
include at least 3 measurements of CD4 count and plasma HIV RNA loads 
obtained within the 12 months prior to screening. 
 
Regimen: 
 
Maraviroc treatment intensification will be provided to all subjects dose-adjusted 
to each participant’s background antiretroviral therapy: 
 
A. with strong CYP3A4 inhibitors, including: 
• 
Protease inhibitors (except tipranavir/ ritonavir) 
• 
Delavirdine 
• 
ketoconazole, itraconazole, clarithromycin, nefazadone, 
telithromycin 
• 
Darunavir/r + etravirine 
 
MVC 150 mg twice daily 
  
B. with non-inducers/ non-inhibitors of CYP3A4, including: 
• 
Tipranavir/ ritonavir 
• 
Nevirapine 
• 
All NRTIs 
• 
Enfuvirtide 
 
MVC 300 mg twice daily 
 
C. with strong CYP3A4 inducers, including: 
• 
Efavirenz, etravirine 
• 
rifampin  
 
MVC 600 mg twice daily 
 
1.0 
STUDY OBJECTIVES 
 
1.1 
Primary Objectives 
 
1.1.1 To characterize changes in gene expression profiles associated with early 
(week 4) and late (week 24) MVC therapy intensification. 
 
1.1.2 To evaluate the association of gene expression profiles induced by MVC 
on the rate of CD4+ T-cell recovery during MVC therapy intensification.  
 
1.2 
Secondary Objectives 
 

 
 
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1.2.1 To compare the rates of phase 2 CD4+ T-cell recovery prior to and during 
24 weeks of MVC therapy intensification. 
  
1.2.2 To evaluate the impact of MVC therapy intensification on persistent 
immune activation and maturation phenotype (as measured by flow 
cytometry) during viral suppression.  
 
1.2.3 To characterize differences in the gene expression profiles associated with 
MVC therapy intensification in individuals receiving a PI/r- vs. NNRTI-
based regimen. 
 
1.2.4 To evaluate the safety and tolerability of adding MVC to a stable 
antiretroviral regimen as assessed by the rate of > grade 2 adverse clinical 
or laboratory events. 
 
1.2.5 To characterize cerebral spinal fluid concentrations of MVC compared to 
plasma concentrations.  
 
1.2.6 To evaluate the impact of MVC therapy intensification on persistent 
immune activation (as measured by soluble and cellular markers) in the 
central nervous system. 
 
2.0 
INTRODUCTION 
 
2.1 
Background (Main study) 
 
Suboptimal CD4+ T-cell recovery during potent antiretroviral therapy (ART) is a 
common clinical dilemma with an incidence as high as 40% [1-4].  Reconstitution 
of CD4+ T-cells during viral suppression follows a biphasic pattern [5].  In the 
first three months of ART, CD4+ T-cells typically increase by 50 to 120 
cells/mm3 [6-8] - primarily as a result of redistribution of T-cells into peripheral 
circulation [9, 10]. The magnitude of this early recovery is likely a function of 
prior T-cell destruction as lower CD4+ T-cell nadirs have been associated with 
limited immune recovery during therapy [2, 11].  This initial burst is followed by 
a second, slower, phase of T-cell repopulation (average rate of 2 to 10 cell/mm3 
increase per month [6-8, 12]) which may continue for as long as 6 years [13]. This 
second phase is often termed the ‘regenerative phase’ as de novo T-cells are 
produced from the thymus and by peripheral expansion. However, in some 
individuals, the phase 2 CD4+ T-cell recovery plateaus and these patients fail to 
recover ‘normal range’ T-cells despite optimal viral suppression [3, 13].  
 
 
We propose to evaluate the potential beneficial immunomodulatory-effects of 
MVC on CD4+ T-cell recovery during optimal viral suppression.  Individuals 
with well-controlled HIV-infection on ART will undergo therapy intensification 
with MVC for 6 months followed by a 3 month post-intensification visit. The 
goals of this study include:   

 
 
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1. To determine the impact of MVC treatment intensification on host genomic 
responses. Whole genome (~38,000 genes) analysis on purified CD4+/CD8+ 
lymphocytes will be used to evaluate changes in gene expression patterns, in 
particular genes associated with proliferation, trafficking and activation, 
before and during MVC treatment intensification. 
 
2. To evaluate differences in the rate of phase 2 CD4+ T-cell recovery before 
and during 6 months of MVC treatment intensification. 
  
3. To characterize changes in immune T-cell subsets (activation, maturation and 
apoptosis) before and during MVC treatment intensification. 
 
4. To develop a gene classifier of MVC treatment-responsive genes and propose 
a model of the impact of CCR5-inhibition on immune reconstitution during 
suppressive ART. 
 
2.2 
Background (CSF Sub-Study) 
 
The central nervous system (CNS) is a frequent site of HIV replication [14] and 
HIV-induced neuronal injury leading to a spectrum of cognitive disorders, 
ranging from aymptomatic neuropsychological impairment to severe HIV-
associated neurocognitive disorders (HAND) [15, 16]. While the incidence of 
HAND has declined in the potent antiretroviral (ARV) era, minor neurocognitive 
disorders (MND) remains a significant source of morbidity among treated HIV-
individuals with a prevalence as high as 50% [17]. HIV neuropathology during 
ARV therapy may result from at least two interdependent mechanisms. First, 
persistent HIV replication in the CNS has been associated with neurocognitive 
syndromes in cross-sectional studies [3, 4] and predicts their future development 
in longitudinal studies [18]. Although ARV therapy reduces HIV replication in 
both the plasma and CSF in early-stage HIV disease, the rate of HIV decline in 
CSF is slower than in plasma among individuals with advanced HIV disease and 
may lead to on-going neuronal injury. Second, HIV infection of perivascular 
macrophages and microglia results in cellular activation of these cells. This 
inflammatory response within the CNS is thought to be an important mediator of 
indirect damage of uninfected neuronal cells leading to the neurodegeneration 
observed in HAND [19] and may persist even after HIV replication is suppressed 
[20]. 
 
In this sub-study we propose to evaluate the pharmacokinetics and therapeutic 
effects of MVC within the CNS among subjects with sub-optimal CD4 recovery 
despite plasma viral suppression. Paired plasma-CSF measures of MVC 
concentrations, HIV RNA and markers of immune activation will be obtained pre- 
and weeks 4 and 24 of MVC-treatment intensification. 
 
2.2.1 Maraviroc 

 
 
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Maraviroc selectively binds to the human chemokine receptor CCR5 present on 
the cell membrane, preventing the interaction of HIV-1 gp120 and CCR5 
necessary for CCR5-tropic HIV-1 to enter cells [21]. CXCR4-tropic and dual-
tropic HIV-1 entry is not inhibited by MVC. 
 
2.1.1.1 Safety and Tolerability 
 
The safety profile of MVC is primarily based on 840 HIV-infected subjects who 
received at least one dose of MVC during two Phase 3 trials (MOTIVATE 1 and 
MOTIVATE 2) [22]. Treatment-experienced, triple-class drug resistant subjects 
with R5 tropic virus only and plasma viral loads above 5000 copies/mL were 
randomized in a 1:2:2 fashion to placebo, MVC once-daily or MVC twice-daily 
plus optimized background therapy (OBT) for 48 weeks. The most common 
adverse events reported with frequency rates higher than placebo, regardless of 
causality, were cough, pyrexia, upper respiratory tract infections, rash, 
musculoskeletal symptoms, abdominal pain and dizziness. Additional adverse 
events that occurred were diarrhea, edema, influenza, esophageal candidiasis, 
sleep disorders, rhinitis, parasomnias, and urinary abnormalities. In both studies, 
the rates of discontinuation due to adverse events were 4.9% in subjects receiving 
MVC twice daily + optimized background therapy (OBT) compared to 5.3% in 
those receiving OBT + placebo. Most of the adverse events reported were judged 
to be mild to moderate in severity.  
 
Specific potential adverse events associated with MVC have been included in the 
package insert as a warning and precaution for use [23]. And these include:  
 
Hepatotoxicity Events:  One case of possible MVC-induced hepatotoxicity with 
allergic features has been reported in a study of healthy volunteers. Although an 
increase in hepatic adverse events was observed during studies of treatment-
experienced subjects with HIV infection, there was no overall increase in ACTG 
Grade 3/4 liver function test abnormalities. In pooled analysis of A4001027 and 
A4001028 the percent of subjects experiencing grade 3/4 laboratory abnormalities 
(without regard to baseline values) receiving MVC (N=421) were similar to those 
that received placebo (N=207) in addition to OBT, including: AST 5xULN: 4.5% 
vs. 2.9%; ALT 5xULN: 2.4% vs. 3.4%; and Total Bili: 5.7% vs. 5.3%. 
 
Cardiovascular Events:  When MVC was administered to healthy volunteers at 
doses higher than the recommended dose, symptomatic postural hypotension was 
seen at a greater frequency than in placebo. At lower doses used in HIV subjects 
in Phase 3 studies, postural hypotension was seen at a rate similar to placebo 
(approximately 0.5%). However, eleven HIV subjects (1.3%) who received MVC 
had cardiovascular events including myocardial ischemia and/or infarction during 
the Phase 3 studies (total exposure 267 patient-years), while no subjects who 
received placebo had such events (total exposure 99 patient-years). These subjects 
generally had cardiac disease or cardiac risk 

 
 
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factors prior to MVC use, and the relative contribution of MV to these events is 
not known. 
 
Potential Risk of Infection:  Maraviroc antagonizes the CCR5 co-receptor located 
on some immune cells, and therefore could potentially increase the risk of 
developing infections. The overall incidence and severity of infection, as well as 
AIDS-defining category C infections, was comparable in the treatment groups 
during the Phase 3 studies. While there was a higher rate of certain upper 
respiratory tract infections reported in the MVC arm compared to placebo (20.0% 
versus 11.5%), there was a lower rate of pneumonia (2.1 % vs. 4.8%). In addition, 
a higher incidence of Herpes virus infections (11.4 per 100 patient-years) was also 
reported in the MVC arm when adjusted for exposure compared to placebo (8.2 
per 100 patient-years).  
 
Potential Risk of Malignancy:  Blockade of the CCR5 inhibitor by MVC 
represents a theoretical risk for decreased immune surveillance and potential 
increased risk of malignancy. However, no increase in malignancy has been 
observed with MVC. 
 
 
2.2.1.2  
Drug Interactions and Special Populations 
 
In vitro studies demonstrated that MVC is principally metabolized by the 
cytochrome P450 CYP3A and to a lesser extent CYP2C9. As a substrate of 
CYP3A and P-gp MVC pharmacokinetics are modulated by inhibitors and 
inducers of these enzymes/transporters and a dose adjustments are required when 
co-administered with those drugs (see section 5.4 Concomitant Medications). 
 
Pregnancy:  There are no adequate and well-controlled studies in pregnant 
women. The incidence of fetal variations and malformations was not increased in 
embryofetal toxicity studies in rats at exposures (AUC) approximately 20-fold 
higher and in rabbits at approximately 5-fold higher than human exposures at the 
recommended daily dose. Maraviroc is a Category B drug for pregnancy (see 
section 4.0 Selection and Enrollment of Subjects). 
 
Renal Impairment:  The safety and efficacy of MVC have not been specifically 
studied in patients with renal impairment. In the absence of metabolic inhibitors, 
renal clearance accounts for approximately 25% of total clearance of MVC. 
Patients with a creatinine clearance of less than 50 mL/min who receive MVC and 
a CYP3A inhibitor may be at an increased risk of adverse effects related to 
increased MVC concentrations, such as dizziness and postural hypotension; these 
subjects will be excluded (see section 4.0 Selection and Enrollment of Subjects). 
 
Hepatic Impairment:  The pharmacokinetics of MVC has not been sufficiently 
studied in patients with hepatic impairment. Because MVC is metabolized by the 
liver, concentrations are likely to be increased in these patients (see section 4.0 
Selection and Enrollment of Subjects). 

 
 
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2.2.1.2  
Impact on CD4 Recovery 
 
There are no study results demonstrating the effect of MVC on clinical 
progression of HIV-1. However, the peripheral CD4 count is an accepted 
prognostic marker for HIV-related morbidity and mortality both among untreated 
and treated patients with viral suppression [24].  Interestingly, the use of CCR5 
antagonists may increase CD4 recovery independent of their effect on viral 
replication. 
 
The Merit study was a phase 3, prospective study of MVC in antiretroviral-naïve 
patients with R5 virus [25]. Subjects were randomized to either efavirenz (EFV) 
600mg once daily (n=361) or MVC 300mg twice-daily (n=360) in combination 
zidovudine/ lamivudine for 48 weeks. Baseline characteristics were similar 
between the EFV and MVC treatment groups (median CD4:  254 vs. 241 
cells/mL; median HIV RNA: 4.88 vs. 4.86 log10 copies/mL). Despite a greater 
proportion of subjects in the EFV arm achieving viral suppression at 48 weeks 
(HIV RNA < 50 copies/mL: 69% vs. 64.4%), those receiving MVC experienced 
significantly greater CD4 recovery than the EFV group (mean CD4 gain: 169 vs. 
142 cells/mm3).  
 
The potential independent benefit in CD4 recovery with MVC has also been 
observed in treatment experienced patients with ongoing viral replication.  Study 
A4001029 was prospective study in treatment-experienced with non-R5 tropic 
virus (i.e. X4, dual/mix or indeterminate) and plasma viral loads above 5000 
copies/mL that were randomized to placebo, MVC once-daily or MRV twice-
daily plus optimized background therapy (OBT) for 48 weeks [26]. In a planned 
interim analysis at week 24, a similar decrease in viral load was observed in all 3 
treatment groups. However, even among subjects with dual or mixed tropic virus 
as baseline those receiving MVC twice-daily (N=52) had significantly greater 
CD4 recovery than the placebo arm (N=54) at week 24 (change in CD4: +62.4 vs. 
+35.7 cells/mL; P<0.05). 
 
These results are consistent with a recent meta-analysis that evaluated difference 
in CD4 recovery during viral suppression among recent Phase 2 and Phase 3 HIV 
trials of new HIV agents [27]. This analysis included 37 treatment arms from 16 
clinical trials, including the above mentioned trials and two additional trials with a 
different CCR5 inhibitor, vicroviroc. In analyses that adjusted for baseline HIV 
RNA and degree of viral suppression, the use of a CCR5 inhibitor was associated 
with a greater CD4 count increase (mean difference: +32 cells/mm3) after 24 
weeks of treatment compared to non-CCR5-containing regimens. Together, these 
data suggest a favorable, independent effect of MVC on CD4 recovery during 
viral suppressive therapy with ART and that MVC is safe in subjects with 
CXCR4 or dual/mixed tropic HIV isolates.  
 
2.3 
Rationale (Main Study) 

 
 
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Blunted CD4+ T-cell responses during viral control may be a consequence of on-
going T-cell destruction in the regenerative phase of CD4 recovery from 
activation-induced apoptosis [4, 28] and/or reduced production from decreased 
thymic output [29, 30].  Occult HIV replication may contribute to both processes. 
R5 HIV envelop glycoprotein (gp) 120 interacts with CCR5 receptors which 
induce a distinct gene expression profile of numerous activation and transcription 
factors, including; nuclear factor of activated T-cells (NFAT), NF-kB and 
mitogen-activated protein kinase (MAPK)-related genes [31]. This receptor 
interaction by gp120 likely creates a replication permissive state in the cell and 
promotes viral replication from quiescent naïve T-cells with very low CCR5 
expression. Further, R5 envelope protein engagement of CCR5 also induces 
caspase gene activity [31] and may consequently increase T-cell apoptosis rates of 
uninfected cells in the peripheral circulation as well as within the thymus itself.  
 
CCR5 inhibitors can improve the clinical status of HIV-infected by two distinct 
mechanisms. First, by blocking HIV entry into CD4+ T-cells, CCR5 inhibitors 
have direct antiviral activity. Second, as the pro-inflammatory state of HIV 
infection up-regulates CCR5 ligands and receptors [32], these receptor antagonists 
may abrogate immune activation and resultant T-cell apoptosis. Importantly, 
MVC binds CCR5 receptors without inducing intracellular signaling or altering 
cell-surface expression [21].  Potentially, MVC intensification during viral 
suppression with ART may further decrease persistent activation-induced 
apoptosis and improve repair and remodeling of lymphoid tissue leading to 
increased CD4+ T-cell recovery and function.   
 
It is well-recognized that the chemosensitivity and prognosis of some cancers is 
correlated with specific gene-expression profiles [33, 34], however, our 
understanding of host gene interactions with HIV during antiretroviral therapy 
and the impact on CD4+ T-cell recovery is at an early stage.  Li et al. performed 
functional genomic analysis to identify treatment-responsive genes in HIV-
infected patients initiating ART [35]. Genomic chip arrays were used to screen 
approximately 12,000 human genes of which ~ 200 genes’ expression appeared to 
be modified in response to HIV therapy. Genes involved in T-cell apoptosis, 
immune activation and some chemokines and cognate receptors (i.e. CCR5, MIP-
1β, RANTES and others) were down-regulated, while genes involved in tissue 
repair and remodeling were up-regulated.  
 
Based upon the biology of CCR5 and its role in HIV infection [36] and ART-
responsive gene expression profiles observed by Li et al. [35], we have selected 
candidate genes involved in immune function whose expression may be further 
altered during CCR5 intensification. We hypothesize that expression will decrease 
among genes involved in immune activation (NF-kB, MAPK, nuclear factor of 
activated T-cells, MYD88 and STAT1), apoptosis (Fas ligand and TRAIL) and 
trafficking/repopulation of T-cells (CCR5, MIP-1α, MIP-1β and RANTES) and 
increase among genes involved in tissue repair (platelet-derived growth factor, 

 
 
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insulin-like growth proteins and osteoblast-specific transcription factor) (Figure 
1).  
 
 
Figure 1. Model of gene expression due to anti-inflammatory affects of 
Maraviroc in combination with suppressive antiretroviral therapy 
 
Immune Activation
NF-kB, MAPK
NFAT
MYD88
STAT1
Apoptosis
Fas ligand
TRAIL
Tissue Repair
Platelet-derived 
growth factor
Insulin-like growth 
factor proteins
Osteoblast-specific 
transcription factor 2
Trafficking/ Repopulation
CCR5
MIP-1a
MIP-1ß
RANTES
 
 
Chemokine receptors and their ligands are both redundant and pleiotropic in 
function and may have a varied spectrum of biologic activities in vivo which may 
not be represented by a small set of selected gene candidates. Further gene 
expression profiles of peripheral blood mononuclear cells differ from T-
lymphocyte subsets [37]. Therefore, whole genome expression (38,000 genes) 
will initially be done on purified CD4+/CD8+ T-cells at baseline, week 4 and at 
week 24 of MVC intensification.  
 
Use of MVC is indicated in combination with other antiretroviral agents for 
treatment-experienced adult patients infected with detectable CCR5-tropic HIV-1 
virus and evidence of multi-drug resistant virus.  The manufactures of MVC 
recommend that the following points should be considered when initiating therapy 
with MVC: 
 
• Consider baseline tropism testing. 
 
• Avoid in patients with dual/mixed or CXCR4-tropic HIV-1 as antiviral 
efficacy was not demonstrated in a phase 2 study of this patient group. 
 
• The safety and efficacy have not been established in treatment-naïve 
adult patients or pediatric patients. [although trials of MVC in naïve 
patients have shown comparable (though not strictly non-inferior) 
virologic efficacy to and EFV-containing regimen in this population] 
 
The current study proposes to use MVC for treatment-experienced patients with 
on-going viral suppression and without evidence of multi-drug resistant virus. 
Since the patients will have undetectable HIV RNA levels, baseline tropism 

 
 
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testing is not possible. The use of MVC in this patient population should be safe 
and offers potential therapeutic benefit for the following reasons: 
 
First, in phase 3 studies, treatment failure on MVC was associated with detection 
of CXCR4-using (i.e., CXCR4- or dual/mixed-tropic) [23]. This CXCR4-using 
HIV virus could have appeared in two ways: 1. due to de novo mutations in viral 
envelope or 2. due to emergence of pre-existing, low frequency variants that were 
not detected on baseline tropism testing.  In both scenarios, as consistent with 
development of drug resistance with other HIV medications, MVC-associated 
drug resistance emerged in the setting of on-going HIV replication (i.e. detectable 
plasma HIV loads). An important difference in the treatment population of this 
study is that subjects would have already initiated ARV therapy and achieved 
viral suppression for at least 12 months prior to study enrollment. In the setting of 
on-going viral suppression it is very unlikely that CXCR4 tropic virus will be 
selected during the 24 weeks of MVC treatment intensification. 
 
Second, the clinical and laboratory safety and tolerance of MVC is comparable to 
standard therapy in both treatment-experienced [26] and treatment-naïve patients 
[25]. Among treatment-naïve patients, the rate of discontinuation due to adverse 
events was less in the MVC arm (4.2%) than among efavirenz-treated subjects 
(13.6%) [25].  
 
Finally, suboptimal CD4+ T-cell recovery during ART is a common clinical 
dilemma and may affect as much as 40% of viral suppressed patients [4].This 
suboptimal CD4+ T-cell response during therapy, or immunologic discordance, 
can have detrimental clinical consequences [38], including an increased rate of 
HIV associated infections, malignancies, and cardiovascular morbidity/mortality. 
In contrast, mortality rates for HIV-infected individuals during the ear of potent 
HAART (2004 to 2006) have life expectancy rates comparable to matched HIV-
negative controls within the first 5 years of seroconversion [39]. 
 
The aim of this study is to evaluate a potentially therapeutic immunomodulatory 
effect of MVC. Several measures of immune homeostasis will be determined in 
this study, including functional genomic analysis and extended T-cell 
phenotyping. Genes responsive to MVC therapy will be identified and categorized 
into functional groups. Based upon existing literature of the identified genes and 
observed immune responses (change in CD4/CD8 subsets) during MVC therapy, 
a model of CCR5 responsive-genes and potential impact on immune recovery will 
be outlined. Potentially, individuals experiencing immune discordance during 
suppressive ART may be better treated by MVC antiretroviral intensification. 
 
2.3.1. Hypotheses 
 
1. We hypothesize that expression will decrease among genes involved in 
immune activation (NF-kB, MAPK, nuclear factor of activated T-cells, 
MYD88 and STAT1), apoptosis (Fas ligand and TRAIL) and 

 
 
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trafficking/repopulation of T-cells (CCR5, MIP-1α, MIP-1β and RANTES) 
and increase among genes involved in tissue repair (platelet-derived growth 
factor, insulin-like growth proteins and osteoblast-specific transcription 
factor). 
 
 
a. The gene expression profiles induced by MVC will be associated with a 
favorable increase in the rate of CD4+ T-cell recovery.  
 
 
b. The rate of CD4 recovery (cells/month) will be greater during MVC 
compared to before.  
 
c. The proportion of cells expressing activation/ apoptosis markers will 
decrease from baseline and this decrease will be associated with improved 
CD4 recovery. 
 
d. The proportion of naïve cells will increase from baseline and this increase 
will be associated with improved CD4 recovery. 
 
e. The rate of CD4 recovery will be greater among those subjects receiving  
PI-containing treatment regimens compared to those reciving NNRTI-
containing treatment regimen. 
 
2.4  
Rationale (CSF – Sub-Study) 
 
HIV replication in the CNS primarily originates from brain macrophages or 
microglia [40]. Considering those HIV strains that infect macrophages primarily 
utilize CCR5 (R5 virus) [41], it is not surprising that most HIV strains isolated 
from individuals with HAD have been R5 tropic [42, 43]. However, paired 
plasma-CSF samplings from neurologically-asymptomatic HIV-infected 
individuals across a range of CD4 counts also demonstrate R5 virus, suggesting 
R5-tropic virus is the predominant stain in the CNS [44]. Potentially, co-receptor 
utilization may actually mediate neuronal injury. HIV-1 R5 strains isolated from 
AIDS patients with HAD were highly fusogenic and demonstrated enhanced 
macrophage tropism despite low of CD4 and CCR5 expression [42, 43]. Although 
these strains showed reduced sensitivity to anti-CD4-antibodies, the CCR5 
inhibitor (TAK-779) appeared to be equally effective as with plasma isolates. 
 
Although markers of immune activation decrease during treated HIV infection, 
levels can remain abnormally high even after several years of HIV suppression 
within the plasma and CSF compartments [45, 46]. One explanation is that an 
inflammatory response, once established, gives rise to a self-sustaining state of 
macrophage and microglia activation [19]. Activated macrophages produce pro-
inflammatory cytokines that both propagate activation-induced apoptosis of 
uninfected cells and increase blood-brain-barrier (BBB) permeability resulting in 
enhanced migration of activated T-cells into the CNS. Potentially, the ‘motor’ for 
neurodegeneration continues after suppression of HIV replication and it is 

 
 
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unknown if MCMD, or other mild HIV cognitive disorders will progress despite 
potent ARV therapy.  In a recent report, the neuropsychological performance of 
60% of individuals who had HAND did not normalize despite suppressive HIV 
therapy [47].  
 
Better penetration of ARVs into the CNS (brain and CSF) is associated with 
improved neuropsychological performance [8, 9]. Some indirect evidence 
suggests MVC may achieve therapeutic concentrations in the CNS.  In a pilot-
study of HIV uninfected women (n=12), MVC 300 mg twice-daily for 7 days 
achieved exposure levels in cervicovaginal fluid and vaginal tissue comparable or 
exceeding plasma concentrations [48], suggesting MVC is able to penetrate 
pharmacokinetic sanctuary sites. In addition, MVC is a substrate for P-
glycoprotein (Pgp). Co-administration of ritonavir, a P-gp inhibitor, increased 
CSF exposure of indinavir by inhibition of P-gp-mediated efflux across the BBB 
[49, 50]. Potentially, co-administration of a ritonavir-boosted protease-inhibitor 
(PI/r) will enhance the CNS penetration of MVC.  
 
2.4.1  Hypotheses 
 
1. Maraviroc (MVC) concentrations in CSF will approximate 24% of the plasma 
Cmin and will vary across the dosing interval.  
 
 
a. Subjects receiving background HIV therapy containing a PI/r will achieve 
higher CSF MVC concentrations than those receiving not receiving a PI/r 
 
2. MVC treatment-intensification will decrease immune activation (activated T- 
cells and pro-inflammatory cytokines) in the CSF. 
 
3. Among subjects with CSF viral replication above 2 copies/mL at baseline, all 
will be suppressed below 2 copies/mL after 4 weeks of MVC treatment-
intensification. 
 
3.0 
STUDY DESIGN 
 
3.1 
Study Design (Main Study) 
 
Thirty patients will be enrolled to evaluate the impact of adding the CCR5 
inhibitor, MVC, to a stable suppressive HIV regimen on the rate of CD4+ T-cell 
recovery and gene expression profiles. At baseline whole genome expression 
(38,000 genes) profiles and extended flow cytometry will be performed on 
purified CD4+/CD8+ T-cells in all subjects. In addition, pre-MVC phase 2 CD4+ 
T-cell recovery rate will be estimated for each subject from historic laboratory 
data obtained during the 12 months prior to the baseline visit. All subjects will 
receive treatment intensification with MVC dose-adjusted to their background 
HIV regimen for 24 weeks. Regular visits will occur on weeks 2, 4, 8, 12 and 24 
to assess efficacy, safety and medication tolerance. Additional microarray and 

 
 
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extended flow cytometric analyses will be performed at weeks 4 and 24 of MVC 
therapy. After 24 weeks of MVC treatment intensification, MVC will be 
discontinued, the original antiretroviral regimen will be maintained and subjects 
will return for a 12 week follow-up visit to evaluate on-going CD4+ T-cell 
recovery, continued HIV RNA suppression and any potential adverse events.  
 
3.2 
Study Design (CSF Sub-Study) 
 
 
This is a sub-study of the MVC treatment-intensification protocol (i.e., a 
“piggyback” protocol). The primary eligibility criteria will be enrollment into the 
MVC parent study, ability to give informed consent to lumbar puncture (LPs), and 
the absence of medications or conditions that would contraindicate lumbar 
puncture (e.g., coagulopathy). Pre-treatment LPs will be performed, followed by a 
LP at week 4 of MVC treatment intensification (i.e., “steady state”). All LPs will 
be performed within one hour of a parent protocol-dictated blood draw, reducing 
the need for separate visits or additional phlebotomy. For subjects willing to 
undergo more than one LP, an additional LP will be performed at week 24 of 
MVC treatment intensification. The primary study outcomes will be measurement 
of MVC concentrations and reductions in markers of immune activation levels in 
CSF at week 4.  
 
The study will aim to obtain 3 LPs in as many subjects as possible with the goal 
being at least two LPs separated by at least 4 weeks in up to 17 participants. After 
informed consent is obtained, subjects will undergo a brief screening to ensure the 
absence of contraindications to LP. If eligible subjects choose to enroll, 
subsequent visits will occur at major visits of the parent protocol (baseline, week 
4 and 24). Based on prior experience we conservatively estimate that 
approximately 60% of subjects in the parent protocol will be willing to consent to 
lumbar puncture an average of 2.5 LPs per consenting subject. In total, we 
estimate that this CSF sub-study will yield approximately 43 LPs from individuals 
taking MVC. Post-dose timing of the lumbar punctures will be limited by the 
parent protocols but we will strive to vary the post-dose lumbar puncture interval 
in order to have approximately equal representation from two intervals.  
 
• 
Interval 1: 
2 - 6 hours post dose  
• 
Interval 2: 
6 - 12 hours post dose  
 
If successful, this variation across the dosing interval will improve the accuracy of 
population pharmacokinetic modeling. 
 
3.3 
PBMC isolation 
 
Viable PBMCs will be collected at pre-entry, baseline (day 0), weeks 4 and 24.  
 
3.4 
Flow Cytometry for CD4 and CD8 T-cells  
 

 
 
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Measurements for CD4+/CD8+ subsets will be determined at screening, weeks 2, 
4, 8, 12, 24 and 12 weeks post CCR5-intensification. In addition, extended 
phenotype characterization will be performed at baseline, pre-entry and weeks 4 
and 24 to determine the proportion of CD4+ and CD8+ lymphocytes that are 
naive (CD45RA+), activated (CD38+/HLA-DR+) or, among CD4+ cells, 
regulatory (CD25+CD127-). 
 
3.5 
Microarray analysis 
 
Whole genome expression (38,000 genes) will initially be done on purified 
CD4+/CD8+ T-cells at baseline, week 4 and at week 24 of MVC intensification.  
However, considering that other immune cells, such as monocytes, also express 
CCR5 these cells will be stored for future microarray analyses. 
 
3.6 
Lumbar Puncture 
 
Standard lumbar puncture-related adverse events will be monitored following all 
visits. Lumbar punctures will be performed under aseptic conditions at the clinical 
facilities of the HNRC by a neurologist, an internist, or by a trained registered 
nurse working under the supervision of the neurologist. Standard risks associated 
with HNRC medical procedures include 1) venipuncture: the risk of pain, 
bruising, and a very low risk infection; and 2) lumbar puncture: the risk of pain, 
bruising and a very low risk of infection as well as a risk of post-dural puncture 
cephalgia which can range from mild to severe.  
 
Routine clinical lab assays (cell counts, glucose, total protein) will be performed 
on all CSF. HIV RNA will be measured with a modified version of the 
Biomerieux assay validated to quantify HIV as low as 2 copies/mL in CSF [51]. 
MVC concentrations will be measured in plasma and CSF. Remaining specimens 
will be aliquoted and then stored at –70C at the HIV Neurobehavioral Research 
Center (HNRC) Specimen Bank.  
 
Local back pain will be minimized by injection of an anesthetic, 1% lidocaine into 
the subcutaneous tissue surrounding the needle puncture site. Oral analgesics and 
anti-inflammatory medications will be provided when necessary. Following LP, 
patients will be observed for 10-15 minutes. Over 3,000 LPs have been performed 
at the HNRC using non-cutting or "pencil point" spinal needles that reduce the 
risk of post-LP cephalgia. A site clinician will be available by pager 24 hours-per-
day to respond to problems, should they occur. If post-LP headache occurs, initial 
conservative management will include recumbency, hydration, and oral 
analgesics. When headaches are prolonged, a blood patch, involving an epidural 
injection of a sample of the subject’s own blood, may be performed by consulting 
anesthesiologists. This is extremely effective in aborting post-LP headache, but is 
only necessary in fewer than 1% of HNRC subjects. Palliative procedures will be 
performed at no cost to the participant.  
 

 
 
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Lumbar punctures will not be performed if any medical contraindication to the 
procedure is identified. LPs will be deferred when factors associated with 
increased risk of bleeding are present, such as a clinical history of bleeding 
diathesis, ongoing treatment with anticoagulants or platelet counts <50,000/mm3. 
LPs also will be deferred when signs of untreated systemic or local infection are 
present. If a subject becomes uncomfortable, the procedure will be discontinued.  
 
4.0 
SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 
Inclusion Criteria (Main Study) 
4.1.1 HIV-1 infection documented by a rapid HIV test or any licensed ELISA 
test kit and confirmed by a different method ELISA, Western blot, rapid 
HIV test, or plasma HIV-1 RNA assay at any time prior to study entry.   
Alternatively, if a licensed ELISA is not available, two HIV-1 RNA 
values >2000 copies/mL at least 24 hours apart by any CLIA certified 
laboratory may be used to document HIV-1 infection at any time prior to 
study entry.  
 
4.1.2 All available CD4+ T cell counts within the last 12 months of screening 
below 350 cells/mm3 (minimum of 3 values obtained > 30 days apart). 
 
4.1.3 CD4+ cell count below than 350 cells/ mm3 determined by site clinical 
laboratory within 30 days of screening.  
 
4.1.4 Subject receiving a stable (for at least 6 months) antiretroviral regimen 
consisting of at least 2 NRTIs and either a protease inhibitor boosted with 
low dose ritonavir or an NNRTI.  A stable regimen is defined as no 
additions or deletions for more than 14 cumulative days.  
 
4.1.5 Subject considered to be receiving initial HIV regimen (history of 
medication substitution for toxicity is allowed).  
 
4.1.6 All available plasma HIV RNA levels within the last 12 months are below 
the level of detection. Isolated values that are detectable but < 1000 copies 
will be allowed as long as the plasma HIV RNA levels before and after 
this detectable time point are undetectable – The subject should have a 
minimum of 3 values obtained > 30 days apart. 
 
4.1.7 Screening plasma HIV RNA levels below level of detection (< 50 copies 
RNA/mL using Roche Amplicor or < 75 copies/mL using Bayer bDNA) 
obtained by site clinical laboratory within 30 days of screening. 
 
4.1.8 Greater than 90% adherence to HIV therapy within the preceding 30 days, 
as determined by self-report. 
 

 
 
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4.1.9 Laboratory values obtained by screening laboratories within 30 days of 
entry: 
 
• Absolute neutrophil count (ANC) ≥ 750/mm3. 
• Hemoglobin ≥ 8.0 g/dL. 
• Platelet count ≥ 50,000/mm3. 
• Calculated creatinine clearance (CrCl) > 50 mL/min as estimated by 
the Cockcroft-Gault equation:   
* For men, (140 - age in years) x (body weight in kg) ÷ (serum 
creatinine in mg/dL x 72) = CrCl (mL/min) 
* For women, multiply the result by 0.85 = CrCl (mL/min)  
• AST (SGOT), ALT (SGPT), and alkaline phosphatase ≤ 5 x ULN. 
• Total bilirubin ≤ 2.5 x ULN (unless subject receiving atazanavir). 
 
4.1.8 Females of childbearing potential must have a negative serum pregnancy 
test at screening and agree to use a double-barrier method of contraception 
throughout the study period. 
 
4.1.9 Karnofsky performance score ≥ 70.  
 
4.1.10 Men and women age ≥ 18 years. 
 
4.1.11 Ability and willingness of subject or legal guardian/representative to give 
written informed consent. 
 
4.2 
Inclusion Criteria (CSF Sub-Study) 
 
4.2.1 Enrollment in the MVC parent protocol.  
 
4.2.2 Willingness to undergo lumbar puncture. 
 
4.3 
Exclusion Criteria (Main Study) 
4.3.1  Current antiretroviral regimen contains tenofovir disoproxil fumarate 
AND didanosine in combination. 
 
4.3.2 History of chronic hepatitis C (defined as HCV antibody positive and 
HCV RNA detectable). 
 
4.3.3 History of chronic active hepatitis B (defined as surface antibody negative, 
surface antigen positive and HBV DNA detectable). 
 
4.3.4 Concurrent use of G-CSF or GM-CSF. 
 
4.3.4 Prior or concurrent use of IL-2. 

 
 
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4.3.5 Prior or concurrent use of a CCR5 inhibitor. 
 
4.3.6 Active drug or alcohol use or dependence that, in the opinion of the 
investigator, would interfere with adherence to study requirements. 
 
4.3.7 Use of any immunomodulator, HIV vaccine, or investigational therapy 
within 30 days of study entry. 
 
4.3.8 Use of human growth hormone within 30 days prior to study entry. 
 
4.3.9 Initiation of testosterone or anabolic steroids within 30 days prior to study 
entry. (Exception: Chronic replacement dosages in patient’s with 
diagnosed hypogonadism is allowed). 
 
4.3.10 Evidence of splenic sequestration or suppressed bone marrow function: 
 
•  Clinical or radiographic evidence of significant splenomegaly. 
 
• 
History of leukemia or lymphoma. 
 
• 
History of myelosuppressive chemotherapy or irradiation 
 
4.4 
Exclusion Criteria (CSF Sub-Study) 
 
4.4.1 Relative or absolute contraindication to lumbar puncture, such as current 
coagulopathy, thrombocytopenia (platelets<50,000/µL), hemophilia, or 
use of anticoagulant medication. 
 
4.5 
Study Enrollment Procedures 
Prior to implementation of this protocol, sites must have the protocol and consent 
form approved by their local institutional review board (IRB). Sites must be 
registered with and approved by the CCTG Data Unit. Site registration must occur 
before any subjects can be enrolled in this study. 
 
Once a candidate for study entry has been identified, details will be carefully 
discussed with the subject. The subject will be asked to read and sign the consent 
form that was approved by both the local IRB and the CCTG Data Center. 
 
A patient identification number (PID) will be assigned to each patient screened 
for the study.  PIDs will include a site code and three-digit extension.  PIDs 
should not be reassigned even if the patient fails to enter the study.  The PID must 
be included on every CRF and patient blood sample.  Each site must maintain a 
master list of PIDs in a central location.  The patient registration and 
inclusion/exclusion CRF will be entered into the online CCTG data system  
 

 
 
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4.6 
Co-enrollment Guidelines  
Co-enrollment in this study and other studies will be discussed with the protocol 
team and will be decided on a case by case basis. 
 
5.0 
STUDY TREATMENT 
 
5.1 
Dosing, Administration, and Duration 
NOTE:  Maraviroc will be dose-adjusted for concomitantly administered HIV 
medications according to the manufacture’s recommendations: 
 
 
5.1.1 Dosing  
 
5.1.1.1  
with strong CYP3A4 inhibitors, including: 
 
• 
Protease inhibitors (except tipranavir/ ritonavir) 
• 
Delavirdine 
• 
ketoconazole, itraconazole, clarithromycin, nefazadone, 
telithromycin 
• 
Darunavir/r + etravirine 
 
MVC 150 mg twice daily 
 
5.1.1.2 
with non-inducers/ non-inhibitors of CYP3A4, including: 
 
• 
Tipranavir/ ritonavir 
• 
Nevirapine 
• 
All NRTIs 
• 
Enfuvirtide 
 
MVC 300 mg twice daily 
 
5.1.1.3  
with strong CYP3A4 inducers, including: 
 
• 
Efavirenz, etravirine 
• 
rifampin  
 
MVC 600 mg twice daily 
 
 
5.1.4 Administration 
 
NOTE: Maraviroc should be co-administered at the same time as the 
subject’s other HIV medications. All other HIV medications should be 
administered according to each medication’s recommended dosing.   
 

 
 
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5.1.4.1 
MVC will be administered as a single 150 or 300 mg tablet 
or two 300 mg tablets PO twice daily with or without food 
 
5.1.3 Duration 
 
5.1.3.1 
Maraviroc Therapy Intensification: Each subject will 
receive 24 weeks of therapy. 
 
5.1.3.2 
Post-Therapy Intensification: After 24 weeks, MVC will be 
discontinued and each subject will continue on baseline 
background HIV regimen, without Maraviroc, for an 
additional 12 weeks.  
 
5.2 
Product Formulation and Preparation  
 
5.2.1 Maraviroc (SelzentryTM, MVC):  150 or 300 mg tablets. Store at room 
temperature; 15º - 30º C (59º – 86º F).  
 
5.3 
Product Supply, Distribution, and Pharmacy 
 
5.3.1 Study Product Acquisition 
 
Study medications will be provided by Pfizer. All other HIV medications 
will not be supplied by the study, but will be made available to patients via 
prescription at cost to the patient and/or patient’s health insurance.  
 
5.3.2 Investigational Agent Accountability 
 
The clinical site pharmacist is required to maintain complete records of all 
study products received from this study. All unused study products must 
be returned to the sponsors after the study is completed or terminated.  
 
5.4 
Concomitant Medications 
5.4.1 Required Medications 
 
5.4.1.1    Study medications (Maraviroc) 
 
5.4.2 Prohibited Medications  
 
NOTE: This list applies only to MVC. Refer to manufacture’s 
recommendations for potential drug interactions/ contraindications for 
background HIV medications.  

 
 
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5.4.2.1    All investigational drugs and HIV vaccines 
 
5.4.2.2       The combination of efavirenz + rifampin 
 
5.4.2.3       Any immunomodulators 
 
5.4.2.4    Systemic cytotoxic chemotherapy 
 
5.4.2.5     All herbal products, including St John’s wort, should be 
avoided because of the unknown drug interactions between 
herbal products and the antiretroviral drugs used in this study. 
 
5.4.3 Precautionary Medications 
 
NOTE:   Refer to the individual package inserts for additional information 
regarding potential drug interactions that may require therapeutic drug monitoring 
and/or adjustment of concomitant medications.  Competition for primary CYP3A 
metabolism or other mechanisms by study drugs could result in inhibition or 
stimulation of the metabolism of these drugs and create the potential for serious 
and/or life-threatening reactions such as cardiac arrhythmias, prolonged or 
increased sedation, and respiratory depression. 
 
5.4.3.1 Systemic medications that interact at CYP3A as substrates, 
inhibitors, or inducers of the enzyme must be used with caution.  
These include but are not limited to: 
  
Agent by Class 
 
Precautionary Concomitant 
Medications 
 
Alternative/complementary 
 
Milk Thistle 
 
 
 
Analgesics  
 
Opioids, including:  
 
    Codeine 
 
    Methadone 
 
    Meperidine 
 
    Morphine 
 
Pentazocine (Talwin™) 
 
 
 
Anesthetics 
 
Propofol (Diprivan™) 
 
 
 
Anti-arrhythmics 
Amiodarone (Cordarone) 
 
Bepridil (Vascor) 
 
Disopyramide (Norpace™) 
 
Encainide (Enkaid™) 

 
 
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Agent by Class 
 
Precautionary Concomitant 
Medications 
 
Lidocaine (Xylocaine™) 
 
Mexiletine (Mexitil™) 
 
Quinidine (Quinidex) 
 
 
 
Anti-convulsants 
 
Carbamazepine (Tegretol™) 
 
Lamotrigine (Lamictal™) 
 
Phenobarbital (Luminal™) 
 
Phenytoin (Dilantin™) 
 
Valproic acid (Depakene™) 
 
 
 
Anti-histamines 
 
Chlorpheniramine (Chlor-Trimetron™ 
and others) 
 
Diphenhydramine (Benadryl™ and 
others) 
 
 
Anti-infectives 
Acyclovir (Zovirax™) 
 
Aminoglycosides 
 
Amphotericin B (Amphocin™, 
    Fungizone™) 
 
Cidofovir (Vistide™) 
 
 
 
Clarithromycin (Biaxin™) 
 
Dapsone 
 
Erythromycin (E-mycin™ and others) 
 
Fluconazole (Diflucan™) 
 
Ganciclovir (Cytovene™) 
 
Isoniazid  
 
Systemic Itraconazole (Sporonox®) 
 
Systemic Ketoconazole (Nizoral®) 
 
Ribavirin (Virazole™) 
 
Rifabutin (Mycobutin®) 
 
 
 
 
Vancomycin (Vancocin™,  
 Vancoled™) 
 
 
Voriconazole (Vfend) 
 
 
 
Beta blockers (selected 
agents listed, caution should 
be exercised for the entire 
class) 
 
Atenolol (Tenormin™) 
 
Metoprolol (Lopressor™, Toprol™) 
 
Propranolol (Inderal™, Inderide™, 

 
 
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Agent by Class 
 
Precautionary Concomitant 
Medications 
and others) 
 
 
 
Calcium channel blockers 
(selected agents listed, 
caution should be exercised 
for the entire class) 
Amlodipine (Norvasc ®) 
 
Diltiazem (Cardizem® and others) 
 
Felodipine (Plendil) 
 
Isradipine (DynaCirc®) 
 
Lacidipine (Lacipil) 
 
Nicardipine (Cardene®) 
 
Nifedipine (Adalat and Procardia®) 
 
Nimodipine (Nimotop®) 
 
Nisoldipine (Sular®) 
 
Nitrendipine (Nitrendipine) 
 
Verapamil (Calan and Isoptin®) 
 
 
 
Hormonal agents 
Estrogens and Progesterones 
 
Glucocorticoids 
 
Hypoglycemics 
Pioglitazone (Actos) 
 
 
H 
HMG Co Reductase 
Inhibitors 
Atorvastatin (Lipitor®) 
 
Fluvastin (Lescol®) 
 
 
 
Psychiatric medications 
Bupropion (Wellbutrin®, Zyban®) 
 
Chlorpromazine (Thorazine) 
 
Clozapine (Clozaril®) 
 
Fluoxetine (Prozac and others) 
 
Nefazodone (Serzone®) 
 
Paroxetine (Paxil) 
 
Risperidone (Risperdal®) 
 
Venlafexine (Effexor®) 
 
 
 
Tricyclic Antidepressants 
(including but not limited to) 
Amitriptyline (Elavil and others) 
 
Desipramine (Norpramin and 
others) 
 
Imipramine (Tofranil and others) 
 
Nortriptyline (Pamelor and others) 
 
 

 
 
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Agent by Class 
 
Precautionary Concomitant 
Medications 
 
Sedative/Hypnotics 
 
All benzodiazepines 
 
Alprazolam (Xanax™) 
 
Clorazepate (Tranxene™) 
 
Diazepam (Valium™) 
 
Estazolam (ProSom™) 
 
Flurazepam (Dalmane™) 
 
Oxazepam (Serax™) 
 
Temazepam (Restoril™) 
 
Busprione (Buspar™) 
 
Zaleplon (Sonata™) 
 
Zolpidem (Ambien™) 
 
 
 
Other agents 
 
Chlorzoxazone (Parafon Forte™) 
 
Cimetidine (Tagamet™) 
 
Naloxone (Narcan™) 
 
Piroxicam 
 
Promethazine (Mepergan™, 
   Phenergan™) 
 
Sildenafil (Viagra®) 
 
Warfarin (Coumadin™) 
 
NOTE:  For additional information and information updates please refer to:  
 
http://www.hivdruginteractions.org/new/Uploaded_Attachment/52_Ma
raviroc%20Oct07.pdf  
5.5 
Adherence Assessment 
Throughout the study, the documentation of adherence to study drugs and 
concomitant HIV medications is essential. During each visit an evaluation of 
adherence to study medications will be done by study personal and the clinical 
importance of strict adherence will be reinforced with subjects. An evaluation of 
study medication adherence will be done during each study visit at weeks 2, 4, 8, 
12, 24 and 36. 
 
6.0 
CLINICAL AND LABORATORY EVALUATIONS 
 

 
 
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6.1 
Schedule of Events – Clinical Evaluations 
 
 
 
Screening 
Pre-Entry 
Entry 
Maraviroc Therapy Intensification 
(24 weeks) 
Post-Maraviroc 
Intensificatoin 
 
Within 30 
days of 
entry 
> 48 hrs 
before 
entry 
Day 
0 
Week 
2 
Week 
4 
Week 
8 
Week 
12 
Week 
24 
Week 
36 
Treatment 
Failure, Tox or 
Premature D/C 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Medical/Medication History 
X 
 
 
 
 
 
 
 
 
 
Documentation of HIV 
X 
 
 
 
 
 
 
 
 
 
Clinical Assessment / AE 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Documentation of within 
criteria HIV RNA and CD4 
prior to screen labs 
X 
 
 
 
 
 
 
 
 
 
Complete Physical Exam 
 
 
X 
 
 
 
 
 
 
X 
Targeted Physical Exam 
 
 
 
 
 
 
X 
X 
X 
 
Start and Dispense Drug 
 
 
X 
 
X 
 
X 
 
 
 
Stop and Collect Drug 
 
 
 
 
 
 
 
X 
 
X 
Concomitant Medications 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Adherence Assessment 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 

 
 
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Schedule of Events – Laboratory Evaluations 
 
Screening 
Pre-Entry 
Entry 
Maraviroc Therapy Intensification 
(24 weeks) 
Post-Maraviroc 
Intensificatoin 
 
Within 30 
days of 
entry 
> 48 hrs 
before 
entry 
Day 
0 
Week 2 
(+ 1 wk) 
Week 4  
(+ 1 wk) 
Week 8 
(+ 2 wk) 
Week 12 
(+ 2 wk) 
Week 24 
(+ 2 wk) 
Week 36 
(+ 2 wk) 
Treatment 
Failure, Tox or 
Premature D/C 
Hematology (local lab) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Prothrombin time (local lab) † 
X 
 
 
 
 
 
 
 
 
 
Chemistry / LFT (local lab) 
X 
 
 
 
X 
 
X 
X 
X 
X 
Pregnancy test (local lab) 
X 
And anytime when suspected 
 
CD4+/CD8+ (local lab) 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
§ CD4 < 350; HIV RNA  < 50 
X 
 
 
 
 
 
 
 
 
 
Plasma HIV-1 RNA PCR 
(local lab) 
X 
 
X 
 
X 
 
 
X 
X 
X 
Plasma for MVC levels † 
 
 
X 
 
X 
 
 
X 
 
 
Extended flow cytometry & PBMC 
collection (UCSD lab) 
 
X 
X 
 
X 
 
 
X 
 
 
Microarray - PBMCs collection 
(local processing in real-time) 
 
 
X 
 
X 
 
 
X 
 
 
Lumbar puncture† 
 
 
X 
 
X 
 
 
X 
 
 
Plasma for storage 
 
 
X 
 
X 
 
 
X 
X 
 
Serum for storage 
 
 
X 
 
X 
 
 
X 
X 
 
Ship ambient sample for extended 
flow in real-time 
 
X 
X 
 
X 
 
 
X 
 
 
Ship frozen all stored PBMCs, 
plasma and serum 
 
 
 
 
 
 
 
 
X 
 
HIV Resistance & Tropism testing  
 
 
 
 
 
 
 
 
 
X 
§ If available within 30 days of screen then do not need to repeat laboratory test and can use value obtained within 90 days as screen value 
† Only for subjects co-enrolled in the central nervous system sub-study

 
 
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6.2 
Definitions for Schedule of Events – Timing of Evaluations 
 
6.2.1 Evaluations Prior to Study Entry 
 
Occur prior to the subject taking any study medications, treatments, or 
interventions.  
 
            Patient Registration 
 
A patient identification number (PID) will be assigned to each patient screened 
for the study.  PIDs will include a site code and three-digit extension.  PIDs 
should not be reassigned even if the patient fails to enter the study.  The PID must 
be included on every CRF and patient blood sample.  Each site must maintain a 
master list of PIDs in a central location.  The patient registration and 
inclusion/exclusion must be entered on-line at www.cfar.ucsd.edu/intranet 
 
Screening Site Clinical Labs  
 
If plasma HIV-1 RNA and CD4+ T-cell counts were obtained at a CLIA-
approved lab no more than 30 days prior to screening and results are available 
then these labs do not need to be repeated. Otherwise, a plasma HIV-1 RNA level 
and a CD4 cell count measurement need to be done at screening. Please record 
actual dates laboratories were done in the CRF.  
 
All other study screening laboratories must be determined within 30 days of study 
entry (Day 0). Screening and entry evaluations must be separated by at least 48 
hours. Hematology, chemistry and pregnancy testing will be coordinated through 
the site’s local laboratory and results will be tracked by the CCTG Data Center.   
 
Once the screening laboratories have been done the patient will be evaluated for 
study eligibility if all other entry criteria are satisfied.   
 
The total blood volume for screening labs is 20 mL. 
 
If the HIV RNA or other laboratory values are outside the eligible range, the site 
may re-screen a patient on one occasion. However, the study will not pay for 
additional re-screening laboratories.  
 
Pre-Entry 
 
Specimens for extended flow cytometry and PBMC storage need to be shipped by 
each site in real-time to the central laboratory (UCSD).  
 

 
 
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The total blood volume for pre-entry labs is 20 mL. 
 
Entry 
 
The entry evaluation should be scheduled within 30 days of the screening visit.  
Plasma and serum for storage should be obtained, however, specimens will be 
stored then shipped in batch on week 36 (end of study) along with other plasma, 
PBMC and serum specimens. The first dose of study medication should be given 
and witnessed by the study coordinator after drawing the entry laboratories.   
 
The total blood volume for entry labs is 73 mL. 
 
Lumbar puncture – 25 mL cerebral spinal fluid 
 
6.2.2 On-Study Evaluations         
 
Evaluations during the MVC treatment intensification period will occur on weeks 
2, 4, 8, 12, and 24. An addition visit will occur after MVC treatment 
intensification on week 36. Study visits at week 2 and 4 will have a visit window 
period of 1 week. For study visits at week 8, 12, 24 and 36 there will be a 2 week 
visit window period. In instances of virologic failure and/or premature treatment 
discontinuation evaluations would also need to occur as soon as possible. 
 
Total blood volume for laboratory evaluations during MVC treatment 
intensification (week 2 to week 24) will be approximately 200 mL.  
 
Lumbar puncture – 25 mL cerebral spinal fluid (week 4 and 24) 
 
Total blood volume for laboratory evaluations during post-MVC treatment 
intensification (week 36) will be approximately 40 mL. 
 
6.2.3 Evaluations and plan for registered subjects that do not complete 
week 4 of the study:  
 
a. Those subjects that do not start treatment will be replaced and will have no 
follow-up evaluations performed. 
 
b. Subjects that discontinue antiretroviral therapy and/or MVC before week 4 
will be replaced and will have no follow-up evaluations performed.  
 
6.2.4 Evaluations and plan for randomized or registered subjects that 
complete week 4 but not the remainder of the study:  
 

 
 
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a. Subjects who complete week 4 of the study but then discontinue their 
antiretroviral regimen and/or MVC will not be replaced and will not be 
discontinued from the study.  
 
6.2.6 Change in Background Antiretrovial Regimen 
 
a. Subjects who change their background treatment regimen before week 4 will 
be discontinued from the study. Those subjects that change their background 
treatment regimen after week 4 and who choose to continue MVC treatment 
intensification will be followed on the study. 
 
b. If the regimen change is due to toxicity, then the subject would be followed 
per criteria of a Change of Therapy Due to Toxicity visit (section 6.1). 
 
6.2.7 Virologic Failure during the MVC treatment intensification portion 
of study 
 
Virologic failure will be decided on a case by case basis by the local site’s study 
investigator in collaboration with the protocol team. Suggested criteria include: 
two consecutive HIV RNA loads > 50 copies/mL. For subjects who develop a 
plasma HIV-1 RNA > 50 copies/mL, a confirmatory plasma HIV-1 RNA test 
must be performed within 4 weeks of the initial HIV-1 RNA sample.  Subjects 
who meet criteria for confirmed virologic failure will undergo real-time genotypic 
resistance and tropism testing (testing not provided by study) and alternative 
regimen will be chosen by the site investigator with recommendations of the 
protocol team. Follow-up intervals will continue per study protocol, but the site 
investigator may schedule additional non-study, safety visits as necessary. The 
patient will be followed off study medication but on study for the remainder of the 
study.  
 
6.2.8 Post-Treatment Evaluations 
 
All randomized subjects who complete the 24 weeks of MVC intensification will 
complete the week 36 post-MVC intensification visit.  
 
6.2.9 Pregnancy  
 
Women who become pregnant during the study will be required to permanently 
discontinue their MVC treatment intensification.  They should be advised to seek 
best available medical care for their pregnancy according to USPH Guidelines 
 
6.3 
Special Instructions and Definitions of Evaluations 
 
6.3.1 Documentation of HIV 
 

 
 
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HIV-1 infection documented by a rapid HIV test or any licensed ELISA test kit 
and confirmed by a different method ELISA, Western blot, rapid HIV test, or 
plasma HIV-1 RNA assay at any time prior to study entry.   Alternatively, if a 
licensed ELISA is not available, two HIV-1 RNA values >2000 copies/mL at 
least 24 hours apart by any CLIA certified laboratory may be used to document 
HIV-1 infection at any time prior to study entry.  
 
6.3.2 Medical and Laboratory History 
 
At screening a medical history will be obtained and must be recorded in the 
source documents.  The medical history should include any previous HIV-related 
diagnoses and AIDS-defining events.  
 
In addition, prior to obtaining screening laboratories, documentation of all historic 
plasma HIV-1 RNA load and CD4+ T-cell counts since initiation of first ARV 
regimen must be recorded in the source documents and on-line CRF form 
(www.cfar.ucsd.edu/intranet). Of note: a minimum of 3 CD4+ T-cell (below 350 
cells/mm3) and HIV RNA values (below 50 copies/mL) obtained > 30 days apart 
must be obtained and recorded. 
 
6.3.3 Medication History 
 
At screening, a complete history or all prior antiretroviral medications will be 
recorded in the CRF. For all other medications, a medication history (only of 
those taken within the last 30 days prior to entry) with actual or estimated start 
and stop dates should be obtained and recorded in the source documents and the 
concomitant medication CRF, including:   
 
• 
All prescription medications.  Including medications taken for the 
treatment or prophylaxis of opportunistic infections. 
 
• 
Non-prescription medications.  
 
• 
Alternative therapies and/or dietary supplements.   
 
• 
Allergies to any medications and their formulations must be 
documented. 
 
6.3.4 Concomitant Medications 
 
During study visits (See section 6.1 for specific dates) all concomitant 
medications taken since the last visit will be recorded in the source documentation 
and entered into the concomitant medication log CRF. 
 
6.3.5 Study Treatment Modifications 
 

 
 
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All modifications to study drug(s) including initial doses, patient-initiated and/or 
protocol-mandated interruptions, modifications, and permanent discontinuation of 
HIV antiretrovirals need be recorded on the CRFs at each visit. The same needs to 
be done for all background antiretroviral agents. 
 
6.3.6 Clinical Assessments 
 
Complete Physical Exam 
 
A complete physical examination will be performed at entry. Documentation must 
include a complete review of systems and any HIV-related, toxicity-related, or 
AIDS-defining events. 
 
 
Targeted Physical Exam 
 
A targeted physical examination will be based on any signs or symptoms 
previously identified that the subject has experienced within 30 days of entry or 
since the last visit.  This examination will be performed at entry, weeks12, 24 and 
36 and in instances of virologic failure or premature treatment discontinuation if 
they should occur. Documentation must include any HIV-related, toxicity-related, 
or AIDS-defining events. 
 
Height and Weight 
 
Height and weight should be measured at study entry. 
 
Signs and Symptoms 
 
All signs, symptoms, deaths, and toxicities must be documented in the subject’s 
record.  At entry, record all signs/symptoms experienced within 30 days of entry 
on the CRFs.  For all other visits including the time of confirmation of virologic 
failure, record all Grade > 2 signs and symptoms, HIV-related and AIDS-defining 
events and deaths on the CRFs that have occurred since the last visit. Any signs or 
symptoms that lead to a change in treatment, regardless of Grade, must be 
recorded on the CRF.  The source document must include date of onset and date 
of resolution, but the CRF will only record prevalence of a given adverse event 
since the previous study visit. 
 
Refer to the Division of AIDS Table for Grading Adult Adverse Experiences, 
which can be found on the CCTG website: www.cctg.ucsd.edu  
 
Diagnoses 
 
The following should be recorded on the CRFs:  HIV-related diagnoses, HIV-
related malignancies, non-HIV related malignancies, myocardial infarctions, 

 
 
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hepatic failures, AIDS-defining events and death.  Any other diagnosis that is, in 
the opinion of the site investigator, associated with study medications, should be 
recorded on the adverse event CRF.  The source document must include date of 
diagnosis and date of resolution. 
 
Karnofsky Performance Status 
 
A Karnofsky performance status must be completed within 30 days before study 
entry. 
 
Vital Signs 
 
Temperature, pulse, and blood pressure collected at all visits and kept as a part of 
the source document. 
 
6.3.7 Laboratory Evaluations 
 
For all visits record all Grade ≥ 2 laboratory toxicities on the CRFs throughout the 
course of the study. All values, regardless of toxicity, of specific laboratories will 
also be recorded on the laboratory CRF; including: wbc, neutrophil count, 
hemoglobin, platelets, blood urea nitrogen, creatinine, glucose, AST/ALT, 
alkaline phosphatase, and total bilirubin. 
 
Any laboratory toxicities that lead to a change in treatment, regardless of Grade, 
must be recorded on the adverse event CRF.  
 
Refer to the Division of AIDS Table for Grading Adult Adverse Experiences, 
which can be found on the CCTG website: www.cctg.ucsd.edu 
 
Hematology:  
 
Hemoglobin, hematocrit, white blood cell count (WBC), differential WBC, 
absolute neutrophil count (ANC), and platelet count will be performed in real 
time at the site’s local laboratory. 
 
Blood volume: 3 mL 
 
Coagulation tests 
 
For subjects enrolled in the CSF Sub-Study: Prothrombin time, partial 
prothrombin time and calculation International Ratio (INR) will be performed in 
real time at the site’s local laboratory. 
 
Blood volume: 3 mL 
 
Liver & Kidney Function Tests 

 
 
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Total bilirubin, AST (SGOT), ALT (SGPT), and alkaline phosphatase, BUN, 
creatinine, electrolytes (sodium, potassium, chloride, and bicarbonate) will be 
performed in real time at the site’s local laboratory. 
 
Blood volume: 7 mL 
 
Pregnancy Test 
 
For women with reproductive potential: Urine β-HCG (urine test must have a 
sensitivity of < 50 mIU/mL) should be done at the site’s local laboratory during 
screening, at study entry and whenever clinically suspected. 
 
5 ml urine 
 
6.3.8 Immunologic Studies 
 
Nadir CD4+ 
 
The subject’s prior nadir CD4+ cell count (absolute value and date) should be 
documented during screening and, when possible, a copy of the nadir CD4+ cell 
count report should be included in the source document. If this documentation is 
not available, then subject recollection will suffice. For subjects who do not know 
the exact nadir value and for whom there is no source documentation, then recall 
of the categorical nadir (e.g., <50, <100, <200 cells/mm3) will suffice. 
 
CD4/CD8 
 
A screening CD4/CD8 count and percentage must be performed at the site’s local 
laboratory within 30 days prior to study entry unless a CD4 value is available 
from a CLIA-certified laboratory within 30 days of screening.  
 
Because of the diurnal variation in CD4+ and CD8+ cell counts; all 
determinations should be obtained consistently in either the morning or the 
afternoon throughout the study, if possible. 
 
Blood volume: 5 mL 
 
 
 
Extended Flow Cytometry Markers 
 
Extended flow markers for activation, maturation and regulatory function will be 
evaluated on CD4+/CD8+ T-cells. Samples will be collected at pre-entry, entry 
and on weeks 4 and 24.  Pre-entry and entry laboratories must be separated by a 
minimum of 48 hours. These analyses will be done on fresh samples in real-time. 
Specimens will need to be shipped ambient, overnight and in real-time to the 
UCSD central laboratory.  

 
 
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Blood volume: 10 mL 
 
6.3.9 Virologic Studies 
 
Plasma HIV-1 RNA 
 
A screening HIV-1 RNA must be performed at the site’s local laboratory within 
30 days prior to study entry unless a HIV-1 RNA value is available from a CLIA-
certified laboratory within 30 days of screening.  
 
Plasma HIV-1 RNA should be performed at the same local laboratory during the 
study and collected at entry, weeks 4, 24, 36 and in instances of virologic failure.  
 
Genotype Resistance and Tropism Assay 
 
Samples for genotypic and viral tropic analysis obtained at the time of virologic 
failure will be tested in real time for subject management by the site’s local 
laboratory. All resistance testing results should be scanned and uploaded on the 
on-line 
data 
collection 
system 
for 
review 
by 
the 
protocol 
team 
(www.cfar.ucsd.edu/intranet). The study does not provide resistance testing. 
 
Stored Plasma 
 
Stored Plasma will be collected at pre-entry, study entry, and weeks 4, 24 and 36.   
 
* Specimens will be stored at the site’s local laboratory and batched 
shipped to the central laboratory (UCSD) after completion of the study.  
  
Blood volume for combined HIV RNA and stored plasma: 15 mL  
 
6.3.10 Specimens for Serum Lipopolysaccharide (LPS) measurements 
 
Stored Serum 
 
Stored Serum will be collected at pre-entry, study entry, and weeks 4, 24 and 36.   
 
* Specimens will be stored at the site’s local laboratory and batched 
shipped to the central laboratory (UCSD) after completion of the study.  
  
Blood volume: 10 mL  
 
6.2.11 Microarray Studies 
 
Blood for PBMCs for microarray studies will be collected at entry and weeks 4 
and 24. Specimens will need immediate on-site processing and storage. All 

 
 
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specimens must be shipped overnight, frozen to the central laboratory 
(UCSD) on week 36.  
 
Blood volume: 30 mL 
 
6.3.12 PBMCs for storage 
 
Blood for PBMCs will be collected and shipped ambient, overnight and in real-
time to the central laboratory (UCSD) at pre-entry, entry and weeks 4 and 24.  
 
Blood volume: 10 mL 
 
6.3.13 Lumbar Puncture 
 
For subjects enrolled in the CSF Sub-Study:  CSF will be collected at baseline, 
weeks 4 and 24 for cell counts, protein, glucose, HIV RNA and markers of 
immune activation.  
 
Cerebral Spinal Fluid volume: 25 mL 
 
 
6.3.14 Plasma MVC plasma concentration  
 
 For subjects enrolled in the CSF Sub-Study: Blood for plasma MVC 
concentrations will be collected at baseline and weeks 4 and 24.  
 
Blood volume: 20 mL 
 
6.3.15 Adherence Assessment 
 
Adherence assessment will be preformed by the study coordinator using standard 
ACTG adherence format on weeks 2, 4, 8, 12, 24, and 36 of therapy and in 
instances of virologic failure and/or premature treatment discontinuation. 
 
6.4 
Off-Drug Requirements 
Additional safety monitoring and reporting of serious adverse experiences (SAEs) 
continues to be required upon completion or discontinuation of study treatment 
regardless of whether a protocol follow-up period is scheduled to occur. Adverse 
experiences occurring during the immediate 8-week period after the last dose of 
study treatment which meet SAE reporting requirements must be reported to the 
CCTG Data Center. Additionally, after 8 weeks OFF study treatment, there are 
four types of events that must be reported to the CCTG Data Center if the 
relationship to the study drug is assessed by the site physician as definitely, 
possibly, or unable to judge: DEATHS, NEW ONSET CANCERS, 
CONGENITAL ANOMALIES, AND PERMANENT DISABILITIES. 
 

 
 
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7 
TOXICITY MANAGEMENT 
 
Specific management of toxicity will be discussed only for the study-provided 
medication, MVC. The management of medication related toxicities should be 
undertaken by the local investigators, with guidance available from the protocol 
team, protocol pharmacist and pharmaceutical sponsor, to insure the optimal 
safety and efficacy for the individual subject.  
 
7.1 
Commonly occurring adverse events 
 
7.1.1 Grade 1 or 2 
 
Subjects who develop a Grade 1 or 2 adverse event or toxicity may continue 
MVC without alteration of the dosage.  Those subjects experiencing Grades 1 or 2 
adverse events which results in discontinuation of the MVC should be removed 
from the study.   
 
7.1.2 Grade 3 
 
 
Management of Grade 3 toxicities should be discussed with the protocol team via 
email. Please refer to the subsequent sections for management of specific events.  
 
In the event that a subject develops a symptomatic Grade 3 reaction considered to 
be MVC-related, the study drug should be discontinued and the subject should be 
followed weekly until resolution of the adverse event. Once Grade 3 is resolved 
the subject should be removed from study.  
 
7.2.3 Grade 4 
 
Management of Grade 4 toxicities should be discussed with the protocol 
team via email. 
 
Subjects who develop a Grade 4 adverse event or toxicity judged to be MVC 
related will have the study drug permanently discontinued.  Exemptions include: 
asymptomatic elevations of CPK, cholesterol or triglycerides. For these 
laboratories, medication may be continued at the discretion of the site investigator 
and laboratories repeated within 2 weeks. For other Grade 4 events, if the toxicity 
or laboratory elevation is thought not to be due to MVC, MVC may be continued 
and laboratories repeated within 2 weeks. If it is not possible for the investigator to 
discern the causative agent or MVC is possible/ probably the causative agent, then 
all MVC must be discontinued.  A new regimen may be chosen at the discretion of 
the local investigator.  Subjects experiencing Grade 4 adverse events requiring 
permanent discontinuation of MVC therapy should be followed weekly until 
resolution of the adverse event.  Once Grade 4 is resolved the subject should be 
removed from study.  

 
 
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7.2.4 Rash 
 
Grade 1 or 2 
 
MVC may be continued without interruption. Subjects with a Grade 1 or 2 rash 
may be treated symptomatically with permitted antipyretic, antihistamine, and/or 
non-steroidal anti-inflammatory medications, but should be monitored closely by 
the local investigator.  
 
Grade 3 or 4 
 
A rash of Grade 3 or 4 necessitates that all MVC should be held for any Grade 3 
or 4 rash unless the rash is determined to be unrelated to MVC. Upon resolution 
to Grade < 1, the subject should be removed from study.  
 
7.2.5 Nausea and Vomiting  
 
Grade 1 or 2 
 
MVC may be continued without interruption.  Subjects with Grade 1 and 2 nausea 
or vomiting may be treated symptomatically with permitted oral antiemetic 
therapies or antiemetic suppositories.  Subjects should be instructed to take 
medications with food.   
 
Grade 3 or 4 
 
Subjects with Grade 3 or 4 MVC-related nausea and vomiting should interrupt 
MVC until the toxicity grade returns to Grade < 2 or to baseline and be treated 
symptomatically.  If Grade ≥ 3 nausea and vomiting recurs upon the resumption 
of MVC despite symptomatic treatment, MVC should again be interrupted and the 
protocol team notified for possible study discontinuation. 
 
7.2.6 Diarrhea 
 
Grade 1 or 2 
 
MVC should be continued without interruption.  Subjects with diarrhea of any 
toxicity grade may be treated symptomatically with permitted antimotility agents. 
 
Grade 3 or 4 
 
For diarrhea that is unresponsive to antimotility agents and for which an 
alternative etiology (e.g., infectious diarrhea) is not established, MVC should be 
interrupted until resolution of diarrhea to Grade ≤ 2 or baseline.  If Grade ≥ 3 
diarrhea recurs upon the resumption of study medications, MVC should be 

 
 
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interrupted and the protocol team should be notified for possible study 
discontinuation. 
  
7.2.7 Hyperglycemia 
 
Fasting hyperglycemia of > 110 to 125 mg/dL is considered evidence of impaired 
glucose tolerance.  A fasting blood glucose level above 126 mg/dL is highly 
suggestive of diabetes mellitus.  Subjects with fasting hyperglycemia may 
continue MVC at the discretion of the investigator, but should be discussed with 
the protocol team via email.  A confirmatory fasting glucose must be obtained 
within 4 weeks and prior to the institution of medical therapy.  Hyperglycemia 
may be treated with oral hypoglycemic agents or insulin according to standard 
guidelines. 
 
7.2.8 AST/ALT Elevations 
 
Grade 1 or 2 
 
MVC may be continued. 
 
Grade 3  
 
All grade 3 or 4 elevations of AST/ALT should be discussed immediately with 
the protocol team via email. MVC may be continued for Grade 3 AST/ALT 
elevations at the discretion of the site investigator after discussion with the 
protocol team.  Careful assessments should be done to rule out the use of alcohol, 
non-study medication-related drug toxicity, or viral hepatitis as the cause of the 
Grade 3 elevation.  The possibility of lactic acidosis syndrome should also be 
explored. 
 
Grade 4 
 
MVC should be held for AST or ALT Grade 4 elevations until the toxicity returns 
to Grade < 2.  If the Grade 4 elevation in AST or ALT recurs, MVC should again 
be interrupted and the protocol team notified for possible study discontinuation. 
 
7.2.9 Creatinine Elevations 
 
Discontinue MVC if confirmed creatinine clearance becomes < 50 mL/min.  
Subjects should be followed as medically indicated until the creatinine returns to 
Grade < 2. The protocol team should be notified within 48 hours of any permanent 
therapy discontinuations. 
 
7.2.10 Anemia/Neutropenia 
 

 
 
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Subjects with Grade 3 or 4 anemia or neutropenia attributed to any of the NRTI’s 
should have all study treatment interrupted until the abnormality returns to Grade 
≤ 2.  Therapy may be resumed after the anemia or neutropenia has returned to 
Grade ≤ 2 using the same dual-NRTI regimen.  If Grade 3 or 4 anemia or 
neutropenia recurs, MVC should again be interrupted and the protocol team 
notified for possible study discontinuation.  
 
Subjects with anemia or neutropenia may be treated off-study with blood 
transfusion and/or erythropoietin (Epogen, Procrit) or G-CSF (Neupogen®) at 
the discretion of the site investigator. 
 
7.2.11 CK Elevations 
 
Asymptomatic elevations in CK or elevations due to exercise should be repeated 
(within 2-4 weeks) to assure that they are transient or due to exercise and will 
not require a change in study treatment.  Elevations in CK > 20 X ULN should be 
repeated after the subject has abstained from exercise for > 24 hours.  For 
persistent CK elevations >20 x ULN should prompt a permanent discontinuation 
of MVC and subjects should be discontinued from study and the protocol team 
should be notified. 
 
8 
CRITERIA FOR TREATMENT DISCONTINUATION 
 
8.1 
Criteria for Treatment Discontinuation 
• MVC drug-related toxicity (see section 7, Toxicity Management). 
• Active drug or alcohol use or dependence that, in the opinion of the 
investigator, would interfere with adherence to study requirements. 
• Requirement for prohibited concomitant medications (see section 5.4.2) 
• Pregnancy or breast-feeding. 
 
8.2 
Criteria for Discontinuation from the Study 
• Failure to complete week 4 whether due to toxicity, poor adherence or need to 
stop drug. 
• Request by the subject to withdraw. 
• Request of the primary care provider if s/he thinks the study is no longer in 
the best interest of the subject. 
• Clinical reasons believed life threatening by the physician, even if not 
addressed in the toxicity management of the protocol. 
• Subject judged by the investigator to be at significant risk of failing to comply 
with the provisions of the protocol as to cause harm to self or seriously 
interfere with the validity of the study results. 

 
 
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• At the discretion of the CCTG, FDA, investigator, or pharmaceutical 
sponsors. 
 
9.0 
STATISTICAL CONSIDERATIONS 
 
9.1 
General Design Issues 
 
This is a pilot study to investigate associations between MVC treatment 
intensification and 1) changes in gene expression as identified by microarray 
analysis and 2) change in the slope of the CD4 recovery.  The study is powered to 
detect a difference in gene expression before and after MVC. Secondary analysis 
will investigate whether a difference in CD4 recovery (measured by CD4 slope) is 
observed before and after MVC treatment intensification. 
 
9.2 
Endpoints 
 
9.2.1 Primary 
 
1. Differences in gene expression profiles obtained at baseline and weeks 
4 and 24. 
 
9.2.2 Secondary 
 
1. CD4+ T-cell absolute count and percentage at baseline, weeks 4 and 
24. 
 
2. The proportion of CD4+/CD8+ T-cell immune activation, maturation, 
regulatory and apoptosis markers at baseline and weeks 4 and 24. 
 
3. Grades > 2 laboratory abnormalities and signs and symptoms.  
 
4. Paired plasma to CSF ratios of MVC concentration at week 4. 
 
5. Soluble immune activation markers in CSF at baseline and week 4. 
 
6. HIV RNA loads in CSF at baseline and week 4. 
 
9.3 
Sample Size and Accrual 
 
Sample size calculations are based on within-patient comparisons of gene 
expression profiles from baseline to week 24. The calculations required to make 
such comparisons will depend on several experimental parameters including 
biological variability of the samples within each class, the expected fold change to 
be detected, technical sensitivity of the microarray technology, and acceptable 
error rates of the results.  As researchers in this field have shown [52], one way to 
ensure acceptable error rates is to control the false discovery rate (FDR), which is 

 
 
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equivalent to setting a minimum specificity.  The FDR is the expected fraction of 
significant genes, which in practice, do not differ in reality.  This differs from the 
false positive rate (FPR), which is the proportion of non-differentially expressed 
genes that, just by chance, appear to differ. 
  
Determining the biological variability of the system is a difficult task, especially 
when there is no pre-existing data available.  The ranges of conditions that can 
contribute to biological variability include environmental conditions, cell types, 
and genotypic variation [53].  Based on an extensive literature review, Zien et al. 
[53] conclude that a value of 0.4 provides a conservative estimate of the 
biological standard deviation (variability between and within classes of biological 
samples). We will consider biological standard deviation values of 0.4 for our 
power calculations. Further, we will consider a technical variation of 0.3 and 0.4. 
 
As a conservative approach, we base the sample size calculations on the 
Wilcoxon Rank Sum test.  This is a non-parametric procedure, in which no 
distributional assumptions are placed on the data. Using the on-line power 
calculator developed by Zien et al. [53] which computes sample sizes for 
microarray experiments, Table 1 provides the approximate statistical power for 
various biological variation, technical variations and signal-to-noise ratios.  Here, 
we consider a Type 1 error of 0.01 and a fold change of 2.  We assumed 500 hits 
from the 38,000 genes. Notice that these power calculations are based on the 
number of samples allocated to the training set (either 20 or 25 per group).  The 
sample size calculations indicate fair power (60-80%) to find a difference in gene 
expression before and after maraviroc treatment.   
 
TABLE 1. Power Calculations (Type 1 error=0.01, Fold change=2.0) 
Baseline 
(N) 
Week 
24 (N) 
Biological 
Variation 
Technical 
Variation 
Signal-to-
noise 
Power 
20 
20 
0.4 
0.3 
3 
77% 
20 
20 
0.4 
0.4 
3 
68% 
20 
20 
0.4 
0.3 
2 
61% 
25 
25 
0.4 
0.3 
3 
88% 
25 
25 
0.4 
0.4 
3 
80% 
25 
25 
0.4 
0.3 
2 
75% 
 
9.4 
Methods of Analysis 
 
 
9.4.1 Analysis of Primary Objective  
 
RNA from a set of 60 samples (30 at baseline and 30 at week 24) will be isolated, 
amplified, labeled and hybridized on the Sentrix Human-6 Expression BeadChip 
containing approximately 38,000 probes per chip. The Illumina platform will be 
used which is a one-color platform using cye 3.  Initially, filtering and pre-
processing methods will be performed on the 38,000 genes in order to eliminate 
genes that are poorly measured or that exhibit aberrant values.  

 
 
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9.4.1.1  
Pre-processing   
 
Microarray data will be pre-processed via the Robust Multichip Average (RMA) 
method [54], as implemented in Bioconductor [55], a suite of programs, for the R 
statistical programming language [56]. RMA pre-processing consists of three 
steps: background adjustment, normalization, and summarization [54]. The RMA 
background noise adjustment corrects for processing effects and cross-
hybridization by using a convolution model [54].  The purpose of normalization is 
to reduce the non-biological variation across the chips in an experiment. Non-
biological variation includes technical variability, which is related to the 
experimental procedure of the assay.  RMA uses the quantile normalization 
technique to adjust the gene expression intensities such that the distributions of 
the probe intensities are the same across all chips [57].  The last step, 
summarization, is a method to calculate a single gene expression value by 
mathematically combining the probe intensities from each probe set.  RMA 
employs the robust multi-chip linear model fitted on a log scale [58]. 
 
9.4.1.2  
Statistical Analysis  
 
We expect to eliminate approximately 2-3% of genes in through pre-processing 
and filtering. The data will be randomly divided into a separate training set and a 
test set. 20 Baseline and 20 Week 24 samples will be used for training. The 
remaining 10 baseline and 10 week 24 samples will be used for testing. Using 
criteria such as 2-fold differences in gene expression between the two measured 
time points within the group of patients and a false discovery rate (the percentage 
of genes that will be identified by chance) of less than 2%, Significance Analysis 
of Microarrays (SAM) [59]) will be applied to the training set to rank order genes 
that best can predict differences in gene expression profiles between the two time 
points.  The SAM method identifies genes with statistically significant changes in 
expression by computing a score for each gene relative to the gene specific 
standard deviation. Genes with scores greater than a certain (adjustable) threshold 
will be declared significant.  
 
The set of highest ranking genes identified with the SAM procedure will then be 
clustered using unsupervised hierarchical clustering analysis [60]. The purpose of 
this clustering analysis is to confirm the results from SAM and to further explore 
the microarray data in order to possibly reveal unknown subclasses. In 
unsupervised hierarchical clustering, no predefined reference vectors are used and 
the data is not partitioned into a particular cluster in a single step. Instead, a series 
of partitions takes place.  Next, we will use methods such as prediction analysis of 
microarrays (PAM) based on nearest shrunken centroids [61] to devise a cross-
validated gene expression predictor for these cluster-defined classes. The PAM 
method is a modification of the more standard nearest-centroid method. Each 
class centroid is shrunk toward the overall centroids after standardizing by the 
within-class standard deviation. The test set will then be used for validation of our 

 
 
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predictor. The genes that best predict the classes will be examined for similarities 
such as possibly participating in common genetic pathways.  
 
9.4.3.1. 
Analysis of Secondary Objectives 
 
Secondary analyses will include descriptive statistics and tests of significance 
between pre- and post-MVC intensification.  All significance tests will be two-
sided and no adjustment for multiple comparisons will be made.  If necessary due 
to assumption failures, appropriate non-parametric statistical tests will be applied. 
 
1.  Differences in the change in CD4+ T-cell absolute count and percentage from 
baseline to week 4 and baseline to week 24 will be compared descriptively via 
separate paired Student t-tests. Repeated CD4+ T-cell absolute count measured at 
different time points (3 historic time-points, baseline, week 4, and week 24) will 
be treated as the outcome variable in a linear mixed-effects model. The primary 
fixed effects will include time, period (MVC vs. pre-MVC), and interaction 
between time and period; random effects will include both intercept and slope 
allowing each subject to have individual starting CD4+ T-cell counts and rate of 
change. Baseline covariate adjustment will be included if necessary.  A significant 
interaction term between time and period with positive coefficient will indicate if 
the rate of CD4 recovery is greater during MVC compared to pre-MVC. 
 
2. Differences in the rate of CD4+ T-cell recovery (absolute count and 
percentage) during MVC intensification in subjects receiving a PI/r- vs. NNRTI-
based regimen will be compared via the linear mixed effects model, The fixed 
effects will include time, regimen (PI/r vs NNRTI), and regimen-by-time 
interaction; random effects will include both intercept and slope.  The regimen-
by-time interaction term in the model will indicate the difference in CD4+ T cell 
recovery rates between the two regimen groups. Baseline covariate adjustment 
will be included if necessary. 
 
3. Differences in gene expression profiles between subjects reciving a PI/r vs. 
NNRTI-based regimen at baseline and weeks 4 and 24 will be examined by 
comparing the gene lists generated in the primary analysis by regimen type.  If 
necessary, statistical modeling will include a dichotomous variable to indicate 
regimen type. 
 
4. Differences in the proportion of CD4+/CD8+ T-cell immune activation, 
maturation, regulatory and apoptosis markers between baseline and weeks 4 and 
24 will be compared cross-sectionally via McNemar’s test or paired t-tests as 
appropriate. 
 
5. Association between change in early immune subsets and phase 2 CD4 
recovery will be assessed via Pearson’s correlation analysis.  
 

 
 
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6.  MVC plasma to CSF ratios at weeks 4 and 24 will be reported via descriptive 
statistics. Differences in MVC concentration ratios between subjects receiving a 
PI/r- vs. NNRTI-based background regimen will be compared via McNemar’s test 
or paired t-tests as appropriate. 
 
7. Descriptive statistics of CNS markers of immune activation will be reported via 
descriptive statistics. Differences in CNS markers of immune activation between 
baseline and weeks 4 and 24 will be compared cross-sectionally via McNemar’s 
test or paired t-tests as appropriate. 
 
8. Association between change in CNS markers of immune activation and MVC 
plasma to CSF ratios will be assessed via Pearson’s correlation analysis. 
 
9.  Descriptive statistics of toxicity/intolerance during MVC treatment 
intensification will be reported via descriptive statistics. Differences in 
proportions of grades > 2 laboratory abnormalities and signs and symptoms will 
be compared via McNemar’s test between time points. 
 
10.  Virologic failure during MVC treatment intensification will be reported via 
descriptive statistics.   
 
9.5  
Monitoring 
 
The safety and tolerability of the study medications will be monitored by means 
of adverse event reports (AER) and monthly toxicity reports that will include 
laboratory and clinical data. These reports will be discussed by the protocol team 
on monthly conference calls.  
 
Data and Safety Monitoring Board, it is the responsibility of the Principal 
Investigator and the CCTG protocol team to interpret the toxicity data and make 
any decisions needed to protect patients from undue risk. Accrual and toxicity 
summaries will be provided to the Protocol Chairs and CCTG Investigators by the 
Data Manager and Biostatistician. 
 
If more than five patients develop virologic failure or discontinue MVC due to an 
adverse event or laboratory toxicity, an independent interim review committee 
will be established to review the study results to date. The interim review 
committee will be composed of at least 3 people (including one statistician) 
outside the protocol team. The committee will make specific recommendations 
about changes to the study protocol.  
 
10.0 
DATA COLLECTION AND MONITORING AND ADVERSE EXPERIENCE 
REPORTING 
 

 
 
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10.1 
Records to Be Kept 
Case report forms (CRF) will be provided for each subject. Subjects must not be 
identified by name on any CRFs. Subjects will be identified by the patient 
identification number (PID) provided by the CCTG Data Unit upon registration. 
 
10.2 
Role of Data Management  
 
10.2.1 Instructions concerning the recording of study data on CRFs will be 
provided by the CCTG Data Unit.  
 
10.2.2 It is the responsibility of the CCTG Data Unit to assure the quality of 
computerized data for this study.   
 
10.3 
Clinical Site Monitoring and Record Availability 
 
10.3.1 Site monitors provided by the CCTG will visit participating clinical 
research sites to review the individual subject records, including consent 
forms, CRFs, supporting data, laboratory specimen records, and medical 
records (physicians’ progress notes, nurses’ notes, individuals’ hospital 
charts), to ensure protection of study subjects, compliance with the 
protocol, and accuracy and completeness of records. The monitors also 
will inspect sites’ regulatory files to ensure that regulatory requirements 
are being followed and sites’ pharmacies to review product storage and 
management. 
 
10.3.2 The investigator will make study documents (e.g., consent forms, drug 
distribution forms, CRFs) and pertinent hospital or clinic records readily 
available for inspection by the local IRB, the site monitors, the Food and 
Drug Administration (FDA), the pharmaceutical sponsor(s), or the 
sponsor’s designee for confirmation of the study data.  
 
10.4 
Serious Adverse Experience (SAE) Reporting 
 
Serious adverse experiences must be documented on the Serious Adverse 
Experience (SAE) Reporting Form and submitted to the CCTG Data Unit. 
 
11.0 
HUMAN SUBJECTS 
 

 
 
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11.1 
Institutional Review Board (IRB) Review and Informed Consent 
This protocol and the informed consent document and any subsequent 
modifications will be reviewed and approved by the IRB or ethics committee 
responsible for oversight of the study. A signed consent form will be obtained 
from the subject. The consent form will describe the purpose of the study, the 
procedures to be followed, and the risks and benefits of participation. A copy of 
the consent form will be given to the subject. 
 
11.2 
Subject Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave 
the site will be identified by coded number only to maintain subject 
confidentiality. All records will be kept locked. All computer entry and 
networking programs will be done with coded numbers only. Clinical information 
will not be released without written permission of the subject, except as necessary 
for monitoring by IRB, the FDA, the OHRP, the pharmaceutical supporter(s), or 
the supporter’s designee. 
 
11.3 
Study Discontinuation 
The study may be discontinued at any time by the IRB, the pharmaceutical 
supporter(s), the FDA, or other government agencies as part of their duties to 
ensure that research subjects are protected.  
 
12.0 
PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by CCTG policies. Any 
presentation, abstract, or manuscript will be made available for review by the 
pharmaceutical supporters prior to submission. 
 
13.0 
BIOHAZARD CONTAINMENT 
 
As the transmission of HIV and other blood-borne pathogens can occur through 
contact with contaminated needles, blood, and blood products, appropriate blood 
and secretion precautions will be employed by all personnel in the drawing of 
blood and shipping and handling of all specimens for this study, as currently 
recommended by the Centers for Disease Control and Prevention and the National 
Institutes of Health. 
 
All infectious specimens will be transported using packaging mandated in the 
Federal Code of Regulations, CDC 42 CFR Part 72. Please also refer to individual 
carrier guidelines, e.g., FedEx, Airborne, for specific instructions. 
 
14.0 
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