Conditions: HIV
Keywords: HIV
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 7
Healthy volunteers: no

Brief summary:
This clinical study proposes to evaluate the combination of maraviroc with an integrase strand transfer inhibitor (either raltegravir or dolutegravir) in antiretroviral-experienced patients to document the efficacy, safety, and tolerability of this combination in order to provide clinicians with a treatment regimen that minimizes the risk of metabolic complications by avoidance of NRTI/NNRTIs and PIs. The development of an alternative ART regimen which lessens the risk of metabolic complications could improve long-term adherence and reduce the risk of certain co-morbidities associated with long-term ART use. If this new combination is found to be as efficacious as the standard regimen with enhanced tolerability and improved metabolic effects, there is great potential for altering the current practice of HIV medicine.

Detailed description:
Description of the study design:

The study will enroll 30 HIV-infected patients on a stable ART regimen with a suppressed HIV RNA \< 50 copies/ml for at least one year. Patients will be switched to the experimental regimen (maraviroc 300 mg twice a day plus either raltegravir 400 mg twice a day or dolutegravir 50 mg once a-day) and followed for 96 weeks. The decision to use raltegravir or dolutegravir will be left to investigator/subject preference, as the two integrate inhibitors are largely interchangeable aside from twice daily (raltegravir) vs. daily (dolutegravir) dosing.

Primary endpoint:

* The primary endpoint is the proportion of patients virologically suppressed (HIV RNA \< 50 copies/ml) at 48 weeks.

Definitions:

* Virologic suppression is an HIV RNA \< 50 copies/ml.
* Virologic failure is an HIV RNA ≥ 50 copies/ml confirmed on 2 separate occasions, separated by \> 1 week after viral suppression.

Secondary endpoints:

* The percent change in total cholesterol, LDL, and HDL at 48 and 96 weeks.
* The number of adverse events.
* The proportion of patients who are virologically suppressed (HIV RNA \< 50 copies/ml) at 96 weeks.

Exploratory endpoints:

* Telomerase activity and telomere length measured at baseline and 24, 48, and 96 weeks.

Arms:
arm 1: Maraviroc 300 mg tablet twice a day plus Raltegravir 400 mg tablet twice a day or Dolutegravir 50 mg tablet once a day for 48 weeks

Interventions: intervention 1: Switch to Maraviroc + Raltegravir or Dolutegravir
Intervention descriptions: intervention 1: Change HIV-infected patients on stable, suppressed ART regimens for at least 1 year to experimental regimen of Maraviroc + Raltegravir or Dolutegravir for 48 weeks

Protocol document:
Prot_SAP_000.pdf: 
1 
 
PROTOCOL NAME:   
Switch to Maraviroc and Integrase Strand Transfer Inhibitor Combination Therapy (a 
Triple Class-Sparing Regimen) for the Treatment of HIV-1-Infected Patients on 
Suppressive Antiretroviral Regimens 
 
 
PROTOCOL STUDY NUMBER:   
HP-00056162 
 
 
PROTOCOL VERSION:   
3.0 
 
 
PROTOCOL VERSION DATE:   
May 26, 2014 
 
 
SPONSOR:     
Institute of Human Virology     
725 West Lombard Street 
Baltimore, MD  21201 
 
 
PRINCIPAL INVESTIGATOR: 
David J. Riedel, MD 
University of Maryland School of Medicine 
Institute of Human Virology 
Room N552 
725 W. Lombard Street 
Baltimore, MD 21201 
410-706-5665 
 
MEDICAL MONITOR: 
Janaki Kuruppu, MD 
University of Maryland School of Medicine 
Institute of Human Virology 
725 W. Lombard St.  
Baltimore, MD 21201 
410-706-2230 
 


2 
 
1. Protocol Summary 
 
 
 
Full Title 
Switch to Maraviroc and Integrase Strand Transfer Inhibitor 
Combination Therapy (a Triple Class-Sparing Regimen) for the 
Treatment of HIV-1-Infected Patients on Suppressive Antiretroviral 
Regimens 
Short Title 
SWIMII: Switch to Maraviroc and Integrase Inhibitor 
Clinical Trial Phase 
III 
Conducted By 
Institute of Human Virology 
Principal Investigator 
David Riedel, MD 
Sample Size 
N = 30 
Study Population 
HIV-infected adults on suppressive antiretroviral therapy for ≥ 1 
year 
Accrual Period 
One year. 
Study Design 
Open label, single arm pilot study 
Study Duration 
Duration per participant is 96 weeks; total planned study duration is 
3 years. 
Study Agent/ 
Intervention Description 
Maraviroc 300 mg PO BID  + either Raltegravir 400 mg PO BID or 
Dolutegravir 50 mg QD 
Primary Objective 
 
Efficacy (virologic suppression proportion) of a regimen containing 
maraviroc and raltegravir/dolutegravir at 48 weeks. 
Secondary Objectives 
Evaluate safety, tolerability, and metabolic effects of the new 
regimen. 
Exploratory 
Objectives 
To determine the effects of the maraviroc + integrase inhibitor 
regimen on telomerase activity and telomere length. 
Endpoints 
HIV RNA at 48 weeks. 
 
 
 
 
2. Background Information and Scientific Rationale 
 
2.1 Background Information 
Outcomes of antiretroviral therapy (ART) have improved over the past two decades, leading to 
substantial reductions in morbidity and mortality related to HIV and AIDS. HIV-infected 
patients now have significantly longer expected life spans than in the 1980s or 1990s. Studies 
have also demonstrated lower rates of toxicity and improved immune (CD4) reconstitution when 
ART is initiated at higher CD4 counts. This, in addition to the improved efficacy, tolerability, 
and simplicity of new agents, has led to revisions in treatment guidelines to begin ART earlier 
after HIV infection.  
At the same time, many studies have demonstrated metabolic complications of antiretroviral 
agents that lead to mitochondrial dysfunction, hyperlipidemia,1 cardiovascular events,2-5 insulin 
resistance, renal toxicity,6 and other morbidities. Many of these complications are secondary to 
side effects and toxicities from specific antiretroviral agents, especially those within the original 


3 
 
three ART classes:  nucleoside/tide reverse transcriptase inhibitors (NRTIs), non-nucleoside 
reverse transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs). These toxicities are 
thought to play a role in the accelerated aging process that is seen in HIV-infected patients. 
Recent work has also shown an effect of NRTIs on telomerase activity which may link the long-
term use of these drugs directly to the process of accelerated aging, providing a mechanism for 
some of the various co-morbidities associated with long-term HIV infection.7  
As the average HIV-infected individual will now spend literally decades on ART, these 
metabolic complications have become important causes of morbidity and mortality in the treated 
patient. Nucleoside/tide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse 
transcriptase inhibitors (NNRTIs), and protease inhibitors (PIs) have been linked with many of 
these metabolic complications, leading to expanded interest in combination regimens that 
minimize metabolic complications by avoiding use of these agents. Numerous studies have 
examined class-sparing regimens focusing on exclusion of NRTIs8-12, but few studies have 
examined regimens excluding all 3 major classes of ART, i.e. NRTIs, NNRTIs, and PIs. 
Maraviroc (a CCR5 co-receptor antagonist) and raltegravir (an integrase strand transfer inhibitor) 
represent two new classes of antiretroviral agents with favorable toxicity profiles. Both were 
approved for the treatment of HIV infection by the FDA in 2007. Both agents have been 
documented to be extremely potent and well-tolerated in antiretroviral naïve and experienced 
patients, making them promising candidates for inclusion in regimens which minimize metabolic 
complications.13,14 A second integrase inhibitor, dolutegravir, was approved by the FDA in late 
2013. It has a similarly favorable metabolic profile as raltegravir and has the dual advantages of 
increased potency and once-daily dosing. (A third integrase inhibitor, elvitegravir, has also 
recently been FDA approved; however, it requires pharmacokinetic boosting with a second drug 
(cobicistat) leading to potential hepatic/metabolic side effects. Additionally, elvitegravir is 
marketed as Stribild™ which is a 4-drug co-formulation with cobicistat, emtricitabine, and 
tenofovir, the latter two drugs (NRTIs) which are specifically excluded from this protocol.) 
 
2.1.1 Description of the study agents 
Maraviroc is a CCR5 co-receptor antagonist, while raltegravir is an integrase strand transfer 
inhibitor. Both were approved for the treatment of HIV infection by the FDA in 2007. 
Dolutegravir, another integrase strand transfer inhibitor, was approved by the FDA in late 2013. 
 
HIV gains entry to cells by first binding to the CD4 receptor, after which it requires a secondary 
binding to a co-receptor before attachment is complete. HIV uses one of two receptors, CCR5 
(CC chemokine receptor 5) or CXCR4 (CXC chemokine receptor 4) to secure its attachment to 
cells.15 HIV that uses CCR5 is denoted as R5- or CCR5-tropic, and HIV that uses CXCR4 is 
called X4- or CXCR4-tropic. Occasionally, the virus is capable of using either co-receptor (dual 
tropism), and some patients harbor mixed populations of viruses (mixed tropism).  
Transmission of HIV is nearly always via R5-tropic strains, and so patients with early HIV 
infection (i.e. high CD4 counts) nearly always have R5-tropism. Cross-sectional studies of HIV-
infected patients have shown that patients who are treatment naïve or otherwise with early 
infection (CD4 count > 300) are much more likely to have R5-tropic virus.16-19 As HIV disease 
and duration progresses, a higher percentage of viruses will shift to X4- or dual tropism.16-19 
Most reports on HIV tropism have been from cohorts of patients with subtype B virus (which 
predominates in the U.S. and Europe). Some studies have found higher proportions of X4- and 


4 
 
dual tropic virus in patients with subtype A and D HIV infections (which are found largely in 
East/central Africa).20-22 
There are two laboratory tests currently used to determine viral tropism. The first is a Trofile. 
The Trofile requires a circulating viral load of > 1,000 copies/ml, and so it is generally 
performed before initiation of ART. The second is a genotypic assay of the HIV envelope V3 
loop.23 Its main advantage is that it can be performed when the viral load is < 1,000 copies/ml, 
even when the patient is receiving ART.24  
Maraviroc is the first drug of a class used to treat HIV that does not target the virus itself, but 
instead works by blocking access to the host’s cellular receptors and thereby limiting the ability 
of the virus to infect new cells and propagate. The drug is only effective against virus that is R5-
tropic and has no effect on HIV that is CXCR4 tropic, dual tropic, or mixed tropic. Advantages 
of maraviroc include its robust efficacy against R5 tropic strains, good tolerability with few 
adverse reactions, lack of cross-resistance with other ART drugs.14,15,25 Disadvantages include 
the requirement of twice-daily dosing and its limitation to R5 tropic strains.25 Maraviroc is 
currently recommended by U.S. guidelines26 as part of an acceptable regimen for ART naïve 
patients and experienced patients failing initial ART. Maraviroc is being investigated for use in 
HIV prevention, intensification, and immune modulation/reconstitution studies.27,28 
 
Raltegravir was the first drug in a class of antiretrovirals known as integrase strand transfer 
inhibitors. The HIV integrase enzyme transfers viral DNA into the host chromosome, an 
essential step in retrovirus replication.29 Integration is also the mechanism by which HIV 
establishes itself for the life of the cell, contributing to life-long persistence of HIV infection. 
Raltegravir has been widely used for the treatment of HIV since its initial approval. Advantages 
of raltegravir include high potency, solid efficacy, low frequency of adverse reactions, and 
minimal drug-drug interactions.13,30,31 Disadvantages include the requirement of twice-daily 
dosing and a relatively low genetic barrier to resistance.30,31 Raltegravir is currently 
recommended by U.S. guidelines26 as part of a preferred regimen for ART naïve and experienced 
patients and is often used in trials of class-sparing novel ART regimens.9-12,32-34 
 
Dolutegravir is also an integrase strand transfer inhibitor. It has a similar, favorable metabolic 
profile as raltegravir and shares the other advantages of high potency, solid efficacy, low 
frequency of adverse reactions, and minimal drug-drug interactions.35 It also has the advantage 
of a higher barrier to resistance than raltegravir and once-daily dosing. Dolutegravir is also now 
recommended by the U.S. guidelines36 as part of a preferred regimen for ART naïve patients. 
 
2.1.2 Summary of relevant clinical studies 
Maraviroc and raltegravir have been used together as part of salvage combination therapy with 
etravirine in triple-class experienced patients.10 This study prospectively enrolled 28 triple-class 
experienced patients with R5 tropic virus who were virologically failing their previous regimen. 
At the end of 48 weeks, 26 of 28 (92%) achieved virologic suppression success with HIV RNA < 
50 copies/ml. Continuation of this study to 96 weeks was subsequently published.37 Twenty-five 
of the original 28 enrolled patients (89%) completed 96 weeks of treatment. By week 96, 24 of 
25 patients (96%) attained HIV RNA <50 copies/ml. Safety and tolerability profiles of this 3-
drug combination were excellent. 
 


5 
 
A pilot study conducted in France was recently published.38 This study enrolled 44 patients on 
suppressive ART and switched to the maraviroc/raltegravir combination regimen. The 
inclusion/exclusion criteria for this study were problematic since the median duration of HIV 
infection was 20 years (IQR 14-24) and the median CD4 nadir was 210 (IQR 150-276), 
suggesting that not all patients were actually R5 tropic, despite DNA trofile assays showing R5. 
This may have led to limited activity of maraviroc in the setting of dual tropic virus. The study 
was stopped early due to five virologic failures, but the decision to stop the study was likely 
premature since a rate of 5/44 failures (11%) is similar to the expected rate of failure in most 
ART switch studies (~10%). Two of the virologic failures had drug levels below the threshold 
for efficacy, suggesting that medication adherence was the proximate cause of failure rather than 
the regimen itself. These significant flaws in the French study make conduct of an appropriately 
conducted clinical trial of this new regimen even more vital at this time. 
 
A recent pilot study combining maraviroc with raltegravir in seven antiretroviral naïve patients 
conducted at the Institute of Human Virology demonstrated potency and efficacy of the 
combination (R. Redfield, unpublished data). In this study, all seven patients achieved rapid viral 
suppression by week 2 (Figure 1). Three patients who have completed the trial to week 48 
remained suppressed throughout the trial. The safety profile to date has been excellent with no 
serious adverse events related to the study drugs. 
 
Figure 1. 
 
2.2 Rationale 
This clinical study proposes to evaluate the combination of maraviroc with an integrase strand 
transfer inhibitor (either raltegravir or dolutegravir) in antiretroviral-experienced patients to 
document the efficacy, safety, and tolerability of this combination in order to provide clinicians 
with a treatment regimen that minimizes the risk of metabolic complications by avoidance of 


6 
 
NRTI/NNRTIs and PIs. The development of an alternative ART regimen which lessens the risk 
of metabolic complications could improve long-term adherence and reduce the risk of certain co-
morbidities associated with long-term ART use. If this new combination is found to be as 
efficacious as the standard regimen with enhanced tolerability and improved metabolic effects, 
there is great potential for altering the current practice of HIV medicine. 
 
2.3 Potential risk and benefits 
The drugs used in this study are currently approved by the U.S. FDA for treatment of HIV 
infection. 
 
2.3.1 Potential risks 
 
Risks of drawing blood 
Drawing blood may cause discomfort, bleeding, and bruising where the blood is drawn. 
Occasionally, there is swelling in the area where the needle enters the body, and there is a small 
risk of infection. There is also a risk of lightheadedness, fainting, and blood clots. 
 
Risks with the new drugs 
The drugs used in this study may have side effects, some of which are listed below. 
 
Risks with use of Raltegravir (RAL, Isentress™) 
 
The most common adverse events reported with raltegravir are headache, other nervous system 
effects and gastrointestinal events; the majority were mild and transient in nature.13 Nervous 
system events (mainly headache) were noted at a similar incidence to placebo in the phase III 
approval studies. 
Skin rashes and hypersensitivity reactions were mild, uncommon and occurred at similar rates 
with raltegravir as with placebo (5.3 vs. 2.5%), and in most cases have been confounded by use 
of concomitant drugs.13 
Rare cases of Stevens–Johnson syndrome possibly associated with raltegravir have been reported 
in post-marketing surveillance, although it has not been possible to establish a true causal 
relationship. 
Also seen in post marketing reports have been thrombocytopenia and rhabdomyolysis.39,40 
Additional serious reactions include allergic reactions. 
 
Abnormal blood tests which have been seen in studies of raltegravir in combination with other 
HIV drugs include elevated liver function tests, increase in pancreatic amylase, and 
asymptomatic increase in creatinine phosphokinase. 
 
Cancers have been seen in people who took raltegravir with other HIV drugs. However, the 
malignancies reported were diverse, with no pattern evident in the number or type, and no trend 
in the time of onset.13 It is unknown if the cancers were related to raltegravir use. 
 
Risks with use of Dolutegravir (DTG, Tivicay™) 
 


7 
 
The most common adverse events reported with dolutegravir are mild to moderate diarrhea, 
fatigue, and headache. Other adverse reactions like insomnia, dizziness, and nausea occurred at 
similar rates (1-3%) as with comparator drugs in clinical trials. Other uncommon (<2%) adverse 
reactions included abdominal pain, abdominal discomfort, flatulence, vomiting, myositis, renal 
impairment, and pruritus (itching). 
 
Abnormal blood tests which have been seen in studies of dolutegravir in combination with other 
HIV drugs include elevated liver function tests, increase in pancreatic lipase, and asymptomatic 
increase in creatinine phosphokinase. 
 
Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion 
of creatinine without affecting renal glomerular function. Increases in serum creatinine occurred 
within the first 4 weeks of treatment and remained stable through 24 to 48 weeks. In treatment-
naïve subjects, a mean change from baseline of 0.11 mg/dL (range: -0.60 mg/dL to 0.62 mg/dL) 
was observed after 48 weeks of treatment. Creatinine increases were comparable by background  
NRTIs and were similar in treatment-experienced subjects. 
 
Hypersensitivity reactions have been reported and were characterized by rash, constitutional 
findings, and sometimes organ dysfunction, including liver injury. The events were reported in 
1% or fewer subjects. 
 
Risks with Use of Maraviroc (MVC, Selzentry™) 
 
Common side effects reported with maraviroc that may or may not be causally related include: 
cough, fever, colds/upper respiratory tract infections, rash, muscle and joint aches, stomach pain, 
diarrhea, edema, sleeping problems, and dizziness.14,27 
 
Serious side effects may include serious skin rash and allergic reactions, and elevations in liver 
function tests. People who are co-infected with hepatitis B or C might be at higher risk of having 
liver problems, although data from trials showed similar rates of liver function test abnormalities 
in patients on maraviroc compared to placebo groups.14 
 
Postural hypotension was reported in patients taking higher doses (than currently approved) of 
maraviroc in clinical studies.14 
 
Post-marketing experience has reported skin and subcutaneous tissue disorders including 
Stevens-Johnson syndrome (a severe and sometimes fatal form of skin rash). 
 
Maraviroc blocks the CCR5 receptor on T cells; this might interfere with some of the normal 
function of CCR5 in the body and may increase the risk of certain infections or cancer. There 
have been higher rates of herpes virus infections in people who took maraviroc compared with 
placebo in studies so far. Cancers have been reported with the use of another drug that works the 
same way as maraviroc. Cancers have occurred in people taking maraviroc, but so far, there has 
not been an increased risk of cancers or any types of cancers when comparing people taking 
maraviroc with either people taking other HIV drugs or placebo. 
 


8 
 
Maraviroc contains soya lecithin. Therefore if you have a medical history of allergy to soya or 
peanuts, you may develop an allergy reaction to maraviroc.  
 
Risks with the novel combination of maraviroc and raltegravir/dolutegravir 
There is a risk that the new regimen may not maintain viral suppression as well as the patient’s 
prior regimen. However, viral load monitoring will be conducted frequently in order to detect 
failure at the earliest juncture and minimize the risk of resistance development (see below under 
2.3.3). If virologic failure occurs, resistance may develop to one or both of these drugs, 
eliminating their possible use from future antiretroviral regimens for the individual patient. 
Resistance to maraviroc, however, is quite rare, and is therefore unlikely. There is no cross-
resistance between maraviroc and other classes of antiretroviral drugs. Because the patient was 
on a previously successful regimen, it is likely that the patient will be able to resume his/her old 
regimen should virologic failure and resistance to the study drugs develop. 
 
There may be risks due to the medications or their combination in this study which are not yet 
known. 
 
2.3.2 Potential benefits 
Subjects may not have personal benefit from this study. It is possible that this new regimen could 
improve certain metabolic parameters and maintain viral suppression to the same degree as their 
previous regimen. Additionally, participation in this study may benefit the community, scientists, 
and doctors who work with HIV by providing increased knowledge about treatment of this 
disease. 
 
2.3.3 Risk to benefit ratio and minimization of risks 
The potential risks verses the benefits are reasonable. These are FDA approved drugs for the 
treatment of HIV infection. The selection criteria and study design of this protocol have been 
carefully chosen to minimize the risks of the study to patients in the following ways: 1) the 
inclusion/exclusion criteria have been designed to minimize the risk that any patient with 
CXCR4-tropic virus (i.e. one who would not respond to maraviroc) will be excluded using a high 
CD4 nadir cut-off threshold; 2) patients to be included are already virologically suppressed, 
which means they have demonstrated the ability to adhere to antiretrovirals, which minimizes the 
risk of poor adherers that could lead to drug resistance; and 3) virologic monitoring will be done 
frequently to minimize the risk of undetected virologic failure and development of resistance. 
Overall, the study has been designed to minimize potential risks. 
 
 
3. Study objectives 
 
3.1 Primary objective 
The primary objective of this study is to evaluate the efficacy of a regimen containing maraviroc 
and raltegravir/dolutegravir at 48 weeks. 
 
3.2 Secondary objective 
The secondary objectives of this study are to evaluate the safety, tolerability, and metabolic 
effects of the new regimen as well as the efficacy at 96 weeks. 


9 
 
 
3.3 Exploratory objectives 
To determine the effects of the maraviroc + integrase inhibitor regimen on telomerase activity 
and telomere length. 
 
 
4. Study design 
This is a pilot, open-label study of maraviroc with either raltegravir or dolutegravir in 
combination for the treatment of ART-experienced adult patients who are currently virologically 
suppressed. 
 
4.1 Description of the study design 
The study will enroll 30 HIV-infected patients on a stable ART regimen with a suppressed HIV 
RNA < 50 copies/ml for at least one year. Patients will be switched to the experimental regimen 
(maraviroc plus either raltegravir or dolutegravir) and followed for 96 weeks. The decision to use 
raltegravir or dolutegravir will be left to investigator/subject preference, as the two integrase 
inhibitors are largely interchangeable aside from twice daily (raltegravir) vs. daily (dolutegravir) 
dosing. 
 
4.2 Study endpoints 
4.2.1 Primary endpoint 
• The primary endpoint is the proportion of patients virologically suppressed (HIV RNA < 
50 copies/ml) at 48 weeks. 
 
Definitions:  • Virologic suppression is an HIV RNA < 50 copies/ml. 
• Virologic failure is an HIV RNA ≥ 50 copies/ml confirmed on 2 separate 
occasions, separated by > 1 week after viral suppression. 
 
4.2.2 Secondary endpoints 
The secondary endpoints are: 
• The percent change in total cholesterol, LDL, and HDL at 48 and 96 weeks. 
• The number of adverse events. 
• The proportion of patients who are virologically suppressed (HIV RNA < 50 copies/ml) 
at 96 weeks. 
 
4.2.3 Exploratory endpoints 
• Telomerase activity and telomere length measured at baseline and 24, 48, and 96 weeks. 
 
 
5. Study population 
 
5.1 Description of the study population 
This study will be conducted among adult patients infected with HIV-1 who are ART-
experienced. 
 
5.1.1 Participant inclusion criteria 


10 
 
• HIV-1 infection 
• Age between 18 and 75 years 
• CD4 count nadir ≥ 250 cells/mm3 
• HIV RNA ≤ 50 copies/ml for ≥ 12 months while taking any ART regimen 
o One virologic blip ≤ 400 copies/ml permissible within the 12 months 
• CCR5 tropic virus as defined by: 
o trofile/tropism testing if available, OR 
o DNA trofile if no trofile/tropism test available and CD4 nadir 250-499 cells/mm3, 
OR 
o CD4 nadir ≥ 500 cells/mm3 
 
5.1.2 Participant exclusion criteria 
• Age < 18 or > 75 years 
• CD4 count nadir < 250 cells/mm3 
• Dual/mixed or X4 tropic virus if tested prior to viral suppression or if performed by 
DNA trofile testing at any time 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) >2.5 times the 
upper limits of normal 
• Women who: 
o are currently pregnant or breastfeeding 
o are of child-bearing age and do not agree to remain abstinent or use (or have their 
partner use) an acceptable method of birth control throughout the study.  
Acceptable method of birth control is defined as intrauterine device (IUD), 
diaphragm with spermicide, contraceptive sponge, condom, vasectomy. 
• History of any malignancy except non-melanoma skin cancer 
• Concomitant use of drugs known to impact or be impacted in terms of pharmacokinetics 
or drug-drug interactions with either raltegravir, dolutegravir, or maraviroc. This 
includes: 
o Inducers of UGT1A1 (such as rifampin, phenytoin, phenobarbital rifabutin, St. 
John’s wort)  
o CYP3A inhibitors (such as ketoconazole, itraconazole, clarithromycin, 
nefazodone, and telithromycin) 
o CYP3A inducers (such as rifampin, carbamazepine, phenobarbital and phenytoin) 
o Dofetilide 
• Subject requires or is anticipated to require any of the prohibited medications noted in 
the protocol 
• Enrollment in an experimental protocol having received investigational agents 
(antiretroviral or non-antiretroviral) within 30 days of study enrollment 
• Chronic active hepatitis B infection as defined by presence of HBsAg 
• Subject has a history or current evidence of any condition, therapy, laboratory 
abnormality or other circumstance that might interfere with the patient’s participation for 
the full duration of the study, such that it is not in the best interest of the patient to 
participate. 
• Subject is unlikely to adhere to the study procedures, keep appointments, or is planning 
to relocate during the study. 


11 
 
 
 
6. Study interventions 
6.1 Study agent acquisition 
Both Maraviroc and Raltegravir/Dolutegravir will be obtained by writing a prescription for the 
subject and obtaining through their insurance. 
Note that in Maryland, every subject who does not have insurance can apply for the AIDS Drug 
Assistance Program (ADAP) so that potential study subjects will be able to access this 
medication even if they do not have insurance. 
 
6.1.1 Study agent #1: Maraviroc (Selzentry™) 
Maraviroc tablets are blue, oval, film-coated tablets debossed with “MVC 300” on one side and 
plain on the other and contain 300 mg of maraviroc. The tablet also contains the following 
inactive ingredients: dibasic calcium phosphate (anhydrous), magnesium stearate, 
microcrystalline cellulose, and sodium starch glycolate. The film coat (Opadry®  II Blue 
[85G20583]) contains FD&C blue #2 aluminum lake, soya lecithin, polyethylene glycol 
(macrogol 3350), polyvinyl alcohol, talc, and titanium dioxide. Maraviroc is chemically 
described as 4,4-difluoro-N-[ (1S)-3-[exo-3-(3-isopropyl-5-methyl-4H-1,2,4-triazol-4-yl)-8-
azabicyclo[3.2.1]oct-8-yl]-1-phenylpropyl ] -cyclohexanecarboxamide. 
 
6.1.2 Study agent #2: Raltegravir (Isentress™) 
Raltegravir tablets are film-coated, pink, oval-shaped, film-coated tablets with "227" on one side 
and contain 400 mg of raltegravir. Each 400 mg film-coated tablet of ISENTRESS for oral 
administration contains 434.4 mg of raltegravir (as potassium salt), equivalent to 400 mg of 
raltegravir free phenol and the following inactive ingredients: microcrystalline cellulose, lactose 
monohydrate, calcium phosphate dibasic anhydrous, hypromellose 2208, poloxamer 407 
(contains 0.01% butylated hydroxytoluene as antioxidant), sodium stearyl fumarate, magnesium 
stearate. In addition, the film coating contains the following inactive ingredients: polyvinyl 
alcohol, titanium dioxide, polyethylene glycol 3350, talc, red iron oxide and black iron oxide. 
The chemical name for raltegravir potassium is N-[(4-Fluorophenyl)methyl]-1,6-dihydro-5-
hydroxy-1-methyl-2-[1-methyl-1-[[(5-methyl-1,3,4-oxadiazol-2-yl)carbonyl]amino]ethyl]-6-oxo-
4-pyrimidinecarboxamide monopotassium salt. 
 
6.1.3 Study agent #3: Dolutegravir (Tivicay™) 
TIVICAY Tablets, 50 mg, are yellow, round, film-coated, biconvex tablets debossed with  
SV 572 on one side and 50 on the other side. Each film-coated tablet of TIVICAY for oral 
administration contains 52.6 mg of dolutegravir sodium, which is equivalent to 50 mg 
dolutegravir free acid, and the following inactive ingredients: D-mannitol, microcrystalline 
cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet 
film-coating contains the inactive ingredients iron oxide yellow, macrogol/PEG, polyvinyl 
alcohol-part hydrolyzed, talc, and titanium dioxide. The chemical name of dolutegravir sodium is 
sodium (4R,12aS)-9-[ [ (2,4-difluorophenyl) methyl]carbamoyl ]-4-methyl-6,8-dioxo-
3,4,6,8,12,12a-hexahydro-2H-pyrido [1',2':4,5] pyrazino[2,1-b][1,3]oxazin-7-olate. 
 
6.2 Assessment of participant compliance with the study agent/intervention 


12 
 
The investigator/study coordinator will review the subject’s estimated adherence to study drugs 
at each visit. 
 
6.3 Concomitant medications and procedures 
No drugs are to be taken within 14 days of the start of the study without the knowledge of the 
investigator. 
 
Non-ART investigational agents must be discontinued for 30 days prior to treatment in this 
study. 
 
Permitted Concomitant Therapy 
The concomitant use of other medications/therapies is allowed unless specifically prohibited in 
the Prohibited Concomitant Medications/Therapies section below. It is the responsibility of the 
investigator to check on potential drug-drug interactions of the study antiretroviral agents with 
other concomitant medications, before placing a subject on a specific medication/therapy. 
 
6.4 Precautionary and prohibited medications and procedures 
Raltegravir and dolutegravir are eliminated mainly via a UDP-glucuronosyltransferase (UGT) 
1A1-mediated glucuronidation pathway and, therefore, the compound may be subject to drug-
drug interactions when co-administered with drugs that are known to be UGT1A1 inducers or 
inhibitors. However, raltegravir/dolutegravir is not anticipated to affect the metabolic clearance 
of drugs metabolized by UGT1A1 given its low UGT1A1 inhibitory (IC50 for the inhibition of 
UGT1A1 >50 uM) and induction potential. Since raltegravir is neither a substrate nor an 
inhibitor of cytochrome P-450 enzymes, raltegravir is not expected to exhibit metabolic drug 
interactions with substrates of cytochromes P-450. Dolutegravir is primarily metabolized via 
UGT1A1 with some contribution from CYP3A. Darunavir/ritonavir, lopinavir/ritonavir, 
rilpivirine, tenofovir, boceprevir, telaprevir, prednisone, rifabutin, and omeprazole had no 
clinically significant effect on the pharmacokinetics of dolutegravir. 
 
Maraviroc is a CYP3A4 and Pgp substrate and therefore is expected to be modulated by inducers 
and inhibitors of these enzymes and transporters. Maraviroc is unlikely to inhibit co-
administered drugs metabolized by the following cytochrome enzymes (CYP1A2, CYP2B6, 
CYP2C8, CYP2C9, CYP2C19 and CYP3A) as it did not inhibit these enzymes in vitro. 
 
Prohibited Medications 
• The medications/therapies below are contraindicated in this study because they are potent 
broad inducers of drug metabolism, inducers of CYP3A (thus potential inducers of 
glucuronidation), and/or inhibitors of glucuronidation and their co-administration with 
raltegravir/dolutegravir and maraviroc will likely result in altered drug levels of 
raltegravir/dolutegravir and/or maraviroc. 
o Rifampin 
o St. John’s Wort 
o Dofetilide 
 
• Any other medications/therapies that may adversely affect the drug levels of the 
antiretroviral agents in the treatment regimen should be avoided to ensure adequate 


13 
 
therapeutic levels of the study medications. Medications specifically contraindicated to 
the study antiretroviral agents selected are prohibited. 
 
• Non-ART investigational agents. 
 
• Immunosuppressive therapy other than intra-lesional or localized electron beam therapy 
for cutaneous Kaposi’s sarcoma. If a patient develops a malignancy (for example 
lymphoma) after allocation, the patient may receive chemotherapy and remain in the 
study if, in the opinion of the investigator, the benefits outweigh the risks. Depending on 
the type of chemotherapy, study medication may need to be interrupted until completion 
of chemotherapy. 
 
6.5 Diet 
Doses of raltegravir/dolutegravir and maraviroc will be consumed without regard to food. 
 
 
7. Study procedures/evaluations 
Study procedures should be performed as close to the scheduled time as possible. See the study 
flow chart in Section 8 for a complete listing of study procedures required at each visit. 
 
7.1 Informed consent 
The investigator will obtain documented consent from each potential subject. Prior to signing the 
document, all potential subjects will be evaluated with a standardized “Evaluation to sign 
consent” form (appendix). Consent must be documented by the subject’s dated signature on an 
official University of Maryland Baltimore Consent Form along with the dated signature of the 
person conducting the consent discussion. 
 
If the subject is illiterate, an impartial witness should be present during the entire informed 
consent reading and discussion. Afterwards, the subject should sign and date the informed 
consent, if capable. The impartial witness should also sign and date the informed consent along 
with the individual who read and discussed the informed consent (i.e., study staff personnel). 
 
A copy of the signed and dated consent form will be given to the subject before participation in 
the trial.  The initial informed consent form and any subsequent revised written informed consent 
form, and any written information provided to the subject must receive the Institutional Review 
Board IRB)/Independent Ethics Committee (IEC) approval/favorable opinion in advance of use. 
The subject or his/her legally acceptable representative must be informed in a timely manner if 
new information becomes available that may be relevant to the patient’s willingness to continue 
participation in the trial. The communication of this information will be provided and 
documented via a revised consent form or addendum to the original consent form and in the 
research chart. 
 
7.2 Assignment of research study number 
For identification purposes during the screening period, each subject will be assigned a unique 
study number. Subjects who are screened multiple times retain the original study number 
assigned at the initial screening visit for any subsequent screening. 


14 
 
 
7.3 Clinical and Laboratory evaluations 
 
7.3.1 Procedures to be performed at screening visit (Day -56 to Day -14) 
• Complete Medical History - A complete medical history is required. 
• Complete Physical Examination - A complete physical examination (including body 
weight, height, and vital signs [temperature, pulse, respiratory rate, and blood pressure]) 
must be obtained. 
• Complete Medication History – A complete review of all medications and supplements 
the patient is currently taking. 
• Urinalysis 
• Serum Pregnancy test for women of child bearing potential 
o Female subjects of childbearing potential will have a serum pregnancy test (HCG) 
performed prior to the study start date. Women who are found to be pregnant will 
be excluded from the study. 
• Blood for Screening Labs obtained within 56 days of study entry)  –  
o CBC with differential 
o Serum Chemistry  
o LFT’s (including AST, ALT, Total bilirubin)CK  
o Hepatitis B 
 Hepatitis B serologies will only be done if documentation of previous tests 
cannot be obtained. 
 Hepatitis B surface Antigen must have been done within the past 12 
months unless evidence of immunity to hepatitis B (i.e. hepatitis B surface 
antibody positive). 
o Hepatitis C 
 Hepatitis C serology will only be done if documentation of previous test 
cannot be obtained 
o HIV-1 Elisa/Western Blot  
 HIV-1 Elisa/Western Blot will only be done if documentation of either a) 
previously positive Elisa/Western Blot test or b) 2 separate HIV-1 RNA 
viral loads ≥500 copies/ml cannot be obtained.   
o HIV-1 RNA PCR 
o CD4 Cell Count 
o DNA Trofile test 
 DNA Trofile test will only be done if none available and: 
• nadir CD4 250 – 499, or 
• patient originates from a region where HIV subtypes A or D are 
prevalent (includes West and East/central Africa)  
o Blood for Serologic/PBMC assays/storage 
 
 
7.3.2 Procedures to be performed at Entry visit, Day 0 
 


15 
 
Initiation of study treatment will be performed on Day 0 once all inclusion criteria, and no 
exclusion criteria, are met. For subjects who meet the eligibility criteria, the following will be 
performed: 
 
• Directed Medical History  
• Directed Physical Examination (including body weight and vital signs [temperature, 
pulse, respiratory rate and blood pressure]). Vital signs and body weight must be 
measured prior to allocating the patient and initiating therapy. 
• Complete Medication History – A complete review of all medications and supplements 
the patient is currently taking. 
• Review of Adverse Events 
• Blood will be collected for safety assessments  
o CBC with differential 
o Serum Chemistry  
o LFT’s (including AST, ALT, Total bilirubin) 
o Lipid Panel (including total cholesterol, LDL, HDL, triglycerides) 
o CK 
o HIV RNA PCR 
o CD4 cell count 
o Tropism 
o Blood for Serologic/PBMC Assays/Storage.  
• Urine Pregnancy Test - For female subjects of childbearing potential, a urine pregnancy 
test will be performed at the site. If the urine pregnancy test result is negative, the subject 
will be eligible for enrollment and the remainder of the Day 0 testing/procedures will be 
performed. If the urine pregnancy test result is positive, the patient will be excluded from 
participation. 
 
Patients must be in a fasted state (for at least 8 hours) for collection of the blood samples for 
safety assessment at the Day 0 visit. 
 
Plasma/PBMCs for archiving will be collected for potential future use regarding virologic 
suppression/resistance, ultra-low copy assays, and/or immunological markers associated with the 
HIV virus. 
 
It is recommended that the subjects take their initial dose of open-label therapy in the clinic.  
 
Subjects will be instructed to take the study medications as follows: 
 
Take 1 tablet from bottle labeled Raltegravir (Isentress™) 400 mg twice a day, ~12 hours (10 to 
14 hours) apart. The tablets can be consumed without regard to food. 
Or 
Take 1 tablet from bottle labeled Dolutegravir (Tivicay™) 50 mg once a day, ~24 hours (22 to 
26 hours) apart. The tablets can be consumed without regard to food. 
And 
Take 1 tablet from bottle labeled Maraviroc (Selzentry™) 300 mg twice a day, ~12 hours (10 to 
14 hours) apart. The tablets can be consumed without regard to food. 


16 
 
 
All containers of study drug will be returned to the study coordinator at each visit, at which time 
the drug supplies for the following time period will be dispensed. The number of tablets 
remaining in the bottle will be counted and recorded in the source documentation.  Note that 
neither Maraviroc nor Raltegravir/Dolutegravir is provided through the study. 
 
At the Day 0 visit, each patient will be given a diary card to record study drug administration. 
 
7.3.3 Procedures to be performed during study treatment (Visit 1 to Visit 15 and 
unscheduled visits) 
 
All subjects must return to the clinic at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96, 
and early discontinuation (if applicable) as noted in the study flow sheet. 
 
During the study visits, the following will be performed: 
• Directed Medical History  
• Directed Physical Examination (including body weight and vital signs [temperature, 
pulse, respiratory rate and blood pressure])  
• Review of Adverse Events 
• Complete Medication History – A complete review of all medications and supplements 
the patient is currently taking. 
• Blood will be collected as noted in the study flow sheet, including for: 
o HIV RNA at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24, 36, 48, 60, 72, 84, 96 and early 
discontinuation (if applicable). 
o Safety measurements will be assessed at weeks 2, 6, 12, 24, 36, 48, 60, 72, 84, 96 
and early discontinuation (if applicable), including: 
 CBC with differential 
 Serum Chemistry  
 LFT’s (including AST, ALT, Total bilirubin) 
 CK 
o CD4 will be measured at Weeks 12, 24, 48, 72, 96 and early discontinuation (if 
applicable). 
o Lipid parameters will be measured at week 24, week 48, week 96, and early 
discontinuation (if applicable). 
 
Subjects must be in a fasted state (for at least 8 hours) for collection of the blood samples for 
safety assessment at Weeks 12, 24, 48, 96 and early discontinuation (if applicable). 
 
Women of childbearing potential will have a urine pregnancy test performed if clinically 
indicated (i.e. if menses are missed or a clinical suspicion of pregnancy) at Weeks 12, 24, 36, 48, 
60, 72, 84, and 96. 
 
Tropism assay will be done at the next visit when the preceding viral load is > 1,000 copies/ml. 
 
Blood samples will be collected (Plasma and PBMCs) for archiving at Weeks 12, 24, 48, 96 and 
early discontinuation (ED) or virologic failure (VF) (if applicable) for potential future use 


17 
 
regarding virologic suppression/resistance, tropism assay, ultra-low copy assays, CCR5 density, 
lipid subfraction analyses and/or immunological markers associated with the HIV virus. 
 
Blood samples will be collected at early discontinuation (if applicable) for possible resistance 
testing/tropism assay. 
 
7.3.4 Virologic failure confirmation visit 
 
This visit will occur at least 1 week following suspected virologic failure. Virologic failure is 
defined as: 
• HIV RNA > 50 copies/ml confirmed on two separate occasions after viral suppression 
<50 copies/ml 
 
Blood will be collected for the following: 
• HIV RNA 
• CD4 cell count 
• Possible HIV resistance testing 
• Possible HIV tropism testing 
• Plasma/PBMC storage from subjects who are suspected of having virologic failure 
 
7.3.5 Discontinuation/Withdrawal from the study 
 
Subjects may withdraw at any time or be dropped from the study at the discretion of the 
investigator should any untoward effects occur. In addition, a subject/patient may be withdrawn 
by the investigator if he/she violates the study plan or for administrative and/or other safety 
reasons. When a subject/patient discontinues/withdraws prior to study completion, all applicable 
activities scheduled for the final study visit should be performed at the time of discontinuation. 
Any adverse experiences which are present at the time of discontinuation/withdrawal should be 
followed in accordance with the safety requirements outlined in Section 9 Safety.  The subject 
will then be referred back to their primary care physician for determination of appropriate 
management of the patient’s HIV infection. 
 
Because there have been no adequate and well controlled studies of raltegravir/dolutegravir and 
maraviroc in pregnant women, if a patient becomes pregnant during the course of the study, the 
investigator, in consultation with the patient, should consider whether the potential benefit 
justifies the potential risk to the fetus of continuing the study therapy. If it is determined that the 
potential benefit does not outweigh the potential risk to the fetus, the patient should be 
discontinued from the study.  
 
All pregnancies must be reported immediately. The outcome of all pregnancies must be reported. 
Subjects who become pregnant will be asked to join a pregnancy registry which collects 
information about the outcome of the pregnancy. 
 
Should a subject develop evidence of dual or X4 tropism during the study, the patient will be 
removed from the study and placed on an appropriate antiretroviral regimen optimized using the 


18 
 
genotype obtained at study discontinuation.  This could include use a combination of NRTIs, 
NNRTIs, and PIs as determined by the patient’s primary HIV physician.  
 
7.4 Clinical and research laboratory evaluations and specimen collection 
The primary measurement for efficacy in the overall study is HIV RNA. Additional 
measurements for efficacy include CD4 counts and viral resistance testing. The key timepoint for 
evaluation of efficacy is Week 48. 
 
Subjects will have ~560 mL (38 tablespoons) of blood drawn during the study. See study flow 
sheet for more detailed information. 
 
Plasma HIV RNA determination will be performed by the same laboratory during the study 
unless that laboratory is no longer able to perform the needed assays.  
 
To evaluate possible development of resistance to raltegravir/dolutegravir and maraviroc, blood 
samples will be collected/archived at Weeks 24, 48, at virologic failure confirmation visit, and at 
early discontinuation visit (if not already obtained at virologic failure confirmation visit) to 
assess resistance to raltegravir/dolutegravir and maraviroc. 
 
 
8. Study schedule 
 
Study procedures should be performed as close to the scheduled time as possible. See the study 
flow chart below for details: 
 
 


19 
 
STUDY VISIT 
SCREEN 
ENTRY 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
ED 
VF 
STUDY WEEK 
-8 TO  -2 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
36 
48 
60 
72 
84 
96 
Obtain Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/ 
Exclusion Criteria 
X 
 
X 
 
 
X 
 
 
X 
 
X 
 
X 
 
 
 
X 
 
 
Complete Medical History 
and Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
X 
X 
Directed Medical History 
and Physical Examination 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
 
 
 
Complete Medication 
History 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Review Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pregnancy test (serum) 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (urine) 
 
X 
 
 
 
 
 
Ⓧ1 
 
 
Ⓧ1 
Ⓧ1 
Ⓧ1 
Ⓧ1 
Ⓧ1 
Ⓧ1 
Ⓧ1 
Ⓧ1 
Ⓧ1 
Blood for Screening Labs: 
CBC with diff, Serum 
chemistry, LFT’s, CK,  
Hep B2, Hep C2, HIV-1 
ELISA/Western blot2 
Ⓧ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
 
HIV-1 RNA PCR 
X 
Ⓧ 
Ⓧ 
X 
Ⓧ 
X 
X 
Ⓧ 
X 
X 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
X 
 
CD4 Cell Count 
 
Ⓧ 
 
 
 
 
 
Ⓧ 
 
 
Ⓧ 
 
Ⓧ 
 
Ⓧ 
 
Ⓧ 
X 
 
Blood for Safety Labs: 
CBC with diff, Serum 
chemistry, LFT’s, CK 
 
X 
Ⓧ 
 
Ⓧ 
 
 
Ⓧ 
 
 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
X 
 
Lipid Panel 
 
Ⓧ 
 
 
 
 
 
 
 
 
Ⓧ 
 
Ⓧ 
 
 
 
Ⓧ 
X 
 
Tropism3 
X3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X3 
X3 
Genotype4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X4 
X4 
Blood for Serologic/PBMC 
Assays/Storage 
X 
X 
 
 
 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
X 
X 
Total blood volume (ml) 
74-84 ml 
69 ml 
 5 ml 
5 ml 
5 ml 
16ml 
5 ml 
33ml 
5 ml 
13ml 
61ml 
13ml 
69ml 
13ml 
16ml 
13ml 
69ml 
79-84 
ml 
53-68 
ml 
Approximate Visit 
Duration (minutes) 
60 
60 
20 
20 
20 
20 
20 
30 
20 
20 
30 
20 
60 
20 
20 
20 
60 
60 
60 
Abbreviations:  ED = Early Discontinuation; VF = Virologic Failure 


20 
 
Footnotes:  Ⓧ represent HIV standard of care blood draws; X represents research related tests/blood draws. 
1.  Pregnancy tests will be ordered if menses are missed or a clinical suspicion of pregnancy. 
2.  HIV-1 ELISA/Western blot (HIV-1 antibody test) will only be done if documentation of either a) previously positive Elisa/Western blot test or b) 2 separate 
HIV-1 RNA viral loads ≥500 copies/ml cannot be obtained.  Hepatitis B and C serologies will only be done if no prior documentation of results exists. Hepatitis 
B surface Antigen must have been done within the past 12 months unless there is evidence of immunity to hepatitis B (i.e. hepatitis B surface antibody positive). 
3. A trofile DNA test will be done during screening for patients with nadir CD4 250 – 499 if there is no trofile testing on record. Blood for tropism testing will be 
drawn at the follow-up visit after a first HIV VL is > 50 copies/ml (i.e. virologic failure confirmation visit) or at the early discontinuation visit if the prior VL is > 
50 copies/ml. However, since assay sensitivity is poor if the viral load is < 1,000 copies/ml, the blood will be stored and only sent for testing if the VL returns > 
1,000 copies/ml. Tropism will only be ordered at early discontinuation if the viral load is > 1,000 copies/ml. 
4. HIV resistance genotype (including genotype for integrase activity) will be done at early discontinuation or virologic failure confirmation if the prior VL is > 
50 copies/ml. 
The virologic failure confirmation visit will occur if the viral load meets virologic failure criteria in the protocol. At that visit blood will be drawn for viral load, 
CD4 cell count, genotype, tropism, and pK trough for raltegravir/dolutegravir and maraviroc. 
 
 
 


21 
 
STUDY VISIT 
SCREEN ENTRY 
01 
02 
03 
04 
05 
06 
07 
08 
09 
10 
11 
12 
13 
14 
15 
ED 
VF 
STUDY WEEK 
-8 TO  -2 
0 
2 
4 
6 
8 
10 
12 
16 
20 
24 
36 
48 
60 
72 
84 
96 
Screening Labs: 
CBC with diff, Serum 
Chemistry, LFT’s, CK 
Tropism, Hep B, Hep C1 
HIV-1 ELISA/Western blot1 
Ⓧ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood for Safety Labs: 
CBC with diff, Serum 
Chemistry, LFT’s, CK 
 
X 
Ⓧ 
 
Ⓧ 
 
 
Ⓧ 
 
 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Ⓧ 
Pregnancy Test (serum) 
3 ml 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV ELISA/Western Blot* 
5 ml* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B/C Serologies* 
5 ml* 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 RNA PCR 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
5 ml 
 
CD4 Cell Count 
 
3 ml 
 
 
 
 
 
3 ml 
 
 
3 ml 
 
3 ml 
 
3 ml 
 
3 ml 
3 ml 
 
CBC with diff 
3 ml 
3 ml 
3 ml 
 
3 ml 
 
 
3 ml 
 
 
3 ml 
3 ml 
3 ml 
3 ml 
3 ml 
3 ml 
3 ml 
3 ml 
 
Serum Chemistry, LFT’s, CK 
5 ml 
5ml 
5 ml 
 
5 ml 
 
 
5 ml 
 
 
5 ml 
5ml 
5ml 
5ml 
5ml 
5ml 
5ml 
5ml 
 
Tropism2 
5 ml2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
5 ml2 
5 ml2 
Genotype2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
10 ml3 
10 
ml3 
Lipid panel 
 
3 ml 
 
 
 
 
 
 
 
 
3 ml 
 
3 ml 
 
 
 
3 ml 
3 ml 
3 ml 
Blood for Serologic /PBMC 
Assays/Storage 
50 ml 
50 ml 
 
 
 
 
 
20 ml 
 
 
50 ml 
 
50 ml 
 
 
 
50 ml 
50 ml 
50 ml 
Total blood volume (ml) 
66-81 ml 
69 ml 
 13 ml 
5 ml 
13 ml 
5 ml 
5 ml 
36 ml 
5 ml 
5 ml 
69 ml 
13 ml 
69 ml 
13 ml 
16 ml 
13 ml 
69 ml 
79-84 
ml 
53-68 
ml 
Abbreviations:  ED = Early Discontinuation; VF = Virologic Failure 
Footnotes: Ⓧ represent HIV standard of care blood draws; X represents research related tests/blood draws. 
* HIV ELISA/Western Blot and Hepatitis B and C serologies will only be done if the patient does not have documentation of previous studies. Hepatitis B 
serologies must have been done within the past 12 months. 
1.  HIV-1 ELISA/Western blot (HIV-1 antibody test) will only be done if documentation of either a) previously positive Elisa/Western blot test or b) 2 separate 
HIV-1 RNA viral loads ≥500 copies/ml cannot be obtained. Hepatitis B and C serologies will only be done if no prior documentation of results exists. Hepatitis 
B surface Antigen must have been done within the past 12 months unless there is evidence of immunity to hepatitis B (i.e. hepatitis B surface antibody positive). 
2. A trofile DNA test will be done during screening for patients with nadir CD4 250 – 499 if there is no trofile testing on record. Blood for tropism testing will be 
drawn at the follow-up visit after a first HIV VL is > 50 copies/ml (i.e. virologic failure confirmation visit) or at the early discontinuation visit if the prior VL is > 
50 copies/ml. However, since assay sensitivity is poor if the viral load is < 1,000 copies/ml, the blood will be stored and only sent for testing if the VL returns > 
1,000 copies/ml. Tropism will only be ordered at early discontinuation if the viral load is > 1,000 copies/ml. 
3. HIV resistance genotype (including genotype for integrase activity) will be done at early discontinuation or virologic failure confirmation if the prior VL is > 
50 copies/ml. 


22 
 
The virologic failure confirmation visit will occur if the viral load meets virologic failure criteria in the protocol.  It will occur at least 1 week following suspicion 
of virologic failure (viral load > 50). At that visit blood will be drawn for viral load, CD4 cell count, genotype, phenotype for integrase activity, tropism, and pK 
trough for raltegravir/dolutegravir and maraviroc 
 
 
Total Blood Volume over whole study duration (96 weeks) for typical completion of study:  484-494 ml 
 


23 
 
9. Assessment of safety 
 
9.1 Specification of safety parameters 
Subjects will be asked about any adverse experiences/events during their clinic visits and the 
information will be recorded on the case report forms. Guidelines for grading the severity of 
adverse experiences are based on Division of Acquired Immunodeficiency Syndrome (DAIDS) 
criteria for grading severity of adverse events. 
 
Decisions to temporarily withhold therapy because of an adverse experience will be reviewed on 
a case-by-case basis by the investigator. 
 
The investigator should consider temporarily withholding therapy if the severity of the adverse 
experience is Grade 3 or above and/or if clinically indicated. The decision to interrupt therapy 
should take into account the subject’s baseline laboratory values and any concomitant medication 
that could be contributory. At the discretion of the investigator, therapy may generally be 
reinitiated when laboratory abnormalities or clinical adverse events return to near normal or 
baseline values. 
 
If after the re-initiation of study therapy, there is a recurrence of the laboratory abnormality or 
clinical adverse event, consideration should be given to permanently discontinuing all study 
therapy. In general, when a clinical or laboratory adverse event occurs which requires 
interruption of study therapy, all study drugs should be interrupted to avoid having a subject 
receive suboptimal therapy which may predispose them to the development of resistance. In 
general, all study medications should be restarted at full dose concomitantly. 
 
9.2 Definition of an adverse event (AE) 
An adverse event is defined as any unfavorable and unintended change in the structure, function, 
or chemistry of the body temporally associated with the use of the study drugs, whether or not 
considered related to the use of the drugs. Any worsening (i.e., any clinically significant adverse 
change in frequency and/or intensity) of a preexisting condition which is temporally associated 
with the use of study drugs, is also an adverse event. 
 
Changes resulting from normal growth and development which do not vary significantly in 
frequency or severity from expected levels are not to be considered adverse events. Examples of 
this may include, but are not limited to onset of menses or menopause occurring at a 
physiologically appropriate time in a woman. 
 
Adverse events may occur in the course of the use of the study drugs in clinical studies or within 
the follow-up period specified by the protocol, or prescribed in clinical practice, from overdose 
(whether accidental or intentional), from abuse, and from withdrawal. 
 
Adverse experiences may also occur in screened subjects during the baseline period as a result of 
a protocol-specified intervention including washout or discontinuation of usual therapy, diet, 
placebo treatment, or a procedure.  Such events will be recorded at each examination on the 
Adverse Event Case Report Forms/Worksheets. 
 


24 
 
9.3 Unexpected Adverse Event 
An unexpected adverse event is defined as an adverse event that is not listed in the current 
investigator’s brochure and includes an event that may be symptomatically and 
pathophysiologically related to a listed event, but differs in having greater severity or specificity. 
 
9.4 Grading of Adverse Events 
The severity of adverse events will be graded according to the Division of Acquired 
Immunodeficiency Syndrome (DAIDS) scale.  Events or laboratory abnormalities not listed will 
be graded as follows: 
• Grade 1/Mild: Transient or mild discomfort; no limitation in activity; no medical 
intervention or therapy required. 
• Grade 2/Moderate:  Mild to moderate limitation in activity.  Some assistance may be 
needed; minimal or no medical intervention and/or therapy required. 
• Grade 3/Severe: Marked limitation in activity, some assistance usually required; medical 
intervention and/or therapy required, hospitalization possible. 
• Grade 4/Life-Threatening:  Extreme limitation in activity, significant assistance required; 
significant medical intervention and/or therapy required hospitalization or hospice care 
probable. 
 
9.4.1 Relationship to Study Drug 
The investigator will make a determination as to whether the adverse event is related to study 
drug or not. Relationship to the study drug will be categorized as “Definite,” “Probable,” 
“Possible,” or “Definitely Not”. 
 
• DEFINITE – There is a strong relationship to the study drug.  The adverse event: 
o Follows a reasonable temporal sequence to the study drug’s administration. 
o The adverse event resolved once the study drug was discontinued (de-challenge). 
o The adverse event reappeared upon re-exposure to the study drug (re-challenge). 
 
• PROBABLE – There may be a relationship to the investigational product.  The adverse 
event: 
o Follows a reasonable temporal sequence from drug administration. 
o Demonstrates a clinically reasonable response pattern to discontinuation of the 
study drug. 
o Is unlikely to be attributed to concurrent disease, drugs or procedures. 
o Could not be reasonably explained by the known characteristics of the patient’s 
clinical state. 
 
• POSSIBLE – The relationship may or can exist, but other factors may also be implicated; 
if the relationship cannot be ruled out, it must be considered possible.  The adverse event: 
o Follows a reasonable temporal sequence from study drug administration. 
o Could have been produced by the patient’s clinical state, environmental and toxic 
factors, or by other modes of therapy administered to the patient. 
o Follows a known pattern of response to the suspected drug. 
 


25 
 
• DEFINITELY NOT – The adverse event is definitely produced by the patient’s clinical 
state or by other modes of therapy administered to the patient and is therefore unrelated 
to administration of the study drug. 
 
9.5 Methods and timing for assessing, recording, analyzing, and managing safety 
parameters 
Adverse events will be evaluated at each study visit, any unscheduled visits, virologic failure 
confirmation visit, and discontinuation/withdrawal from the study visits. 
 
9.6 Stopping rules for the protocol 
Four confirmed virologic failures (13%) will be considered grounds for stopping the study. 
 
 
10. Clinical monitoring structure 
10.1 Safety monitoring plan 
The study will have regularly scheduled monitoring by the IHV Data and Safety Monitoring 
Board (DSMB) and follow its standard protocol. The first DSMB review will occur 6 months 
after the first subject is enrolled and then every 6 months after that. It will meet earlier if any 
concerns are raised by the Medical Monitor as to virologic failure, toxicity, or serious adverse 
experiences related to the study medication. 
 
 
11. Data analysis and statistical considerations 
11.1 Description of the analyses 
 
The primary objective of this open-label single arm study is to describe the efficacy and safety of 
raltegravir/dolutegravir in combination with maraviroc in antiretroviral treatment experienced 
patients.   
 
The statistical analyses will therefore be primarily descriptive. The primary endpoint is the 
proportion of patients virological suppressed (< 50 copies/ml) at 48 weeks. All efficacy and 
safety analyses will provide estimates only; no formal comparisons will be made. All efficacy 
and safety endpoints will be summarized for the whole population. 
 
11.2 Sample Size and Power Calculations 
This is a pilot study in 30 patients to evaluate the novel combination of an integrase inhibitor 
(raltegravir/dolutegravir) and maraviroc. As it is a small pilot study, power calculations are not 
appropriate. 
 
 
12. Ethics/protection of human subjects 
12.1 Institutional review board (IRB) 
The investigator will ensure that this study is conducted in full conformity with the current 
revision of the Declaration of Helsinki, or with the International Conference for Harmonization 
Good Clinical Practice (ICH-GCP) regulations and guidelines, whichever affords the greater 
protection to the subject. 


26 
 
IRB approval from the University of Maryland Baltimore will be obtained prior to initiation of 
this trial. 
 
12.2 Informed consent process 
Before screening the patients, all candidates will be informed in detail about the study drug to be 
administered, and the nature of the clinical investigation, with its risks and benefits. The 
elements of the Informed Consent will be followed. Written consent will be obtained from each 
patient to be involved in the clinical trial by using a modified version the University of 
Maryland’s IRB-approved Informed Consent Form. Consent will be verified by the investigator, 
or a member of the trial staff. The investigator will provide each patient with a signed copy of 
the informed consent, and a signed copy of the original will be placed in the study file. The 
patient will also be informed that they are free to withdraw their consent and discontinue their 
participation in the study at any time without penalty. Premature withdrawal from the study will 
not alter the patient’s entitlement to care at any hospital/clinic supported by the Institute of 
Human Virology/University of Maryland. 
 
12.3 Participant privacy and confidentiality 
Confidentiality will be protected in the following ways: Limited use of identifiers beyond that 
needed for the study. Data abstraction sheets will be kept in a locked cabinet in a locked office at 
the clinical trials unit of the IHV. Data will be entered into a password protected file on a 
password protected computer.  
Privacy will be protected by limiting any discussions with subjects to private or semi-private 
rooms. Stored blood for future research will only use the study identification number with no 
personal health information. Through each phase of the study, privacy protections will be 
maintained. Only the PI and study staff will have access to identifying data. Stored blood for 
future research will only use the study identification number with no personal health information. 
 
 
13. Publication plan 
 
It is expected that the results of the study would be presented at an infectious disease/HIV 
conference (e.g. CROI, IDSA/ICAAC, or IAS/IAC). It is anticipated that the study will generate 
1-3 abstracts.  We anticipate that the study will generate 1-2 manuscripts which will be submitted 
to a journal such as AIDS, Clinical Infectious Diseases, or other journals of a similar caliber. It is 
anticipated that a manuscript would be submitted within 6 months of completion of the final 
analysis of the study data. 
 
 
 
 


27 
 
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