A Phase 2/3 Multicenter, Open-Label, Multicohort, Two-Part
Study Evaluating the Pharmacokinetics (PK), Safety, and
Antiviral Activity of Elvitegravir (EVG) Administered with a
Background Regimen (BR) Containing a Ritonavir-Boosted
Protease Inhibitor (PI/r) in HIV-1 Infected, Antiretroviral
Treatment-Experienced Pediatric Subjects (PROTOCOL NUMBER: GS-US-183-0160, Date of Protocol: 04/25/2013
Although more than 20 different antiretrovirals (ARV) in five classes are available for the treatmentof HIV infection in adults, treatment-experienced pediatric patients who do not have control of their virus continue to have limited treatment options. Children with longstanding HIV infectionare in particular need of new classes of drugs that work to fight against HIV resistant with the existing classes of medications. Currently, HIV-infected children have very limited options forwell-tolerated once daily therapy. No once daily INSTI (Intergrased Strand Transfer Inhibitor-class of drug) is currently approved for use in HIV infected children. Thus, for many children who have experienced and/or failed treatment there is currently a need to find more effective medications to be included in second and later-line regimens. Elvitegravir is an HIV integrase inhibitor that has demonstrated in vitro activity against NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitors), NRTI (Nucleoside/Nucleotide Reverse Transcriptase Inhibitors) or PI (Protease Inhibitors) drug resistant HIV. In clinical studies, elvitegravir has shown significant declines in HIV RNA (amount of virus in blood) in treatment-experienced patients with documented drug resistance. The current study is designed to examine the drug level in the body at different time points by drawing blood samples at specific time points throughout the day (PK-pharmacokinetics), safety and antiviral activity, how the medications works in children, when Elvitegravir added to a BR (Background Regimen) containing a ritonavir-boosted PI in HIV infected, antiretroviral treatment-experienced pediatric subjects. The primary objectives of this study are as follows: To evaluate the steady-state PK and confirm the dose ofritonavir-boosted elvitegravir (EVG/r) in HIV infected,antiretroviral treatment-experienced subjects 4 weeks to<18 years of age To evaluate the safety and tolerability of EVG/r in HIVinfected, antiretroviral treatment-experienced subjects 4 weeksto <18 years of ageThe secondary objective of this study is as follows: To evaluate the antiviral activity of EVG/r in HIV infected,antiretroviral treatment-experienced subjects 4 weeks to<18 years of age who are failing their current HAART regimen.
A5294: A Prospective, Phase III, Open-Label Study of Boceprevir, Pegylated-Interferon Alfa 2b and Ribavirin in HCV/HIV Coinfected SubjectsBoceprevir, Interferon, Ribavirin to Treat HCV/HIV Coinfected Subjects (BIRTH)
For HIV-1-infected individuals, HCV infection is a leading cause of morbidity and mortality,
and the prevalence of HCV infection is higher among those infected with HIV-1. At the time
the study was designed, the standard-of-care (SOC) therapy for HCV infection was treatment
with both PEG-IFN and RBV. This therapy is 40%-45% effective in patients with HCV infection
but is significantly less effective in patients with both HCV and HIV-1 (Shire et al. J
Viral Hepat., 2007). The purpose of this study was to evaluate the effectiveness of adding
BOC (Kwo et al. Lancet, 2010), an HCV protease inhibitor, to SOC therapy in treating HCV
infection (genotype 1) in HCV/HIV-1-coinfected adults.
Participants were enrolled into one of two groups based on previous HCV treatment
1. Group A: HCV treatment-naive participants who had never received treatment with PEG-IFN
or experimental agents used to treat HCV, with or without RBV (N=170, refer to the note
2. Group B: HCV treatment-experienced participants who had received any treatment with
standard interferon or with PEG-IFN with or without RBV, provided the last dose of
treatment was 90 days or more before study entry (N=140, refer to the note below).
Note: The team correspondence with the FDA led to an amendment to close enrollment in
December 2013, prior to the target sample sizes of 170 in Group A and 140 in Group B, as the
study power could be lowered while still meeting the key study objectives.
All participants had to be on stable antiretroviral therapy (ART) for at least 8 weeks prior
to study entry using a dual nucleos(t)ide reverse transcriptase inhibitor (NRTI) backbone
plus one of the following: efavirenz (EFV), raltegravir (RAL), lopinavir (LPV)/ritonavir
(RTV) 400/100 mg twice daily, atazanavir (ATV)/RTV, darunavir (DRV)/RTV 600/100 mg twice
daily OR must not have received any ART for at least 4 weeks immediately prior to entry.
Participation in this study lasted approximately 72 weeks.
HCV treatment-naive participants (Group A) were treated with PEG-IFN and RBV for 4 weeks
(lead-in). Then BOC was added to the treatment regimen (triple therapy). Cirrhotic
participants received 44 weeks of triple therapy. Among non-cirrhotics, the Week 8 HCV RNA
was used to determine total duration of therapy. Those who had undetectable HCV RNA at Week
8 completed therapy at Week 28. Those with detectable HCV RNA at Week 8 received 32 weeks of
triple therapy followed by 12 additional weeks of double-drug therapy with PEG-IFN/RBV. HCV
treatment-experienced participants (Group B) also had a lead-in followed by 32 weeks of
triple therapy and 12 weeks of PEG-IFN/RBV double therapy if non-cirrhotic, or by 44 weeks
of triple therapy if cirrhotic.
Treatment was to be discontinued due to HCV virologic failure if:
1. HCV RNA ≥100 IU/mL at Week 12,
2. detectable HCV RNA at Week 24, or
3. confirmed HCV RNA >1000 IU/mL any time after Week 12.
Undetectable HCV RNA was defined as below the lower limit of quantification (LLOQ) and
target not detected (TND) by Roche COBAS® TaqMan® HCV Test v2.0.
Study visits were scheduled at screening and at Weeks 2, 4, 6, 8, 10, 12, 16, 20, 24 and 28
for both study groups. Group A participants who completed treatment at Week 28 had further
study visits at Weeks 40, 52, 60, and 72. Participants who were prescribed 48-weeks of
therapy (Group A and Group B) had further study visits at Weeks 32, 36, 40, 44, 48, 60, and
72. At each visit, a physical examination and blood collection were conducted. Participants
also completed an HCV treatment adherence questionnaire. Select visits included urine
collection and pregnancy testing (for women of reproductive potential). Plasma, serum, and
peripheral blood mononuclear cells (PBMCs) were be stored for use in future studies. After
experiencing HCV virologic failure as defined above or premature treatment discontinuation
due to safety or other reasons, participants were followed on a separate schedule of events
with visits every 12 weeks from Week 24 to 72. The evaluations at these follow-up visits
were limited to safety evaluations and stored plasma/serum sample collection.
The A5294 study consisted of single-arm evaluations to assess the efficacy of BOC added to
PEG-IFN/RBV in the two study populations:
1. HCV treatment-naive participants (Group A)
2. HCV treatment-experienced participants (Group B).
The two study populations were addressed together in this single trial - rather than in two
separate trials - mainly for administrative efficiency. The analyses were conducted
separately for each Study Group. The study was not designed for comparison. The pooled
summaries for Baseline Characteristics provided in the Results Section in this record were
prepared solely for the ClinicalTrials.gov results submission.
A Phase I/II, Open-Label Trial to Evaluate the Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Etravirine (ETR) in Antiretroviral (ARV) Treatment-Experienced HIV-1 Infected Infants and Children, Aged 2 Months to < 6 Years (IMPAACT P1090, Version 5.0 dated, 03/10/2016)
Nevirapine (NVP) and Efavirenz, the two most widely used non nucleoside reverse transcriptase inhibitor (NNRTI) drugs, have a low genetic barrier for the development of drug resistance mutations, so that, a single amino acid substitution in the viral reverse transcriptase leads to profound reduction in viral susceptibility to both drugs. With the widespread use of first generation NNRTIs as components of combination antiretroviral therapy, and as a component of neonatal prevention of mother to child transmission (PMTCT) treatment regimens, and infant nevirapine during breastfeeding, the number of children harboring virus with one or two NNRTI-resistance mutations will continue to increase. Thus, there is an urgent need to develop alternative therapeutic options for newly diagnosed neonates and infants exposed to single dose NVP containing regimens, as well as for infants and children failing their present HAART regimens. Etravirine (ETR) is a second generation NNRTI and has a structure that allows more molecular flexibility relative to other NNRTIs, allowing ETR to maintain its binding affinity for HIV-1 reverse transcriptase despite binding site changes induced by the presence of common NNRTI resistance mutations. This is a Phase I/II, multicenter, open label 48 week study of the pharmacokinetics, safety and tolerability of ETR in combination with at least 2 active antiretrovirals (ARVs), including a boosted PI and NRTIs for treatment experienced HIV-1-infected infants and children 2 months to < 6 years cohorts. The study will, in a sequential manner, accrue subjects for an initial dose finding intensive PK component for age related cohorts. It is expected that up to 50 subjects will be accrued study wide, to yield at least 36 evaluable* subjects with a minimum of 12 subjects for each of the three cohorts (up to 18 subjects may be enrolled into Cohort 1), whose initial dose was that which was determined optimal for their age cohorts. 3 participants will be enrolled at this site. The total sample size will depend upon the number needed to complete the dose finding stage of the study, the number of subjects who discontinue the study and the number of subjects required for regulatory approval of ETR in these populations. The primary endpoints for this study will be toxicity and failure to meet PK targets. The analysis of dose finding data will consist of descriptive statistics summarizing the safety and PK data from the dose finding phase of the study.
A5279: Phase III Clinical Trial of Ultra-Short-Course Rifapentine/Isoniazid for the Prevention of Active Tuberculosis in HIV-Infected Individuals with Latent Tuberculosis Infection
The World Health Organization (WHO) estimates that in 2009 there were 9.4 million new cases
of TB, and 1.68 million people died as a result of TB. Among new TB cases, 1.1 million
occurred in people who were HIV-coinfected, and 35% of TB deaths were among HIV-coinfected
individuals. In Africa, TB is the leading AIDS-related opportunistic infection. Latent TB
infection occurs when people are infected with the bacteria that cause TB, but they do not
have any symptoms of TB infection. Latent TB can develop into active TB, and HIV-infected
people have an increased risk of progressing from latent TB to active TB. INH is a
medication that is prescribed for people with latent TB to help prevent active TB from
developing. The standard INH treatment regimen is 6 to 9 months; a shorter treatment regimen
may prove to be as effective and may improve adherence. The purpose of this study is to
compare the safety and effectiveness of a 4-week daily regimen of RPT plus INH to a standard
9-month daily INH regimen for TB prevention in HIV-infected individuals.
This study will enroll HIV-infected people who do not have evidence of active TB but who are
at high risk of developing active TB. Participants will be randomly assigned to receive RPT
and INH once a day for 4 weeks or INH once a day for 9 months. All participants will receive
pyridoxine (vitamin B6) with each dose of INH to help prevent possible side effects. Study
visits will occur at baseline and Weeks 2, 4, 8, 12, 16, 20, 24, and 36. At select study
visits, participants will undergo a physical exam, clinical assessment, blood collection,
and a chest radiograph or chest computed tomography (CT) scan (if needed). Some participants
will have their blood stored for future testing. Follow-up study visits will occur every 12
weeks starting at Week 48 and will continue for 3 years after the last participant is
Very Early Intensive Treatment of HIV-Infected Infants to Achieve HIV Remission:A Phase I/II Proof of Concept Study (IMPAACT P1115 Version 1.0, dated March 12, 2014)
IMPAACT P1115 will explore the effects of early intensive ART on achieving HIV remission
(HIV RNA below the limit of detection of detection of the PCR assay) among infants infected
with HIV in utero. Infants in this study will initiate ART within 48 hours of birth and will
first be evaluated to determine whether HIV RNA can be detected in their blood while they
are on ART. Upon reaching two years of age, infants with undetectable HIV RNA will be
evaluated to determine if they meet study criteria to stop taking ART. Infants who meet
these criteria will stop taking ART and will be monitored closely to determine whether HIV
RNA remains undetectable while they are off ART. For any infant who stops ART and then has
HIV RNA detected, ART will be re-started.
The study will also assess the safety and pharmacokinetics of early intensive ART in
Phase I/II Study of High Dose Interleukin 2, Aldesleukin, in Combination With the Histone Deacetylase Inhibitor Entinostat in Patients With Metastatic Renal Cell Carcinoma
I. To evaluate the safety and tolerability of high dose interleukin 2 (aldesleukin) in
combination with entinostat in patients with metastatic renal cell carcinoma (RCC). (Phase
I) II. To monitor toxicity and estimate the efficacy of high dose aldesleukin combined with
entinostat in patients with metastatic RCC. (Phase II)
I. To compare the time-to-tumor progression, progression-free survival and overall survival
of patients with metastatic RCC treated with high dose aldesleukin combined with entinostat
to the historical data of patients treated with high dose aldesleukin alone. (Phase II) II.
To assess the toxicity of high dose aldesleukin combined with entinostat. (Phase II) III. To
evaluate entinostat pharmacodynamics (PD) in blood and tumor samples. (Phase II) IV. To
measure the association between baseline laboratory parameters (e.g. cluster of
differentiation [CD]4+, CD8+, CD4+/forkhead box P3 [Foxp3]), tumor blood metabolism, and a
variety of response variables (e.g. toxicity, response and survival). (Phase II) V. To
explore the relationship between entinostat exposure with PD endpoints (e.g. toxicity and
histone acetylation in peripheral blood mononuclear cells or peripheral blood mononuclear
cells [PBMNCs] and changes in T cell subset population). (Phase II) VI. To evaluate the
modulation of tumor metabolism by fluorodeoxyglucose (FDG, fludeoxyglucose F 18) positron
emission tomography (PET)/computed tomography (CT) scan. (Phase II)
OUTLINE: This is a phase I, dose-escalation study of entinostat followed by a phase II
Patients receive entinostat orally (PO) every 2 weeks beginning on day -14 and high-dose
aldesleukin intravenously (IV) every 8 hours on days 1-5 and 15-19. Courses repeat every 84
days* in the absence of disease progression or unacceptable toxicity.
NOTE: *Patients with evidence of tumor shrinkage may receive up to 3 courses of high-dose
aldesleukin therapy. Patients with stable disease by Response Evaluation Criteria in Solid
Tumors (RECIST) version 1.0 criteria, but without evidence of tumor shrinkage after two
courses will receive only entinostat until disease progression is documented.
After completion of study treatment, patients are followed up at 30 days and then every 3
A Randomized, Double-Blind, Placebo-Controlled Trial of the Safety and Effectiveness of Vitamin D3 50,000 IU Every 4 weeks to Increase Bone Mineral Density and Decrease Tenofovir-Induced Hyperparathyroidism in Youth with HIV Infection Being Treated with Tenofovir-Containing Combination Antiretroviral Therapy (ATN 109 Version 2.0, dated 08/18/2014)
This is a 48 week randomized double-blind, placebo-controlled prospective cohort study of
adolescents and young adults with HIV infection in the ATN who are currently being treated
with cART that includes TDF as one component of the regimen that includes at least three
Food and Drug Administration (FDA)-approved ARVs for at least 180 days. Subjects must have
at least one documented viral load that is below 200 copies/mL that is collected following
initiation of TDF containing cART and greater than 90 days prior to randomization; no viral
load above 200 copies/mL if measured within the 90 days prior to randomization; and an HIV
viral load obtained at screening that is below 200 copies/mL.
Treatment assignments will be balanced by subject sex at birth, age (<20 years vs. >=20
years), and race (African American vs. other). Enrolled subjects will be randomized to
receive vitamin D3 50000 IU or matching placebo, given orally every four weeks by DOT. In
addition to the randomized study agent, all subjects will receive a MVI to be taken orally
once daily. This "standard" MVI will contain ingredients not to exceed 600 IU of vitamin D3
and 200 mg Ca.
DXA measurement of whole-body BMC, and BMD at spine and hip, will be performed at baseline
and study weeks 24 and 48. Blood and urine sampling to assess the Ca-PO4 axis,
PTH-FGF23-vitamin D signaling, bone turnover, and renal glomerular and tubular function will
occur at baseline and study weeks 12, 24, and 48 Blood samples to measure Gluc homeostasis
will be drawn at baseline and week 48, and will be run by batch analysis.
Safety, measured by SCa and SCr, will be monitored by subject's record review at study sites
since these labs will generally be measured as a part of routine clinical care. The ATN109
study will use the SCa and SCr values obtained within 10 weeks at the time of the visit
beginning at the baseline visit. If these evaluations were not performed within the prior 10
weeks they will be drawn at the time of the visit. Viral load and CD4 cell count results
will be recorded for the ATN109 study at screening, baseline and study weeks 12, 24, 48, and
Post-Week 48 provided the evaluations were done within the protocol specified timeframe. If
the evaluations are not performed within the protocol specified timeframes they will be
drawn at the time of the visit.
A5225/HiFLAC: A Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis
A5225/HiFLAC is a phase I/II dose escalation study of the safety and therapeutic effect of high-dose fluconazole alone for the treatment of cryptococcal meningitis (CM) in HIV-infected participants. A cohort treated with amphotericin B deoxycholate alone or in combination with 5-fluorocytosine serve as an internal standard treatment group for the study. The study will proceed in two stages. In Stage 1, Dose Escalation, up to three induction doses of fluconazole will be tested in sequentially enrolled cohorts (24 participants randomized to fluconazole and up to 8 participants randomized to an ampho B-based regimen comprise a cohort). Stage 2, Dose Validation, will not open until the maximum tolerated dose (MTD) of fluconazole has been identified in Stage 1. In Stage 2, induction doses of fluconazole that are found to be safe in Stage 1 will be tested in simultaneously enrolled cohorts. Thus, up to 96 subjects could participate in Stage 2 if all three fluconazole dose levels are deemed safe in stage 1. In each stage, participants will be randomized at entry. There are three doses of fluconazole being studied, 1200 mg, 1600 mg and 2000 mg daily until CSF cultures become negative. The amphotericin B dose is >=0.7 mg/kg.d for 14 days followed by fluconazole at 400 mg daily.Cerebrospinal fluid (CSF) is collected at screening or entry and every 2 weeks through week 10 until a negative culture is obtained. If a negative culture is obtained prior to week 10 the participant will receive fluconazole 400 mg daily until week 10. After week 10 all participants receive fluconazole at 200 mg daily to prevent relapse. Study participation for the participant ends at study week 24.Primary Endpoints:1. Safety - Discontinuation of fluconazole or ampho B, including precipitating and surrounding adverse events.2. Study Drug Activity - Qualitative and quantitative CSF culture results at entry, week 2, and when conducted thereafter. 3. Survival.The analysis plan has been developed to detect a >20% frequency of serious drug related toxic events from fluconazole. The microbial efficacy will be valuated based upon the change in colony counts from the CSF cultures taken at two week intervals until sterile.
A5314: Effect of Reducing Inflammation with Low Dose Methotrexate on Inflammatory Markers and Endothelial Function in Treated and Suppressed HIV Infection
HIV-infected people taking ART have a higher than expected risk of premature CVD. Many
factors likely contribute to this risk, including chronic inflammation. Strategies to reduce
inflammation in HIV-infected people may be beneficial in reducing CVD risk, as well as other
conditions, including kidney disease, bone disease, and neurologic complications. MTX is an
anti-inflammatory medication used to treat people with rheumatoid arthritis. This study will
evaluate the safety and effectiveness of LDMTX at treating inflammation and on endothelial
function in virologically suppressed HIV-infected adults who have CVD or are at increased
risk of CVD.
The total study duration will be 36 weeks. Prior to enrolling in the study, participants
will have a chest X-ray. Participants will be randomly assigned to receive LDMTX or placebo
for 24 weeks. Participants will continue taking their antiretroviral (ARV) medications as
usual; ARVs will not be provided by the study. At study entry, participants will undergo a
medical and medication history, physical examination, blood collection, and adherence
assessments. From study entry through Week 1, participants will receive either 5 mg of MTX
or placebo once a week. For participants who are clinically stable at the Week 1 study
visit, the dose of MTX or placebo will be increased to 10 mg once a week through Week 12.
For participants who are clinically stable at the Week 12 study visit, the dose of MTX or
placebo will be increased to 15 mg once a week through Week 24. Participants who do not meet
the criteria for dose escalation will be re-evaluated at the following study visit. In
addition to LDMTX or placebo, all participants will also receive 1 mg of folic acid once a
day from study entry throughout Week 24. After taking the final dose of LDMTX or placebo,
all participants will continue taking folic acid for an additional 4 weeks.
Additional study visits will occur at Weeks 1, 2, 4, 8, 12, 18, 24, and 36. They will
include a physical examination, blood collection, and adherence assessments; an arm
ultrasound test will also be performed at Weeks 12 and 24. At Week 2, some participants will
also take part in a pharmacokinetic (PK) assessment, which will involve undergoing a blood
collection several times over a 6-hour period.