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
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.
A Prospective, Phase III, Open-Label Study of Boceprevir, Pegylated-Interferon Alfa 2b and Ribavirin in HCV/HIV Coinfected Subjects
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 experience.
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.
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 enrolled.
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 Phase I/II Dose-Finding Study of High-Dose Fluconazole Treatment in AIDS-Associated Cryptococcal Meningitis
CM is the most common central nervous system (CNS) complication of AIDS worldwide and
accounts for up to a third of all deaths from AIDS in many developing countries. Current
treatments for CM are lacking in both effectiveness and accessibility, particularly in
limited-resources settings. Conventional therapies utilizing an amphotericin B deoxycholate
(ampho B)-based regimen require maintaining intravenous access (IV) and monitoring and
treating any associated complications. The price to acquire ampho B can also be prohibitive
to successful treatment. Cumulatively, a treatment course with ampho B is neither cost
effective nor administratively efficient, leaving patients either untreated or inadequately
treated with low-dose regimens of fluconazole alone.
Fluconazole is widely available, inexpensive, can be given orally, has a demonstrated safety
profile over a broad range of doses, and has proven activity against the fungus that causes
CM, Cryptococcus neoformans. All of these factors make fluconazole a potential treatment
option for a wide range of people. However, at its present recommended dosage, fluconazole is
only expected to be successful in 34% to 42% of patients. This rate is lower than regimens
combining fluconazole with other treatments including flucytosine or ampho B.
The purpose of this study was to evaluate whether high-dose fluconazole is safe and effective
for the treatment of CM for up to 10 weeks. This study also collected information about
treating CM with ampho B (either alone or with another drug, either flucytosine or
For this study, 168 HIV-infected people with CM participated for a duration of 24 weeks. This
study proceeded with 2 stages and each stage consisted of up to 4 steps. Participants could
take part in only one stage of the study. Stage 1 measured the maximum tolerated dose (MTD)
of fluconazole in participants. Stage 2 consisted of dose validation and safety monitoring.
In Stage 1, participants were randomly assigned to receive either fluconazole only or an
ampho B-based regimen (a regimen that is either ampho B alone or ampho B in combination with
5-fluorocytosine or fluconazole, according to the local standard of care).Three doses of
fluconazole were tested, and the MTD was found to be 2000 mg/day. The two higher doses of
fluconazole tested in Stage 1 (1600 mg/day and 2000 mg/day doses) were tested further in
Stage 2 of the study.
Participants enrolled in Stage 2 were randomly assigned to receive treatment with either
fluconazole only (at one of the 2 doses (1600 mg/day or 2000 mg/day) found to be safe in
Stage 1) or an ampho B-based regimen.
After randomization in Step 1, participants in both Stage 1 and Stage 2 could be enrolled in
up to three additional steps. In Step 2, participants who were randomly assigned to receive
the ampho B-based regimen and who were intolerant to the regimen (experienced a treatment
limiting toxicity [TLT]) received fluconazole (400-800mg daily). Participants who received
study-provided fluconazole in Step 1 or in Step 2 could be enrolled in Step 3 if they had a
negative cerebrospinal fluid (CSF) culture. Participants in Step 3 received fluconazole
(400mg daily) until Week 10. At Week 10, all participants were enrolled in Step 4 and
received a daily dose of fluconazole of 200mg until the end of the study (Week 24).
Participants in both stages beginning treatment with ampho B received daily ampho B
intravenously for up to 2 weeks.
Before entering the study, potential participants attended a screening visit where they had
CSF collected via lumbar puncture. HIV testing was also conducted, along with clinical
assessments, and a health and medical history questionnaire. Participants had blood
collection, an electrocardiogram (ECG), and a pregnancy test (if applicable) at that visit.
Once accepted into the study, participants again answered questions about their health and
medication history; had a complete physical exam, blood collection, HIV testing, neurological
exam, lumbar puncture, and ECG; and may have had a pregnancy test (if applicable).
Study visits occurred during Weeks 1 (at Days 1, 4, and 7), 2, 4, 6, 8, 10, and 24, and extra
visits could occur for individualized reasons. Total study duration was 24 weeks. Plasma,
urine, serum, and CSF samples were collected from all participants and stored for possible
Note on efficacy population versus safety population: After entering the study, participants
had their CM diagnosis confirmed by testing of the CSF collected via lumbar puncture.
Confirmation could take up to 2 weeks after study entry. Due to the mortality rate of CM,
participants received treatment before CM diagnosis confirmation. Post-entry 12 participants
either reported non-confirmatory baseline results making them ineligible. An additional 2
participants were found to be ineligible for the study but died prior to being found
ineligible (one had non-confirmatory baseline results, one was on a disallowed medication)
All participants (n=168) are included in the safety population. Participants who were
ineligible after study entry were excluded from the efficacy population (n=16). The efficacy
population had 154 participants. Outcomes will specify if the efficacy population is used
instead of the safety population.
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
Use of NNRTI-based regimens as initial therapy for HIV-infected children is increasing,
especially in areas where newborns exposed to HIV-1 receive single-dose nevirapine (NVP) as
part of prevention of mother-to-child transmission (PMTCT) regimens and/or daily NVP for
prevention of transmission through breastfeeding. First-generation NNRTIs have a low genetic
barrier to the development of resistance; in two of the most widely used NNRTIs, NVP and
efavirenz (EFV), even a single amino acid mutation in the virus can lead to a reduction in
the drug's effectiveness. Even short-term use of these NNRTIs, including only a single dose
of NVP, can cause NNRTI resistance. Second-generation NNRTIs are needed as part of ARV
regimens for newly diagnosed infants and children who have been exposed to single-dose NVP or
who have failed their current antiretroviral (ARV) regimens. In this study, the
second-generation NNRTI ETR will be tested for safety, tolerability, and appropriate dosing.
Children will be assigned to one of three cohorts based on age:
- Cohort I: At least 2 but younger than 6 years of age
- Cohort II: At least 1 but younger than 2 years of age
- Cohort III: At least 2 months but less than 1 year of age
Children in all cohorts will be treatment experienced, defined as being on a failing
combination ARV regimen (containing at least 3 ARVs) for at least 8 weeks or having a
treatment interruption of at least 4 weeks with a history of virologic failure while on a
combination ARV regimen (containing at least 3 ARVs).
Children will receive ETR together with an optimized background regimen (OBR) consisting of
at least 2 active agents (a boosted protease inhibitor [PI] and at least 1 additional active
ARV drug). OBR will be based on clinical status, treatment history, resistance data, and
availability of appropriate pediatric dosing and formulations. Some ARVs used as part of the
OBR may be provided by the study. The children will receive an oral dose of ETR twice daily.
Most children will have 11 visits: at screening, entry (Day 0), Day 14 (intensive
pharmacokinetic [PK] visit), and at Weeks 4, 8, 12, 16, 24, 32, 40, and 48. Most visits will
include a physical exam, giving a medical history, discussion of adherence, and blood and
urine collection. The screening and intensive PK visits will also include an
electrocardiogram (ECG). During the intensive PK visit, the child will have blood drawn
approximately 7 times over 12 hours. After the Week 48 visit, children will enter the
long-term follow-up phase of the study and will have a visit every 12 weeks for up to 5
years. These follow-up visits will include giving a medical history and undergoing a physical
exam and blood draw.
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
evaluated the safety and effectiveness of LDMTX at treating inflammation and on endothelial
function in virologically suppressed HIV-infected adults who had CVD or were at increased
risk of CVD.
The total study duration was 36 weeks. Prior to enrolling in the study, participants had a
chest X-ray. Participants were randomly assigned to receive LDMTX or placebo for 24 weeks.
Participants continued taking their antiretroviral (ARV) medications as usual; ARVs were not
provided by the study. At study entry, participants underwent a medical and medication
history, physical examination, blood collection, and adherence assessments. From study entry
through Week 1, participants received either 5 mg of LDMTX or placebo once a week. For
participants who were clinically stable at the Week 1 study visit, the dose of LDMTX or
placebo was increased to 10 mg once a week through Week 12. For participants who were
clinically stable at the Week 12 study visit, the dose of LDMTX or placebo was increased to
15 mg once a week through Week 24. Participants who did not meet the criteria for dose
escalation were re-evaluated at the following study visit. In addition to LDMTX or placebo,
all participants also received 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 continued taking folic
acid for an additional 4 weeks.
Post-entry visits occurred at Weeks 1, 2, 4, 8, 12, 18, 24, and 36. These included a physical
examination, blood collection, and adherence assessments; an arm ultrasound test was
performed at Weeks 12 and 24. At Week 2, some participants took part in a pharmacokinetic
(PK) assessment, which involved undergoing a blood collection several times over a 6-hour
Very Early Intensive Treatment of HIV-Infected Infants to Achieve HIV Remission: A Phase I/II Proof of Concept Study
The purpose of this study is to explore the effects of early intensive antiretroviral therapy
(ART) on achieving HIV remission (HIV RNA below the limit of detection of the assay) among
The study will enroll two cohorts. Cohort 1 will include infants at high risk for in utero
HIV infection. Cohort 2 will include in utero HIV-infected, ART-started infants.
Three early intensive therapy regimens will be assessed. Regimen 1L will include 2 nucleoside
reverse transcriptase inhibitors (NRTIs) plus nevirapine (NVP) plus lopinavir/ritonavir
(LPV/r). Regimen 2R will include 2 NRTIs plus NVP plus raltegravir (RAL). Regimen 2RV will
include 2 NRTIs plus NVP plus RAL plus VRC01 monoclonal antibody.
The study will be conducted in four steps. In Step 1, Cohort 1 infants will be enrolled for
evaluation of HIV infection and initiation of early intensive therapy within 48 hours of
birth. Infants in whom in utero HIV infection is excluded will switch from the study regimen
to standard perinatal prophylaxis per local guidelines within two weeks; these infants will
continue in Step 1 safety monitoring for two additional weeks, undergo final HIV testing at
approximately 12 weeks of age, and then exit the study. Infants in whom in utero HIV
infection is confirmed will enter Step 2 at least two weeks after enrollment in Step 1.
In Step 2, Cohort 1 infants identified with in utero HIV infection and Cohort 2 infants will
receive the study regimen for up to 192 weeks. Beginning at Step 2 Week 84, children who
achieved HIV RNA suppression by Week 24, and maintained suppression thereafter, with no HIV
RNA detected at or after Week 48, will be evaluated for possible treatment cessation.
In Step 3, children in Step 2 who meet criteria for treatment cessation will stop ART, and be
closely monitored for viral rebound for up to five years.
In Step 4, children who experience viral rebound in Step 3 will re-start ART, and be closely
monitored for viral re-suppression on ART until five years of age or six months after
re-suppression, whichever is later.
HIV-uninfected infants will be followed for 12 weeks. HIV-infected infants will be followed
for up to 192 weeks in Step 2 (on ART); those entering Step 3 will be followed for primary
endpoint ascertainment at 48 weeks and for up to a total of five years (off ART) in this