AIDS Clinical Trial Group (ACTG) studies

• Post by: admin
• May 16, 2021

Study period: ACTG protocols are continually developed and registered sites are open to participate

Funding: Studies conducted under ACTG are funded by the United States National Institutes of Health/ National Institutes of Allergy and Infectious Diseases (NIH/NIAID). Funding is provided to clinical sites by reimbursement.

The JCRC is the Clinical Research Site working in collaboration with Case Western Reserve University (CWRU) as the domestic ACTG site. JCRC became an ACTG site (site number 12401) in the year 2006. The JCRC site Principle Investigator is Professor Peter Mugyenyi and Co-PIs are Drs Cissy Kityo, Francis Ssali and Victor Musiime. The US PI responsible for the international site is Prof Robert Salata.

The centre has successfully participated in the following ACTG protocols: A5208, A5207, A5221 and A5234. Recruitment targets for the most part were met, and of particular note, the JCRC distinguished itself as the highest recruiting site for protocols A5207 and A5243.

Currently, JCRC is participating in the following main protocols: A5225, A5264 and A5265, as well as the sub studies A5243 and A5278. There are four other protocols that are expected to start in 2013.

A brief description of these ACTG protocols follows below.

 

Study A5207/MOMS “(Maintaining Options for Mothers Study)”

This was a Phase II Randomized Comparison of 3 antiretroviral strategies administered for 7 or 21 days to reduce the emergence of nevirapine resistant HIV-1 following a single intrapartum dose of nevirapine. Participants included HIV-1 infected women over 13 years of age, with a CD4 cell count above 250 cells/mm; ART naïve, or who expected to receive zidovudine monotherapy during the current pregnancy. In this study all ARV agents (3TC/ZDV, FTC/TDF and LPV/r) were initiated simultaneously with SD NVP at the onset of active labor, which is administered routinely to prevent mother-to-child-transmission of HIV-1. The enrollment target was 420 with 84 participants at each site including Kampala Uganda, Durban, South Africa, Malawi, India and Haiti.

At JCRC, 113 pregnant women and their 116 infants were recruited starting from June 2008. Mothers were followed for 96 weeks after delivery. All infants were followed for 12 weeks after birth. Infants found to be HIV-infected were followed until week 96. The primary objective was to determine whether a 21-day course of ARV therapy was more effective than a 7-day course in suppressing the emergence of NVP-resistant HIV-1 variants at 2 and 6 weeks after completion of ARV therapy in women who received intrapartum SD NVP, as determined by standard genotyping of plasma HIV-1 RNA. 

 

Study A5208 OCTANE: “Optimal Combination Therapy After Nevirapine Exposure”

OCTANE was a randomized, comparative, stratified, open-label, multi center study comprising of two randomized clinical trials conducted concurrently. Both trials compared the virologic response to non-nucleoside reverse transcriptase inhibitors (NNRTI)-based (Arm 1A) versus evaluating the superiority of PI-based ART in women with prior single dose (SD) NVP prophylaxis for mother-to- child-transmission (MTCT) of HIV. Trial 2 evaluated the equivalence of PI-and NNRTI-based ART in women with no prior NVP exposure. The major objectives of the study were to compare the time to virologic failure or death between participants initiating ART with a regimen including LPV/RTV in both trials, and to evaluate the difference in the effect of NNRTI-based and PI-based ART on the time to virologic failure or death in participants from both trials. 

At JCRC, 60 participants were recruited; the target was 64 participants out of 640 participants for the whole trial.

 

Study A5221: A Strategy Study of Immediate vs. Deferred Initiation of ART for HIV-Infected Persons Treated for TB with CD4<200 Cells/mm³”

A5221 was a randomized, open-label study to determine whether starting HIV treatment immediately (within 2 weeks of starting TB treatment) reduces mortality and AIDS-defining events in participants being treated for TB, as compared to deferring HIV treatment (8-12 weeks after start of TB treatment). There were 18 participating sites in total which recruited 800 persons; JCRC recruited 29 participants.

The participants were followed for a period of 48 weeks. The study consisted of two arms; the first arm comprised participants who received immediate ART and the second arm those whose ART was deferred. The primary objective was to compare the proportion of participants who have survived without AIDS progression by week 48. Other objectives included comparing the safety and effectiveness of HIV treatment when it is started at different times after TB treatment has started. 

 

Study A5234: International Trial of Directly Observed Therapy versus Standard of Care for Patients with First Virologic Failure on a Non-Nucleoside Reverse Transcriptase Inhibitor- Containing Antiretroviral Regimen

A5234 was a randomized, prospective, open-label, controlled multicenter study of HIV-1 infected participants who were experiencing, or had experienced, their first baseline virologic

failure on a non-nucleoside reverse transcriptase inhibitor (NNRTI)-based ART regimen. At entry, participants still on their regimen were switched to, and participants who had stopped their regimen started, one of the protease inhibitor (PI)-based HAART study regimens FTC/Tenofovir Disoproxil Fumarate (TDF) 200/300 mg once daily (QD) + Lopinavir/Ritonavir (LPV/RTV) 400/100 mg twice a day (BID) or TDF 300 mg QD + ZDV 300 mg BID + LPV/RTV 400/100 mg BID. 248 participants who met study criteria were randomized to one of two strategies: modified directly observed therapy (mDOT) versus self-administered therapy. Adherence was measured using Medication Event Monitoring System (MEMS) caps and self-report questionnaires. Participants were followed for 52 weeks after randomization.

At JCRC, 102 (51pairs) participants were enrolled; the target was 100 (50 pairs) participants.

A5225/HiFLAC : A phase I /II dose escalation, 24 week study, using high-dose fluconazole alone in the treatment of HIV positive men and women ≥16 years of age, presenting with their first diagnosis of cryptococcal meningitis. For comparison, a cohort treated with amphotericin B alone or in combination with 5-fluorocytosine is included. Cerebrospinal fluid (CSF) is collected and cultured for Cryptococcus at screening or entry and again at week 2. Additional CSF collections and cultures is performed at weeks 4, 6, 8, and 10 as necessary until a negative CSF culture is obtained. Neurological assessments are conducted periodically on all participants. Blood collections for evaluation of drug-drug pharmacokinetics are conducted periodically on participants randomized to high dose fluconazole treatment.

At JCRC, 10 participants were recruited as targeted.

Study A5264: A phase III open label randomized clinical trial to compare the efficacy and safety of ART alone or with delayed chemotherapy (Etoposide) to ART with immediate Etoposide for initial treatment of limited stage AIDS- related Kaposi’s Sarcoma (KS) in individuals who have never been treated for KS and who are currently not receiving ART. Enrollment is ongoing.

 

Study A5278s/AMC 074 is designed to assess the direction and magnitude of pharmacokinetic (PK) interactions between the antiretroviral agents efavirenz/tenofovir/emtricitabine (EFV/TDF/FTC) and the Kaposi’s sarcoma (KS) chemotherapy agents etoposide (ET), vincristine (VCR), and pegylated liposomal doxorubicin (PLD). This sub-study will co-enroll a subset of participants randomized on ACTG parent studies A5263 and A5264 for PK sampling on no more than two occasions. Estimates of participant-specific PK parameters for the parent study agents, obtained by maximum a posteriori (MAP) Bayesian estimation, will be compared to historical control data (KS agents) or estimates obtained for participants on A5264 Arm 1A (antiretroviral agents).

Study A5265: A phase III, open-label, randomized, assessment-blinded clinical trial in non-U.S. sites to compare the safety and efficacy of topical gentian violet (GV) to that of oral nystatin. Therapy will be considered as failed if participants have no clinical improvement (assessed by severity and extent of pseudomembranous candidiasis) during either treatment regimen. Evaluation of signs and symptoms of oral candidiasis (OC) will be done by an evaluator who is blinded to treatment assignment. Quantification of colony forming units (CFUs) of Candida species (spp.) and assessment of the emergence of resistance will be performed using an oropharyngeal swab and a second specimen from oral rinse/throat wash will be collected and stored for future testing. Adherence will be assessed through participant self-report aided by medication diaries and adherence assessment. In addition, study medication bottles will be collected by site staff. Participants will be asked to complete a resource utilization form to quantify the number of clinic visits and hospital days incurred. Enrollment is ongoing.

ACTG studies that started in 2013

The centre has begun the regulatory approval process for the following protocols: A5263, A5274, A5279, A5288, and A5297 expected to start in the course of the year 2013.

 

Study A5263: A prospective, randomized, active-controlled clinical trial to compare oral etoposide (ET) plus ART or bleomycin/vincristine (BV) plus ART to liposomal doxorubicin (PLD) plus ART for the treatment of advanced AIDS-related Kaposi’s sarcoma (KS) in resource limited settings.

Study A5274: In this randomized, open-label, phase IV strategy trial, participants from resource-limited settings (RLS) who present with advanced HIV disease and no probable or confirmed tuberculosis (TB), as defined in the current ACTG diagnosis appendix, and who are initiating antiretroviral treatment (ART) will be randomized to one of two strategy arms: immediate, empiric TB treatment (public health approach) or local standard of care TB treatment (individualized approach). The primary endpoint is survival status in the two arms 24 weeks after randomization. AIDS progression (any new WHO Stage 3 or 4 condition), virologic and CD4+ cell response, HIV and TB drug resistance, and safety and tolerability of, and adherence to HIV and TB drugs will be evaluated, as will the cost-effectiveness of the two strategies

Study A5279: This study is a multicenter, randomized, open-label, phase III clinical trial comparing a 4-week daily rifapentine (RPT)/isoniazid (INH) regimen to a standard 9-month daily INH regimen for the prevention of tuberculosis (TB) in HIV-infected participants without evidence of active TB. The primary objective will be efficacy of TB prevention. The study will also assess safety and tolerability of the regimens, adherence to the treatments, and patterns of antibiotic resistance among Mycobacterium tuberculosis (MTB) isolates in participants who fail on these prophylactic regimens.

Study A5288:  An open-label phase IV, prospective interventional, strategy study in resource-limited settings (RLS) for HIV-infected participants with triple-class experience or resistance to [nucleoside reverse transcriptase inhibitors (NRTIs), non-NRTIs (NNRTIs), and protease inhibitors (PIs)] and who are failing their current regimen. The use of novel agents and contemporary management tools that include standard genotyping, plasma viral load (VL) monitoring will be evaluated. The screening genotype results and antiretroviral (ARV) history will be used to allocate potential participants to one of the four cohorts and for selection of ARV regimen for each potential participant.

At sites where feasible and relevant, the study will also conduct an adherence study. This will be a randomized comparison of cell phone-based adherence intervention plus local standard-of-care adherence procedures (CPI+SOC) versus the SOC adherence procedures.

 

Study A5297: A phase I/II, open-label, proof of concept, two-step, two-arm, controlled randomized clinical trial (RCT) to test the superiority of lopinavir/ritonavir (LPV/r)-based antiretroviral therapy (ART) to non-nucleoside reverse transcriptase (nNRTI)-based ART for clearance of Plasmodium falciparum (Pf) subclinical parasitemia (SCP). 

Participants will be followed for 30 days in order to evaluate parasitemia clearance, Pf parasitemia, gametocytemia, and plasmepsin sequencing. Participants will have blood collected twice at entry, day 3, 6, 9, 12, 20, and 25 and three times for day 15 and day 30. Therefore, on most study days, participants will need to either remain at the clinic for an extended period of time or be willing to return two or three times at approximately 8-hour intervals.