• Small Clinical Trials Advancing HIV Remission and Cure – Due September 1, 2021

    Request for Applications

    Small Clinical Trials Advancing HIV Remission and Cure

    The AIDS Clinical Trials Group (ACTG) Network in collaboration with the NIAID Division of AIDS (DAIDS) has developed a new pathway for the conduct of small experimental trials that aim to advance efforts related to HIV remission and cure utilizing the infrastructure of the ACTG Network.  It is anticipated these studies will be small ( < 30 participants)  and will involve 1-3 clinical research sites experienced at these types of trials. The trials will by nature be intensive and may include specialized assays or procedures, thus making them unsuitable for the ACTG’s larger multi-site studies. Concepts selected for development will be managed by the ACTG’s newly-created Small Clinical Trials Unit (SCTU) with dedicated clinical trial specialists and statistical support. The studies will be conducted at ACTG sites, and the efforts will be coordinated with the ACTG’s Reservoirs, Remission, and Cure Transformative Science Group (Cure TSG). This mechanism is open broadly to investigators with interest in experimental science clinical trials addressing questions important to the HIV cure agenda, and proposing investigators do not need to be affiliated with the ACTG.

    Successful applicants will work with the ACTG SCTU to finalize protocol development and implementation, which will be overseen by the Cure TSG steering committee. The submitting investigator may serve as the study’s chair; additional team members with experience working at ACTG sites will be added to the protocol team. DAIDS will be the sponsor if the study requires an IND/IDE.

    To the extent possible, the ACTG will support all primary endpoint laboratory assays in the currently funded specialty laboratories or through contract laboratories. Secondary, exploratory, and specialized assays can be performed by the applicant but will not be routinely funded by the ACTG. This RFA will not fund assay development. Excess samples will be saved in the ACTG specimen repository and will be available to investigators, both internal and external to the ACTG, for work outside the objectives of the original trial via a standard ACTG request and review process.

    The ACTG Statistical Data Center (SDAC) will lead the analyses of primary endpoint data. Analyses of secondary and exploratory endpoints will be conducted in collaboration with the proposing investigators’ statistical experts and SDAC.

    Applications must demonstrate clear linkage to the DAIDS and ACTG scientific agendas. Examples of areas of particular scientific interest to include but are not limited to:

    • Quantification and characterization of HIV reservoirs and their decay on current antiretroviral therapy or in response to experimental therapies
    • Mechanisms of HIV persistence, immune control and/or immune escape.
    • Therapeutic vaccination to enhance immune clearance of HIV-infected cells
    • Immune-based therapies to clear virus expressing cells and/or control HIV reservoirs
    • Novel therapies to induce HIV expression and deplete HIV reservoirs including combination interventions

    Application Procedure

    • Applications should use PHS 398 forms and proposal format, except that the Research Plan is limited to 6 pages (single-spaced, 11 pt Times New Roman font). Applicants should include the following information in their proposals:
      • Prior and current experience with specific HIV remission and cure studies and a summary of past contributions to the field of HIV remission and cure.
      • Proposed scientific contributions to the ACTG and DAIDS agendas in the area of HIV cure and remission.
      • NIH-format biosketches for the PI/other key personnel.
      • Other Support for key personnel.
    • The grant format should include the following sections:
      • Background
      • Accomplishments
      • Innovation
      • Approach, – should contain the basic design of proposed clinical trial including rationale, hypotheses, objectives and outcomes, study population, intervention and analysis plan
      • Investigators

    A schedule of events may be included as the single appendix.

    Criteria for Evaluation

    Proposals will be evaluated on the basis of significance, originality, feasibility, and likely contribution to the HIV remission/cure agenda of the ACTG and DAIDS.

    Specific criteria will include:

    • Investigators: Are the investigators qualified to design, oversee and perform the proposed work, as judged by past accomplishments (publications; independent peer-reviewed support), and/or patient-oriented AIDS research, and experience working in regulated environment? Access to trainees and junior faculty as collaborators in the work should also be described.
    • Institutional Resources: Does the investigator have the resources and environment to conduct assays that will be done outside of the ACTG specialty or contract labs and participate in the statistical analysis? If the applicant proposes to utilize a non-ACTG laboratory, does the team have the capabilities and resources to meet ACTG standards (e.g. QA/QC, data management) and perform any specialized assays required by the concept proposal? Is the host institution committed to providing the necessary space and other infrastructure needed to complete the required work for the duration of the award?
    • Innovation: Will the study, if successful, advance efforts to understand HIV reservoirs and/or facilitate HIV remission/cure?
    • Approach: Does the concept propose a study focused on an area of scientific interest to the field of HIV reservoirs and/or HIV remission that is investigational and intensive, uses non-standard experimental endpoints, and/or requires specialized assays or procedures, thus making it unsuitable for the ACTG’s larger multi-site studies? If the study requires experimental interventions or devices, are they available to the investigator?

    Application Timelines

    This RFA has twice-yearly receipt dates on March 1st and September 1st.

    An optional Letter of Intent may be submitted by August 1st and April 1st that includes the principal investigator, other key investigators, investigator institution, tentative title of the proposal, primary hypotheses and intention to conduct specialized laboratory assays outside of the ACTG and contract laboratories.

    Release of solicitation:  July 12, 2021

    First application due date: September 1, 2021

    EXPECTED SUPPORT OF FUNDED APPLICATIONS

    1. The funded applications will generally receive an award of 3 years duration.
    2. The ACTG intends to fund up to 2 small clinical trial awards per year.
    3. The ACTG will provide protocol development support, clinical trials expertise, regulatory support, statistical and data support and the sites, staff and laboratory support need to conduct the trial.
    4. Primary and secondary endpoint assays conducted by the ACTG specialty labs or contract labs will be supported by the ACTG.
    5. Each awardee will receive core support of up to 25% FTE up to the NIH salary cap per year, direct costs. (This funding is to support the effort of the PI and other Key Personnel who will be directly involved in the development and conduct of the clinical trial and will be provided as part of protocol development and implementation as per ACTG standard operating procedures.)
    6. Assay performance work that is deemed essential to the trial and conducted outside of the ACTG or contract labs may be supported by the ACTG using a cost-reimbursement model, depending on the nature of the assays and the volume of work required.
    7. Support for exploratory assays is the responsibility of the proposing investigators.

    Application Submission and Questions

    Completed applications are to be submitted on or after August 15, 2021 to a portal available at:  https://actgnetwork.org/submit-a-proposal/.

    Questions about the RFA can be sent to ACTGLeadershipSupport@DLHCorp.com; an F&Q will be developed and posted to the same portal.

  • ACTG announces publication of REPRIEVE sub-study in JAMA Network Open, providing insights into cardiovascular disease risk among people living with HIV

    Los Angeles, Calif. – The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced that findings from a sub-study of REPRIEVE (A5332/A5332s, an international clinical trial studying heart disease prevention in people living with HIV) have been published in the Journal of the American Medical Association Network Open (JAMA Network Open). The study found that approximately half of study participants, who were considered by traditional measures to be at low-to-moderate risk of future heart disease, had atherosclerotic plaque in their coronary arteries.

    While it is well-known that people living with HIV are at increased risk of cardiovascular events, including heart attacks and strokes, little is understood about the prevalence and extent of atherosclerosis in heart blood vessels and associated biological factors. The Mechanistic sub-study of REPRIEVE was designed to specifically identify factors that contribute to cardiovascular disease among people living with HIV.

    “This sub-study of REPRIEVE is seeking to better understand why people living with HIV develop heart disease, even when their HIV is well controlled and they don’t have many traditional risk factors,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. “REPRIEVE is the largest study of cardiovascular disease among people living with HIV and this is an important early report that sets the stage for future important findings.”

    Today’s publication describes baseline data on 755 participants between the ages of 40 and 75 years old, who were enrolled at 31 sites across the United States. The sub-study used coronary CT angiography to assess the amount of plaque in participants’ coronary arteries and then correlated those findings with blood samples that measured inflammation and immune activation.

    Nearly half the participants (49 percent) had plaque in their coronary arteries, though the plaques were mostly seen in just a few areas of the coronary arteries. The presence of plaque was associated with a higher burden of risk factors, but also with higher levels of inflammation independent of traditional risk scores. In almost all individuals (97 percent), the plaque was mild and did not cause a narrowing of more than 50 percent of the coronary artery. While significant narrowing was rare, about one-quarter of participants (23 percent) had plaque with features that could potentially cause problems in the future (also known as vulnerable plaque).

    In the general population, epidemiologic studies have shown that future cardiovascular disease increases with higher ASCVD PCE (atherosclerotic cardiovascular disease pooled cohort equation) risk scores, an index of traditional risk. REPRIEVE recruited participants with low to moderate ASCVD risk and a low average 10-year risk score of 4.5 percent. The clinical significance of mild or even significant plaque in asymptomatic people with low cardiovascular risk is unknown, as is the effectiveness of statin therapy to prevent cardiovascular disease in this population. REPRIEVE will address these important questions by following these participants to determine if the plaque reported in the Mechanistic sub-study of REPRIEVE is clinically significant (whether it is related to future cardiovascular events), whether statin therapy can reduce plaque and markers of inflammation, and if statin therapy can reduce the incidence of heart attacks and strokes.

    “Heart disease is a major cause of illness and death among people living with HIV, including those with well-controlled HIV disease receiving antiretroviral treatment,” said Steven Grinspoon, M.D., Massachusetts General Hospital. “Until now, our understanding of coronary artery disease among people living with HIV has been very limited. These findings significantly expand our knowledge and provide important insights that will lay the foundation to ultimately help us better support the health and well-being of people living with HIV.”

    ###

    About REPRIEVE

    REPRIEVE (the Randomized Trial to Prevent Vascular Events in HIV) has enrolled 7,770 people living with HIV at more than 100 sites in 12 countries around the world in collaboration with the ACTG and is led by Dr. Grinspoon and Michael Lu, M.D., M.P.H., Massachusetts General Hospital and Harvard Medical School; Pamela Douglas, M.D., Duke University; and Heather Ribaudo, Ph.D., Harvard School of Public Health. The Mechanistic sub-study of REPRIEVE was led by Dr. Grinspoon and Udo Hoffmann, M.D., M.P.H., Massachusetts General Hospital. REPRIEVE is supported by the National Institutes of Health’s (NIH) National Heart, Lung, and Blood Institute (NHLBI) and National Institute of Allergy and Infectious Diseases (NIAID) as well as by KOWA Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare.

     

    To read the full press release click here.

  • ACTG announces Camostat will not advance to phase 3 in outpatient treatment study for COVID-19

    Los Angeles, Calif. – The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced that the Camostat treatment group of the COVID-19 outpatient treatment study, ACTIV-2 Outpatient Monoclonal Antibodies and Other Therapies Trial, will not move to phase 3. ACTIV-2 includes both phase 2 and phase 3 evaluations of multiple investigational agents for treating early COVID-19 in a single trial. For information about the trial, please visit the study website.

    Camostat, provided by Sagent Pharmaceuticals (a Nichi-Iko Group Company), is an orally administered protease inhibitor that was dosed as 200 mg every six hours for seven days. The Camostat arm of ACTIV-2 completed phase 2 enrollment with 224 participants on April 26, 2021. When the Therapeutic and Prevention Data and Safety Monitoring Board (DSMB) met on June 14, 2021 to review the data and determine whether Camostat would advance to phase 3, they determined that while there were no safety concerns, the phase 2 data failed to meet the criteria for graduation (which is based on demonstrating early changes in viral shedding or improvement in symptoms). Participants enrolled in phase 2 in the Camostat treatment group will continue to be followed per the ACTIV-2 protocol.

    ACTIV-2 is a randomized, blinded, controlled adaptive platform that allows promising therapies to be added and removed over the course of the study to efficiently test a variety of new agents against placebo within the same trial infrastructure. It is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), which also funds the ACTG. ACTIV-2 is part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership program to create a coordinated research strategy that prioritizes and speeds development of the most promising treatments and vaccines. It also receives support from the Federal COVID Response-Therapeutics, the U.S. government’s multi-agency effort to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics.

     

    To see the complete press release click here.

  • ACTG launches phase 1 combination HIV cure study

    Los Angeles, Calif. – The AIDS Clinical Trials Group (ACTG), the largest global HIV research network, today announced the launch of A5386, a phase 1 HIV cure study evaluating two promising therapies. A5386 will study whether N-803 (a clinical-stage biologic also called Anktiva™) can control HIV alone or together with combination broadly neutralizing antibodies (bNAbs) after participants stop their antiretroviral therapy (ART) and they are carefully monitored.

    In pre-clinical and clinical research, N-803 (an IL-15 superagonist) has exhibited three activities that may help the immune system eliminate HIV reservoirs or control virus rebound. First, N-803 has been shown to reverse HIV latency (the process of no reproduction of HIV within long-lived cells in the immune system), allowing it to be detected by the immune system. Second, it activates NK cells and CD8+ T-cells, two elements of the immune system that specialize in killing virus-infected cells. Finally, it enables NK cells and CD8+ T-cells to move to lymphoid tissues where they will encounter and hopefully eliminate HIV-infected cells.

    The actions of bNAbs (or antibodies that neutralize different variants of HIV) are well-matched to that of N-803. bNAbs neutralize HIV that is produced upon reactivation, preventing new infections; target (label) HIV-infected cells for destruction by NK cells; and may act to boost CD8+ T-cell responses. A5386 will utilize an array of virologic and immunologic tests to evaluate the degree to which each of these expected activities are induced in study participants. Ultimately, the study will test whether this approach results in immune control of HIV when ART is paused with careful monitoring.

    “HIV cure clinical trials remain a fundamental element of the ACTG’s research agenda,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles. “A5386 is particularly exciting as it marries two of the approaches in the HIV cure research space with the most potential. We believe this study will provide important insights as we continue to pursue our ultimate goal of identifying a cure for HIV and making it available to the millions of people living with HIV around the world.”

    A5386 is a phase 1, open-label, randomized study evaluating the safety, tolerability, and efficacy of N-803 both with and without combination bNAbs. It will enroll 46 people living with HIV (23 in each study arm) whose virus has been suppressed by ART for approximately two years, including at least 30 percent cisgender women or transgender men. Participants will undergo leukapheresis (a medical procedure in which white blood cells, or leukocytes, are separated from the blood) to measure their HIV reservoirs and a subset will undergo optional lymph node fine needle aspirations to assess the effect of N-803 on lymphoid tissue. They will then be randomized to one of two arms: N-803 alone or N-803 with combination bNAbs. After receiving treatment, participants will stop taking ART and will be followed closely to monitor for signs that they need to restart ART. Most participants will be followed for approximately 100 weeks after receiving treatment.

    “Pre-clinical studies have shown that this approach enables the immune system to control viral replication and suggest that N-803 and bNAbs will have a complementary effect on each other,” said A5386 Protocol Vice-Chair Richard Brad Jones, Ph.D., Weill Cornell Medicine. “We hope A5386 will demonstrate whether this new approach can enable us to safely decrease the amount of participants’ HIV.”

    A5386 is led by Timothy Wilkin, M.D., M.P.H. (Weill Cornell Medicine), Marina Caskey, M.D., (The Rockefeller University) and Dr. Jones. It is funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and N-803 is provided by ImmunityBio, Inc. NIAID and collaborating NIH Institutes fund the ACTG.

     

    To see the full press release click here.

  • ACTG Announces the Addition of Two Monoclonal Antibodies to ACTIV-2 Outpatient Treatment Study for COVID-19

    Los Angeles, Calif. – The AIDS Clinical Trials Group (ACTG), the largest global HIV research   network, today announced the addition of two monoclonal antibodies, BMS-986414 and BMS-986413, to the COVID-19 outpatient treatment study, ACTIV-2 Outpatient Monoclonal Antibodies and Other Therapies Trial. BMS-986414 and BMS-986413 will be administered as subcutaneous injections (shots) given at one visit. ACTIV-2 includes both phase 2 and phase 3 evaluations of multiple investigational agents for treating early COVID-19 in a single trial. For information about enrolling in the trial, please visit the study website.

     

    “Given that prevention and treatment will continue to be an important part of ending the COVID-19 pandemic, it is key that we identify and develop a variety of treatment options,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles (UCLA). “ACTIV-2 is studying a number of different therapeutic approaches, including infusions, shots, pills, and inhalants, in an effort to ensure that everyone who gets COVID-19 has a treatment option that works for them.”

     

    BMS-986414 and BMS-986413 (developed by a partnership between Rockefeller University and Bristol Myers Squibb) were derived from antibodies from two individuals who had recovered from COVID-19. Because they target two different parts of SARS-CoV-2 (the virus that causes COVID-19), the hope is that the combination therapy will improve efficacy, cover multiple variants, and reduce the likelihood that the virus will develop resistance to the treatment.

     

    ACTIV-2 is a randomized, blinded, controlled adaptive platform that allows promising therapies to be added and removed over the course of the study to efficiently test a variety of new agents against placebo within the same trial infrastructure. In addition to studying the safety and efficacy of investigational therapies, ACTIV-2 also aims to determine whether they can decrease viral shedding, thereby potentially preventing transmission of SARS-CoV-2. Participants who enroll in ACTIV-2 will be randomly assigned to receive BMS-986414 and BMS-986413, another ACTIV-2 agent, or placebo. Other agents currently being evaluated in phase 2 include:

    • SAB-185 (SAB Biotherapeutics): a polyclonal antibody infusion
    • SNG001 (Synairgen): an inhaled formulation of beta interferon
    • Camostat (Sagent Pharmaceuticals): an orally administered serine protease inhibitor

     

    ACTIV-2 also currently includes a phase 3 study of BRII-196 plus BRII-198 (Brii Biosciences), two separately administered monoclonal antibody infusions. In addition, ACTIV-2 has completed enrollment for phase 2 studies evaluating AZD7442 (AstraZeneca), a combination of two monoclonal antibodies, as both a 15-minute infusion and an intramuscular injection, and has completed a phase 2 study of BRII-196 plus BRII-198.

     

    To qualify for ACTIV-2, participants must have tested positive for SARS-CoV-2 in the outpatient setting within 10 days and started experiencing symptoms within eight days of enrolling.

     

    ACTIV-2 is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), which also funds the ACTG. ACTIV-2 is part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership program to create a coordinated research strategy that prioritizes and speeds development of the most promising treatments and vaccines. It also receives support from the Federal COVID Response-Therapeutics, the U.S. government’s multi-agency effort to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics.

     

    “In the lab, BMS-986414 and BMS-986413 have demonstrated activity against a broad range of SARS-CoV-2 variants, which is increasingly important as these variants continue to spread around the world,” said Katya Corado M.D., Lundquist Institute at Harbor-UCLA Medical Center, co-lead investigator of BMS-986414 and BMS-986413 in ACTIV-2. “This is the first subcutaneous injection that we’ve studied in ACTIV-2 and if it is effective, it will provide a treatment option for people with COVID-19 that is easier to administer and that we expect will increase access to antibody therapy.”

     

    ACTIV-2 is led by Kara W. Chew, M.D., M.S., UCLA and Davey Smith, M.D., University of California, San Diego (protocol chairs) and David Alain Wohl, M.D., University of North Carolina (UNC) and Eric S. Daar, M.D., Lundquist Institute at Harbor-UCLA Medical Center (vice-chairs) and supported by Dr. Currier and Joseph J. Eron, M.D., UNC, (ACTG Co-Chair, and co-lead investigator of BMS-986414 and BMS-986413).

     

    For more information about ACTIV-2, please visit www.riseabovecovid.org, www.actgnetwork.org, or clinicaltrials.gov.

     

    To see the full press release click here.

  • ACTG Honors the 40th Anniversary of HIV/AIDS

    The ACTG commemorates the 40th anniversary of the initial publication of reports of what came to be known as HIV/AIDS in CDC’s Morbidity and Mortality Weekly Report (MMWR) on June 5, 1981. ACTG has played a critical role in HIV research for nearly four decades and has done so in close partnership with the HIV community. ACTG research includes landmark studies that have changed the treatment and care of people living with HIV around the world.

     

    “What began with a medical report about five men 40 years ago became a worldwide epidemic that has directly and indirectly affected tens of millions of people,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles, who has been part of the ACTG since 1991. “As a group, the ACTG has participated in the evolution of HIV from what was almost always a fatal diagnosis to a chronic and manageable condition. We are truly humbled that our community-engaged research network has significantly contributed to this dramatic progress over the past four decades and to shifting treatment guidelines and paradigms.”

     

    The ACTG began with 14 AIDS Treatment Evaluation Units which were founded in 1986 and officially became the ACTG a year later. Initial research started with trials of AZT (which became the first treatment approved by the Food and Drug Administration but is rarely used anymore due to toxicity) and therapies for the treatment and prevention of opportunistic infections that caused the deaths of people living with HIV. The ACTG expanded to include international sites in 2002, initially pairing sites in Haiti, Brazil, Peru, and South Africa with mentor sites in the United States. The ACTG now includes 32 international sites among its total 65 sites. Over the years, the ACTG has also expanded its focus to address other diseases, including tuberculosis (TB), hepatitis, and more recently, COVID-19.

     

    “The expansion of the ACTG to include global sites was vital to ensure that our research agenda truly served people living with HIV around the world,” said ACTG International Vice Chair Ian Sanne, FCP, FRCP, University of the Witwatersrand Helen Joseph, who has been with the ACTG since 2012. “It has been a remarkable journey of advancements since the ACTG added the initial international sites nearly two decades ago. Particularly impressive is the way that the international sites have informed ACTG’s research agenda and the impact of that research on international HIV treatment and care.”

     

    The ACTG has partnered with the HIV community from the earliest days of the epidemic, with community members attending ACTG meetings beginning in 1987. By 1990, every ACTG research unit had a community advisory board (CAB) to provide guidance and input into clinical trial protocol development.

     

    “The CABs have always played an important role in the ACTG, including in developing our study protocols,” said Co-Chair of the ACTG’s Global CAB, Estere Mutero, who has been part of the ACTG since 2006. “Through its engagement with diverse populations, the ACTG has become a truly global network, facilitating the participation of communities around the world in our studies.”

     

    Examples of ACTG studies that have influenced or changed the landscape of HIV, TB, and hepatitis include:

    • ACTG 019: Treatment with AZT decreases the rate of progression of HIV; published in the New England Journal of Medicine (NEJM) in 1990
    • ACTG 077: Treatment of Toxoplasma Encephalitis with Clindamycin/ Pyrimethamine; in coordination with the French Agency for Research on AIDS and Viral Hepatitis (ANRS); published in NEJM in 1993
    • ACTG 081: Prevention of Pneumocystis Pneumonia; published in NEJM in 1995
    • ACTG 159: Treatment of Cryptococcal Meningitis; in coordination with the Mycoses Study Group; published in NEJM in 1997
    • ACTG 320: Combination antiretroviral therapy (ART) decreases morbidity and mortality in people with AIDS; published in NEJM in 1997
    • ACTG 5221: Rapid initiation of ART in people with TB; published in NEJM in 2012
    • ACTG 5175: Single-dose combination ART is safe and effective in resource-limited settings; published in PLoS Medicine in 2012
    • ACTG 5208 (OCTANE): Limitations of single-dose NVP and implications for maternal HIV resistance; published in PLoS Medicine in 2012

     

    “ACTG’s efforts have led to treatment regimens that control HIV and allow many people living with HIV to lead healthy long lives,” said ACTG Co-Chair, Joseph J. Eron, M.D., University of North Carolina, who has been part of the ACTG since 1993. “We recognize that there is still much to be done to end the HIV epidemic and the ACTG remains dedicated to the task. We are especially committed to research to find a functional cure and reduce the complications associated with lifelong HIV. And we are proud to continue to move forward with the strong involvement and support of people living with HIV.”

  • STUDY A5349 PUBLISHED IN NEJM

    The ACTG is excited to share the publication in the New England Journal of Medicine of “Four-month Rifapentine Regimens with or without Moxifloxacin for Tuberculosis.” This paradigm-shifting study demonstrates the feasibility of decreasing the length of TB treatment by one-third – a profound advancement in the management of a disease that continues to proliferate globally. Study 31/A5349, which was also presented at the Union World Conference on Lung Health in October 2020, showed that the four-month regimen of rifapentine, isoniazid, pyrazinamide, and moxifloxacin (RPT-MOX) was non-inferior to the currently recommended six-month regimen of rifampicin, isoniazid, ethambutol, and pyrazinamide for the treatment of drug-susceptible pulmonary TB. RPT-MOX was also safe and well-tolerated by study participants. A second four-month regimen of rifapentine, isoniazid, pyrazinamide, and ethambutol did not meet the non-inferiority margin.

    To read more click here.

  • Central monitoring in a randomized, open-label, controlled phase 3 clinical trial for a treatment-shortening regimen for pulmonary tuberculosis

    Contemporary Clinical Trials, May 2021

    The Tuberculosis Trials Consortium Study 31/study A5349 is a large (n=2500) international, multi-site (n=34), randomized, open-label, controlled, three-arm, non-inferiority phase 3 clinical trial comparing two four-month regimens to a standard six-month regimen for treatment of drug-susceptible tuberculosis among adolescents and adults. Due to the number of study sites worldwide, complexities inherent in TB diagnosis and treatment, and the major potential impact of this trial, a strong and timely quality assurance program was critical. In response to these demands, the study team developed interventions to improve study conduct and strengthen study quality. Our central monitoring processes included quality control, quality assurance, and monitoring of real-time data. Specifically, we created a novel, five-tiered methodology for quality management at the central level:

    1. Performance of “real-time” data checks on submitted data, and development of topic-specific intervention reports
    2. Production of site-specific missing forms reports based on the expected study schedule for each participant at the site
    3. Evaluation of protocol compliance according to study-specific quality assurance metrics
    4. Production of critical data reports
    5. Identification and notification of protocol deviations

    The use of primary study data to identify data issues promptly allowed CDC, as the study sponsor, to focus quality assurance and data cleaning activities on prioritized data related to protocol compliance and accurate determination of study endpoints. Our approach enabled us to inform sites about protocol deviations, resolve missing or inconsistent data, and gain a deeper understanding of challenges experienced at clinical trial sites. We anticipate the utility of this method will be seen beyond the world of TB, for any clinical trial sponsor with access to their data in real time. We will continue to build upon the central monitoring process in future studies, with a focus on these approaches.

    Summary and Implications: It is very important to have the best science in every study so that we can trust the results. One of the key challenges in multi-site studies is ensuring that each site performs well. The lessons from this study’s team management plan may help future studies be more successful.

    Bryant, K. E., Yuan, Y., Engle, M., Kurbatova, E. V., Allen-Blige, C., Batra, K., Brown, N. E., Chiu, K. W., Davis, H., Elskamp, M., Fagley, M., Fedrick, P., Hedges, K., Narunsky, K., Nassali, J., Phan, M., Phan, H., Purfield, A. E., Ricaldi, J. N., Robergeau-Hunt, K., ACTG; Tuberculosis Trials Consortium (2021). Central monitoring in a randomized, open-label, controlled phase 3 clinical trial for a treatment-shortening regimen for pulmonary tuberculosis. Contemporary clinical trials104, 106355. Advance online publication. https://doi.org/10.1016/j.cct.2021.106355

  • ACTG Leadership statement on Derek Chauvin Verdict

    April 22, 2021 Alexis Sexton Spotlight
    The ACTG leadership commends the guilty verdict for the murder of George Floyd by former police officer Derek Chauvin. We also recognize that while this is an important moment of accountability, it is only one step in our public reckoning with racially motivated violence – violence that began long before George Floyd’s murder and persists today. We recognize that the only way forward is to dismantle the racism that underpins America’s many structures and institutions. Social justice has always been a central tenant of the HIV response and we are proud to stand with you now as we forge a path toward justice, both as individuals and institutions.
  • ACTG Adds First Polyclonal Antibody to ACTIV-2 Outpatient Treatment Study for COVID-19

    April 21, 2021 Alexis Sexton Spotlight

    Newswise — Los Angeles, Calif. – The AIDS Clinical Trials Group (ACTG), the largest global HIV research   network, today announced the addition SAB-185, a polyclonal antibody therapy, to the COVID-19 outpatient treatment study, ACTIV-2 Outpatient Monoclonal Antibodies and Other Therapies Trial. ACTIV-2 includes both phase 2 and phase 3 evaluations of multiple investigational agents for treating early, symptomatic COVID-19 in a single trial. For information about enrolling in the trial, please visit the study website.

    “While we are thrilled to see the widescale roll-out of COVID-19 vaccines, we know that prevention and treatment will continue to play important roles in ending this pandemic,” said ACTG Chair Judith Currier, M.D., M.Sc., University of California, Los Angeles (UCLA). “Treatment, even among people who are unlikely to advance to severe disease, can have profound benefits, including shortening the duration of symptoms and potentially reducing or eliminating transmission of SARS-CoV-2 – the virus that causes COVID-19 – to others. By evaluating multiple agents across a single platform, ACTIV-2 aims to identify and advance treatments as expeditiously as possible.”

    SAB-185, is the first polyclonal antibody (a treatment containing many different antibodies) to be evaluated in ACTIV-2. SAB-185 is made by cows that have been genetically engineered to make human antibodies. Once the cows developed an immune response and generated antibodies against the spike protein on the surface of SARS-CoV-2, samples of their blood are collected, and the antibodies are separated out and purified. SAB-185 is administered through an intravenous infusion and ACTIV-2 will evaluate two different doses.

    ACTIV-2 is a randomized, blinded, controlled adaptive platform that allows promising therapies to be added and removed over the course of the study to efficiently test a variety of new agents against placebo within the same trial infrastructure. In addition to studying the safety and efficacy of investigational therapies, ACTIV-2 also aims to determine whether they can decrease viral shedding, thereby potentially preventing transmission of SARS-CoV-2. Participants who enroll in ACTIV-2 will be randomly assigned to receive SAB-185, another ACTIV-2 agent, or placebo. Other agents currently being evaluated include:

    • AZD7442 (AstraZeneca): a combination of two monoclonal antibodies being studied as both a 15-minute infusion and an intramuscular injection
    • SNG001 (Synairgen): a nebulized formulation of beta interferon being studied as an inhalant
    • Camostat (Sagent Pharmaceuticals): an orally administered serine protease inhibitor
    • BRII-196 and BRII-198 (Brii Biosciences): two separately administered monoclonal antibody infusions

    To qualify for ACTIV-2, participants must have tested positive for SARS-CoV-2 in the outpatient setting within 10 days and started experiencing symptoms within eight days of enrolling. Participants eligible for the infusion studies, including SAB-185, will have a risk factor that puts them at higher risk of progressing to severe COVID-19, including being age 60 or older, being a current smoker, or having one of the following conditions: chronic lung, kidney, or liver disease; obesity; hypertension; cardiovascular disease; diabetes; or current cancer or immunosuppression. Participants eligible for the other agents may be at higher or lower risk for progressing to severe COVID-19.

    ACTIV-2 is sponsored by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), which also funds the ACTG. ACTIV-2 is part of NIH’s Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV), a public-private partnership program to create a coordinated research strategy that prioritizes and speeds development of the most promising treatments and vaccines. It also receives support from the Federal COVID Response – Therapeutics, the U.S. government’s multi-agency effort to accelerate the development, manufacturing, and distribution of COVID-19 vaccines, therapeutics, and diagnostics.

    “While there has been much deserved enthusiasm about monoclonal antibodies, including those we’re studying in ACTIV-2, we are especially eager to evaluate our first polyclonal antibody,” said Babafemi Taiwo, M.B.B.S., Professor of Medicine and Chief of Infectious Diseases at Northwestern University and lead investigator of SAB-185 in ACTIV-2. “Because it contains many different antibodies, SAB-185 is able to simultaneously attack different parts of the viral spike protein in SARS-CoV-2, making it a potentially very promising and effective treatment option.”

    ACTIV-2 is led by Kara W. Chew, M.D., M.S., UCLA and Davey Smith, M.D., University of California, San Diego (protocol chairs) and David Alain Wohl, M.D., University of North Carolina (UNC) and Eric S. Daar, M.D., Lundquist Institute at Harbor-UCLA Medical Center (vice-chairs) and supported by Dr. Currier and ACTG Co-Chair Joseph J. Eron, M.D., UNC.

     

    For more information about ACTIV-2, please visit www.riseabovecovid.orgwww.actgnetwork.org, or clinicaltrials.gov.

     

    To read the full press release click here.