Small Clinical Trials Advancing HIV Remission And Cure

The 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 sites, laboratories, and other infrastructure of the Network. These studies are anticipated to be small (< 30 participants) and involve 1-3 existing ACTG clinical research sites experienced in these types of trials. The proposed study should not include non-ACTG sites nor ACTG protocol-specific sites. 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 Small Clinical Trials Unit (SCTU) with dedicated clinical trial specialists and statistical support. Concepts deemed high priority that do not require intensive procedures, more participants, or a larger number of sites will be referred to ACTG’s Reservoirs, Remission, and Cure Transformative Science Group (Cure TSG). Approved studies will be conducted only at currently funded Core ACTG sites, and the efforts will be coordinated with the Cure TSG. This mechanism is open broadly to investigators interested in experimental science clinical trials, addressing questions important to the HIV cure agenda. 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 the Cure TSG steering committee will oversee. The submitting investigator may serve as the study’s chair; team members with experience working at ACTG sites, as well as a community representative, will be added to the protocol team. Important note: 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 network 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 and Data Analysis 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 and include the evaluation of a specific intervention. Examples of areas of particular scientific interest 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 reservoir.
• Novel therapies to induce HIV expression and deplete HIV reservoirs, including combination interventions.

Revised Application Procedure

1. Applications must use the PHS 398 biosketch form (for the PI and other key personnel) and limit the research plan/proposal to 6 pages (single-spaced, 11 pt Times New Roman font). We also request that applications include the term participants in place of subjects or patients and
include other people-first language wherever possible.
2. The 6-page research plan/proposal must include the following sections:
• List of investigators
• Background
• Accomplishments
• Innovation
• Approach – should contain the basic design of the proposed clinical trial, including rationale, hypotheses, objectives and outcomes, study population, intervention, and analysis plan.
• Study population must include specific inclusion/exclusion criteria with a justification for any exclusions and a brief description of plans to include women and minorities in the study. In addition, applicants must describe plans to ensure the collection and reporting of participant demographics and demographic diversity of participant specimens. Applicants are encouraged to use the Representative Studies Rubric (RSR) as a resource available here.
• Feasibility and accessibility to and timing of availability of the investigational product(s) should be specifically addressed. Only proposals with a clear plan and timeline for accessing investigational products will be considered for funding. This RFA is not intended to support developing or manufacturing new products for testing in clinical trials.
3. Either the biosketch or the research plan/proposal (limited to 6 pages) must include the information below.
• 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 HIV cure and remission.
• Other Support for key personnel.
4. A schedule of events may be included as a single appendix to the research plan/proposal. The inclusion of a budget is not necessary.
5. The proposed study must not include non-ACTG sites nor ACTG protocol-specific sites. Approved studies will be conducted only at currently funded Core ACTG sites.

Criteria for Evaluation

Proposals will be evaluated based on 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 a 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? Does the study contribute to the diversity of study participant demographics in HIV remission and cure research?

Application Timelines

This RFA has twice-yearly receipt dates on April 1st and October 1st.
A Letter of Intent is required and must be submitted by February 29th and September 5th, respectively and must include:

• The principal investigator.
• Other key investigators.
• Investigator institution.
• Tentative title of the proposal.
• Primary hypotheses.
• Intention to conduct specialized laboratory assays outside of the ACTG and contract laboratories.

Original release of solicitation: July 12, 2021; Revised August 11, 2021; Revised July 12, 2022, Revised July 24, 2023, Revised January 31, 2024
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 annually.
3. The ACTG will provide protocol development support, clinical trial expertise, regulatory support, statistical and data support, and the sites, staff, and laboratory support needed 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, as well as 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 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 should be submitted here, where an FAQ is also available.

Please submit questions about the RFA here.