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Combinatorial Therapy to Induce an HIV Remission

Primary Purpose

HIV/AIDS

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Combination Intervention

About this trial

This is an interventional treatment trial for HIV/AIDS

Eligibility Criteria

18 Years - 67 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Key Inclusion Criteria

Willing and able to provide written informed consent.
Age ≤67 years at the time of enrollment for those who started treatment during early infection and <65 years for those who started treatment during chronic infection.
Documented HIV-1 infection.
On continuous antiretroviral therapy for at least 12 months without any interruptions of greater than 14 consecutive days within the last 1 year, and on a stable regimen that does not include an non-nucleoside reverse transcriptase inhibitor (NNRTI) for at least 4 weeks, without plans to modify ART during the study period.
Screening plasma HIV RNA levels below the level of quantification on all available determinations in past 24 months.
Screening CD4+ T-cell count ≥ 500 cells/mm3.

Key Exclusion Criteria

Subjects receiving a non-nucleoside reverse transcriptase inhibitor
Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
High-level resistance to both 10-1074 and VRC-07 as defined using the PhenoSense Neutralizing Antibody Assay (Monogram Biosciences).
Any history of an HIV-associated malignancy, including Kaposi's sarcoma and any type of lymphoma, or virus-associated cancers.
Active or recent non-HIV-associated malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months.
CD4+ T cell nadir <350 cells/mm3 during the chronic phase of infection (beginning 6 months following the estimated infection date and confirmed on repeat testing).
Active hepatitis B (HBV) infection defined as positive HBV surface antigen test.

9. Active hepatitis C (HCV) infection. 10. Presence of significant abnormalities on electrocardiogram. 11. History of potential immune-mediated medical conditions. Individuals with isolated Raynaud's phenomenon or localized disease requiring topical therapy alone will not be excluded.

Sites / Locations

Zuckerberg San Francisco General Hospital, University of California San Francisco

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Combination intervention arm

Arm Description

All volunteers will receive the combination intervention outlined above.

Outcomes

Primary Outcome Measures

Proportion of participants who experience a new grade 3 or greater adverse event

Proportion of participants achieving post-treatment control.

This will be defined as: Participants who fail to show any consistent rebound above 400 copies RNA/mL between Week 12 of the ATI (when bNAb levels wane) and Week 36 of the ATI Participants who exhibit a rebound and eventually achieve 24 weeks of virus control will be considered as having achieved post-treatment control

Secondary Outcome Measures

Occurrence of any unsolicited adverse events for 28 days after administration of each study agent

Occurrence of any serious adverse events, medically attended adverse event, and potentially immune-mediated medical condition from the time of administration of the first study injection through 12 months after administration of the final study injection

Occurrence of two consecutive measurements HIV RNA >200 copies/mL using conventional assays

Resumptions of antiretroviral therapy after treatment interruption and the events that trigger them

Frequency of confirmed declines (two consecutive measurements) in CD4+ T cell counts (> 50%)

Frequency of confirmed declines (two consecutive measurements) to below 350 cells/mm3

Proportion experiencing any clinically defined episode of acute retroviral syndrome

Magnitude of T cell responses

Breadth of T cell responses

The proportion of participants with at least one additional epitope response at week 14 (2 weeks after last vaccination) compared to their baseline response

Full Information

NCT ID

NCT04357821

First Posted

April 18, 2020

Last Updated

May 8, 2023

Sponsor

University of California, San Francisco

Collaborators

amfAR, The Foundation for AIDS Research, International AIDS Vaccine Initiative, Ichor Medical Systems Incorporated, National Institute of Allergy and Infectious Diseases (NIAID), Rockefeller University, Mologen AG, GeoVax, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT04357821

Brief Title

Combinatorial Therapy to Induce an HIV Remission

Official Title

Combinatorial Therapy With a Therapeutic Conserved Element DNA Vaccine, MVA Vaccine Boost, TLR9 Agonist and Broadly Neutralizing Antibodies: a Proof-of-concept Study Aimed at Inducing an HIV Remission

Study Type

Interventional

2. Study Status

Record Verification Date

May 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

August 1, 2020 (Actual)

Primary Completion Date

December 2024 (Anticipated)

Study Completion Date

December 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

University of California, San Francisco

Collaborators

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Combination approaches will almost certainly be required to generate durable control of HIV in the absence of antiretroviral therapy (a "remission"). In this study, 20 individuals will receive a combination regimen administered during ART and then undergo an analytic treatment interruption (ATI).

Detailed Description

The investigators will perform a single arm study of twenty individuals with HIV infection on effective ART. All participants will receive a combination regimen administered during ART and then undergo an analytic treatment interruption. Our strategy has five stages IL-12 adjuvanted p24CE DNA prime (p24CE/IL-12) at Weeks 0 and 4 IL-12 adjuvanted DNA boost (p24CE plus p55gag) at Week 12 MVA/HIV62B (MVA62B) boost at Week 20 single dose of two bNAbs (VRC07-523LS and 10-1074, which target CD4 binding site and V3 loop, respectively) at week 24 with a TLR9 agonist (lefitolimod) administered weekly between Weeks 24 and 33 (10 doses) ATI with single dose of VRC07 and 10-1074 at Week 34 Follow-up off ART will occur through at least Week 46 (expected) and on or off ART (depending on outcome) through Week 86. Should this approach work, viral load would be expected to rebound in all individuals a few weeks after the bNAb levels decrease to sub-therapeutic levels. This acute rebound would be followed by a new lower viral load set-point and perhaps a long-term remission.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

HIV/AIDS

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

11 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Combination intervention arm

Arm Type

Experimental

Arm Description

All volunteers will receive the combination intervention outlined above.

Intervention Type

Drug

Intervention Name(s)

Combination Intervention

Intervention Description

IL-12 adjuvanted p24CE DNA prime (p24CE/IL-12) at Weeks 0 and 4 IL-12 adjuvanted DNA boost (p24CE plus p55gag) at Week 12 MVA/HIV62B (MVA62B) boost at Week 20 single dose of two bNAbs (VRC07-523LS and 10-1074, which target CD4 binding site and V3 loop, respectively) at week 24 with a TLR9 agonist (lefitolimod) administered weekly between Weeks 24 and 33 (10 doses) ATI with single dose of VRC07 and 10-1074 at Week 34

Primary Outcome Measure Information:

Title

Proportion of participants who experience a new grade 3 or greater adverse event

Time Frame

Week 0 through 86

Title

Proportion of participants achieving post-treatment control.

Description

Time Frame

Week 34 through 86

Secondary Outcome Measure Information:

Title

Occurrence of any unsolicited adverse events for 28 days after administration of each study agent

Time Frame

Week 0 through 62

Title

Time Frame

Week 0 through 86

Title

Occurrence of two consecutive measurements HIV RNA >200 copies/mL using conventional assays

Time Frame

Week 34 to 86

Title

Resumptions of antiretroviral therapy after treatment interruption and the events that trigger them

Time Frame

Week 34 to 86

Title

Frequency of confirmed declines (two consecutive measurements) in CD4+ T cell counts (> 50%)

Time Frame

Week 34 to 86

Title

Frequency of confirmed declines (two consecutive measurements) to below 350 cells/mm3

Time Frame

Week 34 to 86

Title

Proportion experiencing any clinically defined episode of acute retroviral syndrome

Time Frame

Week 34 to 86

Title

Magnitude of T cell responses

Time Frame

Week 14

Title

Breadth of T cell responses

Description

The proportion of participants with at least one additional epitope response at week 14 (2 weeks after last vaccination) compared to their baseline response

Time Frame

Week 14

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Maximum Age & Unit of Time

67 Years

Accepts Healthy Volunteers

Eligibility Criteria

Key Inclusion Criteria Willing and able to provide written informed consent. Age ≤67 years at the time of enrollment for those who started treatment during early infection and <65 years for those who started treatment during chronic infection. Documented HIV-1 infection. On continuous antiretroviral therapy for at least 12 months without any interruptions of greater than 14 consecutive days within the last 1 year, and on a stable regimen that does not include an non-nucleoside reverse transcriptase inhibitor (NNRTI) for at least 4 weeks, without plans to modify ART during the study period. Screening plasma HIV RNA levels below the level of quantification on all available determinations in past 24 months. Screening CD4+ T-cell count ≥ 500 cells/mm3. Key Exclusion Criteria Subjects receiving a non-nucleoside reverse transcriptase inhibitor Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study High-level resistance to both 10-1074 and VRC-07 as defined using the PhenoSense Neutralizing Antibody Assay (Monogram Biosciences). Any history of an HIV-associated malignancy, including Kaposi's sarcoma and any type of lymphoma, or virus-associated cancers. Active or recent non-HIV-associated malignancy requiring systemic chemotherapy or surgery in the preceding 36 months or for whom such therapies are expected in the subsequent 12 months. CD4+ T cell nadir <350 cells/mm3 during the chronic phase of infection (beginning 6 months following the estimated infection date and confirmed on repeat testing). Active hepatitis B (HBV) infection defined as positive HBV surface antigen test. 9. Active hepatitis C (HCV) infection. 10. Presence of significant abnormalities on electrocardiogram. 11. History of potential immune-mediated medical conditions. Individuals with isolated Raynaud's phenomenon or localized disease requiring topical therapy alone will not be excluded.

Facility Information:

Facility Name

Zuckerberg San Francisco General Hospital, University of California San Francisco

City

San Francisco

State/Province

California

ZIP/Postal Code

94110

Country

United States

12. IPD Sharing Statement

Plan to Share IPD

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Combinatorial Therapy to Induce an HIV Remission

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