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Reducing the Residual Reservoir of HIV-1 Infected Cells in Patients Receiving Antiretroviral Therapy (ACTIVATE)

Primary Purpose

HIV Infection

Status

Active

Phase

Phase 1

Locations

United States

Study Type

Interventional

Intervention

Panobinostat

Pegylated Interferon-alpha2a

About this trial

This is an interventional treatment trial for HIV Infection

Eligibility Criteria

18 Years - 65 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Ability and willingness to provide informed consent
HIV-1 infection prior to entry
Receiving suppressive ART therapy for a minimum of 24 consecutive months prior to screening with no interruption of therapy (same ART regimen for at least 12 weeks prior to screening)
Documented suppressed HIV-1 RNA (plasma HIV-1 RNA values <50 copies/ml)
CD4 T cell count ≥ 400 cells/mm3
Negative Hepatitis B surface antigen (HBsAg) or Negative HBV DNA PCR
Negative anti-Hepatitis C virus antibodies (anti-HCV) or negative HCV PCR if anti-HCV antibodies are positive
Negative TB Test (if positive, completed a recommended treatment course for latent TB)
Vaccinated for pneumococcal disease within last 5 years
No clinically significant eye disease
No evidence of clinical coronary heart disease
Not pregnant, planning to become pregnant, or breastfeeding
Willingness to continue to use contraceptives for 90 days after completing treatment
If male, willingness to use a condom during intercourse while taking panobinostat and total of 80 hours after stopping treatment
Not pregnant, planning to become pregnant, or breastfeeding
No evidence of coronary heart disease

Exclusion Criteria:

HIV-1 RNA > 50 copies/mL within 24 months of screening
Severe psychiatric disease, chronic liver disease, past or current evidence of immunologically mediated disease
Severe retinopathy due to diabetes, hypertension, cytomegalovirus or macular degeneration
Evidence of coronary heart disease
History of active thyroid disease requiring medication
Breastfeeding
Presence of a bacterial, fungal, viral or protozoal infection requiring systemic anti-infective therapy
Uncontrolled seizure disorders
History or other evidence of severe illness or other conditions
History of malignancy of any organ system within the past 5 years
Female participants who are pregnant or nursing
History of solid organ transplantation with an existing functional graft
Use of any immunomodulatory agents within 30 days prior to study enrollment or planned use during the trial
Active drug or alcohol use or dependence
Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of drugs, or which may jeopardize the participant in case of participation in the study
Use of HIV protease inhibitor or other strong or moderately strong CYP3A4 inhibitors
History of anaphylaxis, allergy or serious adverse reactions to Interferon-alpha2a/Interferon-alpha2b or panobinostat
Has taken: interleukins, systemic interferons or systemic chemotherapy

Sites / Locations

Massachusetts General Hospital CRS (MGH CRS)

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Arm Label

Arm A

Arm B

Arm C

Arm Description

Participants in Arm A will receive panobinostat as an oral tablet on days 0, 2, and 4 of the treatment week. The dose of panobinostat will be a 15 mg tablet.

Participants in Arm B will receive one subcutaneous injection of pegylated interferon-alpha2a on day 0. The dose of pegylated IFN-alpha2a will be 180 mcg. Simultaneously with interferon-alpha2a, a 15 mg tablet of panobinostat will be administered on day 0. Participants will also receive panobinostat as an oral tablet on days 2 and 4 of the treatment week.

Participants in Arm C will receive one subcutaneous injection of pegylated interferon-alpha2a on day 0.The dose of pegylated IFN-alpha2a will be 180 mcg.

Outcomes

Primary Outcome Measures

Occurrence of Grade ≥ 1 Adverse Events (AEs)

Cumulative frequency and severity of Grade ≥ 1 adverse events, Grade ≥ 1 lab abnormalities or serious adverse events

Change in CD4 T Cell-Associated Proviral HIV-1 DNA from Baseline

Operational measurement of HIV-1 reservoir

Secondary Outcome Measures

Change from baseline in levels of infectious viral units per million CD4 T cells

Change from baseline in histone H3 acetylation in CD4 T cells

Change from baseline in levels of CD4 T cell-associated HIV-1 RNA

Change from baseline in levels of plasma HIV-1 RNA

Change from baseline in levels of CD4 T cell-associated HIV-1 2-LTR circles and chromosomally integrated proviral HIV-1 DNA

Change from baseline in levels of HIV-1 DNA in different CD4 T cell subsets (naïve, T memory stem cells, central-memory, effector-memory, terminally-differentiated)

Change from baseline in frequency and function of innate and adaptive immune effector cell responses

Change from baseline in levels of cellular and soluble immune activation markers

Change from baseline in expression patterns of interferon-stimulated genes (ISG)

Comparison of all immunologically and virological parameters in study participants treated with pegylated Interferon-alpha2a and panobinostat according to HLA class I and IL-28b genotypes

Full Information

NCT ID

NCT02471430

First Posted

June 11, 2015

Last Updated

March 13, 2023

Sponsor

Massachusetts General Hospital

Collaborators

Novartis, Genentech, Inc.

1. Study Identification

Unique Protocol Identification Number

NCT02471430

Brief Title

Reducing the Residual Reservoir of HIV-1 Infected Cells in Patients Receiving Antiretroviral Therapy

Acronym

ACTIVATE

Official Title

A Phase I-II Pilot Study to Assess the Safety and Efficacy of Combined Administration With Pegylated Interferon-alpha2a and the Histone Deacetylase Inhibitor (HDACi) Panobinostat for Reducing the Residual Reservoir of HIV-1 Infected Cells in cART-Treated HIV-1 Positive Individuals

Study Type

Interventional

2. Study Status

Record Verification Date

March 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

May 2016 (Actual)

Primary Completion Date

August 2022 (Actual)

Study Completion Date

December 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Massachusetts General Hospital

Collaborators

Novartis, Genentech, Inc.

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This study is a prospective, open-label, randomized, three-arm, dose-escalation exploratory pilot clinical trial involving HIV-1 infected participants treated with suppressive combination antiretroviral combination therapy (cART). The study will test whether combined treatment with the histone deacetylase inhibitor panobinostat and the immunomodulatory cytokine Interferon-alpha2a can reduce the residual reservoir of HIV-1 infected cells that persist during treatment with currently available antiretroviral drugs.

Detailed Description

This study is a prospective, triple-arm, randomized, open-label, dose-escalation exploratory clinical trial involving HIV-1 infected participants treated with suppressive combination antiretroviral combination therapy (cART). The primary objective of this study is to evaluate a new strategy for reducing the residual reservoir of HIV-1 infected cells that persists despite treatment with current HIV drugs. The clinical trial is conducted in the Infectious Diseases Clinical Trials Unit (CTU) at the Massachusetts General Hospital. The study medication includes two agents: panobinostat is an oral tablet that can reverse HIV-1 latency and awaken HIV from a "sleeping" condition during which it is protected from the human immune system. The second drug is pegylated interferon-alpha2a (IFN-alpha2a), an injectable cytokine that activates the immune system. The combined use of both agents may lead to immune-mediated elimination of HIV-1 infected cells in which viral latency has been reversed by panobinostat. Participants will be randomized to receive a treatment course with panobinostat alone (Arm A, 4 participants total), panobinostat in combination with pegylated IFN-alpha2a (Arm B, 10 participants total), or pegylated IFN-alpha2a alone (Arm C, 4 participants total). Participants receiving panobinostat will undergo one week of treatment (15mg, dosed every second day on Monday, Wednesday, Friday), followed by three weeks off-treatment. Subcutaneous injections with pegylated IFN-alpha2a will be administered at the start of the week-long treatment course (simultaneously with the first dose of panobinostat for Arm B). ART will be continued during the entire treatment duration in all study participants. Participants will undergo close monitoring for side effects during the entire time of study participation. The total study duration will be 2 months.

6. Conditions and Keywords

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

HIV Infection

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1, Phase 2

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Randomized

Enrollment

34 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm A

Arm Type

Experimental

Arm Description

Participants in Arm A will receive panobinostat as an oral tablet on days 0, 2, and 4 of the treatment week. The dose of panobinostat will be a 15 mg tablet.

Arm Title

Arm B

Arm Type

Experimental

Arm Description

Arm Title

Arm C

Arm Type

Experimental

Arm Description

Participants in Arm C will receive one subcutaneous injection of pegylated interferon-alpha2a on day 0.The dose of pegylated IFN-alpha2a will be 180 mcg.

Intervention Type

Drug

Intervention Name(s)

Panobinostat

Other Intervention Name(s)

Farydak, LBH589

Intervention Description

Panobinostat will be administered orally.

Intervention Type

Drug

Intervention Name(s)

Pegylated Interferon-alpha2a

Other Intervention Name(s)

Pegasys

Intervention Description

Pegylated Interferon-alpha2a will be administered subcutaneously in one shot.

Primary Outcome Measure Information:

Title

Occurrence of Grade ≥ 1 Adverse Events (AEs)

Description

Cumulative frequency and severity of Grade ≥ 1 adverse events, Grade ≥ 1 lab abnormalities or serious adverse events

Time Frame

Measured through 1 month after administration of panobinostat and/or interferon-alpha2a

Title

Change in CD4 T Cell-Associated Proviral HIV-1 DNA from Baseline

Description

Operational measurement of HIV-1 reservoir

Time Frame

Measured through 1 week after administration of panobinostat and/or interferon-alpha2a

Secondary Outcome Measure Information:

Title

Change from baseline in levels of infectious viral units per million CD4 T cells

Time Frame