HIV Infection
Conditions
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, 9 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.
Interventions
DRUGPanobinostat
Panobinostat will be administered orally.
Pegylated Interferon-alpha2a will be administered subcutaneously in one shot.
Sponsors
Novartis
Genentech, Inc.
Massachusetts General Hospital
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of Grade ≥ 1 Adverse Events (AEs) | All adverse events measured from day 1 until day 28 after administration of the first dose of panobinostat and/or interferon-alpha2a was recorded. | 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 | Measured through week 4 after administration of panobinostat and/or interferon-alpha2a | Operational measurement of CD4 T cells harboring genome-intact HIV-1 DNA, determined by the IPDA assay. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Histone H3 Acetylation in CD4 T Cells | measured after last dose of PBT on day 4 | CD4 T cells expressing acetylated H3, determined by flow cytometry. |
| Change From Baseline in Levels of CD4 T Cell-associated HIV-1 RNA | measured after last dose of PBT on day 4 | total HIV-1 RNA per ug of RNA in CD4 T cells |
| Change From Baseline in Frequency of Activated NKp30+ NK Cells. | measured after last dose of PBT on day 4 | the proportion of NK cells expressing NKp30 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Arm A (Panobinostat-only Arm) 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.
Panobinostat: Panobinostat will be administered orally. | 4 |
| Arm B (Panobinostat + IFNa2a Arm) 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.
Panobinostat: Panobinostat will be administered orally.
Pegylated Interferon-alpha2a: Pegylated Interferon-alpha2a will be administered subcutaneously in one shot. | 9 |
| Arm C (IFN-a2a-only Arm) 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.
Pegylated Interferon-alpha2a: Pegylated Interferon-alpha2a will be administered subcutaneously in one shot. | 4 |
| Total | 17 |
Baseline characteristics
| Characteristic | Arm A (Panobinostat-only Arm) | Arm B (Panobinostat + IFNa2a Arm) | Arm C (IFN-a2a-only Arm) | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 9 Participants | 4 Participants | 17 Participants |
| Age, Continuous | 49.5 years | 40.4 years | 43.2 years | 43.2 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants | 5 Participants | 1 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 4 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 8 Participants | 2 Participants | 13 Participants |
| Region of Enrollment United States | 4 participants | 9 participants | 4 participants | 17 participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 2 Participants | 3 Participants |
| Sex: Female, Male Male | 3 Participants | 9 Participants | 2 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 4 | 0 / 9 | 0 / 4 |
| other Total, other adverse events | 3 / 4 | 9 / 9 | 4 / 4 |
| serious Total, serious adverse events | 0 / 4 | 0 / 9 | 0 / 4 |
Outcome results
Primary
Change in CD4 T Cell-Associated Proviral HIV-1 DNA From Baseline
Operational measurement of CD4 T cells harboring genome-intact HIV-1 DNA, determined by the IPDA assay.
Time frame: Measured through week 4 after administration of panobinostat and/or interferon-alpha2a
Population: entire study population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A | Change in CD4 T Cell-Associated Proviral HIV-1 DNA From Baseline | baseline | 32.6 HIV copies per million CD4 T cells | Standard Error 14.1 |
| Arm A | Change in CD4 T Cell-Associated Proviral HIV-1 DNA From Baseline | day 28 | 44.7 HIV copies per million CD4 T cells | Standard Error 20.2 |
| Arm B | Change in CD4 T Cell-Associated Proviral HIV-1 DNA From Baseline | baseline | 179 HIV copies per million CD4 T cells | Standard Error 130 |
| Arm B | Change in CD4 T Cell-Associated Proviral HIV-1 DNA From Baseline | day 28 | 108.4 HIV copies per million CD4 T cells | Standard Error 79.8 |
| Arm C | Change in CD4 T Cell-Associated Proviral HIV-1 DNA From Baseline | baseline | 24 HIV copies per million CD4 T cells | Standard Error 18.3 |
| Arm C | Change in CD4 T Cell-Associated Proviral HIV-1 DNA From Baseline | day 28 | 18.7 HIV copies per million CD4 T cells | Standard Error 12.5 |
Primary
Occurrence of Grade ≥ 1 Adverse Events (AEs)
Cumulative frequency and severity of Grade ≥ 1 adverse events, Grade ≥ 1 lab abnormalities or serious adverse events
Time frame: All adverse events measured from day 1 until day 28 after administration of the first dose of panobinostat and/or interferon-alpha2a was recorded.
Population: all study participants
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Arm A | Occurrence of Grade ≥ 1 Adverse Events (AEs) | 5 events |
| Arm B | Occurrence of Grade ≥ 1 Adverse Events (AEs) | 26 events |
| Arm C | Occurrence of Grade ≥ 1 Adverse Events (AEs) | 4 events |
Secondary
Change From Baseline in Frequency of Activated NKp30+ NK Cells.
the proportion of NK cells expressing NKp30
Time frame: measured after last dose of PBT on day 4
Population: entire study population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A | Change From Baseline in Frequency of Activated NKp30+ NK Cells. | baseline | 22.8 percentage of cells | Standard Error 0.9 |
| Arm A | Change From Baseline in Frequency of Activated NKp30+ NK Cells. | day 4 | 23 percentage of cells | Standard Error 1.4 |
| Arm B | Change From Baseline in Frequency of Activated NKp30+ NK Cells. | baseline | 30.9 percentage of cells | Standard Error 3.2 |
| Arm B | Change From Baseline in Frequency of Activated NKp30+ NK Cells. | day 4 | 37.8 percentage of cells | Standard Error 4 |
| Arm C | Change From Baseline in Frequency of Activated NKp30+ NK Cells. | baseline | 21.4 percentage of cells | Standard Error 4.2 |
| Arm C | Change From Baseline in Frequency of Activated NKp30+ NK Cells. | day 4 | 25.5 percentage of cells | Standard Error 5.6 |
Secondary
Change From Baseline in Histone H3 Acetylation in CD4 T Cells
CD4 T cells expressing acetylated H3, determined by flow cytometry.
Time frame: measured after last dose of PBT on day 4
Population: entire study cohort
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A | Change From Baseline in Histone H3 Acetylation in CD4 T Cells | baseline | 2 Percentage of cells | Standard Error 0.64 |
| Arm A | Change From Baseline in Histone H3 Acetylation in CD4 T Cells | day 4 | 23.2 Percentage of cells | Standard Error 17.15 |
| Arm B | Change From Baseline in Histone H3 Acetylation in CD4 T Cells | baseline | 3.1 Percentage of cells | Standard Error 0.76 |
| Arm B | Change From Baseline in Histone H3 Acetylation in CD4 T Cells | day 4 | 14.7 Percentage of cells | Standard Error 3.2 |
| Arm C | Change From Baseline in Histone H3 Acetylation in CD4 T Cells | baseline | 5.5 Percentage of cells | Standard Error 1.47 |
| Arm C | Change From Baseline in Histone H3 Acetylation in CD4 T Cells | day 4 | 8.3 Percentage of cells | Standard Error 3.7 |
Secondary
Change From Baseline in Levels of CD4 T Cell-associated HIV-1 RNA
total HIV-1 RNA per ug of RNA in CD4 T cells
Time frame: measured after last dose of PBT on day 4
Population: entire study population
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Arm A | Change From Baseline in Levels of CD4 T Cell-associated HIV-1 RNA | baseline | 1055.6 HIV RNA copies/ug of RNA | Standard Error 306.9 |
| Arm A | Change From Baseline in Levels of CD4 T Cell-associated HIV-1 RNA | day 4 | 1611.2 HIV RNA copies/ug of RNA | Standard Error 596.6 |
| Arm B | Change From Baseline in Levels of CD4 T Cell-associated HIV-1 RNA | baseline | 630.6 HIV RNA copies/ug of RNA | Standard Error 279.3 |
| Arm B | Change From Baseline in Levels of CD4 T Cell-associated HIV-1 RNA | day 4 | 1138.4 HIV RNA copies/ug of RNA | Standard Error 583.1 |
| Arm C | Change From Baseline in Levels of CD4 T Cell-associated HIV-1 RNA | baseline | 772.5 HIV RNA copies/ug of RNA | Standard Error 302.5 |
| Arm C | Change From Baseline in Levels of CD4 T Cell-associated HIV-1 RNA | day 4 | 958.8 HIV RNA copies/ug of RNA | Standard Error 296 |