Evaluating the Safety and Efficacy of Single-Dose Romidepsin in Combination With Antiretroviral Therapy in HIV-Infected Adults With Suppressed Viral Load

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier:
NCT01933594
First received: August 28, 2013
Last updated: October 1, 2014
Last verified: October 2014

August 28, 2013
October 1, 2014
February 2014
August 2015   (final data collection date for primary outcome measure)
  • Occurrence of Grade 3 or higher adverse events (AEs) [ Time Frame: Measured through 28 days after the administration of RMD or placebo ] [ Designated as safety issue: Yes ]
    Including signs/symptoms, lab toxicities, and /or clinical events that is probably, possibly, or definitely related to study treatment (as judged by the core team, blinded to treatment arm)
  • Change in plasma HIV-1 RNA levels from baseline (average of pre-entry and entry values) as detected by single copy assay [ Time Frame: Measured through 48 hours (average) after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • Change in cell-associated HIV-1 RNA levels in resting CD4 T cells [ Time Frame: Measured through 24 hours after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • Occurrence of Grade 3 or higher adverse events (AEs) [ Time Frame: Measured through 28 days after the administration of RMD or placebo ] [ Designated as safety issue: Yes ]
    Including signs/symptoms, lab toxicities, and /or clinical events that is probably, possibly or definitely related to study treatment (as judged by the core team, blinded to treatment arm)
  • Change in plasma HIV-1 RNA levels from baseline (average of pre-entry and entry values) as detected by single copy assay [ Time Frame: Measured through 48 hours (average) after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • Change in cell-associated HIV-1 RNA levels in resting CD4+ T-cells [ Time Frame: Measured through 24 hours after the administration of RMD or placebo ] [ Designated as safety issue: No ]
Complete list of historical versions of study NCT01933594 on ClinicalTrials.gov Archive Site
  • Changes in plasma HIV-1 RNA levels as detected by single copy assay [ Time Frame: Measured through 28 days after the administration of RMD and placebo ] [ Designated as safety issue: No ]
  • Change in cell-associated HIV-1 RNA levels in resting CD4 T cells [ Time Frame: Measured through 14 days after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • Changes in cell-associated HIV-1 RNA levels in total CD4 T cells [ Time Frame: Measured through 28 days after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • Changes in histone acetylation in total CD4 T cells by flow cytometry [ Time Frame: Measured through 14 days after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • Changes in total HIV-1 DNA and 2-long terminal repeat (LTR) circles in resting or total CD4 T cells [ Time Frame: Measured through 28 days after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • PK parameters (area under the curve [AUC], maximum concentration [Cmax], and minimum concentration [Cmin]) for RMD and co-administered antiretroviral drugs (EFV, DTG, or RAL) [ Time Frame: Measured through 24 hours after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • Number/percent of participants with HIV-1 RNA levels greater than or equal to 200 copies [ Time Frame: Measured through 7 days after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • All reported Grade 2 through 4 AEs [ Time Frame: Measured through 28 or 56 days after the administration of RMD or placebo ] [ Designated as safety issue: Yes ]
    Whether this is measured through 28 or 56 days after the administration of RMD or placebo depends on when the participant's last study visit is.
  • Changes in plasma HIV-1 RNA levels as detected by single copy assay [ Time Frame: Measured through 28 days after the administration of RMD and placebo ] [ Designated as safety issue: No ]
  • Change in cell-associated HIV-1 RNA levels in resting CD4+ T-cells [ Time Frame: Measured through 14 days after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • Changes in cell-associated HIV-1 RNA levels in total CD4+ T-cells [ Time Frame: Measured through 28 days after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • Changes in histone acetylation in total CD4+ T-cells by flow cytometry [ Time Frame: Measured through 14 days after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • Changes in total HIV-1 DNA and 2-long terminal repeat (LTR) circles in resting or total CD4+ T-cells [ Time Frame: Measured through 28 days after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • PK parameters (area under the curve [AUC], maximum concentration [Cmax], and minimum concentration [Cmin]) for RMD and co-administered antiretroviral drugs (EFV or RAL). [ Time Frame: Measured through 24 hours after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • Number/percent of participants with HIV-1 RNA levels greater than 200 copies [ Time Frame: Measured through 7 days after the administration of RMD or placebo ] [ Designated as safety issue: No ]
  • All reported Grade 2 through 4 AEs [ Time Frame: Measured through 28 or 56 days after the administration of RMD or placebo ] [ Designated as safety issue: Yes ]
    Whether this is measured through 28 or 56 days after the administration of RMD or placebo depends on when the participant's last study visit is.
Not Provided
Not Provided
 
Evaluating the Safety and Efficacy of Single-Dose Romidepsin in Combination With Antiretroviral Therapy in HIV-Infected Adults With Suppressed Viral Load
A Phase I/II Study of Single Dose Romidepsin in HIV-Infected Adults With Suppressed Viremia on Antiretroviral Therapy to Assess Safety, Tolerability, and Activation of HIV-1 Expression

Antiretroviral therapy (ART) can reduce HIV to very low levels in the blood, but it cannot cure HIV infection because a small amount of virus remains in cells as a hidden (latent) form. The purpose of this study is to identify single doses of the drug romidepsin (RMD) that are safe and well tolerated, and that induce HIV-1 expression in HIV-1-infected adults who are on either efavirenz (EFV)-, raltegravir (RAL)-, or dolutegravir (DTG)-based ART regimens.

A major challenge in eradicating HIV-1 infection is the persistence of virus in long-lived cells, such as latently infected memory CD4 T cells. One approach for eliminating the HIV-1 reservoir is to activate viral replication in these latently infected CD4 T cells by targeting cellular mechanisms that repress proviral transcription. Histone deacetylase inhibitors (HDACis), such as RMD, induce HIV-1 expression by increasing acetylation and facilitating transcriptional activation of HIV-1. RMD administered in combination with ART may serve as an important component of a strategy to eradicate the HIV-1 latent reservoir. The purpose of this study is to identify single doses of RMD that are safe and well tolerated, and that induce HIV-1 expression in HIV-1-infected adults who are on either EFV-, RAL-, or DTG-based ART regimens.

Participants will be randomly assigned to either the RMD or the placebo arm of one of three cohorts. The three cohorts will differ in the dose of RMD given. Participants will be enrolled into Cohort 1 first; if the dose given to Cohort 1 is well tolerated and no safety concerns are noted, Cohort 2 will be enrolled. If the dose given to Cohort 2 is well tolerated and no safety concerns are noted, Cohort 3 will be enrolled.

This study will last for 28 or 56 days; some participants will attend study visits only through Day 28, and some will return for a study visit on Day 56. Whether a participant continues to Day 56 depends on his or her HIV-1 RNA level at the Day 7 visit or whether the participant experiences a Grade 3 or higher adverse event (AE).

At the screening visit, participants will give a medical history and will undergo a physical exam; blood and urine samples will be collected. At the entry visit, RMD or placebo will be administered as an intravenous (IV) infusion over 4 hours. An electrocardiogram (ECG) will be administered before, immediately after, and 14 days after infusion. Participants will undergo pharmacokinetic (PK) sampling which will require that blood be drawn before the infusion; during the infusion; 4, 6, 12, 24, and 48 hours after the infusion; and on Days 7, 14, and 28. Some participants may also have blood drawn at a Day 56 visit. If participants agree, their blood samples may be stored for future research.

Interventional
Phase 1
Phase 2
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
HIV Infections
  • Drug: Romidepsin
    RMD will be administered over 4 hours via an intravenous (IV) catheter placed into a peripheral vein.
    Other Names:
    • RMD
    • Istodax
  • Drug: Placebo for RMD: 0.9% sodium chloride for injection
    Placebo for RMD will be administered over 4 hours via an IV catheter placed into a peripheral vein.
    Other Name: 0.9% NaCl
  • Experimental: Cohort 1-Arm 1A (RMD)
    Participants in Cohort 1, Arm 1A will receive RMD intravenously (IV) over 4 hours (beginning at Hour 0) at the Day 1 study visit. Dose of RMD will be 0.5 mg/m^2, with total dose based on the participant's body surface area (BSA), which is determined by participant's height and weight.
    Intervention: Drug: Romidepsin
  • Placebo Comparator: Cohort 1-Arm 1B (Placebo for RMD)
    Participants in Cohort 1, Arm 1B will receive 0.9% sodium chloride for injection IV over 4 hours (beginning at Hour 0) at the Day 1 study visit. Dose of sodium chloride for injection placebo will be 0.5 mg/m^2, with total dose based on the participant's BSA, which will be determined by weight and height.
    Intervention: Drug: Placebo for RMD: 0.9% sodium chloride for injection
  • Experimental: Cohort 2-Arm 2A (RMD)
    Participants in Cohort 2, Arm 2A will receive RMD IV over 4 hours (beginning at Hour 0) at the Day 1 study visit. Dose of RMD will be 2 mg/m^2, with total dose based on the participant's BSA, which is determined by participant's height and weight.
    Intervention: Drug: Romidepsin
  • Placebo Comparator: Cohort 2-Arm 2B (Placebo for RMD)
    Participants in Cohort 2, Arm 2B will receive 0.9% sodium chloride for injection IV over 4 hours (beginning at Hour 0) at the Day 1 study visit. Dose of sodium chloride for injection placebo will be 2 mg/m^2, with total dose based on the participant's BSA, which will be determined by weight and height.
    Intervention: Drug: Placebo for RMD: 0.9% sodium chloride for injection
  • Experimental: Cohort 3-Arm 3A (RMD)
    Participants in Cohort 3, Arm 3A will receive RMD IV over 4 hours (beginning at Hour 0) at the Day 1 study visit. Dose of RMD will be 5 mg/m^2, with total dose based on the participant's BSA, which is determined by participant's height and weight.
    Intervention: Drug: Romidepsin
  • Placebo Comparator: Cohort 3-Arm 3B (Placebo for RMD)
    Participants in Cohort 3, Arm 3B will receive 0.9% sodium chloride for injection IV over 4 hours (beginning at Hour 0) at the Day 1 study visit. Dose of sodium chloride for injection placebo will be 5 mg/m^2, with total dose based on the participant's BSA, which will be determined by weight and height.
    Intervention: Drug: Placebo for RMD: 0.9% sodium chloride for injection

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
45
Not Provided
August 2015   (final data collection date for primary outcome measure)

Inclusion Criteria:

  • HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen or plasma HIV-1 RNA. More information on this criterion is available in the protocol.
  • Receiving a raltegravir-, dolutegravir-, efavirenz-based Department of Health and Human Services (DHHS)-recommended antiretroviral therapy (ART) regimen for at least 90 days prior to study entry (i.e., regimens in the DHHS' "not recommended category" are not allowed) with no intention to change for the duration of the study. More information on this criterion is available in the protocol.
  • Documentation of at least two historical HIV-1 RNA measurements less than 50 copies/mL while on ART obtained by standard ultrasensitive assay. Documentation of the first measurement must be from a result obtained between 365 days and 91 days, inclusive, prior to study entry. Documentation of the second measurement must be from a result obtained between 730 days and 366 days, inclusive, prior to study entry. In addition, there must be no HIV-1 RNA values greater than or equal to 50 copies/mL for at least 365 days prior to study entry.
  • CD4 cell count equal to or greater than 300 cells/mm^3 obtained within 90 to 50 days prior to study entry at any United States laboratory that has a Clinical Laboratory Improvement Amendment (CLIA) certification or its equivalent
  • HIV-1 RNA level of fewer than 50 copies/mL obtained by standard ultrasensitive assay within 90 to 50 days prior to study entry
  • HIV-1 RNA level of 0.4 copies/mL or greater obtained by single copy assay (SCA) within 90 to 50 days prior to study entry. This result must be available prior to the pre-entry visit.
  • The following laboratory values obtained within 21 to 0 days prior to study entry by any US laboratory that has a CLIA certification or its equivalent.

    • Absolute neutrophil count (ANC) equal to or greater than 1,500 cells/mm^3
    • Hemoglobin equal to or greater than 12.0 g/dL for men and greater than 11.0 g/dL for women
    • Platelet count equal to or greater than 120,000/mm^3
  • The following laboratory values obtained within 21 to 7 days prior to study entry by any United States laboratory that has a CLIA certification or its equivalent:

    • Creatinine clearance (CrCl) equal to or greater than 60 mL/min. More information on this criterion is available in the protocol.
    • Potassium and magnesium within normal limits.More information on this criterion is available in the protocol.
    • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) less than 2.0 times the upper limit of normal (ULN)
    • Alanine aminotransferase (ALT) (serum glutamic-pyruvic transaminase [SGPT]) less than 2.0 times ULN
    • Alkaline phosphatase less than 2.0 times ULN
    • Total bilirubin less than 2.5 times ULN
  • Hepatitis C virus (HCV) antibody negative result within 90 to 50 days prior to study entry or, if the HCV antibody result is positive, a negative HCV RNA result obtained within 90 to 50 days prior to study entry
  • Negative hepatitis B surface antigen (HBsAg) result obtained within 90 to 50 days prior to study entry
  • For females of reproductive potential, negative serum or urine pregnancy test (urine pregnancy test with a sensitivity of less than or equal to 25 mIU/mL) at the screening visit, pre-entry visit within 21 to 7 days prior to study entry, and at entry prior to romidepsin infusion, by any United States laboratory that has a CLIA certification or its equivalent. Reproductive potential is defined as: girls who have reached menarche, women who have had menses within the past 12 months and who do not have a follicle-stimulating hormone (FSH) greater than 40 IU/L, women who have had menses within the past 24 consecutive months if an FSH measurement is not available, or women who have not undergone surgical sterilization (e.g., hysterectomy, bilateral oophorectomy, or bilateral salpingectomy). More information on this criterion is available in the protocol.
  • Female participants of reproductive potential must refrain from participating in active attempts to become pregnant, and, if participating in sexual activity that could lead to pregnancy, must agree to use at least two reliable forms of contraception that are non-estrogen based. All participants of reproductive potential must be instructed to use contraceptives for 6 months/180 days after completing RMD or placebo infusion. Acceptable forms of contraception include: condoms (male or female) with or without spermicidal agent; diaphragm or cervical cap with spermicide; non-hormonal or progestin-only containing intrauterine device (IUD) (e.g., Mirena, Implanon, Nuva Ring); tubal ligation; or non-estrogen containing formulations of hormonal birth control drugs, given by pills, shots, or placed on or under the skin, for at least 90 days prior to study entry. More information on this criterion is available in the protocol.
  • Karnofsky performance score of at least 80 within 21 to 7 days prior to study entry
  • Ability and willingness to provide written informed consent
  • Site investigator anticipates that a fully active alternative ART regimen could be constructed in the event of virologic failure on the current ART regimen

Exclusion Criteria:

  • History of or current malignancy requiring cytotoxic therapy
  • Bacterial, fungal, or viral infection (other than HIV) requiring systemic therapy within 30 days prior to entry
  • History of or current cytomegalovirus (CMV) end organ disease (e.g., retinitis)
  • History of or current AIDS-related syndromes or symptoms that pose a perceived excessive risk for study drug-related morbidity, as determined by the site investigator
  • Chronic, acute, or recurrent infections that are current and serious in the opinion of the site investigator and for which the participant has not completed at least 14 consecutive days of therapy within 30 days prior to study entry and/or is not clinically stable
  • Active autoimmune disorders including but not limited to: inflammatory bowel diseases, scleroderma, severe psoriasis as determined by the site investigator, systemic lupus erythematosus, rheumatoid arthritis, and optic neuritis
  • History of seizure disorders
  • History of anticonvulsant use within 60 days prior to study entry
  • History of myocardial infarction (MI) within 6 months prior to study entry, history of QTc prolongation (defined as electrocardiogram [ECG] with QTc intervals greater than 450 ms) at any time prior to study entry, New York Heart Association (NYHA) class III or IV heart failure at any time prior to study entry, or family history of prolonged QTc syndrome
  • Breastfeeding
  • Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), HIV vaccine, systemic cytotoxic chemotherapy, or investigational therapy within 60 days prior to study entry. More information on this criterion is available in the protocol.
  • Any vaccination within 30 days prior to entry or intent to receive an elective vaccination (e.g., flu shot, hepatitis A vaccine, or hepatitis B vaccine) during the course of the study.
  • Intent to use cytokines (e.g., interleukin 2 [IL-2] or interleukin 12 [IL-12]) during the course of the study. Prior administration of cytokines is not an exclusion criterion; however, at least 60 days between the most recent cycle of any cytokine and study entry is required.
  • Within 60 days prior to study entry, use of systemic azole antifungals (voriconazole, itraconazole, ketoconazole); dexamethasone; macrolide antibiotics (azithromycin, clarithromycin, erythromycin); ARVs that are inhibitors of, or are metabolized by, cytochrome P450 3A4 (CYP3A4) (atazanavir, ritonavir, nelfinavir, indinavir, saquinavir, darunavir, lopinavir, rilpivirine, maraviroc); cobicistat; warfarin; nefazodone; rifamycins (rifabutin, rifampin, rifapentine); St. John's Wort; carbamazepine; phenytoin; phenobarbital; amiodarone; dofetilide; pimozide; procainamide; quinidine; sotalol; and birth control products containing estrogen; drugs that are p-glycoprotein inhibitors; and drugs that prolong the QTc interval with a risk of Torsades de Pointes. More information on this criterion is available in the protocol.
  • Known allergy, sensitivity, or any hypersensitivity to components of RMD or its formulation
  • Use of histone deacetylase inhibitors (e.g., vorinostat, valproic acid) at any time prior to study entry
  • Active illicit drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements
  • Acute or serious illness requiring systemic treatment and/or hospitalization that is not resolved within 30 days prior to entry
  • Psychosocial conditions that would prevent study compliance and follow-up, as determined by the site investigator
  • Documented opportunistic infections within 60 days prior to entry
  • Known history of poor peripheral venous access
Both
18 Years and older
No
United States
 
NCT01933594
A5315, 11892, ACTG 5315
Yes
National Institute of Allergy and Infectious Diseases (NIAID)
National Institute of Allergy and Infectious Diseases (NIAID)
Not Provided
Study Chair: John Mellors, MD University of Pittsburgh
Study Chair: Deborah McMahon, MD University of Pittsburgh
National Institute of Allergy and Infectious Diseases (NIAID)
October 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP