Safety and Effect on HIV Transcription of Vorinostat in Patients Receiving Suppressive Combination Anti-retroviral Therapy - Full Text View

Sponsor:	Bayside Health
Collaborator:	Merck
Information provided by:	Bayside Health
ClinicalTrials.gov Identifier:	NCT01365065

Purpose

The objective of the study is to assess the safety and ability of vorinostat, a drug currently licensed for the treatment of a type of lymphoma, to 'turn on' dormant HIV infected CD4 T-cells.

Condition	Intervention	Phase
HIV Positive	Drug: Vorinostat	Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	A Pilot Study to Assess the Safety and Effect on HIV Transcription of Vorinostat in Patients Receiving Suppressive Combination Anti-retroviral Therapy

Resource links provided by NLM:

Genetics Home Reference related topics: complement factor I deficiency

MedlinePlus related topics: HIV/AIDS

Drug Information available for: Vorinostat

U.S. FDA Resources

Further study details as provided by Bayside Health:

Primary Outcome Measures:

To evaluate the effect of vorinostat on HIV transcription in CD4 T-cells. [ Time Frame: Day 1 (before drug, 2 and 8 hours after first dose), Day 2, 7, 14, 21 and 28 ] [ Designated as safety issue: Yes ]
The primary (efficacy) endpoint of this study is to evaluate the effect of vorionstat on HIV transcription from latently infected CD4+ T-cells as measured by HIV unspliced RNA in CD4+ T-cells.

Secondary Outcome Measures:

1. To evaluate the safety and tolerability of vorinostat in patients receiving effective combination antiretroviral therapy (cART [ Time Frame: Screening, Day 1, 7, 14,21, and 28 ] [ Designated as safety issue: Yes ]
1. Plasma HIV RNA (standard assay)
2. Adverse events and dose-limiting toxicity
3. CD4 T-cell count
4. Antiretroviral plasma trough concentrations will be measured before and after 14 days of treatment with vorinostat.

Estimated Enrollment:	20
Study Start Date:	May 2011
Estimated Study Completion Date:	February 2012
Estimated Primary Completion Date:	December 2011 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Vorinostat Vorinostat 400mg ( 4 X 100mg ) orally daily for 14 days	Drug: Vorinostat Vorinostat 400mg (4 x 100mg) orally daily for 14 days

Detailed Description:

Treatment of HIV infection with combination antiretroviral therapy (cART) has led to significant improvements in the life expectancy and quality of life of people living with HIV. Nevertheless, life expectancy is significantly lower than uninfected individuals and cART leads to several long term side effects. cART alone is not able to cure HIV infection due to persistence of HIV infection in dormant cells. One potential strategy to eradicate HIV infection is to 'wake up' these dormant infected cells by 'turning on' the cell. The small number of cells that are dormant and infected would start to produce virus and die, but infection of other cells would be prevented by cART. Ultimately this could lead to eradication of dormant infected cells and a potential cure for HIV.

This study is a pilot study in 20 individuals recruited at the Alfred Hospital only.

The hypotheses is that vorinostat will induce HIV transcription in CD4 T-cells with latent HIV infection, it is safe and well tolerated in patients receiving effective cART and will induce histone acetylation in vivo in patients with HIV infection.

The study will run over 12 weeks, involving 9 study visits for the participant. Eligible patients must be between 18 to 60 years of age with confirmed HIV infection, and receiving successful cART as indicated by 'suppressed' HIV virus in blood (plasma HIV RNA <50 copies/ml) for at least 3 years and a strong immune system (two CD4 counts greater than 500 cell/µl in the last 6 months).

Patients will be reviewed at screening and days 1 (three time points), 2, 7, 14, 21, 28 and 84 (week 12). They will have blood tests for HIV viral load assessment, CD4 cell counts, biochemistry, hematology and storage samples. An electrocardiogram of the heart (ECG) will be taken at screening, day 7 and 14.

As part of this study levels of HIV in blood and in white blood cells and the degree to which cells are 'turned on' (histone (H3) acetylation) will be measured at 3 time points on day 1, then once on days 2, 7, 14, 21 and 28. The level of one component of cART will be measured at day 1 and 14.

The safety and how well vorinostat is tolerated will be determined based on physical exams, laboratory tests and questions about any problems patients may have experienced during the study. This study has an Independent Safety Monitoring Committee who in addition to evaluating the overall safety of patients will be responsible for assessing safety of the first patient enrolled prior to any recommendation to continue the study.

Eligibility

Ages Eligible for Study:	18 Years to 60 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

HIV -1 infected adults
HIV-1 plasma RNA <50 copies/ml for at least 3 years with at least 2 viral load measures per year, and most recent viral load within 3 months of screening. Episodes of a single HIV plasma RNA 50-199 copies/ml will not exclude participation if the subsequent HIV plasma RNA was <50 copies/ml.
Receiving combination antiretroviral therapy (at least 3 agents)
In the last 6 months have two CD4 cell count greater than 500 cell/µl
Documented subtype B HIV infection
Detectable HIV RNA on stored specimen
Able to give informed consent

Exclusion Criteria:

Any significant acute medical illness in the past 8 weeks.
Any evidence of an active AIDS-defining opportunistic infection.
Current or recent gastrointestinal disease that may impact the absorption of study drug.
Any gastrointestinal surgery that could impact upon the absorption of study drug.
Active alcohol or substance use that, in the Investigator's opinion, will prevent adequate compliance with study therapy .
Moderate to severe hepatic impairment
Hepatic transaminases (AST or ALT) > 3 x upper limit of normal (ULN)
Hepatitis B infection as indicated by the presence of Hepatitis B surface antigen or detectable DNA levels in blood.
A personal history of clinically significant cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for torsades de pointes (e.g. heart failure).
History of malignancy or transplantation, including skin cancers or Kaposi sarcoma
History of diabetes mellitus
Use of an HIV protease inhibitor.
Receipt of immunomodulating agents, immunization or systemic chemotherapeutic agents within 28 days prior to screening.
Use of an agent definitely or possibly associated with effects on QT intervals within 2 weeks of screening.
Receipt of sodium valproate or other HDAC inhibitor at any time.
Women who are pregnant or breastfeeding, or with a positive pregnancy test during screening or Women of Child Bearing Potential (WOCBP) who are unwilling or unable to use an acceptable method of contraception to avoid pregnancy for the entire study period and for at least 4 weeks before and 4 weeks after the study.
Males who are unwilling or unable to use barrier contraception during vaginal intercourse from the time of enrollment and for 12 weeks after participation in the study are also excluded.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01365065

Locations

Australia, Victoria
The Alfred Hospital - Infectious Diseases Unit	Recruiting
Melbourne, Victoria, Australia, 3004
Contact: Michelle Boglis 03 9076 6908 clinresearch@alfred.org.au
Contact: Janine Roney 03 9076 2296 j.roney@alfred.org.au
Principal Investigator: Sharon Lewin, Professor

Sponsors and Collaborators

Bayside Health

Merck

More Information

No publications provided

Responsible Party:	Professor Sharon Lewin, Monash University and The Alfred Hospital
ClinicalTrials.gov Identifier:	NCT01365065 History of Changes
Other Study ID Numbers:	U1111-1121-9077
Study First Received:	June 1, 2011
Last Updated:	June 2, 2011
Health Authority:	Australia: Theraputic Goods Administration

Additional relevant MeSH terms:

HIV Seropositivity
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes

Immune System Diseases
Vorinostat
Histone Deacetylase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on May 23, 2012