HIV InfectionsPhase 2NCT00614458
MK-0518 Intensification And HDAC Inhibition In Depletion Of Resting CD4+ T Cell HIV Infection
A Phase 2 study testing Raltegravir; valproic acid in people with HIV Infections, run by University of North Carolina, Chapel Hill at 1 site in United States.
Trial summary
The purpose of this research study is to see if HIV that persists despite current antiviral therapy can be targeted by new treatments. We will see if adding Raltegravir (MK-0518) and Valproic acid (VPA) to current ART can decrease the amount of latent HIV. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- HIV Infections
- What is being tested?
- Raltegravir; valproic acid
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 6 participants
- Where
- 1 siteUnited States
- Study dates
- Apr 2007to Sep 2008
- Phase
- Phase 2
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- HIV-1 infection
- Men and women age ≥18 years.
- Ability and willingness of subject or legal guardian/representative to give written informed consent.
- Karnofsky performance status >70.
- Willing to adhere to protocol therapy and judged adherent to antiretroviral therapy, and can comply with time requirements for protocol-specified visits and evaluations.
- On potent antiretroviral therapy, defined as at least 2 nucleoside reverse transcriptase inhibitors (NRTIs) plus at least 1 protease inhibitor (PI) or non-nucleoside reverse transcriptase inhibitor (NNRTI), without changes in the 24 weeks immediately prior to entry. Prior changes in or elimination of medications for easier dosing schedule, intolerance, or toxicity are permitted.
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- Have no contraindications to valproic acid (VPA) therapy (pregnancy, bleeding disorders, history of pancreatitis, history of hepatitis).
- Have adequate vascular access for leukopheresis
- Plasma HIV-1 RNA never > 50 copies/ml on two consecutive occasions for ≥ 6 months.
- CD4 cell count > 300 cells/µl.
- Screening serum fasting glucose below 120 mg/dl, creatinine no more than 1.5 times the upper limit of the normal range, serum AST, ALT, and total bilirubin less than 2 times the upper limit of the normal range, and fasting triglycerides < 400mg/dl.
- Female study volunteers who are not of reproductive potential or whose male partner(s) has undergone successful vasectomy with documented azoospermia or has documented azoospermia for any other reason, are eligible without requiring the use of contraception.
- All women of reproductive potential must have a negative urine beta-HCG pregnancy test performed at screening, day 0, week 4, week 8, week 12, and every scheduled study visit thereafter.
- All study volunteers must agree not to participate in a conception process and, if participating in sexual activity that could lead to pregnancy, the female study volunteer/male partner must use two reliable methods of contraception simultaneously while receiving the protocol-specified medications and for 6 weeks after stopping the medications. Subjects must use a reliable barrier method of contraception along with another form of contraception. For women receiving ritonavir, estrogen-based contraceptives are not reliable and an alternative method should be used.
Who cannot join
- Receiving zidovudine (AZT). Due to the inhibition of zidovudine metabolism mediated by Valproic acid (VPA) a theoretical increase risk of zidovudine-induced anemia exists.
- Using drugs known to interact with valproate or raltegravir (MK-0518)
- Pregnant or nursing.
- Anemic (Hemoglobin < 10gm/dl)
- Seropositive for hepatitis C RNA or hepatitis B surface antigen within 90 days prior to entry.
- Have signs or symptoms of hepatic decompensation
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- Received blood transfusions or hematopoetic growth factors within 90 days.
- Use of any of the following within 90 days prior to entry: systemic cytotoxic chemotherapy, investigational agents, immunomodulators.
- Active drug or alcohol use or dependence.
- Serious illness requiring systemic treatment or hospitalization until subject either completes therapy or has been clinically stable on therapy, in the opinion of the site investigator, for at least 90 days prior to entry.
- Compulsorily detained (involuntarily incarcerated) for treatment of either a psychiatric illness or a physical illness, e.g., infectious disease.
- Treatment for an active AIDS-defining opportunistic infection within 90 days prior to screening.
- For this pilot study of no direct benefit to subjects, non-English speaking patients are excluded. In the future, if this study is expanded to include a larger sample size, this exclusion criterion may be removed.
Trial locations and contacts
1 site in 1 country.
United States1 site
University of North Carolina at Chapel Hill
Chapel Hill, North Carolina, 27599
About this study
Official title: 10493 - MK-0518 Intensification and HDAC Inhibition in Depletion of Resting CD4+ T Cell HIV Infection
The purpose of this research study is to see if HIV that persists despite current antiviral therapy can be targeted by new treatments. We will see if adding Raltegravir (MK-0518) and Valproic acid (VPA) to current ART can decrease the amount of latent HIV.
Read the detailed description
The purpose of this research study is to see if HIV that persists despite current antiviral therapy can be targeted by new treatments. Eradicating this hidden, persistent virus (which we will call "latent HIV") may some day allow HIV to be eliminated from an infected person. Recently it has been discovered that a class of medicines, called histone deacetylase (HDAC) inhibitors, may cause the HIV that hides within some of the cells of your body to be expressed ("unmasked"). The HDAC inhibitor we will use in this study to unmask or flush out the latent HIV within your cells is called valproic acid (VPA) and is commonly used to treat seizures and depression under the brand name Depakote. VPA has been safely given to people with HIV for the treatment of seizures or depression.
In our first study, we recruited 4 volunteers with HIV-1 infection taking antiviral therapy in whom there were <50 copies/ml (undetectable) of HIV virus RNA in their blood for over 6 months. In addition to continuing their anti-HIV medications, we started them on Fuzeon, a new injected anti-HIV medication, for one month. We then added VPA to the anti-HIV medications and Fuzeon for 3 months. At the end of the study, we found that latent HIV was significantly decreased. No safety problems with VPA and antiviral medicines were noted. However, having initiated Fuzeon and VPA simultaneously we could not determine with confidence that our findings were due to the effect of VPA alone.
In the next study we added VPA to the therapy of patients taking standard antiretroviral therapy (ART). Eight patients have been studied so far, but only three have yet had a significant decrease in latent HIV. It may be that VPA does not work in everyone, or that stronger HIV therapy is needed in some people to drain latent HIV. And in a different study, no decrease at all was found in the number of infected cells in people taking ART who were prescribed valproate for other reasons.
In this study, we wish to add a different new anti-HIV medicine, which is a pill, Raltegravir (MK-0518). Raltegravir blocks the virus from permanently entering the DNA of your T cells, and so is called an integrase inhibitor. Raltegravir is investigational. This means the U.S. Food and Drug Administration (FDA) have not yet approved it for sale. We will see if adding Raltegravir and VPA to your current ART can decrease the amount of latent HIV. If adding Raltegravir and VPA to your ART has no effect, you will have reached the end of the study. If adding Raltegravir and VPA decreases latent infection, we will stop VPA but continue Raltegravir to see if this new integrase inhibitor decreases latent infection. This study does not expect to cure your HIV, but only to take the first step towards that far-away goal.
You are asked to join this study because you are infected with the HIV-1 virus; you are 18 years of age; you are able and willing to sign an informed consent.; you are able to have laboratory tests within the study specific criteria; and you have adequate vein access for leukopheresis.
- Conditions
- HIV Infections
- Being tested
- Raltegravir; valproic acid
- Keywords
- latent HIV, resting CD4+ T cell, valproic acid (VPA), Raltegravir (MK-0518) intensification, HIV replication, treatment experienced
- Medical subject headings
- HIV Infections
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Raltegravir; valproic acidDrug
Also called raltegravir (MK 0518), Valproic acid (VPA) (depakote)
raltegravir 400mg po BID; valproic acid 1000mg - 2000mg daily
| Study group | Role | What they receive |
|---|---|---|
| Raltegravir and VPA to ART | Experimental | raltegravir 400mg po BID; valproic acid 1000mg - 2000mg daily Receives: Drug: Raltegravir; valproic acid |
What is being measured
The primary outcome is the main question the study is designed to answer.
A Change in the Number of HIV Infected Cells.
A change in infected cells from prior to the initiation of VPA and MK0518 to after 20 weeks of treatment.
Measured: 20 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted13 Feb 2008 (estimated)
- Study startApr 2007
- Primary completionSep 2008
- Study completionSep 2008
Why it stopped: Due to insufficient funds
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionsStudies of the same condition, open and under way.
- More trials run by University of North Carolina, Chapel HillThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 6 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of North Carolina, Chapel Hill
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID), Abbott, Merck Sharp & Dohme LLC
- Responsible party
- Principal investigator, David Margolis, MD, University of North Carolina, Chapel Hill
- Investigators
- David M Margolis, MD, Principal investigator, University of North Carolina, Chapel Hill
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT00614458
- Sponsor's protocol ID
- 10493
- Other IDs
- R01AI064074, P30AI050410, U01AI067854
- Status last verified
- Sep 2011
- First submitted
- 31 Jan 2008
- Last updated
- 25 Oct 2011
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
Publications
Archin NM, Cheema M, Parker D, Wiegand A, Bosch RJ, Coffin JM, Eron J, Cohen M, Margolis DM. Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection. PLoS One. 2010 Feb 23;5(2):e9390. doi: 10.1371/journal.pone.0009390.
PubMed 20186346
Study at a glance
From the registry record, last updated by the sponsor on 25 Oct 2011. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- 10493 - MK-0518 Intensification and HDAC Inhibition in Depletion of Resting CD4+ T Cell HIV Infection
- ClinicalTrials.gov ID
- NCT00614458
- Acronym / sponsor ID
- 10493
- Conditions
- HIV Infections
- Keywords
- latent HIV, resting CD4+ T cell, valproic acid (VPA), Raltegravir (MK-0518) intensification, HIV replication, treatment experienced
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: Due to insufficient funds
- Enrolment
- 6 participants (actual)
- Lead sponsor
- University of North Carolina, Chapel HillUniversity, hospital or other
- Collaborators
- National Institute of Allergy and Infectious Diseases (NIAID), Abbott, Merck Sharp & Dohme LLC
- Study start
- Apr 2007
- Primary completion
- Sep 2008 (actual)
- Study completion
- Sep 2008 (actual)
- First posted
- 13 Feb 2008 (estimated)
- Results
- Posted 25 Oct 2011
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this research study is to see if HIV that persists despite current antiviral therapy can be targeted by new treatments. We will see if adding Raltegravir (MK-0518) and Valproic acid (VPA) to current ART can decrease the amount of latent HIV.
Detailed description
The purpose of this research study is to see if HIV that persists despite current antiviral therapy can be targeted by new treatments. Eradicating this hidden, persistent virus (which we will call "latent HIV") may some day allow HIV to be eliminated from an infected person. Recently it has been discovered that a class of medicines, called histone deacetylase (HDAC) inhibitors, may cause the HIV that hides within some of the cells of your body to be expressed ("unmasked"). The HDAC inhibitor we will use in this study to unmask or flush out the latent HIV within your cells is called valproic acid (VPA) and is commonly used to treat seizures and depression under the brand name Depakote. VPA has been safely given to people with HIV for the treatment of seizures or depression.
In our first study, we recruited 4 volunteers with HIV-1 infection taking antiviral therapy in whom there were <50 copies/ml (undetectable) of HIV virus RNA in their blood for over 6 months. In addition to continuing their anti-HIV medications, we started them on Fuzeon, a new injected anti-HIV medication, for one month. We then added VPA to the anti-HIV medications and Fuzeon for 3 months. At the end of the study, we found that latent HIV was significantly decreased. No safety problems with VPA and antiviral medicines were noted. However, having initiated Fuzeon and VPA simultaneously we could not determine with confidence that our findings were due to the effect of VPA alone.
In the next study we added VPA to the therapy of patients taking standard antiretroviral therapy (ART). Eight patients have been studied so far, but only three have yet had a significant decrease in latent HIV. It may be that VPA does not work in everyone, or that stronger HIV therapy is needed in some people to drain latent HIV. And in a different study, no decrease at all was found in the number of infected cells in people taking ART who were prescribed valproate for other reasons.
In this study, we wish to add a different new anti-HIV medicine, which is a pill, Raltegravir (MK-0518). Raltegravir blocks the virus from permanently entering the DNA of your T cells, and so is called an integrase inhibitor. Raltegravir is investigational. This means the U.S. Food and Drug Administration (FDA) have not yet approved it for sale. We will see if adding Raltegravir and VPA to your current ART can decrease the amount of latent HIV. If adding Raltegravir and VPA to your ART has no effect, you will have reached the end of the study. If adding Raltegravir and VPA decreases latent infection, we will stop VPA but continue Raltegravir to see if this new integrase inhibitor decreases latent infection. This study does not expect to cure your HIV, but only to take the first step towards that far-away goal.
You are asked to join this study because you are infected with the HIV-1 virus; you are 18 years of age; you are able and willing to sign an informed consent.; you are able to have laboratory tests within the study specific criteria; and you have adequate vein access for leukopheresis.
Study design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Raltegravir and VPA to ART | Experimental | Drug: Raltegravir; valproic acidraltegravir 400mg po BID; valproic acid 1000mg - 2000mg daily |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (14 listed)
- HIV-1 infection
- Men and women age ≥18 years.
- Ability and willingness of subject or legal guardian/representative to give written informed consent.
- Karnofsky performance status >70.
- Willing to adhere to protocol therapy and judged adherent to antiretroviral therapy, and can comply with time requirements for protocol-specified visits and evaluations.
Key exclusion criteria (13 listed)
- Receiving zidovudine (AZT). Due to the inhibition of zidovudine metabolism mediated by Valproic acid (VPA) a theoretical increase risk of zidovudine-induced anemia exists.
- Using drugs known to interact with valproate or raltegravir (MK-0518)
- Pregnant or nursing.
- Anemic (Hemoglobin < 10gm/dl)
- Seropositive for hepatitis C RNA or hepatitis B surface antigen within 90 days prior to entry.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Raltegravir; valproic acidAlso: raltegravir (MK 0518), Valproic acid (VPA) (depakote)raltegravir 400mg po BID; valproic acid 1000mg - 2000mg daily | Drug | Raltegravir and VPA to ART |
Primary outcome
A Change in the Number of HIV Infected Cells.
Time frame: 20 weeks
A change in infected cells from prior to the initiation of VPA and MK0518 to after 20 weeks of treatment.
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Oct 2011.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 20186346Archin NM, Cheema M, Parker D, Wiegand A, Bosch RJ, Coffin JM, Eron J, Cohen M, Margolis DM. Antiretroviral intensification and valproic acid lack sustained effect on residual HIV-1 viremia or resting CD4+ cell infection. PLoS One. 2010 Feb 23;5(2):e9390. doi: 10.1371/journal.pone.0009390.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
David M Margolis, MD principal investigator
University of North Carolina, Chapel Hill
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Raltegravir; valproic acid in people with HIV Infections, run by University of North Carolina, Chapel Hill at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 14 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 25 Oct 2011. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 25 Oct 2011). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
A Change in the Number of HIV Infected Cells. (time frame: 20 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT00614458, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Oct 2011.