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HIV InfectionPhase 1/2CLEARNCT01680094

Safety and Effect of The HDAC Inhibitor Panobinostat on HIV-1 Expression in Patients on Suppressive HAART

A Phase 1/2 study testing Panobinostat in people with HIV Infection, run by University of Aarhus at 1 site in Denmark.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The purpose of this study is to assess the safety and ability of panobinostat to re-activate HIV transcription in latently infected CD4+ T-cells among HIV-infected patients on stable antiretroviral therapy Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
HIV Infection
What is being tested?
Panobinostat
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
15 participants
Where
1 siteDenmark
Study dates
Sep 2012to Jan 2014
Phase
Phase 1/2
Are there results?
None posted in the registry

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

  • Documented HIV-1 infection
  • Age >18 years
  • HIV-1 plasma RNA <50 copies/ml for at least 2 years with at least 2 viral load measures per year. 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 HAART, defined as at least 2 nucleoside/nucleotide reverse transcriptase inhibitors plus a non-nucleoside reverse transcriptase inhibitor, integrase inhibitor, or a protease inhibitor
  • CD4+ T-cell count >500/mm3 on minimum 2 occasions in the last 12 months prior to study entry
  • Able to give informed consent

Who cannot join

  • 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 the investigational drug
  • Any gastrointestinal surgery that could impact upon the absorption of the investigational drug
  • Active alcohol or substance use that, in the Investigator's opinion, will prevent adequate compliance with study therapy
  • Patient has the following laboratory values within 3 weeks before starting the investigational drug (lab tests may be repeated, as clinically indicated, to obtain acceptable values before failure at screening is concluded but supportive therapies are not to be administered within the week prior to screening tests for ANC or platelet count)
Show all 26Show fewer
  • Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN)
  • Serum total bilirubin ≥1.5 ULN
  • Serum creatinine levels ≥1.5 x ULN, or calculated creatinine clearance ≤60 ml/min
  • Platelet count ≤100 x109/L
  • Absolute neutrophil count ≤1.5x109/L
  • Serum potassium, magnesium, phosphorus outside normal limits
  • Total calcium (corrected for serum albumin) or ionized calcium ≤lower normal limits
  • Hepatitis B or C infection as indicated by the presence of Hepatitis B surface antigen (HBsAg) or hepatitis C virus RNA (HCV-RNA) 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 a protease inhibitor
  • Receipt of immunomodulating agents, immunization or systemic chemotherapeutic agents within 28 days prior to study entry
  • Use of an agent definitely or possibly associated with effects on QT intervals within 2 weeks of screening
  • ECG at screening that shows QTc >450 msec when calculated using the Fridericia formula from either lead V3 or V4
  • Known resistance to >2 classes of ART
  • Known hypersensitivity to the components of panobinostat or its analogues
  • Current use of sodium valproate or other HDAC inhibitor
  • 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 (according to the Danish Medicines Agency guidelines) to avoid pregnancy for the entire study period and for at least 4 weeks before and 4 weeks after study treatment
  • Males or females who are unwilling or unable to use barrier contraception during sexual intercourse for the entire study period, including at least 4 weeks before, 4 weeks after study treatment, and when plasma HIV-RNA is detectable using standard assays

Trial locations and contacts

1 site in 1 country.

Denmark1 site
  • Department of Infectious Diseases, Aarhus University Hospital

    Aarhus, 8200

Other trials in Denmark

About this study

Official title: The Safety and Efficacy of The Histone Deacetylase Inhibitor Panobinostat for Purging HIV-1 From The Latent Reservoir (CLEAR) Study

The purpose of this study is to assess the safety and ability of panobinostat to re-activate HIV transcription in latently infected CD4+ T-cells among HIV-infected patients on stable antiretroviral therapy

Read the detailed description

Despite effective highly active antiretroviral treatment (HAART), HIV-infection persists and rebounds upon treatment interruption, presumably due to latently infected resting CD4+ T-cells. To achieve eradication of HIV-infection this reservoir of latently HIV-infected cells must be depleted.

Several therapeutic strategies are considered in HIV-cure related research. One approach is to exploit the ability of histone deacetylase (HDAC) inhibitors to reactivate HIV-1 expression in latently infected cells in the presence of HAART.

This is an investigator initiated single-group, non-randomized interventional phase I/II trial designed to evaluate the safety and ability of oral panobinostat to activate HIV-transcription in latently infected CD4+ T-cells of HIV-infected patients on suppressive HAART. The study will enrol 16 patients. Each subject will be used as his/her own control in a before-after design: endpoints measured after study intervention will be compared to baseline for each subject.

The main study will comprise three phases:

  1. A pre-treatment screening/observation phase of 4 weeks (weeks 0-4)
  2. A treatment phase of 8 weeks (weeks 4-12), where 20 mg panobinostat will be administered orally on days 1, 3, and 5 (TIW) every other week (QOW) while maintaining background HAART (co-therapy)
  3. A post-treatment follow-up phase of 24 weeks (weeks 12-36) to evaluate the effect of study treatment

Study participants will be reviewed 13 times during the course of study treatment and follow-up. Blood will be drawn for HIV viral load assessments, CD4 cell counts, biochemistry, hematology and additional immunological and virological analyses. An electrocardiogram of the heart (ECG) will be taken at screening, day 10 and 24 post treatment initiation.

The safety and tolerability of panobinostat will be evaluated based on physical exams, laboratory tests and questions about any problems patients may have experienced during the study. A pre-specified schedule based will guide dose modification in case of unacceptable adverse effects.

Conditions
HIV Infection
Being tested
Panobinostat
Keywords
HIV Infection, Panobinostat, Lentivirus Infections, Retroviridae Infections, RNA Virus Infections, Virus Diseases, Sexually Transmitted Diseases, Viral, Sexually Transmitted Diseases, Immunologic Deficiency Syndromes, Immune System Diseases, Histone Deacetylase Inhibitors, Therapeutic Uses
Medical subject headings
HIV Infections, Lentivirus Infections, Retroviridae Infections, RNA Virus Infections, Virus Diseases, Sexually Transmitted Diseases, Viral, Sexually Transmitted Diseases, Immunologic Deficiency Syndromes

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PanobinostatDrug

    Also called LBH589

    20 mg panobinostat will be administered orally on days 1, 3, and 5 (TIW) every other week (QOW) for a period of 8 weeks while maintaining background HAART

Study groups in NCT01680094
Study groupRoleWhat they receive
PanobinostatExperimental20 mg panobinostat will be administered orally on days 1, 3, and 5 (TIW) every other week (QOW) for a period of 8 weeks while maintaining background HAART
Receives: Drug: Panobinostat

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Change from baseline in HIV transcription in latently infected CD4+ T-cells as measured by copies of unspliced HIV-RNA in the CD4+ T-cells of HIV-infected patients on suppressive HAART

    Measured: Day 1 (before study drug and 2 hours after first dose), Day 2, 5, 10, 15, 24, 29, 38, 43, 52

Secondary outcomes (5)
  1. Change from baseline in the size of the latent HIV-reservoir as measured by copies of proviral HIV-DNA per 10⁶ CD4+ T-cells

    Measured: 12 and 32 weeks after initiation of study treatment

  2. Change from baseline in the frequency of cells latently infected with replication competent HIV expressed as infectious units per million (IUPM)

    Measured: 12 weeks after initiation of study treatment

  3. Safety evaluation, as measured by adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR), and serious unexpected serious adverse reactions (SUSAR)

    Measured: Active follow-up until 32 weeks after initiation of study treatment

  4. Plasma HIV-RNA as measured by the single copy assay

    Measured: Day 1 (before study drug and 2 hours after first dose), Day 2, 5, 10, 15, 24, 29, 38, 43, 52, 84, 224

  5. During an optional HAART-interruption study (if performed, see below): 1) Time to viremia >1000 copies/ml; 2) Time to meet criteria to restart HAART

    Upon completion of the study, subjects may be invited to participate in an additional observational study in which HAART will be interrupted to evaluate the effect of study treatment on virological control. Enrolment into this study is optional and conditioned by the following criteria pertaining to the effect of study treatment on the latent HIV-1 reservoir:

    • Significant increase in unspliced HIV-RNA during in accordance with the primary endpoint measure
    • CD4+ T-cell count >500/mm3

    Measured: To be performed upon completion of 32 weeks follow-up based on the below specified criteria

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Sep 2012 (estimated)
  2. Study startSep 2012
  3. Primary completionSep 2013
  4. Study completionJan 2014

Resources

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 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
15 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01680094
Sponsor's protocol ID
CLEAR0001
Acronym
CLEAR
Status last verified
Feb 2014
First submitted
3 Sep 2012
Last updated
25 Feb 2014
Results posted
No
Data monitoring committee
Yes

Publications

  • Corley MJ, Pang APS, Rasmussen TA, Tolstrup M, Sogaard OS, Ndhlovu LC. Candidate host epigenetic marks predictive for HIV reservoir size, responsiveness to latency reversal, and viral rebound. AIDS. 2021 Nov 15;35(14):2269-2279. doi: 10.1097/QAD.0000000000003065.

    PubMed 34482353
  • Garrido C, Tolstrup M, Sogaard OS, Rasmussen TA, Allard B, Soriano-Sarabia N, Archin NM, Margolis DM. In-vivo administration of histone deacetylase inhibitors does not impair natural killer cell function in HIV+ individuals. AIDS. 2019 Mar 15;33(4):605-613. doi: 10.1097/QAD.0000000000002112.

    PubMed 30830886
  • Bjerg Christensen A, Dige A, Vad-Nielsen J, Brinkmann CR, Bendix M, Ostergaard L, Tolstrup M, Sogaard OS, Rasmussen TA, Randel Nyengaard J, Agnholt J, Denton PW. Administration of Panobinostat Is Associated with Increased IL-17A mRNA in the Intestinal Epithelium of HIV-1 Patients. Mediators Inflamm. 2015;2015:120605. doi: 10.1155/2015/120605. Epub 2015 Dec 1.

    PubMed 26696749
  • Rasmussen TA, Tolstrup M, Brinkmann CR, Olesen R, Erikstrup C, Solomon A, Winckelmann A, Palmer S, Dinarello C, Buzon M, Lichterfeld M, Lewin SR, Ostergaard L, Sogaard OS. Panobinostat, a histone deacetylase inhibitor, for latent-virus reactivation in HIV-infected patients on suppressive antiretroviral therapy: a phase 1/2, single group, clinical trial. Lancet HIV. 2014 Oct;1(1):e13-21. doi: 10.1016/S2352-3018(14)70014-1. Epub 2014 Sep 15.

    PubMed 26423811

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Panobinostat in people with HIV Infection, run by University of Aarhus at 1 site in Denmark.

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 6 inclusion and 26 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: finished, as of the sponsor's last update on 25 Feb 2014. 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 Denmark. 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 combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

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?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

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?

Change from baseline in HIV transcription in latently infected CD4+ T-cells as measured by copies of unspliced HIV-RNA in the CD4+ T-cells of HIV-infected patients on suppressive HAART (time frame: Day 1 (before study drug and 2 hours after first dose), Day 2, 5, 10, 15, 24, 29, 38, 43, 52). 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 NCT01680094, which also lists 4 linked publications.

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 Feb 2014.

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CLEAR Clinical Trial NCT01680094 | AzTrials