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.
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
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:
- A pre-treatment screening/observation phase of 4 weeks (weeks 0-4)
- 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)
- 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 group | Role | What they receive |
|---|---|---|
| Panobinostat | Experimental | 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 Receives: Drug: Panobinostat |
What is being measured
The primary outcome is the main question the study is designed to answer.
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)
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
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
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
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
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.
- First posted6 Sep 2012 (estimated)
- Study startSep 2012
- Primary completionSep 2013
- Study completionJan 2014
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (4)Papers the sponsor has linked to this study.
- Other trials for HIV InfectionStudies of the same condition, open and under way.
- More trials run by University of AarhusThe 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 1/2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 15 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Aarhus
- Sponsor type
- University, hospital or other
- Collaborators
- Massachusetts General Hospital, Monash University, University of Sydney, Novartis, Aarhus University Hospital
- Responsible party
- Sponsor
- Investigators
- Lars Østergaard, MD,DMSc,PhD, Study director, Aarhus University HospitalThomas A Rasmussen, MD, Principal investigator, Aarhus University Hospital
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 34482353Garrido 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 30830886Bjerg 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 26696749Rasmussen 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
Study at a glance
From the registry record, last updated by the sponsor on 25 Feb 2014. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Safety and Efficacy of The Histone Deacetylase Inhibitor Panobinostat for Purging HIV-1 From The Latent Reservoir (CLEAR) Study
- ClinicalTrials.gov ID
- NCT01680094
- Acronym / sponsor ID
- CLEAR / CLEAR0001
- Conditions
- HIV Infection
- Keywords
- HIV Infection, Panobinostat, Lentivirus Infections, Retroviridae Infections, RNA Virus Infections, Virus Diseases, Sexually Transmitted Diseases, Viral, Sexually Transmitted Diseases
- Phase
- Phase 1/2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 15 participants (actual)
- Lead sponsor
- University of AarhusUniversity, hospital or other
- Collaborators
- Massachusetts General Hospital, Monash University, University of Sydney, Novartis, Aarhus University Hospital
- Study start
- Sep 2012
- Primary completion
- Sep 2013 (actual)
- Study completion
- Jan 2014 (actual)
- First posted
- 6 Sep 2012 (estimated)
- Results
- Not posted in the source record
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 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
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:
- A pre-treatment screening/observation phase of 4 weeks (weeks 0-4)
- 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)
- 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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Panobinostat | Experimental | Drug: Panobinostat20 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 |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (26 listed)
- 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
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 |
|---|---|---|
| PanobinostatAlso: LBH58920 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 | Drug | Panobinostat |
Primary outcome
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
5 secondary outcomes
Change from baseline in the size of the latent HIV-reservoir as measured by copies of proviral HIV-DNA per 10⁶ CD4+ T-cells
Time frame: 12 and 32 weeks after initiation of study treatment
Change from baseline in the frequency of cells latently infected with replication competent HIV expressed as infectious units per million (IUPM)
Time frame: 12 weeks after initiation of study treatment
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)
Time frame: Active follow-up until 32 weeks after initiation of study treatment
Plasma HIV-RNA as measured by the single copy assay
Time frame: Day 1 (before study drug and 2 hours after first dose), Day 2, 5, 10, 15, 24, 29, 38, 43, 52, 84, 224
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
Time frame: To be performed upon completion of 32 weeks follow-up based on the below specified criteria
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Feb 2014.
- Derived from this study: PubMed 34482353Corley 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.
- Derived from this study: PubMed 30830886Garrido 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.
- Derived from this study: PubMed 26696749Bjerg 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.
- Derived from this study: PubMed 26423811Rasmussen 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.
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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.
Lars Østergaard, MD,DMSc,PhD study director
Aarhus University Hospital
Thomas A Rasmussen, MD principal investigator
Aarhus University Hospital
1 site in 1 country: see every site and its status.
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.