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

NCT01680094 | Completed Phase 1 DMC

• 1 other identifier: CLEAR0001
• Study Type: interventional
• Target: 15
• Locations: 1 country
• Sites: 1

Brief 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

Conditions

HIV Infection

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

Outcome Measures

Primary Outcomes (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

  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

  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)

  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)

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

• Plasma HIV-RNA as measured by the single copy assay

  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

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

Study Arms (1)

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

Drug: Panobinostat

Interventions

Panobinostat DRUG

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

Also known as: LBH589

Panobinostat

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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)
• 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)

Sponsors & Collaborators

• University of Aarhus: lead
• Massachusetts General Hospital: collaborator
• Monash University: collaborator
• University of Sydney: collaborator
• Novartis: collaborator
• Aarhus University Hospital: collaborator

Study Sites (1)

Department of Infectious Diseases, Aarhus University Hospital

Aarhus, 8200, Denmark

Location

Related Publications (4)

• 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.

  PMID: 34482353 DERIVED

• 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.

  PMID: 30830886 DERIVED

• 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.

  PMID: 26696749 DERIVED

• 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.

  PMID: 26423811 DERIVED

MeSH Terms

Conditions

HIV Infections; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Interventions

Panobinostat

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Genital Diseases; Urogenital Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Hydroxamic Acids; Hydroxylamines; Amines; Organic Chemicals; Hydroxy Acids; Carboxylic Acids; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Lars Østergaard, MD,DMSc,PhD

  Aarhus University Hospital

  STUDY DIRECTOR

• Thomas A Rasmussen, MD

  Aarhus University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 3, 2012
• First Posted: September 6, 2012
• Study Start: September 1, 2012
• Primary Completion: September 1, 2013
• Study Completion: January 1, 2014
• Last Updated: February 25, 2014

Record last verified: 2014-02

Locations

DK (1)