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Summary
EudraCT Number:2012-000240-94
Sponsor's Protocol Code Number:CLEAR0001
National Competent Authority:Denmark - DHMA
Clinical Trial Type:EEA CTA
Trial Status:Completed
Date on which this record was first entered in the EudraCT database:2012-04-23
Trial results
Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL
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A. Protocol Information
A.1Member State ConcernedDenmark - DHMA
A.2EudraCT number2012-000240-94
A.3Full title of the trial
The Safety and Efficacy of The Histone Deacetylase Inhibitor Panobinostat for Purging HIV-1 from The Latent Reservoir (CLEAR) Study
Sikkerhed og Effekt af Histone Deacetylase Inhibitoren Panobinostat til Eradikation af Det Latente HIV-1 Reservoir (CLEAR) Studiet
A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
The Safety and Efficacy of Panobinostat for Eradicating The Latent Reservoir of HIV-infection (CLEAR) Study
Sikkerhed og Effekt af Histone Deacetylase Inhibitoren Panobinostat til Eradikation af Det Latente HIV-1 Reservoir (CLEAR) Studiet
A.3.2Name or abbreviated title of the trial where available
CLEAR
A.4.1Sponsor's protocol code numberCLEAR0001
A.7Trial is part of a Paediatric Investigation Plan No
A.8EMA Decision number of Paediatric Investigation Plan
B. Sponsor Information
B.Sponsor: 1
B.1.1Name of SponsorAarhus University Hospital
B.1.3.4CountryDenmark
B.3.1 and B.3.2Status of the sponsorNon-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1Name of organisation providing supportAarhus University Hospital
B.4.2CountryDenmark
B.4.1Name of organisation providing supportNovartis Healthcare
B.4.2CountryDenmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1Name of organisationAarhus University Hospital
B.5.2Functional name of contact pointDepartment of Infectious Diseases
B.5.3 Address:
B.5.3.1Street AddressBrendstrupgaardsvej 100
B.5.3.2Town/ cityAarhus N
B.5.3.3Post code8200
B.5.3.4CountryDenmark
B.5.4Telephone number004578452841
B.5.5Fax number004578452848
B.5.6E-mailthomrasm@rm.dk
D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3IMP RoleTest
D.2 Status of the IMP to be used in the clinical trial
D.2.1IMP to be used in the trial has a marketing authorisation No
D.2.1.2Country which granted the Marketing AuthorisationDenmark
D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
D.2.5.1Orphan drug designation number
D.3 Description of the IMP
D.3.1Product namepanobinostat
D.3.2Product code LBH589
D.3.4Pharmaceutical form Capsule, hard
D.3.4.1Specific paediatric formulation No
D.3.7Routes of administration for this IMPOral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8INN - Proposed INNPANOBINOSTAT
D.3.9.1CAS number 404950-80-7
D.3.9.4EV Substance CodeSUB31049
D.3.10 Strength
D.3.10.1Concentration unit mg milligram(s)
D.3.10.2Concentration typeequal
D.3.10.3Concentration number5 to 20
D.3.11 The IMP contains an:
D.3.11.1Active substance of chemical origin Yes
D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
The IMP is a:
D.3.11.3Advanced Therapy IMP (ATIMP) No
D.3.11.3.1Somatic cell therapy medicinal product No
D.3.11.3.2Gene therapy medical product No
D.3.11.3.3Tissue Engineered Product No
D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
D.3.11.5Radiopharmaceutical medicinal product No
D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
D.3.11.7Plasma derived medicinal product No
D.3.11.8Extractive medicinal product No
D.3.11.9Recombinant medicinal product No
D.3.11.10Medicinal product containing genetically modified organisms No
D.3.11.11Herbal medicinal product No
D.3.11.12Homeopathic medicinal product No
D.3.11.13Another type of medicinal product No
D.8 Information on Placebo
E. General Information on the Trial
E.1 Medical condition or disease under investigation
E.1.1Medical condition(s) being investigated
Human Immunodeficiency Virus (HIV) Infection
E.1.1.1Medical condition in easily understood language
Human Immunodeficiency Virus (HIV) Infection
E.1.1.2Therapeutic area Diseases [C] - Virus Diseases [C02]
MedDRA Classification
E.1.2 Medical condition or disease under investigation
E.1.2Version 14.1
E.1.2Level LLT
E.1.2Classification code 10020172
E.1.2Term HIV infection NOS
E.1.2System Organ Class 10021881 - Infections and infestations
E.1.2 Medical condition or disease under investigation
E.1.2Version 14.1
E.1.2Level LLT
E.1.2Classification code 10020192
E.1.2Term HIV-1
E.1.2System Organ Class 10021881 - Infections and infestations
E.1.3Condition being studied is a rare disease No
E.2 Objective of the trial
E.2.1Main objective of the trial
To re-activate HIV transcription in latently infected CD4+ T-cells as measured by an increase >0.5 log10 from baseline in copies of unspliced HIV-RNA/μg total RNA in the CD4+ T-cells of HIV-infected patients on suppressive HAART
E.2.2Secondary objectives of the trial
• To evaluate the effect of oral panobinostat on the size of the latent HIV-1 reservoir
• To evaluate the safety and tolerability of oral panobinostat in HIV-infected patients receiving HAART
• To evaluate the effect of oral panobinostat on the immunological control of HIV-infection
• To characterize the immunological events induced by oral panobinostat with regard to HIV-specific immunity, T-cell phenotype, immune activation, and cytokine production
• To characterize the phylogenetic relationship between episomal HIV-DNA and plasma HIV-RNA induced by oral panobinostat and how these relate to proviral HIV-DNA and the persistent low-level viremia present prior to study intervention
• To describe genetic, virological, and immunological predictors of treatment response
E.2.3Trial contains a sub-study No
E.3Principal inclusion criteria
• 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
E.4Principal 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 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)
o Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN)
o Serum total bilirubin ≥1.5 ULN
o Serum creatinine levels ≥1.5 x ULN, or calculated creatinine clearance ≤60 ml/min
o Platelet count ≤100 x109/L
o Absolute neutrophil count ≤1.5x109/L
o Serum potassium, magnesium, phosphorus outside normal limits
o 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
• Has 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
E.5 End points
E.5.1Primary end point(s)
Change from baseline in HIV transcription in latently infected CD4+ T-cells as measured by copies of unspliced HIV-RNA/μg total RNA in the CD4+ T-cells of HIV-infected patients on suppressive HAART
E.5.1.1Timepoint(s) of evaluation of this end point
Unspliced HIV-RNA to be evaluated repeatedly during study treatment (week 4-12)
E.5.2Secondary end point(s)
• Change from baseline to week 16 and 36 in the size of the latent HIV-reservoir, as measured by copies of proviral HIV-DNA per 10⁶ CD4+ T-cells
• Change from baseline to week 16 and 36 in the frequency of cells latently infected with replication competent HIV, as measured by the HIV reactivation assay and expressed as infectious units per million (IUPM)
• Safety evaluation, as measured by adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR), serious unexpected serious adverse reactions (SUSAR), and dose-limiting toxicity
• Plasma HIV-RNA, as measured by the single copy assay
• During the optional HAART-interruption study (if performed)
o Time to viremia >1000 copies/ml during cessation of HAART
o Time to meet criteria to restart HAART

E.5.2.1Timepoint(s) of evaluation of this end point
At week 16 and 36 post study enrollment as indicated

Plasma HIV-RNA (single copy assay) to be evaluated repeatedly during study treatment (week 4-12)

Viral rebound measures during HAART interruption to be measured repeatedly during optional HAART interruption
E.6 and E.7 Scope of the trial
E.6Scope of the trial
E.6.1Diagnosis No
E.6.2Prophylaxis No
E.6.3Therapy Yes
E.6.4Safety Yes
E.6.5Efficacy Yes
E.6.6Pharmacokinetic No
E.6.7Pharmacodynamic No
E.6.8Bioequivalence No
E.6.9Dose response No
E.6.10Pharmacogenetic No
E.6.11Pharmacogenomic No
E.6.12Pharmacoeconomic No
E.6.13Others No
E.7Trial type and phase
E.7.1Human pharmacology (Phase I) Yes
E.7.1.1First administration to humans No
E.7.1.2Bioequivalence study No
E.7.1.3Other Yes
E.7.1.3.1Other trial type description
First administration in HIV-infected humans
E.7.2Therapeutic exploratory (Phase II) Yes
E.7.3Therapeutic confirmatory (Phase III) No
E.7.4Therapeutic use (Phase IV) No
E.8 Design of the trial
E.8.1Controlled No
E.8.1.1Randomised No
E.8.1.2Open Yes
E.8.1.3Single blind No
E.8.1.4Double blind No
E.8.1.5Parallel group No
E.8.1.6Cross over No
E.8.1.7Other Yes
E.8.1.7.1Other trial design description
One-armed interventional proof-of-concept study
E.8.2 Comparator of controlled trial
E.8.2.1Other medicinal product(s) Information not present in EudraCT
E.8.2.2Placebo Information not present in EudraCT
E.8.2.3Other Information not present in EudraCT
E.8.2.4Number of treatment arms in the trial1
E.8.3 The trial involves single site in the Member State concerned Yes
E.8.4 The trial involves multiple sites in the Member State concerned No
E.8.5The trial involves multiple Member States No
E.8.6 Trial involving sites outside the EEA
E.8.6.1Trial being conducted both within and outside the EEA No
E.8.6.2Trial being conducted completely outside of the EEA No
E.8.7Trial has a data monitoring committee No
E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
Last visit of the last subject undergoing the trial
E.8.9 Initial estimate of the duration of the trial
E.8.9.1In the Member State concerned years1
E.8.9.1In the Member State concerned months8
E.8.9.1In the Member State concerned days
F. Population of Trial Subjects
F.1 Age Range
F.1.1Trial has subjects under 18 No
F.1.1.1In Utero No
F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
F.1.1.3Newborns (0-27 days) No
F.1.1.4Infants and toddlers (28 days-23 months) No
F.1.1.5Children (2-11years) No
F.1.1.6Adolescents (12-17 years) No
F.1.2Adults (18-64 years) Yes
F.1.2.1Number of subjects for this age range: 16
F.1.3Elderly (>=65 years) Information not present in EudraCT
F.2 Gender
F.2.1Female Yes
F.2.2Male Yes
F.3 Group of trial subjects
F.3.1Healthy volunteers No
F.3.2Patients Yes
F.3.3Specific vulnerable populations No
F.3.3.1Women of childbearing potential not using contraception No
F.3.3.2Women of child-bearing potential using contraception Yes
F.3.3.3Pregnant women No
F.3.3.4Nursing women No
F.3.3.5Emergency situation No
F.3.3.6Subjects incapable of giving consent personally No
F.3.3.7Others No
F.4 Planned number of subjects to be included
F.4.1In the member state16
G. Investigator Networks to be involved in the Trial
N. Review by the Competent Authority or Ethics Committee in the country concerned
N.Competent Authority Decision Authorised
N.Date of Competent Authority Decision2012-04-10
N.Ethics Committee Opinion of the trial applicationFavourable
N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
N.Date of Ethics Committee Opinion2012-05-09
P. End of Trial
P.End of Trial StatusCompleted
P.Date of the global end of the trial2014-01-16
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