Early Administration of Romidepsin and 3BNC117 in Treatment-naïve HIV Patients Starting ART (eCLEAR)

• ClinicalTrials.gov Identifier: NCT03041012
• Recruitment Status: Recruiting
• First Posted: February 2, 2017
• Last Update Posted: October 14, 2019
• Sponsor: Aarhus University Hospital
• Collaborators: Rigshospitalet, Denmark; Hvidovre University Hospital; Odense University Hospital; Aalborg University Hospital; Herning Hospital; Hammersmith Hospitals NHS Trust; St Mary's Hospital, London
• Information provided by (Responsible Party): University of Aarhus ( Aarhus University Hospital )

Study Description

Brief Summary:

To evaluate the effect of early viral reactivation by latency reversing agents (LRA) and/or administration of potent broadly neutralizing antibodies (bNAb) on the size of the latent HIV-1 reservoir in treatment naïve HIV-1 patients initiating antiretroviral therapy (ART)

Condition or disease	Intervention/treatment	Phase
Hiv	Drug: Romidepsin; Drug: 3BNC117; Drug: Antiretrovirals	Phase 2

Detailed Description:

The study will be conducted among ART naïve HIV-1-infected patients.

Subjects will continue ART while receiving LRA romidepsin and/or bNAb 3BNC117.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Factorial Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Early Administration of Latency Reversing Therapy and Broadly Neutralizing Antibodies to Limit the Establishment of the HIV-1 Reservoir During Initiation of Antiretroviral Treatment - a Randomized Controlled Trial
• Actual Study Start Date: January 20, 2017
• Estimated Primary Completion Date: March 20, 2020
• Estimated Study Completion Date: April 20, 2021

Arms and Interventions

Arm	Intervention/treatment
Placebo Comparator: antiretrovirals; Standard of care	Drug: Antiretrovirals; Combination antiretroviral therapy; Other Name: ART
Active Comparator: antiretrovirals + romidepsin; Standard of care + LRA	Drug: Romidepsin; 5mg/m2 romidepsin will be administered IV on days 10, 17, and 24 after initiating ART; Other Name: Istodax; Drug: Antiretrovirals; Combination antiretroviral therapy; Other Name: ART
Active Comparator: antiretrovirals + 3BNC117; Standard of care + bNAb	Drug: 3BNC117; 30 mg/kg 3BNC117 will be administered IV on day 7 and 21 after initiating ART; Other Name: Broadly neutralizing antibody; Drug: Antiretrovirals; Combination antiretroviral therapy; Other Name: ART
Active Comparator: antiretrovirals + romidepsin + 3BNC117; Standard of care + LRA + bNAb	Drug: Romidepsin; 5mg/m2 romidepsin will be administered IV on days 10, 17, and 24 after initiating ART; Other Name: Istodax; Drug: 3BNC117; 30 mg/kg 3BNC117 will be administered IV on day 7 and 21 after initiating ART; Other Name: Broadly neutralizing antibody; Drug: Antiretrovirals; Combination antiretroviral therapy; Other Name: ART

Outcome Measures

Primary Outcome Measures :

1. Plasma HIV RNA kinetics [ Time Frame: 3 months ]
   Time to undetectable (<20 c/mL)
2. Quantification of the size of the proviral HIV reservoir [ Time Frame: 1 year ]
   Copies of total HIV-1 DNA per 10⁶ CD4+ T cells as measured by digital droplet PCR

Secondary Outcome Measures :

1. Incidence of treatment emerging events (Safety and tolerability) [ Time Frame: 1 year ]
   Frequence and severity of adverse events (AE), adverse reactions (AR), serious adverse events (SAE), serious adverse reactions (SAR) and suspected unexpected serious adverse reactions (SUSAR).
2. Quantification of the integrated HIV DNA [ Time Frame: 1 year ]
   Integrated HIV-1 DNA in CD4+ T cells (copies per million cells) as measured by alu-PCR.
3. Quantification of the size of the replication-competent HIV reservoir [ Time Frame: 1 year ]
   The frequency of CD4+ T cells latently infected with replication competent HIV as measured by infectious units per million (IUPM) CD4+ T cells in a viral outgrowth assay
4. Immune reconstitution [ Time Frame: 1 year ]
   Absolute CD4+ and CD8+ T cell count
5. Analytic treatment interruption (ATI) study [ Time Frame: 64 weeks ]
   Time to plasma HIV RNA >5000 c/mL on two consecutive measurements

Other Outcome Measures:

1. Plasma cytokine and immune activation biomarker levels [ Time Frame: 1 year ]
   Soluble IL-6, sCD14, sCD163

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Documented HIV-1 infection
• CD4+ T cell count >200/µL on last visit prior to study entry
• ART naïve
• Able to give informed consent

Exclusion Criteria:

• Any significant acute medical illness (not including primary HIV infection) in the past 8 weeks
• Any evidence of an active AIDS-defining opportunistic infection
• Active alcohol or substance use that, in the Investigator's opinion, will prevent adequate compliance with study therapy

• The following laboratory values at screening, but the values can be repeated within the screening period, but test results must be available before baseline (day 0) and checked for eligibility:

  • Hepatic transaminases (AST or ALT) ≥3 x upper limit of normal (ULN)
  • Serum total bilirubin ≥3 ULN
  • Estimated glomerular filtration rate (eGFR) ≤60 mL/min (based on serum creatinine or other appropriate validated markers)
  • Platelet count ≤100 x10^9/L
  • Absolute neutrophil count ≤1x10^9/L
  • Serum potassium, magnesium, phosphorus outside ≥1.5 ULN/LLN
  • Total calcium (corrected for serum albumin) or ionized calcium ≥1.5 ULN/LLN
  • 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
• ECG at screening that shows QTc >450 ms when calculated using the Fridericia formula from either lead V3 or V4 [86]

• Use of:

  • Warfarin or warfarin-derivatives
  • HDACi
  • An agent definitely or possibly associated with effects on QT intervals within 2 weeks of screening
  • Drugs that induce or inhibit CYP3A4 or P-gp

• History of:

  • Clinically significant cardiac disease, symptomatic or asymptomatic arrhythmias, syncopal episodes, or additional risk factors for Torsades de pointes (e.g. heart failure)
  • Malignancy or transplantation, including skin cancers or Kaposi sarcoma
  • Diabetes mellitus
• Receipt of strong immunosuppressive or systemic chemotherapeutic agents within 28 days prior to study entry
• Known resistance to >2 classes of ART
• Known hypersensitivity to the components of romidepsin, 3BNC117 or their analogues
• 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 non-estrogen containing contraceptions (according to the Danish Medicines Agency guidelines) to avoid pregnancy for the 3 week study period and 4 weeks after study treatment or until undetectable plasma HIV-1 RNA using standard assays
• Males or females who are unwilling or unable to use barrier contraception during sexual intercourse for the 3-week study period, and 4 weeks after study treatment or until undetectable plasma HIV-1 RNA using standard assays

Contacts and Locations

Contacts

Contact: Ole S Søgaard, MD PhD; +45 78452842; olesoega@rm.dk

Contact: Jesper D Gunst, MD; +45 78452844; jesdam@rm.dk

Locations

Denmark

Department of Infectious Diseases; Recruiting

Aalborg, Denmark

Contact: Henrik Nielsen

Dept. of Infectious Diseases, Aarhus University Hospital; Recruiting

Aarhus, Denmark, 8200

Contact: Jesper D Gunst, MD +45 78452844 jesdam@rm.dk

Department of Infectious Diseases; Recruiting

Hvidovre, Denmark

Contact: Thomas Benfield

Department of Infectious Diseases; Recruiting

København, Denmark

Contact: Jan Gerstoft

Department of Infectious Diseases; Recruiting

Odense, Denmark

Contact: Isik S. Johansen

United Kingdom

Guy's and St Thomas'; Recruiting

London, United Kingdom

Contact: Julie Fox julie.fox@kcl.ac.uk

Contact: Uzu Hiromi Hiromi.Uzu@gstt.nhs.uk

Imperial College Healthcare NHS Trust; Recruiting

London, United Kingdom

Contact: John Thornhill john.thornhill@nhs.net

Principal Investigator: Sarah Fidler

Sponsors and Collaborators

Aarhus University Hospital

Rigshospitalet, Denmark

Hvidovre University Hospital

Odense University Hospital

Aalborg University Hospital

Herning Hospital

Hammersmith Hospitals NHS Trust

St Mary's Hospital, London

Investigators

• Principal Investigator: Ole S Søgaard, MD PhD; Aarhus University Hospital

More Information

• Responsible Party: Aarhus University Hospital
• ClinicalTrials.gov Identifier: NCT03041012
• Other Study ID Numbers: eCLEAR-001; 2015-002234-53 ( EudraCT Number )
• First Posted: February 2, 2017
• Last Update Posted: October 14, 2019
• Last Verified: October 2019

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Individual deidentified participant data (including data dictionaries) will be shared following the publication of the primary and secondary endpoints as outlined in this protocol. Data to be shared includes deidentified data points in published, peer-reviewed articles. Additional, related documents will also be available (study protocol, informed consent form). Data will become available following publication with no planned end date.
• Supporting Materials: Study Protocol; Informed Consent Form (ICF); Analytic Code
• Time Frame: Individual deidentified participant data (including data dictionaries) will be shared following the publication of the primary and secondary endpoints as outlined in this protocol. Data will become available following publication with no planned end date.
• Access Criteria: Access to the data sharing will be given to researchers who provide a methodologically sound proposal for any type of analysis and requires IRB/Ethics committee approval (if applicable). Proposal should be addressed to olesoega@rm.dk.

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by University of Aarhus ( Aarhus University Hospital ):

HIV-1; Latency Reversal Agent; Immunotherapy

Additional relevant MeSH terms:

Anti-Retroviral Agents; Romidepsin; Antiviral Agents; Anti-Infective Agents; Antibiotics, Antineoplastic; Antineoplastic Agents