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Enhancement by Poly-ICLC During HIV-1 Infection (Poly-ICLC)

13. Februar 2018 aktualisiert von: Nina Bhardwaj

Simultaneous Disruption of Latency and Immune Enhancement by Poly-ICLC During HIV-1 Infection

This study involves researching new approaches to treating HIV infection. Currently, HIV infection is treated with combinations of drugs called antiretrovirals. These drugs protect cells from infection by interfering with the viruses' ability to make copies of itself by infecting new target cells. Though these drugs are very effective, they cannot cure HIV infection and must be taken each and every day at prescribed doses to maintain their beneficial effect. This research study is investigating a new approach that involves an addition to existing medications.

The study is investigating a medication called Poly-ICLC (Hiltonol®, Oncovir), which is an adjuvant. Adjuvants are medications that are designed to boost your body's immune responses resulting from a vaccine. The investigators want to test whether Poly-ICLC is an adjuvant that is effective in HIV-infected patients. A vaccine is not given in this study, but just investigating the adjuvant, Poly-ICLC, to determine whether it may be safe and useful in future vaccines that could be used to treat HIV, called therapeutic vaccines. One goal of future therapeutic vaccines is to reduce the virus that remains persistently inside of cells in a dormant or resting state despite treatment with HIV medications. This persistent pool is termed the "latent virus pool" or "viral reservoir". One tactic to reduce this viral reservoir is to first stimulate HIV to start replicating in order to force it out of hiding. Once viral replication occurs, the infected cells may then be recognized and killed by cells of the immune system. Therefore, we also want to see what effect Poly-ICLC has on the virus that lives inside of cells. Specifically, the investigators want to look at whether Poly-ICLC increases the level of virus inside your cells while also improving your immune system's responses.

The investigators are doing this research in hope to find new ways to treat HIV infection that may reduce exposure to medications that are called antiretrovirals. Antiretrovirals are medications used to treat HIV infection. They are very effective but have side effects and have to be taken each and every day and cannot cure HIV.

Studienübersicht

Detaillierte Beschreibung

Effective combination antiretroviral therapy (cART) has dramatically altered the morbidity and mortality associated with human immunodeficiency virus (HIV-1) infection. Nevertheless, the current treatment paradigm of lifelong antiviral therapy with near perfect patient adherence to avoid the emergence of drug resistant HIV remains less than ideal and this therapeutic approach has clear limitations.

In addition to long term toxicities associated with currently preferred therapies, combination therapy for HIV-1 infection cannot address the issue of viral persistence. HIV-1 persists in both blood and tissue despite long-term suppression with antiretroviral agents (ARVs). Eradication strategies for HIV-1 are likely to require a multi-faceted approach to reduce the latent reservoir, with key components focusing upon both the disruption of viral latency and the enhancement of cytotoxic T lymphocyte (CTL) function to promote killing of infected cells. In order to successfully achieve these objectives, agents that safely stimulate replication of the latent reservoir AND explore approaches to enhance HIV-specific adaptive immunity to augment CTL function must be investigated. The investigators propose that this may be accomplished with a single therapeutic modality that is devised appropriately. Certain adjuvants may possess immunostimulatory properties that trigger transient activation of viral transcription while simultaneously enhancing HIV-specific CTL function and, thus, may play an important role in such a vaccine.

Here, the investigators propose a proof of concept clinical trial to determine the ability of Poly-ICLC (Hiltonol®, Oncovir), to safely activate the latent viral reservoir and enhance innate immunity when administered to HIV-infected individuals. This randomized, double-blinded, placebo-controlled study will administer two doses of Poly-ICLC to HIV-infected individuals whom are virologically suppressed on combination anti-retroviral therapy (cART). The investigators hypothesize that Poly-ICLC will be safe and well-tolerated and will transiently disrupt viral latency while enhancing innate immune responses. Should this be the case, then Poly-ICLC would be an ideal modality to combine with a therapeutic HIV vaccine to reduce the number of latently infected CD4+ T cells in treated HIV-1 infected individuals.

Studientyp

Interventionell

Einschreibung (Tatsächlich)

15

Phase

  • Phase 2
  • Phase 1

Kontakte und Standorte

Dieser Abschnitt enthält die Kontaktdaten derjenigen, die die Studie durchführen, und Informationen darüber, wo diese Studie durchgeführt wird.

Studienorte

    • New York
      • New York, New York, Vereinigte Staaten, 10065
        • The Rockefeller University Hospital

Teilnahmekriterien

Forscher suchen nach Personen, die einer bestimmten Beschreibung entsprechen, die als Auswahlkriterien bezeichnet werden. Einige Beispiele für diese Kriterien sind der allgemeine Gesundheitszustand einer Person oder frühere Behandlungen.

Zulassungskriterien

Studienberechtigtes Alter

18 Jahre bis 55 Jahre (Erwachsene)

Akzeptiert gesunde Freiwillige

Nein

Studienberechtigte Geschlechter

Alle

Beschreibung

Inclusion Criteria:

  • HIV-1 infection documented by previous HIV-1 serology or rapid test, or documented plasma HIV-1 RNA of >2000 copies/ml
  • On stable cART regimen in accordance with the DHHS "Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents" with documented virologic suppression (VL<50 copies/ml) for ≥ 48 weeks.
  • Baseline cell associated HIV-1 RNA is detectable (≥10copies/µg RNA)
  • Laboratory values obtained within 30 days prior to study entry.

    • VL < 50 copies/ml
    • CD4+ T cell count > 500 cells/mm3
    • Absolute neutrophil count (ANC) ≥500/mm3
    • Hemoglobin ≥9.0 g/dL if female; 10 g/dL if male
    • Platelet count ≥75,000/mm3
    • AST (SGOT), ALT (SGPT) ≤3.5 × ULN
    • Alkaline phosphatase< 2.5 ULN
    • Total bilirubin ≤2.5 x ULN
    • Lipase ≤2.5 x ULN
    • Calculated creatinine clearance ≥70 mL/min as estimated by the Cockcroft-Gault equation:
  • For men(140-age in yrs)x(body wt in kg)÷(serum creatinine in mg/dLx72)=CrCl (mL/min)*

    *For women, multiply the result by 0.85 = CrCl (mL/min)

  • NOTE: A program to assist in calculations is available on the DMC web site at: http://www.fstrf.org/ACTG/ccc.html
  • For women of reproductive potential, negative serum or urine pregnancy test
  • Female candidates of reproductive potential is defined as girls who have reached menarche or women who have not been post-menopausal for at least 24 consecutive months (i.e., who have had menses within the preceding 24 months) or have not undergone surgical sterilization (e.g., hysterectomy, or bilateral oophorectomy, or bilateral tubal ligation).
  • Contraception requirements
  • Female candidates of reproductive potential, who are participating in sexual activity that could lead to pregnancy, must agree that they will use at least two reliable barrier methods of contraception while receiving the protocol-specified treatments and for at least 24 weeks after completing stage I of the study.
  • Men and women aged 18-55 years.
  • Ability and willingness of subject to give written informed consent.
  • Adequate venous access for phlebotomy

Exclusion Criteria:

  • Previous immune based therapy
  • History of vascular disease including h/o coronary artery disease, angina/MI, TIA/CVA, peripheral vascular disease/claudication
  • Strong family history of cardiovascular disease
  • Hyperlipidemia requiring medication
  • Diabetes
  • History of Tobacco use (≥10 pack years)
  • HIV-related nephropathy
  • History of vascular disease including history of coronary artery disease, angina/MI, TIA/CVA, peripheral vascular disease/claudication, poorly controlled hypertension
  • Pregnancy or currently breast-feeding
  • Desire to become pregnant during the course of study
  • Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), systemic cytotoxic chemotherapy, or investigational therapy within 30 days prior to study entry.
  • Known allergy/sensitivity to study drugs or their formulations.
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
  • History of autoimmunity
  • Chronic Hepatitis B (HepBSAg+) or C (HCV RNA positive)
  • Current imprisonment or involuntary incarceration in a medical facility for psychiatric or physical (e.g., infectious disease) illness.
  • Participation in any other clinical trial within 30 days prior to screening.
  • Receipt of routine vaccination(s) within 7 days of study entry, or anticipated receipt of routine vaccination(s) during the first 4 weeks of the study. If routine vaccinations are to be administered following the first 4 weeks of the study, they cannot be administered within 7 days prior to weeks 16 and 48 follow up visits.
  • Multi-drug resistant (MDR) HIV-1 precluding standard 3-drug therapy
  • Any other clinical conditions or prior therapy that, in the opinion of the investigator, would make the subject unsuitable for the study or unable to comply with the requirements.

Studienplan

Dieser Abschnitt enthält Einzelheiten zum Studienplan, einschließlich des Studiendesigns und der Messung der Studieninhalte.

Wie ist die Studie aufgebaut?

Designdetails

  • Hauptzweck: Behandlung
  • Zuteilung: Zufällig
  • Interventionsmodell: Parallele Zuordnung
  • Maskierung: Doppelt

Waffen und Interventionen

Teilnehmergruppe / Arm
Intervention / Behandlung
Experimental: Arm A: Poly-ICLC
Arm A (N=15): Patients will receive an injection of 1.4 mg of Poly-ICLC (Hiltonol®, Oncovir) subcutaneously on day 1 and day 2.
Poly-ICLC (Hiltonol®, Oncovir) Administration - On days 1 and 2, patients randomized to this arm will be injected subcutaneously in the arm with 1.4 mg of Poly-ICLC (Hiltonol®, Oncovir). Each subject will receive a total of 2 SC doses of Poly-ICLC. The volume of each injection is 0.7ml. The investigators who are blinded will not be present at the time of injection by the study nurse.
Andere Namen:
  • Poly-ICLC (Hiltonol®, Oncovir)
Placebo-Komparator: Arm B: Normal Saline
Arm B: (N=5): Patients will receive an injection of normal saline subcutaneously on day 1 and day 2.
Normal Saline - On days 1 and 2, patients randomized to this arm will be injected subcutaneously in the arm with normal saline obtained from the Rockefeller University Pharmacy. Each subject will receive a total of 2 SC doses of normal saline. The volume of each injection is 0.7ml. The investigators who are blinded will not be present at the time of injection by the study nurse.
Andere Namen:
  • Placebo

Was misst die Studie?

Primäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
Number Participants With Adverse Events
Zeitfenster: Up to 48 weeks
Safety measured by number of participants with adverse events.
Up to 48 weeks

Sekundäre Ergebnismessungen

Ergebnis Maßnahme
Maßnahmenbeschreibung
Zeitfenster
Plasma Interferon-gamma-inducible Protein-10 (IP-10) Level
Zeitfenster: Day 2 and Day 4
One of the biomarkers of cellular immune activation and exhaustion quantified by flow cytometry. Normal range is 7.8-500 pg/ml.
Day 2 and Day 4
CD8 CD38 (Mean of Fluorescence)
Zeitfenster: Day 8
the CD38-activation marker on CD8 T-cells (CD8/CD38).
Day 8
NK Cell Number
Zeitfenster: at 48 weeks
Natural killer cells or NK cells are part of the innate immune defense against infection and cancer.
at 48 weeks
Percent Change in CD4+ Tcell-associated HIV-1 RNA as Compared to Baseline
Zeitfenster: Baseline, Day 2, Day 4, Day 8, Day 28
CD4+ Tcell-associated HIV-1 RNA to determine whether Poly-ICLC disrupts viral latency in HIV-1-infected individuals on anti-retroviral therapy.Viral transcription assessed by monitoring cell associated HIV-1 RNA. Percent change compared to baseline.
Baseline, Day 2, Day 4, Day 8, Day 28

Mitarbeiter und Ermittler

Hier finden Sie Personen und Organisationen, die an dieser Studie beteiligt sind.

Sponsor

Ermittler

  • Hauptermittler: Martin Markowitz, MD, Aaron Diamond AIDS Research Center
  • Studienleiter: Nina Bhardwaj, MD, PhD, Icahn School of Medicine at Mt. Sinai
  • Hauptermittler: Elizabeth Miller, MD, Icahn School of Medicine at Mount Sinai

Publikationen und hilfreiche Links

Die Bereitstellung dieser Publikationen erfolgt freiwillig durch die für die Eingabe von Informationen über die Studie verantwortliche Person. Diese können sich auf alles beziehen, was mit dem Studium zu tun hat.

Allgemeine Veröffentlichungen

Studienaufzeichnungsdaten

Diese Daten verfolgen den Fortschritt der Übermittlung von Studienaufzeichnungen und zusammenfassenden Ergebnissen an ClinicalTrials.gov. Studienaufzeichnungen und gemeldete Ergebnisse werden von der National Library of Medicine (NLM) überprüft, um sicherzustellen, dass sie bestimmten Qualitätskontrollstandards entsprechen, bevor sie auf der öffentlichen Website veröffentlicht werden.

Haupttermine studieren

Studienbeginn

1. April 2014

Primärer Abschluss (Tatsächlich)

26. Juli 2016

Studienabschluss (Tatsächlich)

26. Juli 2016

Studienanmeldedaten

Zuerst eingereicht

21. Februar 2014

Zuerst eingereicht, das die QC-Kriterien erfüllt hat

24. Februar 2014

Zuerst gepostet (Schätzen)

25. Februar 2014

Studienaufzeichnungsaktualisierungen

Letztes Update gepostet (Tatsächlich)

13. März 2018

Letztes eingereichtes Update, das die QC-Kriterien erfüllt

13. Februar 2018

Zuletzt verifiziert

1. Februar 2018

Mehr Informationen

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