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

tiistai 13. helmikuuta 2018 päivittänyt: 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.

Tutkimuksen yleiskatsaus

Yksityiskohtainen kuvaus

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.

Opintotyyppi

Interventio

Ilmoittautuminen (Todellinen)

15

Vaihe

  • Vaihe 2
  • Vaihe 1

Yhteystiedot ja paikat

Tässä osiossa on tutkimuksen suorittajien yhteystiedot ja tiedot siitä, missä tämä tutkimus suoritetaan.

Opiskelupaikat

    • New York
      • New York, New York, Yhdysvallat, 10065
        • The Rockefeller University Hospital

Osallistumiskriteerit

Tutkijat etsivät ihmisiä, jotka sopivat tiettyyn kuvaukseen, jota kutsutaan kelpoisuuskriteereiksi. Joitakin esimerkkejä näistä kriteereistä ovat henkilön yleinen terveydentila tai aiemmat hoidot.

Kelpoisuusvaatimukset

Opintokelpoiset iät

18 vuotta - 55 vuotta (Aikuinen)

Hyväksyy terveitä vapaaehtoisia

Ei

Sukupuolet, jotka voivat opiskella

Kaikki

Kuvaus

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.

Opintosuunnitelma

Tässä osiossa on tietoja tutkimussuunnitelmasta, mukaan lukien kuinka tutkimus on suunniteltu ja mitä tutkimuksella mitataan.

Miten tutkimus on suunniteltu?

Suunnittelun yksityiskohdat

  • Ensisijainen käyttötarkoitus: Hoito
  • Jako: Satunnaistettu
  • Inventiomalli: Rinnakkaistehtävä
  • Naamiointi: Kaksinkertainen

Aseet ja interventiot

Osallistujaryhmä / Arm
Interventio / Hoito
Kokeellinen: 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.
Muut nimet:
  • Poly-ICLC (Hiltonol®, Oncovir)
Placebo Comparator: 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.
Muut nimet:
  • Plasebo

Mitä tutkimuksessa mitataan?

Ensisijaiset tulostoimenpiteet

Tulosmittaus
Toimenpiteen kuvaus
Aikaikkuna
Number Participants With Adverse Events
Aikaikkuna: Up to 48 weeks
Safety measured by number of participants with adverse events.
Up to 48 weeks

Toissijaiset tulostoimenpiteet

Tulosmittaus
Toimenpiteen kuvaus
Aikaikkuna
Plasma Interferon-gamma-inducible Protein-10 (IP-10) Level
Aikaikkuna: 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)
Aikaikkuna: Day 8
the CD38-activation marker on CD8 T-cells (CD8/CD38).
Day 8
NK Cell Number
Aikaikkuna: 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
Aikaikkuna: 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

Yhteistyökumppanit ja tutkijat

Täältä löydät tähän tutkimukseen osallistuvat ihmiset ja organisaatiot.

Sponsori

Tutkijat

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

Julkaisuja ja hyödyllisiä linkkejä

Tutkimusta koskevien tietojen syöttämisestä vastaava henkilö toimittaa nämä julkaisut vapaaehtoisesti. Nämä voivat koskea mitä tahansa tutkimukseen liittyvää.

Yleiset julkaisut

Opintojen ennätyspäivät

Nämä päivämäärät seuraavat ClinicalTrials.gov-sivustolle lähetettyjen tutkimustietueiden ja yhteenvetojen edistymistä. National Library of Medicine (NLM) tarkistaa tutkimustiedot ja raportoidut tulokset varmistaakseen, että ne täyttävät tietyt laadunvalvontastandardit, ennen kuin ne julkaistaan ​​julkisella verkkosivustolla.

Opi tärkeimmät päivämäärät

Opiskelun aloitus

Tiistai 1. huhtikuuta 2014

Ensisijainen valmistuminen (Todellinen)

Tiistai 26. heinäkuuta 2016

Opintojen valmistuminen (Todellinen)

Tiistai 26. heinäkuuta 2016

Opintoihin ilmoittautumispäivät

Ensimmäinen lähetetty

Perjantai 21. helmikuuta 2014

Ensimmäinen toimitettu, joka täytti QC-kriteerit

Maanantai 24. helmikuuta 2014

Ensimmäinen Lähetetty (Arvio)

Tiistai 25. helmikuuta 2014

Tutkimustietojen päivitykset

Viimeisin päivitys julkaistu (Todellinen)

Tiistai 13. maaliskuuta 2018

Viimeisin lähetetty päivitys, joka täytti QC-kriteerit

Tiistai 13. helmikuuta 2018

Viimeksi vahvistettu

Torstai 1. helmikuuta 2018

Lisää tietoa

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Kliiniset tutkimukset HIV-1 Infected Adults With Chronic HIV-1 Infection

Kliiniset tutkimukset Arm A: Poly-ICLC

3
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