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

2018년 2월 13일 업데이트: 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.

연구 개요

상세 설명

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.

연구 유형

중재적

등록 (실제)

15

단계

  • 2 단계
  • 1단계

연락처 및 위치

이 섹션에서는 연구를 수행하는 사람들의 연락처 정보와 이 연구가 수행되는 장소에 대한 정보를 제공합니다.

연구 장소

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

참여기준

연구원은 적격성 기준이라는 특정 설명에 맞는 사람을 찾습니다. 이러한 기준의 몇 가지 예는 개인의 일반적인 건강 상태 또는 이전 치료입니다.

자격 기준

공부할 수 있는 나이

18년 (성인)

건강한 자원 봉사자를 받아들입니다

아니

연구 대상 성별

모두

설명

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.

공부 계획

이 섹션에서는 연구 설계 방법과 연구가 측정하는 내용을 포함하여 연구 계획에 대한 세부 정보를 제공합니다.

연구는 어떻게 설계됩니까?

디자인 세부사항

  • 주 목적: 치료
  • 할당: 무작위
  • 중재 모델: 병렬 할당
  • 마스킹: 더블

무기와 개입

참가자 그룹 / 팔
개입 / 치료
실험적: 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.
다른 이름들:
  • Poly-ICLC (Hiltonol®, Oncovir)
위약 비교기: 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.
다른 이름들:
  • 위약

연구는 무엇을 측정합니까?

주요 결과 측정

결과 측정
측정값 설명
기간
Number Participants With Adverse Events
기간: Up to 48 weeks
Safety measured by number of participants with adverse events.
Up to 48 weeks

2차 결과 측정

결과 측정
측정값 설명
기간
Plasma Interferon-gamma-inducible Protein-10 (IP-10) Level
기간: 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)
기간: Day 8
the CD38-activation marker on CD8 T-cells (CD8/CD38).
Day 8
NK Cell Number
기간: 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
기간: 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

공동 작업자 및 조사자

여기에서 이 연구와 관련된 사람과 조직을 찾을 수 있습니다.

스폰서

수사관

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

간행물 및 유용한 링크

연구에 대한 정보 입력을 담당하는 사람이 자발적으로 이러한 간행물을 제공합니다. 이것은 연구와 관련된 모든 것에 관한 것일 수 있습니다.

일반 간행물

연구 기록 날짜

이 날짜는 ClinicalTrials.gov에 대한 연구 기록 및 요약 결과 제출의 진행 상황을 추적합니다. 연구 기록 및 보고된 결과는 공개 웹사이트에 게시되기 전에 특정 품질 관리 기준을 충족하는지 확인하기 위해 국립 의학 도서관(NLM)에서 검토합니다.

연구 주요 날짜

연구 시작

2014년 4월 1일

기본 완료 (실제)

2016년 7월 26일

연구 완료 (실제)

2016년 7월 26일

연구 등록 날짜

최초 제출

2014년 2월 21일

QC 기준을 충족하는 최초 제출

2014년 2월 24일

처음 게시됨 (추정)

2014년 2월 25일

연구 기록 업데이트

마지막 업데이트 게시됨 (실제)

2018년 3월 13일

QC 기준을 충족하는 마지막 업데이트 제출

2018년 2월 13일

마지막으로 확인됨

2018년 2월 1일

추가 정보

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