Poly-ICLC in Treated HIV Infection

This study is currently recruiting participants. (see Contacts and Locations)
Verified October 2014 by Mount Sinai School of Medicine
Sponsor:
Collaborators:
The Campbell Foundation
Oncovir, Inc.
Information provided by (Responsible Party):
Nina Bhardwaj, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier:
NCT02071095
First received: February 21, 2014
Last updated: October 14, 2014
Last verified: October 2014
  Purpose

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. In this research study we are investigating a new approach that involves an addition to existing medications.

We are 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. We want to test whether Poly-ICLC is an adjuvant that is effective in HIV-infected patients. We are not giving a vaccine 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, we want to look at whether Poly-ICLC increases the level of virus inside your cells while also improving your immune system's responses.

We are doing this research because we 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.


Condition Intervention Phase
HIV-1 Infected Adults With Chronic HIV-1 Infection
Drug: Poly-ICLC
Drug: Normal Saline
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
Official Title: Simultaneous Disruption of Latency and Immune Enhancement by Poly-ICLC During HIV-1 Infection

Resource links provided by NLM:


Further study details as provided by Mount Sinai School of Medicine:

Primary Outcome Measures:
  • To establish if Poly-ICLC is safe and well tolerated in HIV-1-infected subjects on combination anti-retroviral therapy [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: Yes ]
    The primary objective of the trial will be to monitor for safety in each Arm. Patients will be randomized 3:1 to receive the study agent versus placebo. Comparisons among the Arms on the proportions of Poly ICLC-related adverse events will be made using Fisher's exact test.


Secondary Outcome Measures:
  • To confirm that Poly-ICLC enhances innate immune responses in HIV-infected subjects on anti-retroviral therapy, and that its immunostimulatory properties are transient in nature. [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
    Poly-ICLC enhancement of DC and Natural Killer (NK) cells activation and function will be assessed. Biomarkers of cellular immune activation and exhaustion will be quantified by flow cytometry (HLA-DR, CD38, PD-1, CTLA-4) and transcriptional profiling of PBMC. Systemic immune activation will be determined by measuring levels of circulating cytokines and soluble markers (type I IFN, TNF, IL-6, sCD14, C-reactive protein, D-dimer, IL-12)


Other Outcome Measures:
  • To determine whether Poly-ICLC disrupts viral latency in HIV-1-infected individuals on anti-retroviral therapy. [ Time Frame: Up to 48 weeks ] [ Designated as safety issue: No ]
    Viral transcription will be assessed by monitoring cell associated HIV-1 RNA. The viral reservoir will be evaluated by measuring proviral HIV-1 DNA, and plasma viremia


Estimated Enrollment: 20
Study Start Date: April 2014
Estimated Study Completion Date: June 2017
Estimated Primary Completion Date: December 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 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.
Drug: Poly-ICLC
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.
Other Name: Poly-ICLC (Hiltonol®, Oncovir)
Placebo Comparator: Normal Saline
Arm B: (N=5): Patients will receive an injection of normal saline subcutaneously on day 1 and day 2.
Drug: Normal Saline
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.
Other Name: Placebo

Detailed Description:

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, we must investigate agents that safely stimulate replication of the latent reservoir AND explore approaches to enhance HIV-specific adaptive immunity to augment CTL function. We 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, we 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). We 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.

  Eligibility

Ages Eligible for Study:   18 Years to 55 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  • 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02071095

Contacts
Contact: Elizabeth A Miller, MD 212-241-0062 elizabeth.a.miller@mssm.edu

Locations
United States, New York
The Rockefeller University Hospital Recruiting
New York, New York, United States, 10065
Contact: Elizabeth A Miller, MD    212-241-0062    elizabeth.a.miller@mssm.edu   
Principal Investigator: Elizabeth A Miller, MD         
Sponsors and Collaborators
Nina Bhardwaj
The Campbell Foundation
Oncovir, Inc.
Investigators
Study Director: Nina Bhardwaj, MD, PhD Icahn School of Medicine at Mt. Sinai
Principal Investigator: Elizabeth Miller, MD Mount Sinai School of Medicine
Principal Investigator: Natin Markowitz, MD Aaron Diamond AIDS Research Center
  More Information

Publications:
Zhang, Z., Yuan, B., Lu, N., Facchinetti, V. & Liu, Y.J. DHX9 pairs with IPS-1 to sense double-stranded RNA in myeloid dendritic cells. J Immunol 187, 4501-4508 (2011).

Responsible Party: Nina Bhardwaj, Professor, Medicine - Director, Immunotherapy Program, Mount Sinai School of Medicine
ClinicalTrials.gov Identifier: NCT02071095     History of Changes
Other Study ID Numbers: GCO 13-0482, Campbell Foundation, 1R21AI110736-01
Study First Received: February 21, 2014
Last Updated: October 14, 2014
Health Authority: United States: Food and Drug Administration

Keywords provided by Mount Sinai School of Medicine:
Human immunodeficiency virus 1
Combined Antiretroviral Therapy
Poly-ICLC

Additional relevant MeSH terms:
Communicable Diseases
HIV Infections
Infection
Immune System Diseases
Immunologic Deficiency Syndromes
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Sexually Transmitted Diseases
Sexually Transmitted Diseases, Viral
Virus Diseases
Poly ICLC
Immunologic Factors
Interferon Inducers
Pharmacologic Actions
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on October 23, 2014