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HIV-1-Gag Conserved-Element DNA Vaccine as Therapeutic Vaccination in HIV-Infected Persons With Viral Suppression on Antiretroviral Therapy

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ClinicalTrials.gov Identifier: NCT03560258
Recruitment Status : Not yet recruiting
First Posted : June 18, 2018
Last Update Posted : November 14, 2018
Sponsor:
Information provided by (Responsible Party):
National Institute of Allergy and Infectious Diseases (NIAID)

Brief Summary:
This study will evaluate the safety, immunogenicity, and preliminary assessment of efficacy of a novel vaccine encoding conserved elements (CE) of the HIV-1 Gag core protein, p24Gag, as a therapeutic vaccine in HIV-1 infected persons who are on antiretroviral therapy (ART). The study aims to induce potent virus-specific cytotoxic T lymphocytes (CTL) responses.

Condition or disease Intervention/treatment Phase
HIV Infections Biological: p24CE1/2 pDNA vaccine Biological: p24CE1/2 pDNA vaccine admixed with full-length p55^gag pDNA vaccine Biological: Full-length p55^gag pDNA vaccine Biological: Placebo Phase 1 Phase 2

Detailed Description:

This study will evaluate the safety, immunogenicity, and preliminary assessment of efficacy of a novel vaccine encoding conserved elements (CE) of the HIV-1 Gag core protein, p24Gag, as a therapeutic vaccine in HIV-1 infected persons who are on antiretroviral therapy (ART).

The study will randomly assign participants to one of three groups. Participants in Arm 1 will receive p24CE1/2 pDNA vaccine at Weeks 0 and 4, followed by p24CE1/2 pDNA admixed with full-length p55^gag pDNA vaccine at Weeks 12 and 24. Participants in Arm 2 will receive full-length p55^gag pDNA vaccine at Weeks 0, 4, 12, and 24. Participants in Arm 3 will receive placebo at Weeks 0, 4, 12, and 24.

Study visits will occur at Weeks 0, 4, 6, 12, 24, 26, and 48 and may include physical examinations and blood and urine collection. Some participants may undergo leukapheresis and stool sample collection.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: HIV-1-Gag Conserved-Element DNA Vaccine (p24CE) as Therapeutic Vaccination in HIV-Infected Persons With Viral Suppression on Antiretroviral Therapy
Estimated Study Start Date : November 17, 2018
Estimated Primary Completion Date : June 15, 2019
Estimated Study Completion Date : September 17, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Experimental: Arm 1: p24CE1/2 pDNA + full-length p55^gag pDNA vaccine
Participants will receive p24CE1/2 pDNA vaccine at Weeks 0 and 4, followed by p24CE1/2 pDNA admixed with full-length p55^gag pDNA vaccine at Weeks 12 and 24.
Biological: p24CE1/2 pDNA vaccine
4 mg administered by one injection/electroporation

Biological: p24CE1/2 pDNA vaccine admixed with full-length p55^gag pDNA vaccine
2 mg p24CE1/2 pDNA admixed with 2 mg full-length p55^gag pDNA administered by one injection/electroporation

Experimental: Arm 2: Full-length p55^gag pDNA vaccine
Participants will receive full-length p55^gag pDNA vaccine at Weeks 0, 4, 12, and 24.
Biological: Full-length p55^gag pDNA vaccine
4 mg full-length p55^gag pDNA vaccine administered by one injection/electroporation

Placebo Comparator: Arm 3: Placebo
Participants will receive placebo at Weeks 0, 4, 12, and 24.
Biological: Placebo
1 mL placebo administered by one injection/electroporation




Primary Outcome Measures :
  1. The number of conserved elements (CEs) with a CD4 and/or CD8 T cell response compared to baseline in an individual study participant. [ Time Frame: Measured at Week 26 ]
    A CE response (for a participant at a given timepoint) is defined by a criterion that uses Fisher's exact test to compare the proportion of peptide-stimulated CD4 and/or CD8 T cells that are cytokine positive to the proportion that are cytokine positive in the unstimulated sample (negative control), and applying a stringent p-value of 10e-5 as a cutoff. For this primary endpoint, we will sum the CD4 and CD8 responses.

  2. Occurrence of at least one greater than or equal to Grade 3 adverse event (AE) except injection site pain or tenderness of less than 48 hours duration, that is possibly, probably, or definitely related to study treatment. [ Time Frame: Measured through Week 28 ]
    Grade 4 AEs and deaths at any time on study will be considered a primary safety outcome.


Secondary Outcome Measures :
  1. The number of CEs with a CD4 T cell response compared to baseline in an individual study participant. [ Time Frame: Measured at Week 26 ]
    A CE response (for a participant at a given timepoint) is defined by a criterion that uses Fisher's exact test to compare the proportion of peptide-stimulated CD4 and/or CD8 T cells that are cytokine positive to the proportion that are cytokine positive in the unstimulated sample (negative control), and applying a stringent p-value of 10e-5 as a cutoff.

  2. The number of CEs with a CD8 T cell response compared to baseline in an individual study participant. [ Time Frame: Measured at Week 26 ]
    A CE response (for a participant at a given timepoint) is defined by a criterion that uses Fisher's exact test to compare the proportion of peptide-stimulated CD4 and/or CD8 T cells that are cytokine positive to the proportion that are cytokine positive in the unstimulated sample (negative control), and applying a stringent p-value of 10e-5 as a cutoff.

  3. The total magnitude of CD4 T cell responses against each CE added together in each study arm compared to baseline. [ Time Frame: Measured at Week 26 ]
    The change in total magnitude of CD4 T cell responses against each CE added together among study arms will be compared using the two-sided Wilcoxon rank-sum test.

  4. The total magnitude of CD8 T cell responses against each CE added together in each study arm compared to baseline. [ Time Frame: Measured at Week 26 ]
    The change in total magnitude of CD8 T cell responses against each CE added together among study arms will be compared using the two-sided Wilcoxon rank-sum test.



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry and confirmed by a licensed Western blot or a second antibody test by a method other than the initial rapid HIV and/or E/CIA, or by HIV-1 antigen, plasma HIV-1 RNA assay. NOTE: The term "licensed" refers to a U.S. FDA-approved kit, which is required for all IND studies. WHO (World Health Organization) and CDC (Centers for Disease Control and Prevention) guidelines mandate that confirmation of the initial test result must use a test that is different from the one used for the initial assessment. A reactive initial rapid test should be confirmed by either another type of rapid assay or an E/CIA that is based on a different antigen preparation and/or different test principle (e.g., indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load.
  • Receiving a stable ART regimen for a minimum of 2 years prior to study entry and with no changes in the components of their antiretroviral therapy for at least 90 days prior to study entry. One of the agents must include an integrase inhibitor, non-nucleoside reverse transcriptase inhibitors (NNRTI), or a boosted-protease inhibitor (PI). NOTE: Changes in the ART regimen for reasons other than virologic breakthrough during the 2-year period are acceptable.
  • CD4 cell count greater than 500 cells/mm^3 obtained within 60 days prior to study entry at any U.S. laboratory that has a CLIA certification or its equivalent.
  • Nadir CD4 cell count greater than 350 cells/mm^3. NOTE: Candidate recall or documentation is acceptable.
  • One documented plasma HIV-1 RNA that is below the limit of detection of an FDA-approved assay between 24 and 36 months prior to the screening HIV-1 RNA, one documented plasma HIV-1 RNA that is below the limit of detection of an FDA-approved assay between 12 and 24 months prior to the screening HIV-1 RNA, and one documented HIV-1 RNA that is below the limit of detection of an FDA-approved assay collected fewer than 12 months prior to the screening HIV-1 RNA (see the protocol). NOTE: A single, unconfirmed plasma HIV-1 RNA above the limit of detection but less than 400 copies/mL is allowed if followed by an HIV-1 RNA below detectable limits, but not in the 6 months prior to screening.
  • Plasma HIV-1 RNA level that is below the limit of detection of an FDA-approved assay within 60 days prior to study entry.
  • The following laboratory values obtained within 60 days prior to entry by any U.S. laboratory that has a CLIA certification or its equivalent:

    • Absolute neutrophil count (ANC) greater than or equal to 750 cells/mm^3
    • Hemoglobin greater than or equal to 10.0 g/dL for men and greater than or equal to 9.0 g/dL for women
    • Platelet count greater than or equal to 100,000/mm^3
    • Prothrombin time (PT), partial thromboplastin time (PTT), and INR less than 1.5 x upper limit of normal (ULN)
    • Creatinine clearance greater than or equal to 50 mL/min estimated by the Cockcroft-Gault equation. NOTE: A program for calculating creatinine clearance by the Cockcroft-Gault method is available on www.fstrf.org.
    • Alanine aminotransferase (ALT) (SGPT) less than or equal to 2.5 x ULN
    • Total bilirubin less than 1.6 x ULN (if on atazanavir less than or equal to 5 x ULN)
  • HCV antibody negative result within 60 days prior to study entry or, if the HCV antibody result is positive, a negative HCV RNA result prior to study entry.
  • Negative HBsAg result obtained within 60 days prior to study entry.
  • Men and women age greater than or equal to 18 to less than or equal to 65 years
  • Documentation of the availability of the stored pre-entry peripheral blood mononuclear cell (PBMC) specimens for T cell assays. Sites must receive confirmation from the processing lab via phone, e-mail, or fax that specimens have been entered into the ACTG Laboratory Data Management System (LDMS).
  • Ability and willingness of participant or legal guardian/representative to provide informed consent
  • Ability and willingness of participant to continue cART throughout the study.
  • For females of reproductive potential, negative serum or urine pregnancy test within 15 days prior to entry by any clinic or laboratory that has a CLIA certification or its equivalent, or is using a point of care (POC)/CLIA-waived test. NOTE: Reproductive potential is defined as girls who have reached menarche and women who have not been post-menopausal for at least 12 consecutive months with follicle-stimulating hormone (FSH) greater than or equal to 40 IU/mL or 24 consecutive months if an FSH is not available, or have not undergone surgical sterilization (e.g., hysterectomy, bilateral oophorectomy, tubal ligation, or salpingectomy).
  • If participating in sexual activity that could lead to pregnancy, willingness of female participants to use two forms of effective contraception while receiving study medication and for 3 months after stopping study medication is required.

    • NOTE A: Effective forms of contraception include:
    • Barrier methods (condoms [male or female] with or without a spermicidal agent, diaphragm, or cervical cap [with spermicide])
    • Hormone-based contraception (oral, patch, parenteral, implants, or vaginal ring)
    • Intrauterine device (IUD)
    • NOTE B: If the female participant is not of reproductive potential (women who are post-menopausal as defined above, or women who have undergone surgical sterilization [e.g., hysterectomy, bilateral oophorectomy, tubal ligation or salpingectomy]), she is eligible without requiring the use of a contraceptive method. Acceptable documentation of surgical sterilization and menopause is participant-reported history.
  • Indication of willingness to have the leukapheresis procedure. NOTE: Leukapheresis will be required if the study has reached 50% of the accrual target and less than 20 participants have agreed to have the leukapheresis procedure.

Exclusion Criteria:

  • History of malignancy within the last 5 years prior to study entry or current malignancy requiring cytotoxic therapy. NOTE: A history of non-melanoma skin cancer (e.g., basal cell carcinoma or squamous cell skin cancer) is not exclusionary.
  • History of HIV-related opportunistic infections within the last 5 years prior to study entry. NOTE: The CDC classifications are available on the A5369 protocol-specific webpage (PSWP).
  • History of or active autoimmune disorders including but not limited to inflammatory bowel diseases, scleroderma, severe psoriasis, myocarditis, uveitis, pneumonitis, systemic lupus erythematosus, rheumatoid arthritis, optic neuritis, myasthenia gravis, adrenal insufficiency, autoimmune thyroiditis, or sarcoidosis. NOTE: For questions related to the definition of autoimmune disorders, sites should contact the A5369 core team per the Study Management section.
  • Bleeding diathesis or condition associated with prolonged bleeding time that would contraindicate IM injection.
  • A skin-fold measurement of the cutaneous and subcutaneous tissue for eligible injection sites (on the medial deltoid or vastus lateralis muscles) that does not exceed 50 mm. NOTE: The skin-fold measurement must be conducted in accordance with the procedure described in the TDS-IM Instructions for Use (see A5369 MOPS).
  • Use of any prior HIV vaccine (prophylactic and/or therapeutic) within 1 year prior to study entry. NOTE: A documented study placebo recipient may participate.
  • Use of any investigational treatment within 6 months prior to study entry.
  • Any licensed or experimental non-HIV vaccination (e.g., hepatitis B, influenza, pneumococcal polysaccharide) within 4 weeks prior to study entry. NOTE: Participants with anticipated need to receive non-HIV vaccinations within 2 weeks prior to the scheduled study vaccination #2 (week 4), or #3 (week 12), or #4 (week 24) injection should be excluded.
  • Use of any infusion blood product or immune globulin within 3 months prior to study entry.
  • Acute or serious illness, in the opinion of the site investigator, requiring systemic treatment and/or hospitalization within 30 days prior to entry.
  • Use of immunomodulators (e.g., interleukins, interferons, cyclosporine), systemic cytotoxic chemotherapy, or investigational therapy within 60 days prior to study entry. NOTE: Participants receiving stable physiologic glucocorticoid doses, defined as prednisone less than or equal to 10 mg/day or the equivalent, will not be excluded. Stable physiologic glucocorticoid doses should not be discontinued for the duration of the study. In addition, participants receiving inhaled or topical corticosteroids will not be excluded.
  • Intent to use immunomodulators (e.g., IL-2, IL-12, interferons, or TNF modifiers) during the course of the study.
  • Known or suspected hypersensitivity to any vaccine component, including hypersensitivity to amide-type local anesthetics, such as lidocaine (Xylocaine), mepivacaine (Polocaine/Carbocaine), etidocaine (Duranest), bupivacaine (Marcaine), or prilocaine.
  • Current use of any electronic stimulation device, such as cardiac demand pacemakers, automatic implantable cardiac defibrillator, nerve stimulators, or deep brain stimulators.
  • History of cardiac arrhythmia or palpitations (e.g., supraventricular tachycardia, atrial fibrillation, frequent ectopy, or sinus bradycardia [i.e., less than 50 beats per minute on exam]) prior to study entry. NOTE: Sinus arrhythmia is not excluded.
  • History of syncope or fainting episode within 1 year of study entry.
  • Seizure disorder or any history of prior seizure.
  • Extensive tattoos covering the site of administration (upper left and right medial deltoid muscles and left and right vastus lateralis muscles).
  • Presence of any surgical or traumatic metal implants at the site of administration (medial deltoid or vastus lateralis muscles).
  • Immune deficiency other than HIV.
  • Breastfeeding or pregnancy.
  • Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements.
  • Current HCV antiviral therapy.
  • Type I or type II diabetes mellitus.
  • Weight less than 50 kg or greater than 200 kg.
  • Known to have been started on antiretroviral therapy within 3 months of the presumed or known date of first acquiring HIV-1 infection; i.e., treated during acute HIV-1 infection.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03560258


Locations
United States, Illinois
Rush University CRS Not yet recruiting
Chicago, Illinois, United States, 60612
Contact: Antoinette Lewis    312-942-2050    antoinette_lewis@rush.edu   
United States, Massachusetts
Massachusetts General Hospital CRS (MGH CRS) Not yet recruiting
Boston, Massachusetts, United States, 02114
Contact: Theresa Flynn, R.N., M.S.N., A.N.P., B.S.N.    617-724-0072    tflynn@partners.org   
Brigham and Women's Hospital Therapeutics Clinical Research Site (BWH TCRS) CRS Not yet recruiting
Boston, Massachusetts, United States, 02115
Contact: Cheryl E. Keenan, R.N.    617-732-5635    CKeenan@BWH.Harvard.edu   
United States, Pennsylvania
Penn Therapeutics, CRS Not yet recruiting
Philadelphia, Pennsylvania, United States, 19104
Contact: Eileen B. Donaghy, C.R.N.P.    215-349-8092    eileen.donaghy2@uphs.upenn.edu   
United States, Tennessee
Vanderbilt Therapeutics (VT) CRS Not yet recruiting
Nashville, Tennessee, United States, 37204
Contact: Beverly O. Woodward, M.S.N., R.N.    615-936-8516    beverly.o.woodward@vanderbilt.edu   
United States, Washington
University of Washington AIDS CRS Not yet recruiting
Seattle, Washington, United States, 98104-9929
Contact: Christine Jonsson    206-744-8886    cjonsson@u.washington.edu   
Sponsors and Collaborators
National Institute of Allergy and Infectious Diseases (NIAID)
Investigators
Study Chair: Jeffrey M. Jacobson, MD Lewis Katz School of Medicine at Temple University

Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
ClinicalTrials.gov Identifier: NCT03560258     History of Changes
Other Study ID Numbers: ACTG A5369
38398 ( Registry Identifier: DAIDS-ES Registry Number )
First Posted: June 18, 2018    Key Record Dates
Last Update Posted: November 14, 2018
Last Verified: November 2018

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

Additional relevant MeSH terms:
HIV Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Vaccines
Immunologic Factors
Physiological Effects of Drugs