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Therapeutic Vaccination in Treated HIV Disease

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ClinicalTrials.gov Identifier: NCT03606213
Recruitment Status : Recruiting
First Posted : July 30, 2018
Last Update Posted : August 31, 2018
Sponsor:
Collaborators:
National Institute of Allergy and Infectious Diseases (NIAID)
University of California, Los Angeles
Inovio Pharmaceuticals
Information provided by (Responsible Party):
Steven Deeks, University of California, San Francisco

Brief Summary:
The central premise of our program is that durable control of HIV in the absence of antiretroviral therapy ("remission") will require the generation of de novo potent and sustained HIV-specific CD8+ cell responses that target evolutionarily conserved epitopes. Our program is inspired by the recent success of VGX-3100 (Inovio), a DNA therapeutic vaccine for HPV that leads to histopathologic regression of pre-malignant lesions in people and is associated with a potent, sustained boost to HPV-specific CD8+ T cell populations. A closely related multi-clade gag/pol/env DNA vaccine administered with an IL-12 DNA plasmid (PENNVAX, Inovio) has been studied for HIV prevention and is known to be both safe and highly immunogenic. In a randomized placebo-controlled study we will compare the immunogenicity and anti-reservoir activities of gag/pol DNA versus gag/pol/env DNA (both administered with IL-12). We will determine for the first time in established HIV disease whether presence of env in a DNA vaccine blunts T cell responses to more conserved Gag-specific and Pol-specific epitopes. We will also determine if Env-specific responses (which will presumably be mediated by antibodies and ADCC) have a measurable effect on reservoir.

Condition or disease Intervention/treatment Phase
HIV-1-infection Biological: PENNVAX-GP Biological: INO-6145 Biological: INO-9012 Device: CELLECTRA® 2000 Phase 1 Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 60 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Single (Participant)
Primary Purpose: Treatment
Official Title: Safety, Immunogenicty and Anti-Reservoir Activity of an Electroporation-Administered HIV DNA Vaccine Encoding GAG, POL and ENV Proteins With IL-12 Plasmid in HIV-Infected Adults on Antriretroviral Therapy.
Actual Study Start Date : August 1, 2018
Estimated Primary Completion Date : December 1, 2020
Estimated Study Completion Date : December 1, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: HIV/AIDS

Arm Intervention/treatment
Placebo Comparator: Cohort A - Arm 1
Placebo will be administered by electoporation at Day 0 and Weeks 4, 8 and 12
Device: CELLECTRA® 2000
Electroporation (EP) is a technology in which an electrical field is applied to increase the permeability of cell membranes and thereby enhance the uptake of drugs, vaccines, or other agents into target cells. This technology has been used in the last decade in both therapeutics and vaccinations. EP is currently being used to deliver cancer vaccines and therapeutics as well as in gene therapy. The expression levels are increased by as much as 3 orders of magnitude over plasmid injection alone.
Other Name: Electroporation device

Active Comparator: Cohort A - Arm 2
Active gag/pol, env and IL-12 plasmids (PENNVAX-GP and INO-9102)) administered by electoporation (CELLECTRA-2000) at Day 0 and Weeks 4, 8 and 12.
Biological: PENNVAX-GP
PENNVAX®-GP is a circular, double stranded, deoxyribonucleic acid consisting of expression plasmids that encode synthetic HIV-1 multiclade consensus Gag, Pol and Env proteins.
Other Name: HIV DNA vaccine

Biological: INO-9012
The IL-12 DNA adjuvant (INO-9012) consists of a single plasmid containing a dual promoter system for expression of both the IL-12 p35 and p40 genes necessary for production of the active heterodimeric (p70) IL-12 protein.
Other Name: IL-12 DNA adjuvant

Device: CELLECTRA® 2000
Electroporation (EP) is a technology in which an electrical field is applied to increase the permeability of cell membranes and thereby enhance the uptake of drugs, vaccines, or other agents into target cells. This technology has been used in the last decade in both therapeutics and vaccinations. EP is currently being used to deliver cancer vaccines and therapeutics as well as in gene therapy. The expression levels are increased by as much as 3 orders of magnitude over plasmid injection alone.
Other Name: Electroporation device

Active Comparator: Cohort A - Arm 3
Active gag/pol and IL-12 plasmids (INO-6145 INO-9012) will be administered by electroporation (CELLECTRA-2000) at Day 0 and Weeks 4, 8 and 12.
Biological: INO-6145
INO-6145 is a circular, double stranded, deoxyribonucleic acid consisting of expression plasmids that encode synthetic HIV-1 multiclade consensus Gag and Pol proteins.
Other Name: HIV DNA vaccine

Biological: INO-9012
The IL-12 DNA adjuvant (INO-9012) consists of a single plasmid containing a dual promoter system for expression of both the IL-12 p35 and p40 genes necessary for production of the active heterodimeric (p70) IL-12 protein.
Other Name: IL-12 DNA adjuvant

Device: CELLECTRA® 2000
Electroporation (EP) is a technology in which an electrical field is applied to increase the permeability of cell membranes and thereby enhance the uptake of drugs, vaccines, or other agents into target cells. This technology has been used in the last decade in both therapeutics and vaccinations. EP is currently being used to deliver cancer vaccines and therapeutics as well as in gene therapy. The expression levels are increased by as much as 3 orders of magnitude over plasmid injection alone.
Other Name: Electroporation device

Active Comparator: Cohort B - Arm 1
A single arm study of gag/pol/env/IL-12 DNA plasmids PENNVAX-GP and INO-9102) administered by electoporation (CELLECTRA-2000) will be performed in HIV-infected adults for whom ART was initiated during acute HIV infection.
Biological: PENNVAX-GP
PENNVAX®-GP is a circular, double stranded, deoxyribonucleic acid consisting of expression plasmids that encode synthetic HIV-1 multiclade consensus Gag, Pol and Env proteins.
Other Name: HIV DNA vaccine

Biological: INO-9012
The IL-12 DNA adjuvant (INO-9012) consists of a single plasmid containing a dual promoter system for expression of both the IL-12 p35 and p40 genes necessary for production of the active heterodimeric (p70) IL-12 protein.
Other Name: IL-12 DNA adjuvant

Device: CELLECTRA® 2000
Electroporation (EP) is a technology in which an electrical field is applied to increase the permeability of cell membranes and thereby enhance the uptake of drugs, vaccines, or other agents into target cells. This technology has been used in the last decade in both therapeutics and vaccinations. EP is currently being used to deliver cancer vaccines and therapeutics as well as in gene therapy. The expression levels are increased by as much as 3 orders of magnitude over plasmid injection alone.
Other Name: Electroporation device




Primary Outcome Measures :
  1. The proportion of participants with grade 3 or higher treatment-related adverse events as defined by the Division of AIDS (DAIDS) Table for Grading the Severity of Adult and Pediatric Adverse Events, Corrected Version 2.1 [ Time Frame: Week 64 ]
    Counts and proportions of adverse events will be presented in frequency tables and characterized for each arm with 95% Clopper-Pearson Confidence Intervals.

  2. The change in the magnitude and breadth of T cell responses will be evaluated by the IFN-γ enzyme-linked immunospot (ELISpot) assay. [ Time Frame: Baseline and Week 14 ]
    Gag-specific responses will be characterized in detail via matrix mapping, while pools of 15 overlapping peptides will used to evaluate responses to Pol, Env and Nef (internal control).


Secondary Outcome Measures :
  1. HIV reservoir size [ Time Frame: Baseline and Week 64 ]
    Frequency of circulating CD4+ T cells harboring replication-competent HIV as measured using multiplex digital droplet PCR assay to quantify the total number of intact proviruses.



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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:

  1. Willing and able to provide written informed consent
  2. Male or female, age ≥ 18 and ≤ 65 years
  3. 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 or plasma HIV-1 RNA viral load.
  4. For Cohort A participants, ART initiated during chronic infection (e.g., more than 6 months after estimated date of infection, or as determined by site investigator and/or available medical records).
  5. For Cohort B participants, ART initiated during "hyperacute" HIV infection (Fiebig I/II) or early HIV infection (Fiebig III/IV).
  6. On continuous antiretroviral therapy for at least 24 months without any interruptions of greater than 14 consecutive days, and on a stable regimen for at least 8 weeks, without plans to modify ART during the study period
  7. Screening plasma HIV RNA levels < 40 copies/mL on all available determinations in past 24 months (isolated single values ≥ 40 but < 200 copies/mL will be allowed if they were preceded and followed by undetectable viral load determinations)
  8. Screening CD4+ T-cell count ≥ 350 cells/mm3
  9. Creatinine Clearance (CrCl) > 60 mL/min via Cockroft-Gault method at screening
  10. The following laboratory criteria must be met at screening:

    • Absolute neutrophil count (ANC) ≥ 1000 neutrophils/mm3
    • Hemoglobin ≥ 10.0 g/dL
    • Platelet count ≥ 100,000/uL
    • Aspartate aminotransferase (AST) ≤ 2x upper limit of normal (ULN)
    • Alanine aminotransferase (ALT) ≤ 2x ULN

Exclusion Criteria:

1. Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study

a. Acceptable birth control is defined as the following: i. For female participants of childbearing potential, two of the following forms of contraception are required, one of which must be a barrier method:

1. Condoms (male of female) with or without a spermicidal agent 2. Diaphragm or cervical cap with spermicide 3. Intrauterine device (IUD) with published data showing that expected failure rate is < 1% per year 4. Tubal ligation 5. Hormone-based contraceptive such as oral birth control pills ii. Male participants participating in sexual activity that could lead to pregnancy must agree to at least one reliable method of contraception of the above listed 2. Active malignancy requiring systemic chemotherapy or surgery in the preceding 3 months or for whom such therapies are expected in the subsequent 6 months 3. Active (untreated) HCV or HBV infection 4. Decompensated liver disease as defined by the presence of ascites, encephalopathy, esophageal or gastric varices, or persistent jaundice 5. Serious illness requiring systemic treatment and/or hospitalization in the 3 months prior to study enrollment 6. Concurrent treatment with immunomodulatory drugs, and/or exposure to any immunomodulatory drug in the 4 weeks prior to study enrollment (e.g. corticosteroid therapy equal to or exceeding a dose of 15 mg/day of prednisone for more than 10 days, IL-2, interferon-alpha, methotrexate, cancer chemotherapy). NOTE: use of inhaled or nasal steroid is not exclusionary.

7. Serious medical or psychiatric illness that, in the opinion of the site investigator, would interfere with the ability to adhere to study requirements or to give informed consent.

8. Active drug or alcohol use or dependence that, in the opinion of the site investigator, would interfere with adherence to study requirements or to give informed consent.

9. Unable to undergo leukapheresis procedure 10. Acute or chronic bleeding or clotting disorder that would contraindicate IM injections or use of blood thinners (e.g. anticoagulants or antiplatelet drugs) within 2 weeks of Day 0; 11. Less than two acceptable sites available for IM injection considering the deltoid and anterolateral quadriceps muscles; 12. Tattoos, keloids or hypertrophic scars located within 2 cm of intended treatment site; 13. Cardioverter-defibrillator or pacemaker (to prevent a life-threatening arrhythmia) that is located in ipsilateral deltoid injection site (unless deemed acceptable by a cardiologist); 14. Metal implants or implantable medical device within the intended treatment site (i.e. electroporation area)


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): NCT03606213


Contacts
Contact: Steven G Deeks, MD 415-206-3103 Steven.Deeks@ucsf.edu
Contact: Rebecca Hoh 415-476-4082 ext 139 Rebecca.Hoh@ucsf.edu

Locations
United States, California
University of California, Los Angeles Recruiting
Los Angeles, California, United States, 90025
Contact: Kara Chew, MD    310-825-0796    KChew@mednet.ucla.edu   
Contact: Judith Currier, MD    (310) 206-3474    JSCurrier@mednet.ucla.edu   
Principal Investigator: Judith Currier, MD         
Sub-Investigator: Kara Chew, MD         
Zuckerberg San Francisco General Hospital (ZSFG) Recruiting
San Francisco, California, United States, 94110
Contact: Steven G Deeks, MD    415-206-3103    Steven.Deeks@ucsf.edu   
Contact: Rebecca Hoh    415-476-4082 ext 139    Rebecca.Hoh@ucsf.edu   
Principal Investigator: Steven G Deeks, MD         
Sponsors and Collaborators
Steven Deeks
National Institute of Allergy and Infectious Diseases (NIAID)
University of California, Los Angeles
Inovio Pharmaceuticals
Investigators
Principal Investigator: Steven Deeks, MD University of California, San Francisco

Responsible Party: Steven Deeks, Professor, University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03606213     History of Changes
Other Study ID Numbers: DAIDS-ES 38409
U01AI131296 ( U.S. NIH Grant/Contract )
First Posted: July 30, 2018    Key Record Dates
Last Update Posted: August 31, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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

Keywords provided by Steven Deeks, University of California, San Francisco:
HIV Vaccine
Electroporation

Additional relevant MeSH terms:
Vaccines
Interleukin-12
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic
Angiogenesis Inhibitors
Angiogenesis Modulating Agents
Growth Substances
Growth Inhibitors
Antineoplastic Agents