A Phase Il of a Therapeutic, Recombinant, Biologically Active HIV-1 Tat Protein Vaccine in HIV-Infected, Anti-Tat Negative, ARV-Treated Adult Volunteers (ISS T-003)

March 3, 2016 updated by: Barbara Ensoli, MD

A Phase Il, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Immunogenicity and Safety of a Therapeutic, Recombinant, Biologically Active HIV-1 Tat Protein Vaccine in HIV-Infected, Anti-Tat Negative, ARV-Treated Adult Volunteers

Tat is a key HIV regulatory protein produced very early after infection, prior to virus integration, and necessary for viral gene expression, cell-to-cell virus transmission and disease progression. Previous studies in natural HIV infection, indicated that the presence of a Tat-specific immune response correlates with a lower incidence and reduced risk of progression to AIDS as compared to anti-Tat negative individuals suggesting that an immune response to Tat may exert a protective role and control the progression to AIDS in vivo. Moreover, Tat is conserved in its immunogenic regions (both B and T cell) among all subtypes. subtypes. Recent data, in fact, indicate an effective cross-clade recognition of clade B strain-derived (BH-10) Tat protein from the HTLV-IIIB lab-adapted virus strain (Buttò, 2003), which was isolated about 30 years ago (Ratner, 1985), by sera from individuals infected with viruses circulating at the present in Italy and in Africa, thus reflecting the high degree of conservation of the corresponding Tat regions and providing strong formal evidence that a Tat-based vaccine may indeed be used in the different geographic areas of the world, since it is capable of inducing a broad immune response against different virus clades. Based on this rationale and on the positive results of preclinical (Cafaro, Nat Med 1999) and phase I preventive and therapeutic clinical trials with Tat protein (ISS P-001 and ISS T-001, respectively) (Ensoli AIDS 2008, Vaccine 2009; Longo Vaccine 2009; Bellino RRCT, 2009) a phase II therapeutic, open label, clinical study with Tat protein (ISS T-002, ClinicalTrials.gov NCT00751595) was sponsored by ISS and activated in 11 clinical sites in Italy in HIV-infected HAART-treated subjects (Ensoli F, Retrovirology 2015).In this study, subjects are randomized into two arms to receive 3 or 5 vaccinations monthly; each arm is composed of two treatment groups, receiving 7, 5 or 30 µg of Tat, respectively.Results obtained in 168 individuals after trial completion (48 weeks), as well as after a follow-up of 144 weeks for a subgroup of vaccines, indicated that Tat vaccination is safe, immunogenic and capable of reducing the immune dysregulation which persists despite HAART in treated individuals (Ensoli et al,PLoS ONE 2010). Anti-Tat Abs were induced in most patients (79%), with the highest frequency and durability in the Tat 30 µg groups (89%) particularly when given 3 times (92%) (Ensoli B.,PLoS ONE 2010; Ensoli F., Retrovirology 2015). Moreover, vaccination promoted a durable and significant restoration of T, B, natural killer (NK) cells, and CD4+ and CD8+ central memory subsets. Moreover, a significant reduction of blood proviral DNA was seen after week 72, particularly under PI-based regimens and with Tat 30 µg given 3 times (30 μg, 3x), reaching a predicted 70% decay after 3 years from vaccination with a half-life of 88 weeks. This decay was significantly associated with anti-Tat IgM and IgG Abs and neutralization of Tat-mediated entry of oligomeric Env in dendritic cells, which predicted HIV-1 DNA decay. Finally, the 30 μg, 3x group was the only one showing significant increases of NK cells and CD38+HLA-DR+/CD8+ T cells, a phenotype associated with increased killing activity in elite controllers (Ensoli F., Retrovirology 2015). These data indicate that Tat immunization represents a promising pathogenesis-driven intervention to intensify HAART efficacy (Ensoli et al,PLoS ONE 2010).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Based on this, the ISS T-003 study in South Africa was started; the study was a phase II, randomized, double-blinded, placebo controlled, clinical trial to evaluate the immunogenicity (as a primary end-point) and the safety (as a secondary end-point), of a therapeutic, recombinant, biologically active HIV-1 Tat vaccine in HIV-1 infected, anti-Tat antibody negative, ARV-treated adult volunteers with chronically suppressed HIV-1 infection as indicated by a HIV-1 plasma viraemia < 400 copies/ml, and a CD4+ T cell count ≥ 200 cells/μl, at screening and documented at least once during the 12 month period prior to screening, irrespective of the pre-ARV CD4 nadir.

After a screening period of up to 21 days, the study duration will be 48 weeks, including an 8 week treatment phase (during which 3 vaccinations will be administered at 4-week intervals) and a 40 week follow-up phase.

This study will be conducted at 1 clinical site in South Africa. 200 Subjects were randomized in a 1:1 ratio to one of the two treatment groups (Tat 30 mcg or placebo administered intradermally, 3 times).

Study Type

Interventional

Enrollment (Actual)

200

Phase

  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • South Africa
    • Gaueg
      • Medunsa, Gaueg, South Africa, 0204
        • Medunsa Clinical Research Unit (MeCRU)

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 45 years (Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Male and female volunteers aged 18-45 years (inclusive)
  • Anti-Tat antibody negative
  • HIV-1 infected individuals currently receiving treatment with ARVs
  • Chronically suppressed HIV-1 infection as indicated by a HIV-1 plasma viraemia < 400 copies/ml and a CD4+ T cell count ≥ 200 cells/μl at screening, and documented at least once during the 12 month period prior to screening, irrespective of the pre-ARV CD4 nadir.
  • Negative pregnancy test for females of childbearing potential (not sterilized and still menstruating or within 1 year of the last menses) to be performed during the screening phase and immediately before each vaccination, and use of an acceptable method of contraception (double barrier methods, combined oral contraceptives, injectable contraceptives or intra-uterine devices) for at least 3 weeks prior to the first vaccination and for the duration of the study
  • Has provided written informed consent.
  • Agrees to stay in contact with the research site for the duration of the study

Exclusion Criteria:

  • Acute illness on Study Day 0
  • Body temperature >=37.5 °C on Study Day 0
  • Any current AIDS-related opportunistic disease
  • Any current neoplastic disease
  • Known history of malignant neoplastic diseases [NOTE: Subjects with known history of non-malignant neoplastic diseases that are completely resolved according to the fulfilment of all the specific recovery criteria, in agreement with the current guidelines in medical oncology, are eligible]
  • Known history of encephalopathy, neuropathy or unstable CNS pathology, immunodeficiency, autoimmune disease, angina or cardiac arrhythmias, or any other clinically significant medical problems in the opinion of the investigator
  • Any evidence, as judged by the investigator, of unstable cardio-vascular disease (e.g. unstable hypertensive disease needing modification or introduction of an anti-hypertensive treatment)
  • Chest radiography showing evidence of active or acute cardiac or pulmonary disease within 6 months prior to the study screening visit [Note if no previous chest X-ray available, this will be performed at screening];
  • Known history of anaphylaxis or serious adverse reactions to vaccines
  • Known history of serious allergic reaction to any substance, requiring hospitalization or emergent medical care (e.g. Steven-Johnson syndrome, bronchospasm, or hypotension)
  • Active pulmonary tuberculosis within 12 months of screening as evidenced by chest radiography and/or medical history.
  • Any known medical or psychiatric condition which precludes subject compliance with the protocol, specifically, persons with psychotic disorders, major affective disorders and/or suicidal ideation are to be excluded
  • Current use of psychotropic drugs prescribed for major psychotic disorders
  • Concomitant participation in any study with an investigational product or device
  • Current or prior therapy with immunomodulator, immunosuppressive and/or anticoagulant drugs within 30 days prior to administration of the investigational product
  • Live attenuated vaccines within 60 days of the first administration of the investigational product [NOTE: Medically indicated sub-unit or killed vaccines (e.g., influenza, pneumococcal, hepatitis A and B) are permitted, but must have been administered at least 4 weeks prior to the first administration of the investigational product]
  • Known receipt of blood products or immunoglobulins during the year prior to screening
  • Previous participation in an HIV-1 vaccine trial (subjects who are known to have previously participated in the placebo arm of an HIV-1 vaccine trial, and so have never received an investigational HIV-1 vaccine, are eligible for inclusion)
  • Known drug and/or alcohol abuse in the year prior to screening
  • Use in the last 6 months or concomitant use of anti-CCR5 inhibitors and/or integrase inhibitors and/or fusion inhibitors
  • Pregnant or lactating females

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Triple

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Group A, Tat
Recombinant biologically active Tat 30 mcg in Phosphate saline buffer, pH 7.4, 1% sucrose, 1% Human Serum Albumin; administered intradermally 3 times at weeks 0, 4 & 8
Biological: Tat
Recombinant biologically active Tat 30 mcg in Phosphate saline buffer, pH 7.4, 1% sucrose, 1% Human Serum Albumin
Placebo Comparator: group B, Placebo
Phosphate saline buffer, pH 7.4, 1% sucrose, 1% Human Serum Albumin, administered intradermally 3 times at weeks 0, 4 & 8
Biological: Placebo
Phosphate saline buffer, pH 7.4, 1% sucrose, 1% Human Serum Albumin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Immunogenicity of Tat protein
Time Frame: up to 48 weeks

Induction of specific anti-Tat humoral immune response in terms of IgM, IgG or IgA anti-Tat antibodies.

The induction, magnitude and persistence of the humoral response to the administered vaccination schedule will be compared between the active and placebo groups.
up to 48 weeks

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
safety of the Tat protein
Time Frame: baseline; up to 48 weeks
Changes in physical examination findings from baseline;
baseline; up to 48 weeks
safety of the Tat protein
Time Frame: baseline; up to 48 weeks
Changes in vital signs from baseline;
baseline; up to 48 weeks
safety of the Tat protein
Time Frame: up to 48 weeks
Adverse events (including local and systemic reactions to the vaccination schedule occurring during the course of the study);
up to 48 weeks
safety of the Tat protein
Time Frame: baseline; up to 48 weeks
Changes in standard laboratory safety parameters from baseline
baseline; up to 48 weeks

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Barbara Ensoli, MD

Collaborators

Italian Ministry of Foreign Affairs - General Direction for Cooperation and Development

Investigators

  • Study Director: Barbara BE Ensoli, MD, Istituto Superiore Sanita

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Helpful Links

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

March 1, 2012

Primary Completion (Actual)

May 1, 2014

Study Completion (Actual)

July 1, 2014

Study Registration Dates

First Submitted

January 17, 2012

First Submitted That Met QC Criteria

January 19, 2012

First Posted (Estimate)

January 20, 2012

Study Record Updates

Last Update Posted (Estimate)

March 4, 2016

Last Update Submitted That Met QC Criteria

March 3, 2016

Last Verified

March 1, 2016

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • ISS T-003

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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