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)

This study has been completed.
Sponsor:
Collaborator:
Italian Ministry of Foreign Affairs - General Direction for Cooperation and Development
Information provided by (Responsible Party):
Barbara Ensoli, MD, Istituto Superiore di Sanità
ClinicalTrials.gov Identifier:
NCT01513135
First received: January 17, 2012
Last updated: March 3, 2016
Last verified: March 2016
  Purpose
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).

Condition Intervention Phase
HIV Infections
Biological: Tat
Biological: Placebo
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: 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

Resource links provided by NLM:


Further study details as provided by Istituto Superiore di Sanità:

Primary Outcome Measures:
  • Immunogenicity of Tat protein [ Time Frame: up to 48 weeks ] [ Designated as safety issue: No ]

    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.



Secondary Outcome Measures:
  • safety of the Tat protein [ Time Frame: baseline; up to 48 weeks ] [ Designated as safety issue: Yes ]
    Changes in physical examination findings from baseline;

  • safety of the Tat protein [ Time Frame: baseline; up to 48 weeks ] [ Designated as safety issue: Yes ]
    Changes in vital signs from baseline;

  • safety of the Tat protein [ Time Frame: up to 48 weeks ] [ Designated as safety issue: Yes ]
    Adverse events (including local and systemic reactions to the vaccination schedule occurring during the course of the study);

  • safety of the Tat protein [ Time Frame: baseline; up to 48 weeks ] [ Designated as safety issue: Yes ]
    Changes in standard laboratory safety parameters from baseline


Enrollment: 200
Study Start Date: March 2012
Study Completion Date: July 2014
Primary Completion Date: May 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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

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).

  Eligibility

Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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
  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: NCT01513135

Locations
South Africa
Medunsa Clinical Research Unit (MeCRU)
Medunsa, Gaueg, South Africa, 0204
Sponsors and Collaborators
Barbara Ensoli, MD
Italian Ministry of Foreign Affairs - General Direction for Cooperation and Development
Investigators
Study Director: Barbara BE Ensoli, MD Istituto Superiore Sanita
  More Information

Additional Information:
Publications:

Responsible Party: Barbara Ensoli, MD, PhD, Istituto Superiore di Sanità
ClinicalTrials.gov Identifier: NCT01513135     History of Changes
Other Study ID Numbers: ISS T-003 
Study First Received: January 17, 2012
Last Updated: March 3, 2016
Health Authority: South Africa: Medicines Control Council

Keywords provided by Istituto Superiore di Sanità:
HIV,
HAART-treated
participants
Tat protein,
Therapeutic immunization

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

ClinicalTrials.gov processed this record on August 30, 2016