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)
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 20 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.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. Preliminary results obtained from 87 subjects enrolled in the phase II trial ISST-002 ongoing in Italy, indicate that Tat vaccination is safe, immunogenic and capable of reducing the immune dysregulation which persists despite HAART in treated individuals, opening new avenues for a most effective treatment of HIV/AIDS (Ensoli et al,PLoS ONE 2010).
|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|
- 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.
- 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
|Study Start Date:||March 2012|
|Estimated Study Completion Date:||July 2014|
|Estimated Primary Completion Date:||July 2014 (Final data collection date for primary outcome measure)|
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
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
Phosphate saline buffer, pH 7.4, 1% sucrose, 1% Human Serum Albumin
Based on this, the ISS T-003 study in South Africa was started; the study is a phase II, randomized, double-blinded, placebo controlled, clinical trial to evaluate (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 will be randomized in a 1:1 ratio to one of the two treatment groups (Tat 30 mcg or placebo administered intradermally, 3 times).
|Medunsa Clinical Research Unit (MeCRU)|
|Medunsa, Gaueg, South Africa, 0204|
|Study Director:||Barbara BE Ensoli, MD||Istituto Superiore Sanita|