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

Information source: Istituto Superiore di Sanit
ClinicalTrials.gov processed this data on August 23, 2015
Link to the current ClinicalTrials.gov record.

Condition(s) targeted: HIV Infections

Intervention: Tat (Biological); Placebo (Biological)

Phase: Phase 2

Status: Completed

Sponsored by: Barbara Ensoli, MD

Official(s) and/or principal investigator(s):
Barbara BE Ensoli, MD, Study Director, Affiliation: Istituto Superiore Sanita

Summary

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).

Clinical Details

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

Study design: Allocation: Randomized, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator), Primary Purpose: Treatment

Primary outcome: Immunogenicity of Tat protein

Secondary outcome:

safety of the Tat protein

safety of the Tat protein

safety of the Tat protein

safety of the Tat protein

Detailed description: 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).

Eligibility

Minimum age: 18 Years. Maximum age: 45 Years. Gender(s): Both.

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

Locations and Contacts

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

Related info

Related info

Related publications:

Ensoli B, Fiorelli V, Ensoli F, Lazzarin A, Visintini R, Narciso P, Di Carlo A, Tripiciano A, Longo O, Bellino S, Francavilla V, Paniccia G, Arancio A, Scoglio A, Collacchi B, Ruiz Alvarez MJ, Tambussi G, Tassan Din C, Palamara G, Latini A, Antinori A, D'Offizi G, Giuliani M, Giulianelli M, Carta M, Monini P, Magnani M, Garaci E. The preventive phase I trial with the HIV-1 Tat-based vaccine. Vaccine. 2009 Dec 11;28(2):371-8. doi: 10.1016/j.vaccine.2009.10.038. Epub 2009 Oct 29.

Longo O, Tripiciano A, Fiorelli V, Bellino S, Scoglio A, Collacchi B, Alvarez MJ, Francavilla V, Arancio A, Paniccia G, Lazzarin A, Tambussi G, Din CT, Visintini R, Narciso P, Antinori A, D'Offizi G, Giulianelli M, Carta M, Di Carlo A, Palamara G, Giuliani M, Laguardia ME, Monini P, Magnani M, Ensoli F, Ensoli B. Phase I therapeutic trial of the HIV-1 Tat protein and long term follow-up. Vaccine. 2009 May 26;27(25-26):3306-12. doi: 10.1016/j.vaccine.2009.01.090. Epub 2009 Feb 7.

Ensoli B, Bellino S, Tripiciano A, Longo O, Francavilla V, Marcotullio S, Cafaro A, Picconi O, Paniccia G, Scoglio A, Arancio A, Ariola C, Ruiz Alvarez MJ, Campagna M, Scaramuzzi D, Iori C, Esposito R, Mussini C, Ghinelli F, Sighinolfi L, Palamara G, Latini A, Angarano G, Ladisa N, Soscia F, Mercurio VS, Lazzarin A, Tambussi G, Visintini R, Mazzotta F, Di Pietro M, Galli M, Rusconi S, Carosi G, Torti C, Di Perri G, Bonora S, Ensoli F, Garaci E. Therapeutic immunization with HIV-1 Tat reduces immune activation and loss of regulatory T-cells and improves immune function in subjects on HAART. PLoS One. 2010 Nov 11;5(11):e13540. doi: 10.1371/journal.pone.0013540.

Bellino S, Francavilla V, Longo O, Tripiciano A, Paniccia G, Arancio A, Fiorelli V, Scoglio A, Collacchi B, Campagna M, Lazzarin A, Tambussi G, Din CT, Visintini R, Narciso P, Antinori A, D'Offizi G, Giulianelli M, Carta M, Di Carlo A, Palamara G, Giuliani M, Laguardia ME, Monini P, Magnani M, Ensoli F, Ensoli B. Parallel conduction of the phase I preventive and therapeutic trials based on the Tat vaccine candidate. Rev Recent Clin Trials. 2009 Sep;4(3):195-204. Review.

Ensoli B, Fiorelli V, Ensoli F, Lazzarin A, Visintini R, Narciso P, Di Carlo A, Monini P, Magnani M, Garaci E. The therapeutic phase I trial of the recombinant native HIV-1 Tat protein. AIDS. 2008 Oct 18;22(16):2207-9. doi: 10.1097/QAD.0b013e32831392d4.

Ensoli B, Fiorelli V, Ensoli F, Cafaro A, Titti F, Buttò S, Monini P, Magnani M, Caputo A, Garaci E. Candidate HIV-1 Tat vaccine development: from basic science to clinical trials. AIDS. 2006 Nov 28;20(18):2245-61. Review.

Buttò S, Fiorelli V, Tripiciano A, Ruiz-Alvarez MJ, Scoglio A, Ensoli F, Ciccozzi M, Collacchi B, Sabbatucci M, Cafaro A, Guzmán CA, Borsetti A, Caputo A, Vardas E, Colvin M, Lukwiya M, Rezza G, Ensoli B; Tat Multicentric Study Group. Sequence conservation and antibody cross-recognition of clade B human immunodeficiency virus (HIV) type 1 Tat protein in HIV-1-infected Italians, Ugandans, and South Africans. J Infect Dis. 2003 Oct 15;188(8):1171-80. Epub 2003 Sep 30.

Rezza G, Fiorelli V, Dorrucci M, Ciccozzi M, Tripiciano A, Scoglio A, Collacchi B, Ruiz-Alvarez M, Giannetto C, Caputo A, Tomasoni L, Castelli F, Sciandra M, Sinicco A, Ensoli F, Buttò S, Ensoli B. The presence of anti-Tat antibodies is predictive of long-term nonprogression to AIDS or severe immunodeficiency: findings in a cohort of HIV-1 seroconverters. J Infect Dis. 2005 Apr 15;191(8):1321-4. Epub 2005 Mar 14.

Bellino S, Tripiciano A, Picconi O, Francavilla V, Longo O, Sgadari C, Paniccia G, Arancio A, Angarano G, Ladisa N, Lazzarin A, Tambussi G, Nozza S, Torti C, Focà E, Palamara G, Latini A, Sighinolfi L, Mazzotta F, Di Pietro M, Di Perri G, Bonora S, Mercurio VS, Mussini C, Gori A, Galli M, Monini P, Cafaro A, Ensoli F, Ensoli B. The presence of anti-Tat antibodies in HIV-infected individuals is associated with containment of CD4+ T-cell decay and viral load, and with delay of disease progression: results of a 3-year cohort study. Retrovirology. 2014 Jun 24;11:49. doi: 10.1186/1742-4690-11-49.

Monini P, Cafaro A, Srivastava IK, Moretti S, Sharma VA, Andreini C, Chiozzini C, Ferrantelli F, Cossut MR, Tripiciano A, Nappi F, Longo O, Bellino S, Picconi O, Fanales-Belasio E, Borsetti A, Toschi E, Schiavoni I, Bacigalupo I, Kan E, Sernicola L, Maggiorella MT, Montin K, Porcu M, Leone P, Leone P, Collacchi B, Palladino C, Ridolfi B, Falchi M, Macchia I, Ulmer JB, Buttò S, Sgadari C, Magnani M, Federico MP, Titti F, Banci L, Dallocchio F, Rappuoli R, Ensoli F, Barnett SW, Garaci E, Ensoli B. HIV-1 tat promotes integrin-mediated HIV transmission to dendritic cells by binding Env spikes and competes neutralization by anti-HIV antibodies. PLoS One. 2012;7(11):e48781. doi: 10.1371/journal.pone.0048781. Epub 2012 Nov 13.

Starting date: March 2012
Last updated: August 8, 2014

Page last updated: August 23, 2015

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