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Safety and Immunogenicity Study of a Candidate Tuberculosis Vaccine in Human Immunodeficiency Virus (HIV)-Positive Adults

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01262976
First received: December 16, 2010
Last updated: December 5, 2016
Last verified: December 2016
  Purpose

The purpose of the study is to assess the safety and immunogenicity of a GlaxoSmithKline (GSK) Biologicals' candidate tuberculosis vaccine (692342) administered to Human Immunodeficiency Virus (HIV)-positive adults aged 18 to 59 years, living in a tuberculosis endemic region.

Subjects will be followed-up for 3 years.

Subjects will be enrolled in 3 cohorts:

  • HIV-positive adults on highly active antiretroviral therapy
  • HIV-positive adults not on highly active antiretroviral therapy
  • HIV-negative adults

Each cohort will have 2 groups.


Condition Intervention Phase
Tuberculosis
Biological: GSK's investigational vaccine 692342
Biological: Physiological saline
Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Prevention
Official Title: Safety and Immunogenicity of GSK Biologicals' Candidate Tuberculosis Vaccine (692342) When Administered to HIV-positive Adults Living in a Tuberculosis Endemic Region

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • Number of subjects with grade 3 solicited local symptoms [ Time Frame: During the 7-day (Days 0-6) post-vaccination period following each dose and across doses ] [ Designated as safety issue: No ]
    Solicited local symptoms assessed were pain and swelling. Grade 3 pain = pain that prevented normal activity. Grade 3 swelling = swelling spreading beyond 50 millimeters (mm) of injection site.

  • Number of subjects with grade 3 solicited general symptoms [ Time Frame: During the 7-day (Days 0-6) post-vaccination period following each dose and across doses ] [ Designated as safety issue: No ]
    Solicited general symptoms assessed were fatigue, temperature [defined as axillary temperature equal to or above (≥) 37.5 degrees Celsius (°C)], gastrointestinal symptoms (gastro) [nausea, vomiting, diarrhoea and/or abdominal pain], headache, malaise and myalgia. Grade 3 symptom = symptom that prevented normal activity. Grade 3 fever = fever ≥ 39.5 °C.

  • Number of subjects with grade 3 unsolicited adverse events (AEs) [ Time Frame: During the 30-day (Days 0-29) post-vaccination period ] [ Designated as safety issue: No ]
    An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset out-side the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination. Grade 3 AE = an AE which prevented normal, everyday activities. Related = AE assessed by the investigator as related to the vaccination.

  • Number of subjects with serious adverse events (SAEs) [ Time Frame: From screening up to one month post Dose 2 ] [ Designated as safety issue: No ]
    Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

  • Number of subjects with grade 3 and grade 4 haematological and biochemical levels [ Time Frame: At Day 0 ] [ Designated as safety issue: No ]
    Haematological and biochemical parameters assessed were haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALT], aspartate aminotransferase [AST], red blood cells [RBC] and creatinine [CREA].

  • Number of subjects with grade 3 and grade 4 haematological and biochemical levels [ Time Frame: At Day 7 ] [ Designated as safety issue: No ]
    Haematological and biochemical parameters assessed were haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALT], aspartate aminotransferase [AST], red blood cells [RBC] and creatinine [CREA].

  • Number of subjects with grade 3 and grade 4 haematological and biochemical levels [ Time Frame: At Day 30 ] [ Designated as safety issue: No ]
    Haematological and biochemical parameters assessed were haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALT], aspartate aminotransferase [AST], red blood cells [RBC] and creatinine [CREA].

  • Number of subjects with grade 3 and grade 4 haematological and biochemical levels [ Time Frame: At Day 37 ] [ Designated as safety issue: No ]
    Haematological and biochemical parameters assessed were haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALT], aspartate aminotransferase [AST], red blood cells [RBC] and creatinine [CREA].

  • Number of subjects with grade 3 and grade 4 haematological and biochemical levels [ Time Frame: At Day 60 ] [ Designated as safety issue: No ]
    Haematological and biochemical parameters assessed were haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALT], aspartate aminotransferase [AST], red blood cells [RBC] and creatinine [CREA].


Secondary Outcome Measures:
  • Anti-Mycobacterium tuberculosis fusion protein (M72) specific antibody concentrations [ Time Frame: At Day 0, 30, 60, 210 and Year 1 ] [ Designated as safety issue: No ]
    Concentration of M72-specific antibodies, as measured by the enzyme-linked immunosorbent assay (ELISA), were given in ELISA units per milliliter (EU/mL) and expressed as geometric mean concentrations (GMCs).

  • Number of seroconverted subjects for M72-specific antibodies [ Time Frame: At Day 0, 30, 60, 210 and Year 1 ] [ Designated as safety issue: No ]
    A seroconverted subject for M72 antibodies was defined as a seronegative subject at baseline, with the appearance of M72 antibody concentration higher than or equal to (≥) the cut-off value of 2.8 EL.U/mL post vaccination. Antibody concentrations below the cut-off value of the assay were given an arbitrary value of half the cut-off value for the purpose of GMC calculation.

  • Frequency of M72-cluster of differentiation 4 (CD4+) T cells expressing at least 2 immune markers [ Time Frame: At Day 0, 7, 30, 37, 60, 210 and Year 1 ] [ Designated as safety issue: No ]
    Among immune markers expressed after background reduction were interleukin-2 (IL-2), interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α) and cluster of differentiation 40 - ligand (CD40-L).

  • Frequency of M72-cluster of differentiation 4 (CD4+) T cells expressing any combination of cytokines [ Time Frame: At Day 0, 7, 30, 37, 60, 210 and Year 1 ] [ Designated as safety issue: No ]
    Among cytokines expressed after background reduction were cluster of differentiation 40-ligand (CD40-L), interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α).

  • Frequency of M72-cluster of differentiation 4 (CD4+) T cells expressing any combination of cytokines [ Time Frame: At Day 0, 7, 30, 37, 60, 210 and Year 1 ] [ Designated as safety issue: No ]
    Among cytokines expressed after background reduction were cluster of differentiation 40-ligand (CD40-L) interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α).

  • Frequency of M72-cluster of differentiation 8 (CD8+) T cells expressing at least 2 immune markers [ Time Frame: At Day 0, 7, 30, 37, 60, 210 and Year 1 ] [ Designated as safety issue: No ]
    Among immune markers expressed after background reduction were interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α).

  • Frequency of M72-cluster of differentiation 8 (CD8+) T cells expressing any combination of cytokines [ Time Frame: At Day 0, 7, 30, 37, 60, 210 and Year 1 ] [ Designated as safety issue: No ]
    Among cytokines expressed after background reduction were cluster of differentiation 40-ligand (CD40-L) interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α).

  • Frequency of M72-cluster of differentiation 8 (CD8+) T cells expressing any combination of cytokines [ Time Frame: At Day 0, 7, 30, 37, 60, 210 and Year 1 ] [ Designated as safety issue: No ]
    Among cytokines expressed after background reduction were cluster of differentiation 40-ligand (CD40-L), interleukin-2 (IL-2), interferon-gamma (IFN-γ) and tumour necrosis factor-alpha (TNF-α).

  • Number of subjects with any solicited local symptoms [ Time Frame: During the 7-Day (Days 0-6) post-vaccination period following each dose and across doses ] [ Designated as safety issue: No ]
    Solicited local symptoms assessed were pain and swelling. Any = occurrence of the symptom regardless of intensity grade.

  • Number of subjects with any solicited general symptoms [ Time Frame: During the 7-Day (Days 0-6) post-vaccination period following each dose and across doses ] [ Designated as safety issue: No ]
    Solicited general symptoms assessed were fatigue, gastrointestinal symptoms (Gastro), headache, malaise, myalgia and temperature. Any = occurrence of the symptom regardless of intensity grade.

  • Number of subjects with any unsolicited AEs [ Time Frame: During the 30-Day (Days 0-29) post-vaccination period ] [ Designated as safety issue: No ]
    An unsolicited AE covers any untoward medical occurrence in a clinical investigation subject temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as the occurrence of any unsolicited AE regardless of intensity grade or relation to vaccination.

  • Number of subjects with SAEs [ Time Frame: From one month post Dose 2 up to Year 1 ] [ Designated as safety issue: No ]
    Serious adverse events (SAEs) assessed include medical occurrences that result in death, are life threatening, require hospitalization or prolongation of hospitalization or result in disability/incapacity.

  • Number of subjects presenting different grades of haematological and biochemical values [ Time Frame: At Day 0, 7, 30, 37 and 60 ] [ Designated as safety issue: No ]
    Biochemical and haematological parameters included haemoglobin [Hgb], white blood cells [WBC], platelets [PLA], alanine aminotransferase [ALA]. Levels assessed were - normal, grade 1 and grade 2.

  • Number of subjects presenting different grades of haematological and biochemical values [ Time Frame: At Day 0, 7, 30, 37 and 60 ] [ Designated as safety issue: No ]
    Biochemical and haematological parameters included aspartate aminotransferase [AST], creatinine [CREA] and red blood cells [RBC]. Levels assessed were - normal, grade 1 and grade 2.


Enrollment: 240
Study Start Date: January 2011
Study Completion Date: June 2015
Primary Completion Date: July 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Group A
HIV-positive subjects on highly active anti retroviral therapy will receive GlaxoSmithKline's (GSK's) investigational vaccine 692342.
Biological: GSK's investigational vaccine 692342
Intramuscular, 2 doses
Placebo Comparator: Group B
HIV-positive subjects on highly active anti retroviral therapy will receive physiological saline.
Biological: Physiological saline
Intramuscular, 2 doses
Experimental: Group C
Treatment naïve HIV-positive subjects will receive GSK's investigational vaccine 692342.
Biological: GSK's investigational vaccine 692342
Intramuscular, 2 doses
Placebo Comparator: Group D
Treatment naïve HIV-positive subjects will receive physiological saline.
Biological: Physiological saline
Intramuscular, 2 doses
Experimental: Group E
HIV negative subjects will receive GSK's investigational vaccine 692342.
Biological: GSK's investigational vaccine 692342
Intramuscular, 2 doses
Placebo Comparator: Group F
HIV negative subjects will receive physiological saline.
Biological: Physiological saline
Intramuscular, 2 doses

Detailed Description:
This Protocol Posting has been updated following Protocol Amendment 1, February 2011, leading to the update of the outcome measures and the inclusion and exclusion criteria.
  Eligibility

Ages Eligible for Study:   18 Years to 59 Years   (Adult)
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Subjects who the investigator believes that they can and will comply with the requirements of the protocol.
  • A male or female between, and including, 18 and 59 years of age at the time of the first vaccination.
  • Written informed consent obtained from the subject prior to any study procedure.
  • Female subjects of non-childbearing potential may be enrolled in the study.
  • Female subjects of childbearing potential may be enrolled in the study, if the subject:

    • has practiced adequate contraception for 30 days prior to vaccination,
    • has a negative pregnancy test on the day of vaccination, and
    • has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series.
  • Clinically acceptable laboratory values at screening as determined by the investigator.
  • No evidence of tuberculosis disease with no evidence of pulmonary pathology as confirmed by chest X-ray.
  • No history of extra pulmonary tuberculosis.
  • Based on their medical history, all subjects must have no history of chemotherapy for tuberculosis.

Additional inclusion criteria for subjects to be enrolled in HIV+ on highly active antiretroviral therapy cohort:

  • Subjects must be HIV-positive and under care of a physician for at least 6 months.
  • Subjects must have a CD4+T cell count >= 250 cells/mm3 at screening.
  • Subjects must be stable on highly active antiretroviral therapy for at least 6 months, with an undetectable HIV viral load level at screening.

Additional inclusion criteria for subjects to be enrolled in HIV+ treatment naïve cohort:

  • Subjects must be HIV-positive and under care of a physician for at least 6 months
  • Subjects must be highly active antiretroviral therapy-naïve (never received anti-retroviral therapy after HIV diagnosis)
  • Subjects must have a CD4 + T cell count above 350 cells/mm3 at screening.
  • Subjects for whom commencement of highly active antiretroviral therapy is not expected based on current assessment within next year.
  • Subjects must have a viral load between 5000 - 80000 copies/mL at screening.

Additional inclusion criteria for subjects to be enrolled in HIV-negative cohort

• Subjects must be negative for HIV-1.

Exclusion Criteria:

  • Use of any investigational or non-registered product other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period.
  • Administration of a registered live vaccine not foreseen by the study within 30 days preceding the first dose of study vaccine and administration of a registered inactivated vaccine within 14 days preceding the first dose of study vaccine.
  • History of previous administration of experimental Mtb vaccines.
  • History of previous exposure to components of the investigational vaccine within 30 days preceding the first dose of study vaccine
  • Chronic administration of immunosuppressant or other immune-modifying drugs within six months prior to the first vaccine/product dose. For corticosteroids, this will mean prednisone >= 20 mg/kg/day, or equivalent. Inhaled and topical steroids are allowed.
  • Any condition or illness or medication, which in the opinion of the Investigator might interfere with the evaluation of the safety or immunogenicity of the vaccine.
  • Planned participation or participation in another experimental protocol with an experimental product during the study period.
  • Administration of any immunoglobulin, any immunotherapy and/or any blood products within the three months preceding the first dose of study vaccination, or planned administrations during the study period.
  • Subjects taking any of the following medication: chronic administration of systemic steroids, interleukins, systemic interferon or systemic chemotherapy.
  • History of allergic reactions or anaphylaxis to any drug or vaccine.
  • History of allergic disease or reactions likely to be exacerbated by any component of the vaccine.
  • History of chronic alcohol consumption and/or drug abuse which in the Investigator's opinion would put the subject at risk.
  • Pregnant female, lactating female or female planning to become pregnant or stop contraception.
  • Acute or chronic clinically relevant pulmonary, cardiovascular, hepatic or renal function abnormality as determined by physical examination or laboratory screening tests.

Additional exclusion criteria for subjects to be enrolled in HIV+ on highly active antiretroviral therapy cohort:

  • Any change in anti-retroviral drug regimen within 12 weeks prior to screening.
  • Any chronic drug therapy, other than highly active antiretroviral therapy or prophylaxis for opportunistic HIV related infections, birth control pills, anti-histamines for seasonal allergies and SSRIs.
  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: NCT01262976

Locations
India
GSK Investigational Site
Tharamani Chennai, India, 600113
Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01262976     History of Changes
Other Study ID Numbers: 113935 
Study First Received: December 16, 2010
Last Updated: December 5, 2016
Health Authority: India: Central Drugs Standard Control Organization

Keywords provided by GlaxoSmithKline:
Tuberculosis vaccine

Additional relevant MeSH terms:
Tuberculosis
Acquired Immunodeficiency Syndrome
HIV Infections
HIV Seropositivity
Mycobacterium Infections
Actinomycetales Infections
Gram-Positive Bacterial Infections
Bacterial Infections
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Slow Virus Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Vaccines
Immunologic Factors
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on December 09, 2016