Clinical trial NCT01755598: Study to Evaluate the Efficacy of GlaxoSmithKline (GSK) Biologicals' Candidate Tuberculosis (TB) Vaccine in Adults
Official title: Efficacy of GSK Biologicals' Candidate Tuberculosis (TB) Vaccine GSK 692342 Against TB Disease, in Adults Living in a TB Endemic Region
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Tuberculosis
Tuberculosis Vaccines
Keywords: Positive Interferon-γ release assay
Efficacy
Adults
Tuberculosis vaccine
Endemic region
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
Collaborators: name: Aeras
First posted: 2012-12-24
Enrollment: 3575
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: The purpose of this study is to evaluate the protective efficacy of two doses of GSK Biologicals' candidate TB vaccine against pulmonary TB, as compared to placebo. The efficacy will be evaluated in adults living in TB endemic countries and aged 18 - 50 years because pulmonary TB occurs frequently in these countries and age range. In addition, the safety and immunogenicity of the candidate tuberculosis vaccine will be evaluated in a subset of volunteers.

Detailed description: Case Definitions:

• First case definition: A subject with clinical suspicion of pulmonary TB disease, with MTB complex identified from a sputum specimen, taken before initiation of TB treatment, by Xpert MTB/RIF and/or microbiological culture and confirmed HIV-negative at the time of TB diagnosis.

• Second case definition: A subject with clinical suspicion of pulmonary TB disease, with MTB complex identified from a sputum specimen, taken before initiation of TB treatment, by Xpert MTB/RIF and confirmed HIV-negative at the time of TB diagnosis.

• Third case definition: A subject with clinical suspicion of pulmonary TB disease, with MTB complex identified from a sputum specimen, taken up to four weeks after initiation of TB treatment, by Xpert MTB/RIF and/or microbiological culture and confirmed HIV-negative at the time of TB diagnosis.

• Fourth case definition: A subject with clinical suspicion of pulmonary TB disease, with MTB complex identified from a sputum specimen, taken up to four weeks after initiation of TB treatment, by Xpert MTB/RIF and/or microbiological culture.

• Fifth case definition: A subject for whom a clinician has diagnosed TB disease and has decided to treat the patient with TB treatment.

Eligibility criteria: Inclusion Criteria:

* Subjects who, in the opinion of the investigator, can and will comply with the requirements of the protocol.
* A male or female between, and including, 18 and 50 years of age at the time of obtaining informed consent.
* Written (or thumb printed and witnessed) informed consent obtained from the subject.
* Baseline positive IGRA test result.
* Baseline negative HIV screen.
* Baseline negative clinical screening questionnaire and negative sputum sample for Pulmonary TB disease.
* Healthy subjects or those with chronic well-controlled disease as established by medical history and clinical examination.
* Female subjects of non-childbearing potential may be enrolled in the study.

  * Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy or post-menopause.
* Female subjects of childbearing potential may be enrolled in the study, if the subject:

  * has practiced adequate contraception for 25 days prior to vaccination, and
  * has a negative pregnancy test on the day of screening and the day of first vaccination, and
  * has agreed to continue adequate contraception during the entire vaccination period and for 2 months after completion of the vaccination series.

Exclusion Criteria:

* Current TB disease or history of TB disease and/or treatment for TB.
* Use of any investigational or non-registered product other than the study vaccines within 30 days preceding the first dose of study vaccine, or planned use during the study period.
* Planned administration/administration of a vaccine not foreseen by the study protocol in the period starting 30 days before and ending 30 days after each dose of vaccine.
* History of previous administration of experimental Mtb vaccines.
* Chronic administration of immunosuppressants or other immune-modifying drugs within six months prior to the first vaccine dose. 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.
* Any confirmed or suspected immunosuppressive or immunodeficient condition, based on medical history and physical examination.
* Planned participation or participation in another experimental protocol during the study.
* Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product.
* Administration of immunoglobulins and/or any blood products within the 3 months preceding the first dose of study vaccine or planned administration during the study period.
* History of any reaction or hypersensitivity likely to be exacerbated by any component of the vaccines.
* History of medically confirmed autoimmune disease.
* Pregnant or lactating female.
* Female planning to become pregnant or planning to discontinue contraceptive precautions during the vaccination period and/or before 2 months after completion of the vaccination series.

Primary outcomes:
measure: Incident Rates of Definite Pulmonary Tuberculosis (TB) Disease, Not Associated With HIV-infection, Meeting the Case Definition 1
timeFrame: From Day 60 (i.e one month after Dose 2) up to Year 3: follow-up period for cases ends at the first occurrence of an event. For the non-cases: follow-up period ends at the date of the Month 36 visit or last contact date whichever comes first
Secondary outcomes:
measure: Incident Rates of Definite Xpert MTB/Rif Positive Pulmonary TB Disease, Not Associated With HIV-infection, Meeting the Case Definition 2
timeFrame: From Day 60 (i.e one month after Dose 2) up to Year 3: follow-up period for cases ends at the first occurrence of an event. For the non-cases: follow-up period ends at the date of the Month 36 visit or last contact date whichever comes first
measure: Incident Rates of Definite Pulmonary TB Disease, Not Associated With HIV-infection Meeting the Case Definition 3
timeFrame: From Day 60 (i.e one month after Dose 2) up to Year 3: follow-up period for cases ends at the first occurrence of an event. For the non-cases: follow-up period ends at the date of the Month 36 visit or last contact date whichever comes first
measure: Incident Rates of Microbiological Pulmonary TB Disease, Meeting the Case Definition 4
timeFrame: From Day 60 (i.e one month after Dose 2) up to Year 3: follow-up period for cases ends at the first occurrence of an event. For the non-cases: follow-up period ends at the date of the Month 36 visit or last contact date whichever comes first
measure: Incidence Rates of Clinical TB Disease, Meeting the Case Definition 5
timeFrame: From Day 60 (i.e one month after Dose 2) up to Year 3: follow-up period for cases ends at the first occurrence of an event. For the non-cases: follow-up period ends at the date of the Month 36 visit or last contact date whichever comes first
measure: Number of Subjects With Serious Adverse Events (SAEs).
timeFrame: From Day 0 up to Year 3 (during the entire study period)
measure: Number of Subjects With Any Unsolicited Adverse Events (AEs).
timeFrame: During the 30-day follow-up period following vaccination, across doses (i.e. day of vaccination and 29 subsequent days after each vaccine dose)
measure: Number of Subjects With Any Solicited Local AEs in the Safety and Immune Sub-cohort
timeFrame: During the 7-day follow-up period (i.e. day of vaccination and 6 subsequent days) after each vaccine dose
measure: Number of Subjects With Any Solicited General AEs in the Safety and Immune Sub-cohort
timeFrame: During the 7-day follow-up period (i.e.: day of vaccination and 6 subsequent days) after each vaccine dose
measure: Number of Subjects With Any Potential Immune-mediated Diseases (pIMDs)
timeFrame: From Day 0 to 6 months post-dose 2 (i.e. at Month 7)
measure: Number of Subjects With Grade Equal or Greater Than 2 of Severity for Haematological and Biochemichal Abnormal Laboratory Values in the Safety and Immune Sub-cohort
timeFrame: Days 0, 7, 30 and 37
measure: Desciptive Statistics of the Frequency of M72-specific CD4+ T-cells Expressing Any Combination of Immune Markers in the Safety and Immune Sub-cohort
timeFrame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3)
measure: Desciptive Statistics of the Frequency of M72-specific CD8+ T-cells Expressing Any Combination of Immune Markers in the Safety and Immune Sub-cohort
timeFrame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3)
measure: M72-specific Antibody Concentrations as Measured by Enzyme Linked Immuno Sorbent Assay (ELISA) in the Safety and Immune Sub-cohort
timeFrame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3)
measure: Number of Seropositive Subjects for M72 Antibodies Measured by ELISA in the Safety and Immune Sub-cohort
timeFrame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3)
Other outcomes:
Locations:
city: Kisumu
country: Kenya
facility: GSK Investigational Site
city: Pretoria
country: South Africa
facility: GSK Investigational Site
state: Gauteng
city: Soweto
country: South Africa
facility: GSK Investigational Site
state: Gauteng
city: Klerksdorp
country: South Africa
facility: GSK Investigational Site
state: North-West
city: Western Cape
country: South Africa
facility: GSK Investigational Site
state: Western Province
city: Worcester
country: South Africa
facility: GSK Investigational Site
state: Western Province
city: Cape Town
country: South Africa
facility: GSK Investigational Site
city: Cape Town
country: South Africa
facility: GSK Investigational Site
city: Lusaka
country: Zambia
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Tait DR, Hatherill M, Van Der Meeren O, Ginsberg AM, Van Brakel E, Salaun B, Scriba TJ, Akite EJ, Ayles HM, Bollaerts A, Demoitie MA, Diacon A, Evans TG, Gillard P, Hellstrom E, Innes JC, Lempicki M, Malahleha M, Martinson N, Mesia Vela D, Muyoyeta M, Nduba V, Pascal TG, Tameris M, Thienemann F, Wilkinson RJ, Roman F. Final Analysis of a Trial of M72/AS01E Vaccine to Prevent Tuberculosis. N Engl J Med. 2019 Dec 19;381(25):2429-2439. doi: 10.1056/NEJMoa1909953. Epub 2019 Oct 29.
citation: Van Der Meeren O, Hatherill M, Nduba V, Wilkinson RJ, Muyoyeta M, Van Brakel E, Ayles HM, Henostroza G, Thienemann F, Scriba TJ, Diacon A, Blatner GL, Demoitie MA, Tameris M, Malahleha M, Innes JC, Hellstrom E, Martinson N, Singh T, Akite EJ, Khatoon Azam A, Bollaerts A, Ginsberg AM, Evans TG, Gillard P, Tait DR. Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis. N Engl J Med. 2018 Oct 25;379(17):1621-1634. doi: 10.1056/NEJMoa1803484. Epub 2018 Sep 25.