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Study to Evaluate the Efficacy of GlaxoSmithKline (GSK) Biologicals' Candidate Tuberculosis (TB) Vaccine in Adults

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ClinicalTrials.gov Identifier: NCT01755598
Recruitment Status : Completed
First Posted : December 24, 2012
Results First Posted : December 3, 2019
Last Update Posted : December 3, 2019
Sponsor:
Collaborator:
Aeras
Information provided by (Responsible Party):
GlaxoSmithKline

Tracking Information
First Submitted Date  ICMJE December 19, 2012
First Posted Date  ICMJE December 24, 2012
Results First Submitted Date  ICMJE November 12, 2019
Results First Posted Date  ICMJE December 3, 2019
Last Update Posted Date December 3, 2019
Actual Study Start Date  ICMJE August 19, 2014
Actual Primary Completion Date November 16, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 12, 2019)
Incident Rates of Definite Pulmonary Tuberculosis (TB) Disease, Not Associated With HIV-infection, Meeting the Case Definition 1 [ Time Frame: 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 ]
The incidence rate of definite pulmonary TB disease (or 100 Person-years rate) was calculated as the number of subjects reporting at least one case (n) in a group, over the sum of follow-up period expressed in years (T) in the same group, and multiplied by 100. Case definition 1 = subject with clinical suspicion of pulmonary TB disease*, with Mycobacterium tuberculosis (Mtb) complex identified from sputum specimen, taken before initiation of TB treatment, by Xpert MTB/RIF (Nucleic Acid Amplification Test to detect Mtb complex and resistance to rifampicin in sputum samples) and/or microbiological culture and confirmed Human Immunodeficiency Virus (HIV)-negative at the time of TB diagnosis. *Clinical suspicion of pulmonary TB defined as subject presenting with 1 or more of the following symptoms: unexplained cough > 2 weeks, unexplained fever > 1 week, night sweats, unintentional weight loss, pleuritic chest pains, haemoptysis, fatigue or shortness of breath on exertion.
Original Primary Outcome Measures  ICMJE
 (submitted: December 19, 2012)
Incident cases of definite pulmonary TB disease not associated with HIV-infection meeting the first case definition. [ Time Frame: Over a period starting 1 month post dose 2 (Month 2) and lasting up to 35 months post last vaccination (Month 36). ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: November 12, 2019)
  • Incident Rates of Definite Xpert MTB/Rif Positive Pulmonary TB Disease, Not Associated With HIV-infection, Meeting the Case Definition 2 [ Time Frame: 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 ]
    The incidence rate of definite Xpert MTB/Rif positive pulmonary TB disease, expressed in terms of 100 Person-years rate, was calculated as the number of subjects reporting at least one case (n) in a group over the sum of follow-up period expressed in years (T) in the same group, and multiplied by 100. Case definition 2 = 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. *Clinical suspicion of pulmonary TB was defined as a subject presenting with one or more of the following symptoms: unexplained cough > 2 weeks, unexplained fever > 1 week, night sweats, unintentional weight loss, pleuritic chest pains, haemoptysis, fatigue or shortness of breath on exertion.
  • Incident Rates of Definite Pulmonary TB Disease, Not Associated With HIV-infection Meeting the Case Definition 3 [ Time Frame: 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 ]
    The incidence rate of definite pulmonary TB disease (or 100 Person-years rate) was calculated as the number of subjects reporting at least one case (n) in a group, over the sum of follow-up period expressed in years (T) in the same group, and multiplied by 100. Case definition 3 = 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.*Clinical suspicion of pulmonary TB was defined as a subject presenting with one or more of the following symptoms: unexplained cough > 2 weeks, unexplained fever > 1 week, night sweats, unintentional weight loss, pleuritic chest pains, haemoptysis, fatigue or shortness of breath on exertion.
  • Incident Rates of Microbiological Pulmonary TB Disease, Meeting the Case Definition 4 [ Time Frame: 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 ]
    The incidence rate of Microbiological pulmonary TB disease (or 100 Person-years rate) was calculated as the number of subjects reporting at least one case (n) in a group, over the sum of follow-up period expressed in years (T) in the same group, and multiplied by 100. Case definition 4 = 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.*Clinical suspicion of pulmonary TB was defined as a subject presenting with one or more of the following symptoms: unexplained cough > 2 weeks, unexplained fever > 1 week, night sweats, unintentional weight loss, pleuritic chest pains, haemoptysis, fatigue or shortness of breath on exertion.
  • Incidence Rates of Clinical TB Disease, Meeting the Case Definition 5 [ Time Frame: 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 ]
    The incidence rate of Clinical TB disease (or 100 Person-years rate) was calculated as the number of subjects reporting at least one case (n) in a group, over the sum of follow-up period expressed in years (T) in the same group, and multiplied by 100. Case definition 5 = a subject for whom a clinician has diagnosed TB disease and has decided to treat the patient with TB treatment.
  • Number of Subjects With Serious Adverse Events (SAEs). [ Time Frame: From Day 0 up to Year 3 (during the entire study period) ]
    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 Any Unsolicited Adverse Events (AEs). [ Time Frame: During the 30-day follow-up period following vaccination, across doses (i.e. day of vaccination and 29 subsequent days after each vaccine dose) ]
    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 Any Solicited Local AEs in the Safety and Immune Sub-cohort [ Time Frame: During the 7-day follow-up period (i.e. day of vaccination and 6 subsequent days) after each vaccine dose ]
    Assessed solicited local symptoms were pain, redness and swelling. Any = occurrence of the symptom regardless of intensity grade. Any redness/swelling symptom was scored as injection site redness/swelling with a diameter equal or larger than (≥) 20 millimeters (mm).
  • Number of Subjects With Any Solicited General AEs in the Safety and Immune Sub-cohort [ Time Frame: During the 7-day follow-up period (i.e.: day of vaccination and 6 subsequent days) after each vaccine dose ]
    Assessed solicited general symptoms were fatigue, fever [defined as axillary temperature equal to or above 37.5 degrees Celsius (°C)], respiratory symptoms (including cough, blood in sputum, purulent sputum, shortness of breath or difficulties breathing, chest wall pain) headache, malaise and myalgia. Any = occurrence of the symptom regardless of intensity grade and relation to vaccination.
  • Number of Subjects With Any Potential Immune-mediated Diseases (pIMDs) [ Time Frame: From Day 0 to 6 months post-dose 2 (i.e. at Month 7) ]
    Potential immune-mediated diseases (pIMDs) are a subset of AEs that include autoimmune diseases and other inflammatory and/or neurologic disorders of interest which may or may not have an autoimmune aetiology.
  • 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 [ Time Frame: Days 0, 7, 30 and 37 ]
    Abnormal laboratory values include haematological abnormalities (haemoglobin level, white blood cells and platelets) and biochemical abnormalities (alanine aminotransferase, aspartate aminotransferase and creatinine). Grading was defined based on the Food and Drug Administration [FDA], 2007. Guidance for Industry, Toxicity Grading Scale for Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials. Alanine Aminotransferase = ALA; Aspartate Aminotransferase = ASP; Creatinine = CREA; Hemoglobin (Change from baseline) = HEM (baseline); Hemoglobin (decrease) = HEM (decrease); Leukocytes (White Blood Cells) (Decrease) = WBC (decrease); Leukocytes (White Blood Cells) (Increase) = WBC (increase); Platelets = PLA; Total Bilirubin = BIL.
  • Desciptive Statistics of the Frequency of M72-specific CD4+ T-cells Expressing Any Combination of Immune Markers in the Safety and Immune Sub-cohort [ Time Frame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3) ]
    The frequency of M72-specific CD4 + T-cells per million cells were identified after in vitro stimulation expressing any combination of immune markers ( Interleukin-2 (IL-2), cluster of differentiation 40-ligand (CD40-L), tumor necrosis factor alpha (TNF-) and interferon-gamma (IFN-) after background subtraction for each treatment group.
  • Desciptive Statistics of the Frequency of M72-specific CD8+ T-cells Expressing Any Combination of Immune Markers in the Safety and Immune Sub-cohort [ Time Frame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3) ]
    The frequency of M72-specific CD8 + T-cells per million cells were identified after in vitro stimulation expressing any combination of immune markers ( Interleukin-2 (IL-2), cluster of differentiation 40-ligand (CD40-L), tumor necrosis factor alpha (TNF-) and interferon-gamma (IFN-) after background subtraction for each treatment group.
  • M72-specific Antibody Concentrations as Measured by Enzyme Linked Immuno Sorbent Assay (ELISA) in the Safety and Immune Sub-cohort [ Time Frame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3) ]
    Mycobacterium tuberculosis M72-specific antibody geometric mean concentrations (GMCs) with exact 95% Confidence Interval (CI) were measured by Enzyme Linked Immuno Sorbent Assay (ELISA) and expressed in ELISA unit per milliliter (EU/mL). The cut-off of the assay was 2.8 EU/mL. The Geometric Mean Concentration (GMC) calculations were performed by taking the anti-log of the mean of the log10 concentration transformations. For descriptive statistics purposes only, antibody concentrations below the cut-off value of the assay was given an arbitrary value of half the cut-off value for the purpose of GMC calculation.
  • Number of Seropositive Subjects for M72 Antibodies Measured by ELISA in the Safety and Immune Sub-cohort [ Time Frame: Prior to dose 1 (Day 0) and post-dose 2 (Day 60, Year 1, Year 2 and Year 3) ]
    A seronegative subject was a subject whose antibody concentration was below 2.8 EU/mL, while a seropositive subject was a subject whose antibody concentration was greater than or equal to 2.8 EU/mL.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 19, 2012)
  • Incident cases of definite Xpert MTB/RIF pulmonary TB disease not associated with HIV-infection, meeting the second case definition. [ Time Frame: Over a period starting 1 month post dose 2 (Month 2) and lasting up to 35 months post last vaccination (Month 36). ]
  • Incident cases of definite pulmonary TB disease meeting the third case definition. [ Time Frame: Over a period starting 1 month post dose 2 (Month 2) and lasting up to 35 months post last vaccination (Month 36). ]
  • Incident cases of definite pulmonary TB disease meeting the fourth case definition. [ Time Frame: Over a period starting 1 month post dose 2 (Month 2) and lasting up to 35 months post last vaccination (Month 36). ]
  • Incident cases of clinical TB disease meeting the fifth case definition. [ Time Frame: Over a period starting 1 month post dose 2 (Month 2) and lasting up to 35 months post last vaccination (Month 36). ]
  • Occurrence of serious adverse events. [ Time Frame: During the entire study period (Day 0 to Month 36). ]
  • Occurrence of unsolicited adverse events. [ Time Frame: During the 30 day follow-up period following vaccination (day of vaccination and 29 subsequent days after each vaccine dose). ]
  • Occurrence of solicited local and general adverse events in the safety and immune sub-cohort. [ Time Frame: During the 7 day follow-up period following vaccination (day of vaccination and 6 subsequent days after each vaccine dose). ]
  • Occurrence of all potential immune-mediated diseases (pIMDs). [ Time Frame: Over a period starting at Day 0 until 6 months post dose 2 (Month 7). ]
  • Evaluation of Cell-mediated Immune (CMI) responses in the safety and immune sub-cohort in terms of frequency of M72-specific CD4+/CD8+ T cells expressing TNF-α and/or IFN-γ and/or IL-2 and/or CD40L per million cells identified after in vitro stimulation. [ Time Frame: Prior to dose 1 (Day 0), 1 month post dose 2 (Day 60) and Years 1, 2 and 3. ]
  • Evaluation of humoral responses with respect to components of the study vaccine, in the safety and immune sub-cohort in terms of M72-specific antibody titres and seropositivity rates as measured by ELISA. [ Time Frame: Prior to dose 1 (Day 0), 1 month post dose 2 (Day 60) and Years 1, 2 and 3. ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study to Evaluate the Efficacy of GlaxoSmithKline (GSK) Biologicals' Candidate Tuberculosis (TB) Vaccine in Adults
Official Title  ICMJE Efficacy of GSK Biologicals' Candidate Tuberculosis (TB) Vaccine GSK 692342 Against TB Disease, in Adults Living in a TB Endemic Region
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Prevention
Condition  ICMJE
  • Tuberculosis
  • Tuberculosis Vaccines
Intervention  ICMJE
  • Biological: GSK Biologicals' investigational TB vaccine (GSK692342)
    2 doses administered intramuscularly in the deltoid region of the arm.
  • Biological: Placebo
    2 doses administered intramuscularly in the deltoid region of the arm.
Study Arms  ICMJE
  • Experimental: M72AS01 Group
    Subjects, between, and including, 18 and 50 years of age, who received 2 doses of M72/AS01E according to random assignment, one month apart (Day 0 and Day 30) by intramuscular injection in the deltoid region of the arm.
    Intervention: Biological: GSK Biologicals' investigational TB vaccine (GSK692342)
  • Placebo Comparator: Control group
    Subjects, between, and including,18 and 50 years of age, who received 2 doses of Placebo according to random assignment, one month apart (Day 0 and Day 30) by intramuscular injection in the deltoid region of the arm.
    Intervention: Biological: Placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: November 12, 2019)
3575
Original Estimated Enrollment  ICMJE
 (submitted: December 19, 2012)
7000
Actual Study Completion Date  ICMJE November 16, 2018
Actual Primary Completion Date November 16, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 50 Years   (Adult)
Accepts Healthy Volunteers  ICMJE Yes
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Kenya,   South Africa,   Zambia
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT01755598
Other Study ID Numbers  ICMJE 115616
Has Data Monitoring Committee Not Provided
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: Yes
Plan Description: IPD is available via the Clinical Study Data Request site (click on the link provided below)
Supporting Materials: Study Protocol
Supporting Materials: Statistical Analysis Plan (SAP)
Supporting Materials: Informed Consent Form (ICF)
Supporting Materials: Clinical Study Report (CSR)
Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.
URL: https://clinicalstudydatarequest.com/Posting.aspx?ID=20104
Responsible Party GlaxoSmithKline
Study Sponsor  ICMJE GlaxoSmithKline
Collaborators  ICMJE Aeras
Investigators  ICMJE
Study Director: GSK Clinical Trials GlaxoSmithKline (for GlaxoSmithKline; Human Genome Sciences Inc., a GSK Company; Sirtris, a GSK Company; Stiefel, a GSK Company; ViiV Healthcare)
PRS Account GlaxoSmithKline
Verification Date November 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP