Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register allows you to search for protocol and results information on:
  • interventional clinical trials that are conducted in the European Union (EU) and the European Economic Area (EEA);
  • clinical trials conducted outside the EU / EEA that are linked to European paediatric-medicine development.
  • Learn   more about the EU Clinical Trials Register   including the source of the information and the legal basis.


    The EU Clinical Trials Register currently displays   37733   clinical trials with a EudraCT protocol, of which   6184   are clinical trials conducted with subjects less than 18 years old.
    The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    Clinical Trial Results:
    A phase IV, single-blind, randomized, multicenter study to assess the immunogenicity and safety of GSK Biologicals’ dTpa vaccine (Boostrix™) using a new syringe presentation in healthy adolescents aged 10–15 years.

    Summary
    EudraCT number
    2013-003768-30
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    03 Sep 2012

    Results information
    Results version number
    v2(current)
    This version publication date
    24 Jul 2016
    First version publication date
    13 May 2015
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Data (typos and numbers) were corrected.

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    114778
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01362322
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    GlaxoSmithKline Biologicals
    Sponsor organisation address
    Rue de l’Institut 89, Rixensart, Belgium,
    Public contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Scientific contact
    Clinical Trials Call Center, GlaxoSmithKline Biologicals, 44 2089904466, GSKClinicalSupportHD@gsk.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Jan 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    03 Sep 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    03 Sep 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate that Boostrix™ administered using the new syringe presentation is non-inferior to Boostrix™ administered using the previous syringe presentation, in terms of immune response to all vaccine antigens, one month after booster vaccination.
    Protection of trial subjects
    All subjects were supervised after vaccination/product administration with appropriate medical treatment readily available. Vaccines were administered by qualified and trained personnel. Vaccines were administered only to eligible subjects that had no contraindications to any components of the vaccines.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    05 Jul 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Chile: 295
    Country: Number of subjects enrolled
    Mexico: 376
    Worldwide total number of subjects
    671
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    671
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    During the screening the following steps occurred: check for inclusion/exclusion criteria, contraindications/precautions, medical history of the subjects and signing informed consent forms.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Single blind
    Roles blinded
    Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Boostrix-New Group
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Boostrix™
    Investigational medicinal product code
    Other name
    dTpa
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of vaccine, in a new syringe presentation, was administered in the deltoid of the non-dominant arm, at Day 0.

    Arm title
    Boostrix-Prev Group
    Arm description
    -
    Arm type
    Active comparator

    Investigational medicinal product name
    Boostrix™
    Investigational medicinal product code
    Other name
    dTpa
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose of vaccine, in a previous syringe presentation, was administered in the deltoid of the non-dominant arm, at Day 0.

    Number of subjects in period 1
    Boostrix-New Group Boostrix-Prev Group
    Started
    335
    336
    Completed
    330
    329
    Not completed
    5
    7
         Consent withdrawn by subject
    3
    1
         Lost to follow-up
    2
    6

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    Boostrix-New Group
    Reporting group description
    -

    Reporting group title
    Boostrix-Prev Group
    Reporting group description
    -

    Reporting group values
    Boostrix-New Group Boostrix-Prev Group Total
    Number of subjects
    335 336 671
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    11.9 ± 1.59 11.9 ± 1.61 -
    Gender categorical
    Units: Subjects
        Female
    179 178 357
        Male
    156 158 314

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    Boostrix-New Group
    Reporting group description
    -

    Reporting group title
    Boostrix-Prev Group
    Reporting group description
    -

    Primary: Anti-D and Anti-T antibody concentrations

    Close Top of page
    End point title
    Anti-D and Anti-T antibody concentrations
    End point description
    End point type
    Primary
    End point timeframe
    Before (PRE) and one month after (POST) booster vaccination
    End point values
    Boostrix-New Group Boostrix-Prev Group
    Number of subjects analysed
    321
    319
    Units: IU/mL
    geometric mean (confidence interval 95%)
        Anti-D PRE
    0.472 (0.403 to 0.553)
    0.456 (0.392 to 0.53)
        Anti-D POST
    6.784 (6.178 to 7.45)
    6.493 (5.915 to 7.128)
        Anti-T PRE
    0.956 (0.835 to 1.095)
    0.899 (0.789 to 1.026)
        Anti-T POST
    18.937 (17.313 to 20.713)
    18.515 (16.851 to 20.342)
    Statistical analysis title
    Adjusted ratios of GMCs for anti-D
    Statistical analysis description
    To demonstrate that the Boostrix™ vaccine administered using the new-syringe presentation was non-inferior to Boostrix™ vaccine administered using the previous-syringe, in terms of immune response to all vaccine antigens, one month after booster vaccination.
    Comparison groups
    Boostrix-New Group v Boostrix-Prev Group
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    Method
    ANCOVA
    Parameter type
    Adjusted Ratio
    Point estimate
    0.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.09
    Notes
    [1] - The upper limit (UL) of the 95% confidence interval (CI) on the geometric mean concentration (GMC) ratios [Boostrix-Prev Group over Boostrix-New Group] for anti-diphtheria (anti-D)antibodies was ≤ 1.5 (clinical limit for non-inferiority).
    Statistical analysis title
    Adjusted ratios of GMCs for anti-T
    Statistical analysis description
    To demonstrate that the Boostrix™ vaccine administered using the new-syringe presentation was non-inferior to Boostrix™ vaccine administered using the previous-syringe, in terms of immune response to all vaccine antigens, one month after booster vaccination.
    Comparison groups
    Boostrix-New Group v Boostrix-Prev Group
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    Method
    ANCOVA
    Parameter type
    Adjusted Ratio
    Point estimate
    0.97
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.86
         upper limit
    1.1
    Notes
    [2] - The upper limit (UL) of the 95% confidence interval (CI) on the geometric mean concentration (GMC) ratios [Boostrix-Prev Group over Boostrix-New Group] for anti-tetanus (anti-T) antibodies was ≤ 1.5 (clinical limit for non-inferiority).

    Primary: Anti-PT, Anti-FHA, Anti-PRN antibody concentrations

    Close Top of page
    End point title
    Anti-PT, Anti-FHA, Anti-PRN antibody concentrations
    End point description
    End point type
    Primary
    End point timeframe
    Before (PRE) and one month after (POST) booster vaccination
    End point values
    Boostrix-New Group Boostrix-Prev Group
    Number of subjects analysed
    321
    319
    Units: EU/mL
    geometric mean (confidence interval 95%)
        Anti-PT PRE [N=320;319]
    7.5 (6.6 to 8.7)
    7.2 (6.3 to 8.2)
        Anti-PT POST [N=318;318]
    140.2 (126 to 156.1)
    125.9 (112.7 to 140.7)
        Anti-FHA PRE [N=316;315]
    48.9 (43.3 to 55.2)
    49.4 (43.6 to 56)
        Anti-FHA POST [N=319;319]
    1080.2 (995.2 to 1172.5)
    1013.7 (940 to 1093.2)
        Anti-PRN PRE [N=321;319]
    14 (12.3 to 15.9)
    13.4 (11.9 to 15)
        Anti-PRN POST [N=321;318]
    652.4 (572.1 to 743.9)
    619.2 (546 to 702.2)
    Statistical analysis title
    Adjusted ratios of GMCs for anti-PT
    Statistical analysis description
    To demonstrate that the Boostrix™ vaccine administered using the new-syringe presentation was non-inferior to Boostrix™ vaccine administered using the previous-syringe, in terms of immune response to all vaccine antigens, one month after booster vaccination.
    Comparison groups
    Boostrix-New Group v Boostrix-Prev Group
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [3]
    Method
    ANCOVA
    Parameter type
    Adjusted Ratio
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.82
         upper limit
    1.04
    Notes
    [3] - The upper limit (UL) of the 95% confidence interval (CI) on the geometric mean concentration (GMC) ratios [Boostrix-Prev Group over Boostrix-New Group] for anti-pertussis toxoid (anti-PT) antibodies was ≤ 1.5 (clinical limit for non-inferiority).
    Statistical analysis title
    Adjusted ratios of GMCs for anti-FHA
    Statistical analysis description
    To demonstrate that the Boostrix™ vaccine administered using the new-syringe presentation was non-inferior to Boostrix™ vaccine administered using the previous-syringe, in terms of immune response to all vaccine antigens, one month after booster vaccination.
    Comparison groups
    Boostrix-New Group v Boostrix-Prev Group
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [4]
    Method
    ANCOVA
    Parameter type
    Adjusted Ratio
    Point estimate
    0.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.83
         upper limit
    1.03
    Notes
    [4] - The upper limit (UL) of the 95% confidence interval (CI) on the geometric mean concentration (GMC) ratios [Boostrix-Prev Group over Boostrix-New Group] for anti-filamentous haemagglutinin (anti-FHA) antibodies was ≤ 1.5 (clinical limit for non-inferiority).
    Statistical analysis title
    Adjusted ratios of GMCs for anti-PRN
    Statistical analysis description
    To demonstrate that the Boostrix™ vaccine administered using the new-syringe presentation was non-inferior to Boostrix™ vaccine administered using the previous-syringe, in terms of immune response to all vaccine antigens, one month after booster vaccination.
    Comparison groups
    Boostrix-New Group v Boostrix-Prev Group
    Number of subjects included in analysis
    640
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [5]
    Method
    ANCOVA
    Parameter type
    Adjusted Ratio
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.85
         upper limit
    1.13
    Notes
    [5] - The upper limit (UL) of the 95% confidence interval (CI) on the geometric mean concentration (GMC) ratios [Boostrix-Prev Group over Boostrix-New Group] for anti-pertactin (anti-PRN) antibodies was ≤ 1.5 (clinical limit for non-inferiority).

    Secondary: Number of seropositive subjects against Diphtheria and Tetanus with antibody concentrations (anti-D, anti-T) above or equal to (≥)0.1 IU/mL

    Close Top of page
    End point title
    Number of seropositive subjects against Diphtheria and Tetanus with antibody concentrations (anti-D, anti-T) above or equal to (≥)0.1 IU/mL
    End point description
    A seroprotected subject was defined as a subject whose antibody concentration was greater than or equal to (≥) 0.1. international units per milliliter (IU/mL), as assessed by the Enzyme Linked Immunosorbent Assay (ELISA). The POST results are the primary outcome variables.
    End point type
    Secondary
    End point timeframe
    Before (PRE) and one month after (POST) booster vaccination
    End point values
    Boostrix-New Group Boostrix-Prev Group
    Number of subjects analysed
    321
    319
    Units: subjects
        Anti-D PRE
    284
    286
        Anti-D POST
    320
    319
        Anti-T PRE
    311
    314
        Anti-T POST
    321
    319
    No statistical analyses for this end point

    Secondary: Number of seroprotected subjects against Diphtheria and Tetanus with antibody concentrations (anti-D, anti-T) above ≥1 IU/mL

    Close Top of page
    End point title
    Number of seroprotected subjects against Diphtheria and Tetanus with antibody concentrations (anti-D, anti-T) above ≥1 IU/mL
    End point description
    End point type
    Secondary
    End point timeframe
    Before (PRE) and one month after (POST) booster vaccination
    End point values
    Boostrix-New Group Boostrix-Prev Group
    Number of subjects analysed
    321
    319
    Units: subjects
        Anti-D PRE
    83
    89
        Anti-D POST
    315
    310
        Anti-T PRE
    151
    143
        Anti-T POST
    321
    319
    No statistical analyses for this end point

    Secondary: Number of subjects with anti-pertussis toxoid (anti-PT), anti-filamentous haemagglutin (anti-FHA) and anti pertactin (anti-PRN) antibody concentrations ≥5 ELISA units per milliliter (EU/mL)

    Close Top of page
    End point title
    Number of subjects with anti-pertussis toxoid (anti-PT), anti-filamentous haemagglutin (anti-FHA) and anti pertactin (anti-PRN) antibody concentrations ≥5 ELISA units per milliliter (EU/mL)
    End point description
    End point type
    Secondary
    End point timeframe
    Before (PRE) and one month after (POST) booster vaccination
    End point values
    Boostrix-New Group Boostrix-Prev Group
    Number of subjects analysed
    321
    319
    Units: subjects
        Anti-PT PRE [N=320;319]
    175
    175
        Anti-PT POST [N=318;318]
    316
    315
        Anti-FHA PRE [N=316;315]
    310
    310
        Anti-FHA POST [N=319;319]
    319
    319
        Anti-PRN PRE [N=321;319]
    269
    272
        Anti-PRN POST [N=321;318]
    321
    318
    No statistical analyses for this end point

    Secondary: Number of subjects with booster response to diphtheria and tetanus antibodies

    Close Top of page
    End point title
    Number of subjects with booster response to diphtheria and tetanus antibodies
    End point description
    End point type
    Secondary
    End point timeframe
    One month after booster vaccination
    End point values
    Boostrix-New Group Boostrix-Prev Group
    Number of subjects analysed
    321
    319
    Units: subjects
        Anti-D
    257
    252
        Anti-T
    266
    270
    No statistical analyses for this end point

    Secondary: Number of subjects with a booster response to PT, FHA and PRN antibodies.

    Close Top of page
    End point title
    Number of subjects with a booster response to PT, FHA and PRN antibodies.
    End point description
    End point type
    Secondary
    End point timeframe
    One month after booster vaccination
    End point values
    Boostrix-New Group Boostrix-Prev Group
    Number of subjects analysed
    321
    318
    Units: subjects
        Anti-PT [N=317;318]
    298
    295
        Anti-FHA [N=314;315]
    305
    304
        Anti-PRN [N=321;318]
    315
    317
    No statistical analyses for this end point

    Secondary: Number of subjects with any solicited local symptoms

    Close Top of page
    End point title
    Number of subjects with any solicited local symptoms
    End point description
    End point type
    Secondary
    End point timeframe
    Within 4 days (Days 0-3) post vaccination period
    End point values
    Boostrix-New Group Boostrix-Prev Group
    Number of subjects analysed
    330
    329
    Units: subjects
        Any Pain
    237
    248
        Any Redness
    113
    94
        Any Swelling
    98
    90
    No statistical analyses for this end point

    Secondary: Number of subjects with any solicited general symptoms

    Close Top of page
    End point title
    Number of subjects with any solicited general symptoms
    End point description
    End point type
    Secondary
    End point timeframe
    Within 4 days (Days 0-3) post vaccination period
    End point values
    Boostrix-New Group Boostrix-Prev Group
    Number of subjects analysed
    330
    329
    Units: subjects
        Any Fatigue
    83
    86
        Any Gastrointestinal symptoms
    32
    42
        Any Headache
    88
    108
        Any Temperature
    9
    6
    No statistical analyses for this end point

    Secondary: Number of subjects with unsolicited adverse events (AEs)

    Close Top of page
    End point title
    Number of subjects with unsolicited adverse events (AEs)
    End point description
    End point type
    Secondary
    End point timeframe
    Within 31 days (Days 0-30) post vaccination period
    End point values
    Boostrix-New Group Boostrix-Prev Group
    Number of subjects analysed
    335
    336
    Units: subjects
        Any unsolicited AEs
    44
    45
    No statistical analyses for this end point

    Secondary: Number of subjects with serious adverse events (SAEs)

    Close Top of page
    End point title
    Number of subjects with serious adverse events (SAEs)
    End point description
    End point type
    Secondary
    End point timeframe
    During the entire study period
    End point values
    Boostrix-New Group Boostrix-Prev Group
    Number of subjects analysed
    335
    336
    Units: subjects
        Any SAEs
    1
    0
    No statistical analyses for this end point

    Adverse events

    Close Top of page
    Adverse events information
    Timeframe for reporting adverse events
    Solicited symptoms during the 4-day post-vaccination period, Unsolicited AEs during the 31-day post-vaccination period, SAEs during the entire period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Boostrix-New Group
    Reporting group description
    -

    Reporting group title
    Boostrix-Prev Group
    Reporting group description
    -

    Serious adverse events
    Boostrix-New Group Boostrix-Prev Group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 336 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Injury
    alternative assessment type: Non-systematic
         subjects affected / exposed
    1 / 335 (0.30%)
    0 / 336 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Boostrix-New Group Boostrix-Prev Group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    237 / 335 (70.75%)
    248 / 336 (73.81%)
    General disorders and administration site conditions
    Pain
         subjects affected / exposed [1]
    237 / 330 (71.82%)
    248 / 329 (75.38%)
         occurrences all number
    237
    248
    Redness
         subjects affected / exposed [2]
    113 / 330 (34.24%)
    98 / 329 (29.79%)
         occurrences all number
    94
    90
    Swelling
         subjects affected / exposed [3]
    98 / 330 (29.70%)
    90 / 329 (27.36%)
         occurrences all number
    98
    90
    Fatigue
         subjects affected / exposed [4]
    83 / 330 (25.15%)
    86 / 329 (26.14%)
         occurrences all number
    83
    86
    Gastrointestinal symptoms
         subjects affected / exposed [5]
    32 / 330 (9.70%)
    42 / 329 (12.77%)
         occurrences all number
    32
    42
    Headache
         subjects affected / exposed [6]
    88 / 330 (26.67%)
    108 / 329 (32.83%)
         occurrences all number
    88
    108
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Solicited local and general symptoms were reported only for subjects with a symptom sheet completed.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Solicited local and general symptoms were reported only for subjects with a symptom sheet completed.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Solicited local and general symptoms were reported only for subjects with a symptom sheet completed.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Solicited local and general symptoms were reported only for subjects with a symptom sheet completed.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Solicited local and general symptoms were reported only for subjects with a symptom sheet completed.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Solicited local and general symptoms were reported only for subjects with a symptom sheet completed.

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 May 2012
    At the European Medicines Agency’s (EMA) request, GSK Biologicals has updated its procedure for emergency unblinding during the conduct of a clinical study. According to the revised procedure, the responsibility and the decision to break the treatment code in emergency situations resides solely with the investigator and consequently, the investigator will have full authority to break the treatment code. The Emergency unblinding is not applicable for open and single blind studies anymore. Therefore the section has been deleted.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
    EU Clinical Trials Register Service Desk: https://servicedesk.ema.europa.eu
    European Medicines Agency © 1995-2020 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    Legal notice
    EMA HMA