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    Clinical Trial Results:
    Effects of MagneB6® (470.0 mg Magnesium Lactate Dihydrate + 5.0 mg Pyridoxine Hydrochloride, Coated Tablet) Supplementation (8 Weeks) on Stress Levels of Chronically Stressed Subjects, with Suboptimal Serum Magnesium Levels- A Randomized, Single-blind Active Comparator, Multicentric Clinical Trial - Comparison with Magnespasmyl® (465.4 mg Magnesium Lactate Dihydrate, Coated Tablet)

    Summary
    EudraCT number
    		 2015-003749-24
    Trial protocol
    		 FR  
    Global end of trial date
    04 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 Apr 2018
    First version publication date
    19 Apr 2018
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MGLACC07810
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Study Name: MB6 SUPERIORITY
    Sponsors
    Sponsor organisation name
    Sanofi-Aventis Group
    Sponsor organisation address
    54 Rue La Boétie, Paris, France, 75008
    Public contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.com
    Scientific contact
    Trial Transparency Team, Sanofi aventis recherche & développement, Contact-US@sanofi.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?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    30 Jun 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superiority of Magne B6® (Magnesium [Mg] + vitamin B6) versus Magnespasmyl® (Mg only) supplementation on stress level, evaluated by the stress subscale from the Depression Anxiety Stress Scale (DASS)-42 test, in chronically stressed subjects, with suboptimal serum Mg levels.
    Protection of trial subjects
    Subjects were fully informed of all pertinent aspects of the clinical trial as well as the possibility to discontinue at any time in language and terms appropriate for the subject and considering the local culture. During the course of the trial, subjects were provided with individual subject cards indicating the nature of the trial the subject is participating, contact details and any information needed in the event of a medical emergency. Collected personal data and human biological samples were processed in compliance with the Sanofi-Aventis Group Personal Data Protection Charter ensuring that the Group abides by the laws governing personal data protection in force in all countries in which it operates.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    04 May 2016
    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
    France: 264
    Worldwide total number of subjects
    264
    EEA total number of subjects
    264
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    264
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was conducted at 4 centres in France. A total of 854 subjects were screened between 04 May 2016 and 25 January 2017 of whom 586 were screen failures. Screen failures were mainly due to exclusion criteria met.

    Pre-assignment
    Screening details
    		 A total of 268 subjects were randomized in the study. Of which, 264 subjects were treated in 1:1 ratio to the MagneB6® and Magnespasmyl® arms. The randomization was stratified by sex on a 1:1 ratio.

    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
    		 Investigator [1]

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 MagneB6®
    Arm description
    		 Subjects received two tablets of MagneB6® (470.0 mg Mg lactate dihydrate + 5.0 mg pyridoxime hydrochloride) three times per day during the 8 week treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    MagneB6®
    Investigational medicinal product code
    Z0889
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 6 coated tablets of MagneB6® per day, divided in three intakes, at meal time (2 tablets to be swallowed during each meal: breakfast, lunch, dinner).

    Arm title
    		 Magnespasmyl®
    Arm description
    		 Subjects received two tablets of Magnespasmyl® 47.4 mg three times per day during the 8 week treatment period.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Magnespasmyl®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received 6 coated tablets of Magnespasmyl® (465.4 mg Mg lactate dihydrate) per day, divided in three intakes, at meal time (2 tablets to be swallowed during each meal: breakfast, lunch, dinner).

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Only investigator was blinded in this trial.
    Number of subjects in period 1
    		MagneB6® Magnespasmyl®
    Started
    132
    132
    Completed
    130
    130
    Not completed
    2
    2
         Consent withdrawn by subject
    2
    1
         Adverse event
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MagneB6®
    Reporting group description
    		 Subjects received two tablets of MagneB6® (470.0 mg Mg lactate dihydrate + 5.0 mg pyridoxime hydrochloride) three times per day during the 8 week treatment period.

    Reporting group title
    Magnespasmyl®
    Reporting group description
    		 Subjects received two tablets of Magnespasmyl® 47.4 mg three times per day during the 8 week treatment period.

    Reporting group values
    		 MagneB6® Magnespasmyl® Total
    Number of subjects
    		 132 132 264
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 31.2 ± 8.4 32.1 ± 8.6 -
    Gender categorical
    Units: Subjects
        Female
    		 98 97 195
        Male
    		 34 35 69

    End points

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    End points reporting groups
    Reporting group title
    MagneB6®
    Reporting group description
    		 Subjects received two tablets of MagneB6® (470.0 mg Mg lactate dihydrate + 5.0 mg pyridoxime hydrochloride) three times per day during the 8 week treatment period.

    Reporting group title
    Magnespasmyl®
    Reporting group description
    		 Subjects received two tablets of Magnespasmyl® 47.4 mg three times per day during the 8 week treatment period.

    Primary: Change From Baseline in DASS-42 Stress Subscale at Week 8: Modified Intent to Treat (mITT) Population

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    End point title
    		 Change From Baseline in DASS-42 Stress Subscale at Week 8: Modified Intent to Treat (mITT) Population
    End point description
    DASS-42 is a 42-item questionnaire consisting of 3 sub-scales (depression, anxiety and stress) to measure the negative emotional states of depression, anxiety and stress. Each sub-scale contains 14 items. The stress sub-scale items were scored on a 4-point rating scale: 0 (Did not apply to me at all) to 3 (Applies to me most of the time). The sub-scale score ranges from 0 to 42, where cut-off score from 0-14= normal, 15-18= mild, 19-25= moderate, 26-33= severe and 34-42= extremely severe stress level. Analysis was performed on mITT population which included all subjects randomized in the study with at least one consumption of study product (MagneB6® or Magnespasmyl®) and an evaluable DASS-42 stress score at baseline and at least one during the treatment period.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    132
    132
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    -12.44 (-13.83 to -11.05)
    -11.72 (-13.10 to -10.33)
    Statistical analysis title
    		 MagneB6® vs. Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from analysis of covariance (ANCOVA), adjusted on sex and interaction between visit and DASS-42 stress at Day 1 (Baseline). Missing data was imputed by last observation carried forward (LOCF) method.
    Comparison groups
    MagneB6® v Magnespasmyl®
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4472
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.72
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.15
         upper limit
    		 2.59

    Primary: Change From Baseline in DASS-42 Stress Subscale at Week 8: Strict Per Protocol Set (SPPS) Population

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    End point title
    		 Change From Baseline in DASS-42 Stress Subscale at Week 8: Strict Per Protocol Set (SPPS) Population
    End point description
    DASS-42 is a 42-item questionnaire consisting of 3 sub-scales (depression, anxiety and stress) to measure the negative emotional states of depression, anxiety and stress. Each sub-scale contains 14 items. The stress sub-scale items were scored on a 4-point rating scale: 0 (Did not apply to me at all) to 3 (Applies to me most of the time). The sub-scale score ranges from 0 to 42, where cut-off score from 0-14= normal, 15-18= mild, 19-25= moderate, 26-33= severe and 34-42= extremely severe stress level. Analysis was performed on SPPS population which included all subjects of the mITT without any major protocol deviation, analysed in the group to which they were allocated by randomization with a DASS-42 scale for chronic stress at Day 1 (baseline) >18.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    117
    116
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    -13.26 (-14.81 to -11.71)
    -12.21 (-13.73 to -10.68)
    Statistical analysis title
    		 MagneB6® vs. Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from ANCOVA, adjusted on sex and interaction between visit and DASS-42 stress at Day 1 (Baseline). Missing data was imputed by LOCF method.
    Comparison groups
    Magnespasmyl® v MagneB6®
    Number of subjects included in analysis
    233
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3095
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    1.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.99
         upper limit
    		 3.1

    Primary: Change From Baseline in DASS-42 Stress Subscale (for Subjects with Normal to Moderate DASS-42 Stress Scale) at Week 8 - mITT Population

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    End point title
    		 Change From Baseline in DASS-42 Stress Subscale (for Subjects with Normal to Moderate DASS-42 Stress Scale) at Week 8 - mITT Population
    End point description
    DASS-42 is a 42-item questionnaire consisting of 3 sub-scales (depression, anxiety and stress) to measure the negative emotional states of depression, anxiety and stress. Each sub-scale contains 14 items. The stress sub-scale items were scored on a 4-point rating scale: 0 (Did not apply to me at all) to 3 (Applies to me most of the time). The sub-scale score ranges from 0 to 42, where cut-off score from 0-14= normal, 15-18= mild, 19-25= moderate, 26-33= severe and 34-42= extremely severe stress level. Analysis was performed on mITT population. Number of subjects analysed=subjects with available data for this end point.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    41
    35
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    -8.20 (-10.01 to -6.40)
    -10.56 (-12.48 to -8.65)
    Statistical analysis title
    		 MagneB6® vs. Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from ANCOVA, adjusted on sex. Missing data were imputed by LOCF method.
    Comparison groups
    MagneB6® v Magnespasmyl®
    Number of subjects included in analysis
    76
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0784
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    -2.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.99
         upper limit
    		 0.27

    Primary: Change From Baseline in DASS-42 Stress Subscale (for Subjects with Normal to Moderate DASS-42 Stress Scale) at Week 8 - SPPS Population

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    End point title
    		 Change From Baseline in DASS-42 Stress Subscale (for Subjects with Normal to Moderate DASS-42 Stress Scale) at Week 8 - SPPS Population
    End point description
    DASS-42 is a 42-item questionnaire consisting of 3 sub-scales (depression, anxiety and stress) to measure the negative emotional states of depression, anxiety and stress. Each sub-scale contains 14 items. The stress sub-scale items were scored on a 4-point rating scale: 0 (Did not apply to me at all) to 3 (Applies to me most of the time). The sub-scale score ranges from 0 to 42, where cut-off score from 0-14= normal, 15-18= mild, 19-25= moderate, 26-33= severe and 34-42= extremely severe stress level. Analysis was performed on SPPS population. Number of subjects analysed=subjects with available data for this end point.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    41
    32
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    -9.73 (-11.82 to -7.65)
    -11.69 (-14.05 to -9.33)
    Statistical analysis title
    		 MagneB6® vs. Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from ANCOVA, adjusted on sex. Missing data were imputed by LOCF method.
    Comparison groups
    MagneB6® v Magnespasmyl®
    Number of subjects included in analysis
    73
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2199
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    -1.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.11
         upper limit
    		 1.2

    Primary: Change From Baseline in DASS-42 Stress Subscale (for Subjects with Severe or Extremely Severe DASS-42 Stress Scale) at Week 8 - mITT Population

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    End point title
    		 Change From Baseline in DASS-42 Stress Subscale (for Subjects with Severe or Extremely Severe DASS-42 Stress Scale) at Week 8 - mITT Population
    End point description
    DASS-42 is a 42-item questionnaire consisting of 3 sub-scales (depression, anxiety and stress) to measure the negative emotional states of depression, anxiety and stress. Each sub-scale contains 14 items. The stress sub-scale items were scored on a 4-point rating scale: 0 (Did not apply to me at all) to 3 (Applies to me most of the time). The sub-scale score ranges from 0 to 42, where cut-off score from 0-14= normal, 15-18= mild, 19-25= moderate, 26-33= severe and 34-42= extremely severe stress level. Analysis was performed on mITT population. Number of subjects analysed=subjects with available data for this end point.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    78
    84
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    -16.36 (-18.27 to -14.44)
    -13.20 (-15.05 to -11.36)
    Statistical analysis title
    		 MagneB6® vs. Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from ANCOVA, adjusted on sex. Missing data were imputed by LOCF method.
    Comparison groups
    MagneB6® v Magnespasmyl®
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0203
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    3.16
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.5
         upper limit
    		 5.82

    Primary: Change From Baseline in DASS-42 Stress Subscale (for Subjects with Severe or Extremely Severe DASS-42 Stress Scale) at Week 8 - SPPS Population

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    End point title
    		 Change From Baseline in DASS-42 Stress Subscale (for Subjects with Severe or Extremely Severe DASS-42 Stress Scale) at Week 8 - SPPS Population
    End point description
    DASS-42 is a 42-item questionnaire consisting of 3 sub-scales (depression, anxiety and stress) to measure the negative emotional states of depression, anxiety and stress. Each sub-scale contains 14 items. The stress sub-scale items were scored on a 4-point rating scale: 0 (Did not apply to me at all) to 3 (Applies to me most of the time). The sub-scale score ranges from 0 to 42, where cut-off score from 0-14= normal, 15-18= mild, 19-25= moderate, 26-33= severe and 34-42= extremely severe stress level. Analysis was performed on SPPS population. Number of subjects analysed=subjects with available data for this end point.
    End point type
    Primary
    End point timeframe
    Baseline, Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    76
    84
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    -16.09 (-18.02 to -14.16)
    -13.20 (-15.04 to -11.36)
    Statistical analysis title
    		 MagneB6® vs. Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from ANCOVA, adjusted on sex. Missing data were imputed by LOCF method.
    Comparison groups
    MagneB6® v Magnespasmyl®
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0339
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    2.89
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.22
         upper limit
    		 5.56

    Secondary: Change From Baseline in DASS-42 Stress Subscale at Week 4

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    End point title
    		 Change From Baseline in DASS-42 Stress Subscale at Week 4
    End point description
    DASS-42 is a 42-item questionnaire consisting of 3 sub-scales (depression, anxiety and stress) to measure the negative emotional states of depression, anxiety and stress. Each sub-scale contains 14 items. The stress sub-scale items were scored on a 4-point rating scale: 0 (Did not apply to me at all) to 3 (Applies to me most of the time). The sub-scale score ranges from 0 to 42, where cut-off score from 0-14= normal, 15-18= mild, 19-25= moderate, 26-33= severe and 34-42= extremely severe stress level. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    132
    132
    Units: units on a scale
        arithmetic mean (confidence interval 95%)
    -8.94 (-10.22 to -7.65)
    -7.58 (-8.86 to -6.30)
    Statistical analysis title
    		 MagneB6® vs. Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from analysis of covariance (ANCOVA), adjusted on sex. Missing data were imputed by LOCF method.
    Comparison groups
    MagneB6® v Magnespasmyl®
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.1203
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.36
         upper limit
    		 3.06

    Secondary: Change From Baseline in Anxiety Subscore at Week 4 and 8

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    End point title
    		 Change From Baseline in Anxiety Subscore at Week 4 and 8
    End point description
    DASS-42 is a 42-item questionnaire consisting of 3 sub-scales (depression, anxiety and stress) to measure the negative emotional states of depression, anxiety and stress. Each sub-scale contains 14 items. The anxiety sub-scale items were scored on a 4-point rating scale: 0 (Did not apply to me at all) to 3 (Applies to me most of the time). The sub-scale score ranges from 0 to 42, where cut-off score from 0-7= normal, 8-9= mild, 10-14= moderate, 15-19= severe and 20-42= extremely severe anxiety level. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    132
    132
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Change at Week 4
    -5.30 (-6.29 to -4.31)
    -5.66 (-6.65 to -4.68)
        Change at Week 8
    -7.98 (-8.95 to -7.01)
    -8.60 (-9.57 to -7.63)
    Statistical analysis title
    		 Change at Week 4: MagneB6® vs. Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from ANCOVA, adjusted on sex and interaction between visit and DASS-42 anxiety at D1. Missing data were imputed by LOCF method.
    Comparison groups
    MagneB6® v Magnespasmyl®
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    -0.37
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.69
         upper limit
    		 0.95
    Statistical analysis title
    		 Change at Week 8: MagneB6® v Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from ANCOVA, adjusted on sex and interaction between visit and DASS-42 anxiety at D1. Missing data were imputed by LOCF method.
    Comparison groups
    MagneB6® v Magnespasmyl®
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    -0.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.91
         upper limit
    		 0.68

    Secondary: Change From Baseline in Depression Subscore at Week 4 and 8

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    End point title
    		 Change From Baseline in Depression Subscore at Week 4 and 8
    End point description
    DASS-42 is a 42-item questionnaire consisting of 3 sub-scales (depression, anxiety and stress) to measure the negative emotional states of depression, anxiety and stress. Each sub-scale contains 14 items. The depression sub-scale items were scored on a 4-point rating scale: 0 (Did not apply to me at all) to 3 (Applies to me most of the time). The sub-scale score ranges from 0 to 42, where cut-off score from 0-9= normal, 10-13= mild, 14-20= moderate, 21-27= severe and 28-42= extremely severe depression. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    132
    132
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Change at Week 4
    -5.42 (-6.47 to -4.37)
    -5.01 (-6.05 to -3.96)
        Change at Week 8
    -7.71 (-8.85 to -6.57)
    -7.69 (-8.83 to -6.55)
    Statistical analysis title
    		 Change at Week 4: MagneB6® vs. Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from ANCOVA, adjusted on sex and interaction between visit and DASS-42 depression at Day 1 (Baseline). Missing data were imputed by LOCF method.
    Comparison groups
    Magnespasmyl® v MagneB6®
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.42
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.98
         upper limit
    		 1.81
    Statistical analysis title
    		 Change at Week 8: MagneB6® vs. Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from ANCOVA, adjusted on sex and interaction between visit and DASS-42 depression at Day 1 (Baseline). Missing data were imputed by LOCF method.
    Comparison groups
    MagneB6® v Magnespasmyl®
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.51
         upper limit
    		 1.55

    Secondary: Change From Baseline in Total DASS-42 Scale at Week 4 and 8

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    End point title
    		 Change From Baseline in Total DASS-42 Scale at Week 4 and 8
    End point description
    DASS-42 is a 42-item questionnaire consisting of 3 sub-scales (depression, anxiety and stress) to measure the negative emotional states of depression, anxiety and stress. Each sub-scale containing 14 items were scored on a 4-point rating scale: 0 (Did not apply to me at all) to 3 (Applies to me most of the time). The total scores (DASS-42 stress + DASS-42 depression + DASS-42 anxiety) ranged from 0 to 126, where higher scores indicated higher level of depression, anxiety or/and stress. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    132
    132
    Units: units on a scale
    arithmetic mean (confidence interval 95%)
        Change at Week 4
    -19.66 (-22.55 to -16.78)
    -18.28 (-21.15 to -15.41)
        Change at Week 8
    -28.14 (-31.28 to -25.00)
    -28.03 (-31.16 to -24.90)
    Statistical analysis title
    		 Change at Week 4: MagneB6® v Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from ANCOVA, adjusted on sex and interaction between visit and DASS-42 total at D1. Missing data were imputed by LOCF method.
    Comparison groups
    Magnespasmyl® v MagneB6®
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    1.38
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.44
         upper limit
    		 5.2
    Statistical analysis title
    		 Change at Week 8: MagneB6® vs. Magnespasmyl®
    Statistical analysis description
    Difference in adjusted mean was analysed from ANCOVA, adjusted on sex and interaction between visit and DASS-42 total at D1. Missing data were imputed by LOCF method.
    Comparison groups
    MagneB6® v Magnespasmyl®
    Number of subjects included in analysis
    264
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 ANCOVA
    Parameter type
    		 Difference in adjusted means
    Point estimate
    0.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.1
         upper limit
    		 4.31

    Secondary: Change from Baseline in Cortisol Awakening Response (CAR) at Week 4 and 8

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    End point title
    		 Change from Baseline in Cortisol Awakening Response (CAR) at Week 4 and 8
    End point description
    CAR is an allostatic indicator used as a biomarker to quantify stress levels. This test was done by subjects at home on 2 days (the day before visit & day of visit [except for baseline visit)]). Three saliva samples were collected by day: 0, 30 & 45 minutes after awakening & before breakfast on Day 2 and 3 (for baseline), Day 27 and 28 (for Week 4) and Day 55 and 56 (for Week 8). CAR kits were dispensed to subjects for saliva cortisol sampling. Change from baseline at Week 4 and Week 8 was measured by the mean over 2 days of total area under the curve (AUCt) (0, 30 and 45 minutes) of CAR. Difference in adjusted mean was analysed from ANCOVA, adjusted on sex. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    132
    132
    Units: nmol/L
    arithmetic mean (confidence interval 95%)
        Change at Week 4
    -14.04 (-53.48 to 25.40)
    -5.42 (-44.71 to 33.87)
        Change at Week 8
    -2.62 (-47.07 to 41.84)
    6.29 (-37.99 to 50.58)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Absolute Increase of Cortisol (AINC) at Week 4 and 8

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    End point title
    		 Change from Baseline in Absolute Increase of Cortisol (AINC) at Week 4 and 8
    End point description
    Change from baseline at Week 4 and Week 8 was measured by the mean over 2 days of AINC (maximum value of cortisol at 30 and 45 minutes minus 0 minutes). Difference in adjusted mean was analysed from ANCOVA, adjusted on sex. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    132
    132
    Units: nmol/L
    arithmetic mean (confidence interval 95%)
        Change at Week 4
    0.11 (-1.27 to 1.49)
    0.30 (-1.08 to 1.67)
        Change at Week 8
    -0.01 (-1.26 to 1.24)
    0.80 (-0.45 to 2.04)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Mean Increase of Cortisol (MINC) at Week 4 and 8

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    End point title
    		 Change from Baseline in Mean Increase of Cortisol (MINC) at Week 4 and 8
    End point description
    Change from baseline at Week 4 and Week 8 was measured by mean over 2 days of MINC (mean value of cortisol at 30 and 45 minutes minus 0 minutes). Difference in adjusted mean was analysed from ANCOVA, adjusted on sex. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    132
    132
    Units: nmol/L
    arithmetic mean (confidence interval 95%)
        Change at Week 4
    0.36 (-0.74 to 1.47)
    0.14 (-0.96 to 1.25)
        Change at Week 8
    0.21 (-0.79 to 1.20)
    0.63 (-0.36 to 1.63)
    No statistical analyses for this end point

    Secondary: Change from Baseline in Local Erythrocyte (Red Blood Cells [RBCs]) Magnesium at Week 4 and 8

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    End point title
    		 Change from Baseline in Local Erythrocyte (Red Blood Cells [RBCs]) Magnesium at Week 4 and 8
    End point description
    Difference in adjusted means were analysed. Adjusted mean from ANCOVA, adjusted on sex. Analysis was performed on mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 4 and Week 8
    End point values
    		 MagneB6® Magnespasmyl®
    Number of subjects analysed
    132
    132
    Units: mmol/L
    arithmetic mean (confidence interval 95%)
        Change at Week 4
    0.03 (-0.01 to 0.08)
    0.04 (-0.01 to 0.09)
        Change at Week 8
    0.01 (-0.03 to 0.06)
    0.02 (-0.03 to 0.06)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All Adverse Events (AEs) were collected from signature of the informed consent form up to the last visit (Week 8) regardless of seriousness or relationship to investigational product.
    Adverse event reporting additional description
    Reported AEs are treatment-emergent AEs that is AEs that developed/worsened from first study drug intake up to 8 weeks. Safety population included all subjects included in the study with at least one consumption of study product. Subjects were analysed according to the actual treatment received.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    MagneB6®
    Reporting group description
    		 Subjects received two tablets of MagneB6® (470.0 mg Mg lactate dihydrate + 5.0 mg pyridoxime hydrochloride) three times per day during the 8 week treatment period.

    Reporting group title
    Magnespasmyl®
    Reporting group description
    		 Subjects received two tablets of Magnespasmyl® 47.4 mg three times per day during the 8 week treatment period.

    Serious adverse events
    		 MagneB6® Magnespasmyl®
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 MagneB6® Magnespasmyl®
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    54 / 132 (40.91%)
    52 / 132 (39.39%)
    Injury, poisoning and procedural complications
    Ligament sprain
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Rib fracture
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Sunburn
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    3 / 132 (2.27%)
    1 / 132 (0.76%)
         occurrences all number
    3
    1
    Formication
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    2
    Headache
         subjects affected / exposed
    11 / 132 (8.33%)
    13 / 132 (9.85%)
         occurrences all number
    11
    16
    Hypersomnia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Migraine
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Presyncope
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 132 (0.76%)
         occurrences all number
    1
    1
    Fatigue
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 132 (0.76%)
         occurrences all number
    1
    1
    Vessel puncture site haematoma
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Abdominal distension
         subjects affected / exposed
    2 / 132 (1.52%)
    0 / 132 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain
         subjects affected / exposed
    3 / 132 (2.27%)
    8 / 132 (6.06%)
         occurrences all number
    3
    12
    Abdominal pain upper
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 132 (1.52%)
         occurrences all number
    0
    2
    Constipation
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    7 / 132 (5.30%)
    12 / 132 (9.09%)
         occurrences all number
    8
    21
    Dry mouth
         subjects affected / exposed
    2 / 132 (1.52%)
    0 / 132 (0.00%)
         occurrences all number
    2
    0
    Dyspepsia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Dysphagia
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Faeces soft
         subjects affected / exposed
    3 / 132 (2.27%)
    2 / 132 (1.52%)
         occurrences all number
    3
    2
    Flatulence
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Frequent bowel movements
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal inflammation
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Nausea
         subjects affected / exposed
    2 / 132 (1.52%)
    3 / 132 (2.27%)
         occurrences all number
    2
    3
    Vomiting
         subjects affected / exposed
    2 / 132 (1.52%)
    2 / 132 (1.52%)
         occurrences all number
    5
    2
    Reproductive system and breast disorders
    Metrorrhagia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Epistaxis
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Oropharyngeal pain
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 132 (0.76%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Dermatitis acneiform
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 132 (0.76%)
         occurrences all number
    1
    1
    Rash
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 132 (0.76%)
         occurrences all number
    1
    1
    Rash papular
         subjects affected / exposed
    2 / 132 (1.52%)
    1 / 132 (0.76%)
         occurrences all number
    2
    1
    Skin reaction
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Sleep disorder
         subjects affected / exposed
    2 / 132 (1.52%)
    0 / 132 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    4 / 132 (3.03%)
    2 / 132 (1.52%)
         occurrences all number
    4
    2
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal stiffness
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Myalgia
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    3 / 132 (2.27%)
    0 / 132 (0.00%)
         occurrences all number
    3
    0
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 132 (1.52%)
         occurrences all number
    0
    2
    Cystitis
         subjects affected / exposed
    0 / 132 (0.00%)
    2 / 132 (1.52%)
         occurrences all number
    0
    2
    Eczema infected
         subjects affected / exposed
    1 / 132 (0.76%)
    0 / 132 (0.00%)
         occurrences all number
    1
    0
    Gastroenteritis
         subjects affected / exposed
    3 / 132 (2.27%)
    2 / 132 (1.52%)
         occurrences all number
    3
    2
    Influenza
         subjects affected / exposed
    1 / 132 (0.76%)
    1 / 132 (0.76%)
         occurrences all number
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    4 / 132 (3.03%)
    1 / 132 (0.76%)
         occurrences all number
    4
    1
    Rhinitis
         subjects affected / exposed
    6 / 132 (4.55%)
    1 / 132 (0.76%)
         occurrences all number
    6
    1
    Sinusitis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Tonsillitis
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Vaginal infection
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    0 / 132 (0.00%)
    1 / 132 (0.76%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Feb 2016
    Following changes were made: - Change in names and addresses of team's representative. - Addition of a table summarizing blood sample volume per subject during the study. - Procedures for the analysis of Erythrocyte Mg, Serum vitamin B6 and CAR.

    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
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