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    Clinical Trial Results:
    A phase III randomised study of folic acid supplementation in the management of menopausal symptoms in cancer survivors and healthy postmenopausal women

    Summary
    EudraCT number
    		 2013-004246-41
    Trial protocol
    		 GB  
    Global end of trial date
    30 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Dec 2020
    First version publication date
    25 Dec 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RG_13-198
    Additional study identifiers
    ISRCTN number
    		 ISRCTN98158824
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 CRCTU Reference No: MX3009
    Sponsors
    Sponsor organisation name
    Sandwell and West Birmingham Hospitals NHS Trust
    Sponsor organisation address
    Dudley Road, Birmingham , United Kingdom, B18 7QH
    Public contact
    Jocelyn Bell, Sandwell and West Birmingham Hospitals NHS Trust, +44 01215074811, jocelyn.bell@nhs.net
    Scientific contact
    Jocelyn Bell, Sandwell and West Birmingham Hospitals NHS Trust, +44 01215074811, jocelyn.bell@nhs.net
    Sponsor organisation name
    University of Birmingham
    Sponsor organisation address
    Vincent Drive, Birmingham , United Kingdom, B15 2TT
    Public contact
    Sean Jennings, University of Birmingham, +44 01214158011, researchgovernance@contacts.bham.ac.uk
    Scientific contact
    Sean Jennings, University of Birmingham, +44 01214158011, researchgovernance@contacts.bham.ac.uk
    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
    11 Nov 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this trial is to assess the efficacy of folic acid supplementation in terms of relief of the frequency and severity of vasomotor symptoms as compared to placebo
    Protection of trial subjects
    The trial was performed in accordance with the recommendations guiding physicians in biomedical research involving human subjects, adopted by the 18th World Medical Association General Assembly, Helsinki, Finland, June 1964, amended at the 48th World Medical Association General Assembly, Somerset West, Republic of South Africa, October 1996. The trial was conducted in accordance with the Research Governance Framework for Health and Social Care, the applicable UK Statutory Instruments, (which include the Medicines for Human Use Clinical Trials 2004 and subsequent amendments and the Data Protection Act 1998 and Human Tissue Act 2008) and GCP. This trial was carried out under a Clinical Trial Authorisation in accordance with the Medicines for Human Use Clinical Trials regulations. The protocol was submitted to and approved by the REC prior to circulation. Before any patients are enrolled into the trial, the Principal Investigator at each site was required to obtain local Research and Development (R&D) approval. Sites were not be permitted to enrol patients until written confirmation of R&D approval was received by the FOAM Trial Office. It was the responsibility of the Principal Investigator to ensure that all subsequent amendments gained the necessary local approval. The individual clinicians’ had the responsibility to take immediate action if they thought necessary to protect the health and interest of individual patients.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A - the test IMP, Folic acid is being used versus a placebo only
    Actual start date of recruitment
    01 Feb 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 164
    Worldwide total number of subjects
    164
    EEA total number of subjects
    164
    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)
    151
    From 65 to 84 years
    13
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 164 patients have been recruited and randomised. 83 patients were allocated to Folic Acid and 81 patients were allocated to Placebo.

    Pre-assignment
    Screening details
    		 Screening commenced following consent and prior to patient randomisation in order to confirm eligibility. Detailed screening information was described in the protocol.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Folic Acid
    Arm description
    		 5mg folic acid
    Arm type
    		 Experimental

    Investigational medicinal product name
    folic acid
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5mg tablet taken orally, once daily for 12 weeks

    Arm title
    		 Placebo
    Arm description
    		 folic acid-matched-placebo
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    5mg tablet taken orally, once daily for 12 weeks

    Number of subjects in period 1
    		Folic Acid Placebo
    Started
    83
    81
    Completed
    74
    69
    Not completed
    9
    12
         Lost to follow-up
    9
    12

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Folic Acid
    Reporting group description
    		 5mg folic acid

    Reporting group title
    Placebo
    Reporting group description
    		 folic acid-matched-placebo

    Reporting group values
    		 Folic Acid Placebo Total
    Number of subjects
    		 83 81 164
    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)
    		 55.4 ( 5.1 ) 56.2 ( 5.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 83 81 164
        Male
    		 0 0 0
    Patient subgroup
    Units: Subjects
        Healthy Woman
    		 67 66 133
        Breast Cancer Survivor
    		 14 14 28
        Endometrial Cancer Survivor
    		 2 1 3
    BMI
    Units: Subjects
        ≤ 30
    		 64 63 127
        > 30
    		 19 18 37
    Baseline Folate
    Units: μg/L
        arithmetic mean (standard deviation)
    		 7.8 ( 3.1 ) 7.6 ( 3.1 ) -
    Hot flushes at screening
    Units: integer
        arithmetic mean (standard deviation)
    		 85 ( 37 ) 85 ( 51 ) -

    End points

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    End points reporting groups
    Reporting group title
    Folic Acid
    Reporting group description
    		 5mg folic acid

    Reporting group title
    Placebo
    Reporting group description
    		 folic acid-matched-placebo

    Primary: Change in daily Hot Flush Score at 12 weeks from randomisation based on the composite score B calculation

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    End point title
    		 Change in daily Hot Flush Score at 12 weeks from randomisation based on the composite score B calculation
    End point description
    The mean change and associated standard deviation of composite score B between randomisation and week 12 will be presented for both treatment arms and statistically compared between the groups using a two-sample t-test. The difference in the mean change along with the 95% CI will be presented.
    End point type
    Primary
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    74
    69
    Units: score
        arithmetic mean (standard deviation)
    -6.98 ( 10.30 )
    -4.57 ( 9.46 )
    Statistical analysis title
    		 Unadjusted: primary analysis
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.149
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.41
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.68
         upper limit
    		 0.87
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.66
    Statistical analysis title
    		 Adjusted: secondary analysis
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    143
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.098
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.61
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.72
         upper limit
    		 0.49

    Secondary: Change in daily Hot Flush Score at 12 weeks from randomisation based on the composite score B calculation - secondary outcome sensitivity analysis: multiple imputation

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    End point title
    		 Change in daily Hot Flush Score at 12 weeks from randomisation based on the composite score B calculation - secondary outcome sensitivity analysis: multiple imputation
    End point description
    A sensitivity analysis which accounts for missing data via multiple-imputation for the primary outcome analysis. Patients are required to have data available for week 1 to be included in the multiple imputation analysis. This analysis will be performed via a regression based imputation model using a bootstrap approach. Details are provided in the SAP.
    End point type
    Secondary
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    80
    78
    Units: score
        arithmetic mean (standard deviation)
    -6.78 ( 10.2 )
    -4.09 ( 9.82 )
    Statistical analysis title
    		 Unadjusted analysis - t-test
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.099
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.69
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.88
         upper limit
    		 0.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.63
    Statistical analysis title
    		 Adjusted analysis - linear regression model
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.071
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (net)
    Point estimate
    -2.82
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.87
         upper limit
    		 0.24
    Variability estimate
    Standard error of the mean
    Dispersion value
    1.56

    Secondary: Change in daily Hot Flush Score based on the composite score B calculation - secondary outcome multilevel model

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    End point title
    		 Change in daily Hot Flush Score based on the composite score B calculation - secondary outcome multilevel model
    End point description
    The longitudinal nature of the primary outcome data will allow multivariable mixed model regression to investigate repeated measurements from baseline through to 12 weeks as random effects, incorporating clinically relevant baseline covariates and stratification factors as fixed effects.
    End point type
    Secondary
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    80
    78
    Units: integer
    80
    78
    Statistical analysis title
    		 multilevel mixed-effects model
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.8
         upper limit
    		 1.39

    Secondary: Change in daily Hot Flush Score at 4 weeks from randomisation based on the composite score B calculation

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    End point title
    		 Change in daily Hot Flush Score at 4 weeks from randomisation based on the composite score B calculation
    End point description
    End point type
    Secondary
    End point timeframe
    between randomisation and week 4
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    78
    77
    Units: score
        arithmetic mean (standard deviation)
    -3.96 ( 8.28 )
    -3.93 ( 8.13 )
    No statistical analyses for this end point

    Secondary: Change in daily Hot Flush Score at 8 weeks from randomisation based on the composite score B calculation

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    End point title
    		 Change in daily Hot Flush Score at 8 weeks from randomisation based on the composite score B calculation
    End point description
    End point type
    Secondary
    End point timeframe
    between randomisation and week 8
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    75
    74
    Units: score
        arithmetic mean (standard deviation)
    -5.84 ( 9.19 )
    -4.49 ( 8.97 )
    No statistical analyses for this end point

    Secondary: Change from randomisation in Hot Flush Severity at week 4 based on the severity score B calculation

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    End point title
    		 Change from randomisation in Hot Flush Severity at week 4 based on the severity score B calculation
    End point description
    End point type
    Secondary
    End point timeframe
    between randomisation and week 4
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    78
    76
    Units: score
        arithmetic mean (standard deviation)
    -0.09 ( 0.23 )
    -0.06 ( 0.30 )
    No statistical analyses for this end point

    Secondary: Change from randomisation in Hot Flush Severity at week 8 based on the severity score B calculation

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    End point title
    		 Change from randomisation in Hot Flush Severity at week 8 based on the severity score B calculation
    End point description
    End point type
    Secondary
    End point timeframe
    between randomisation and week 8
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    75
    71
    Units: score
        arithmetic mean (standard deviation)
    -0.12 ( 0.37 )
    -0.06 ( 0.35 )
    No statistical analyses for this end point

    Secondary: Change from randomisation in Hot Flush Severity at week 12 based on the severity score B calculation

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    End point title
    		 Change from randomisation in Hot Flush Severity at week 12 based on the severity score B calculation
    End point description
    End point type
    Secondary
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    74
    68
    Units: score
        arithmetic mean (standard deviation)
    -0.17 ( 0.39 )
    -0.09 ( 0.33 )
    No statistical analyses for this end point

    Secondary: Change from randomisation in Hot Flush Severity based on the severity score B calculation - multilevel model

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    End point title
    		 Change from randomisation in Hot Flush Severity based on the severity score B calculation - multilevel model
    End point description
    End point type
    Secondary
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    80
    78
    Units: integer
    80
    78
    Statistical analysis title
    		 multilevel mixed-effects model
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.253
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.03

    Secondary: Change from randomisation in daily frequency of hot flushes (mild, moderate and severe) at week 4 as calculated using frequency score B

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    End point title
    		 Change from randomisation in daily frequency of hot flushes (mild, moderate and severe) at week 4 as calculated using frequency score B
    End point description
    End point type
    Secondary
    End point timeframe
    between randomisation and week 4
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    78
    77
    Units: score
        arithmetic mean (standard deviation)
    -1.70 ( 3.34 )
    -2.05 ( 4.00 )
    No statistical analyses for this end point

    Secondary: Change from randomisation in daily frequency of hot flushes (mild, moderate and severe) at week 8 as calculated using frequency score B

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    End point title
    		 Change from randomisation in daily frequency of hot flushes (mild, moderate and severe) at week 8 as calculated using frequency score B
    End point description
    End point type
    Secondary
    End point timeframe
    between randomisation and week 8
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    75
    74
    Units: score
        arithmetic mean (standard deviation)
    -2.65 ( 3.77 )
    -2.57 ( 4.29 )
    No statistical analyses for this end point

    Secondary: Change from randomisation in daily frequency of hot flushes (mild, moderate and severe) at week 12 as calculated using frequency score B

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    End point title
    		 Change from randomisation in daily frequency of hot flushes (mild, moderate and severe) at week 12 as calculated using frequency score B
    End point description
    End point type
    Secondary
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    74
    69
    Units: score
        arithmetic mean (standard deviation)
    -3.29 ( 4.34 )
    -2.59 ( 4.74 )
    No statistical analyses for this end point

    Secondary: Change from randomisation in daily frequency of hot flushes (mild, moderate and severe) as calculated using frequency score B - multilevel model

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    End point title
    		 Change from randomisation in daily frequency of hot flushes (mild, moderate and severe) as calculated using frequency score B - multilevel model
    End point description
    End point type
    Secondary
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    80
    78
    Units: integer
    80
    78
    Statistical analysis title
    		 multilevel mixed-effects model
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    158
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.979
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.01
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.97
         upper limit
    		 0.94

    Secondary: The number of responders at weeks 4, 8 and 12; defined as a reduction in daily Hot Flush Score of ≥50% from randomisation as calculated using composite score B

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    End point title
    		 The number of responders at weeks 4, 8 and 12; defined as a reduction in daily Hot Flush Score of ≥50% from randomisation as calculated using composite score B
    End point description
    End point type
    Secondary
    End point timeframe
    between week 4 and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    83
    81
    Units: integer
        week 4
    14
    15
        week 8
    20
    28
        week 12
    27
    24
    Statistical analysis title
    		 multilevel mixed-effects model
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    164
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.7
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.12
         upper limit
    		 0.08

    Secondary: Utian Quality of Life week 4

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    End point title
    		 Utian Quality of Life week 4
    End point description
    The mean and standard deviation of the change from randomisation in QoL data as measured by the UQoL Scale at week 4
    End point type
    Secondary
    End point timeframe
    between randomisation and week 4
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    79
    77
    Units: score
    arithmetic mean (standard deviation)
        Occupational score
    -1.37 ( 5.39 )
    -1.83 ( 5.08 )
        Health score
    -0.58 ( 4.68 )
    -0.34 ( 3.75 )
        Emotional score
    1.06 ( 4.76 )
    -0.05 ( 4.01 )
        Sexual score
    -0.06 ( 1.98 )
    -0.60 ( 2.35 )
        Total score
    -0.95 ( 12.43 )
    -2.82 ( 9.14 )
    No statistical analyses for this end point

    Secondary: Utian Quality of Life week 8

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    End point title
    		 Utian Quality of Life week 8
    End point description
    The mean and standard deviation of the change from randomisation in QoL data as measured by the UQoL Scale at week 8
    End point type
    Secondary
    End point timeframe
    between randomisation and week 8
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    77
    74
    Units: score
    arithmetic mean (standard deviation)
        Occupational score
    -0.83 ( 5.16 )
    -2.42 ( 6.04 )
        Health score
    0.30 ( 4.69 )
    -0.78 ( 4.20 )
        Emotional score
    1.34 ( 5.11 )
    -0.54 ( 5.12 )
        Sexual score
    0.08 ( 2.37 )
    -0.59 ( 2.69 )
        Total score
    0.88 ( 12.54 )
    -4.34 ( 12.69 )
    No statistical analyses for this end point

    Secondary: Utian Quality of Life week 12

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    End point title
    		 Utian Quality of Life week 12
    End point description
    The mean and standard deviation of the change from randomisation in QoL data as measured by the UQoL Scale at week 12
    End point type
    Secondary
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    76
    71
    Units: score
    arithmetic mean (standard deviation)
        Occupational score
    -0.75 ( 6.13 )
    -1.24 ( 5.87 )
        Health score
    0.25 ( 4.67 )
    -0.27 ( 4.32 )
        Emotional score
    1.22 ( 5.06 )
    0.27 ( 5.78 )
        Sexual score
    -0.04 ( 2.61 )
    -0.27 ( 1.96 )
        Total score
    0.68 ( 13.35 )
    -1.51 ( 13.34 )
    No statistical analyses for this end point

    Secondary: Utian Quality of Life - multilevel models

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    End point title
    		 Utian Quality of Life - multilevel models
    End point description
    The change in QoL from randomisation will then be investigated over time using multilevel mixed-effects model
    End point type
    Secondary
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    81
    81
    Units: integer
    81
    81
    Statistical analysis title
    		 Occupational score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.767
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.53
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.97
         upper limit
    		 4.03
    Statistical analysis title
    		 Health score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.281
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -1.59
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.49
         upper limit
    		 1.3
    Statistical analysis title
    		 Emotional score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.229
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.2
         upper limit
    		 5.01
    Statistical analysis title
    		 Sexual score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.089
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    1.36
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.21
         upper limit
    		 2.93
    Statistical analysis title
    		 Total score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.569
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.38
         upper limit
    		 9.79

    Secondary: Greene Climacteric Scale week 4

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    End point title
    		 Greene Climacteric Scale week 4
    End point description
    Change from randomisation in other menopausal symptoms using the Greene Climacteric Scale at week 4
    End point type
    Secondary
    End point timeframe
    between randomisation and week 4
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    80
    78
    Units: score
    arithmetic mean (standard deviation)
        Psychological score
    -2.31 ( 4.56 )
    -2.21 ( 4.78 )
        Psychological (anxiety) score
    -1.46 ( 2.77 )
    -1.35 ( 2.66 )
        Psychological (depression) score
    -0.85 ( 2.40 )
    -0.86 ( 2.63 )
        Somatic score
    -1.64 ( 4.01 )
    -1.64 ( 3.06 )
        Vasomotor score
    -0.95 ( 1.90 )
    -1.24 ( 1.77 )
        Sexual Dysfunction score
    -0.13 ( 0.92 )
    -0.21 ( 0.99 )
        Total score
    -5.03 ( 8.33 )
    -5.29 ( 7.69 )
    No statistical analyses for this end point

    Secondary: Greene Climacteric Scale week 8

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    End point title
    		 Greene Climacteric Scale week 8
    End point description
    Change from randomisation in other menopausal symptoms using the Greene Climacteric Scale at week 8
    End point type
    Secondary
    End point timeframe
    between randomisation and week 8
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    77
    73
    Units: score
    arithmetic mean (standard deviation)
        Psychological score
    -3.05 ( 4.90 )
    -2.68 ( 5.35 )
        Psychological (anxiety) score
    -1.97 ( 2.99 )
    -1.58 ( 2.96 )
        Psychological (depression) score
    -1.08 ( 2.53 )
    -1.11 ( 2.81 )
        Somatic score
    -1.77 ( 3.22 )
    -1.59 ( 2.93 )
        Vasomotor score
    -1.05 ( 2.06 )
    -1.40 ( 1.76 )
        Sexual Dysfunction score
    -0.21 ( 1.00 )
    -0.14 ( 0.99 )
        Total score
    -6.08 ( 8.72 )
    -5.81 ( 8.33 )
    No statistical analyses for this end point

    Secondary: Greene Climacteric Scale week 12

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    End point title
    		 Greene Climacteric Scale week 12
    End point description
    Change from randomisation in other menopausal symptoms using the Greene Climacteric Scale at week 12
    End point type
    Secondary
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    77
    72
    Units: score
    arithmetic mean (standard deviation)
        Psychological score
    -3.39 ( 5.43 )
    -2.72 ( 5.71 )
        Psychological (anxiety) score
    -2.06 ( 3.28 )
    -1.42 ( 3.13 )
        Psychological (depression) score
    -1.32 ( 2.94 )
    -1.31 ( 2.98 )
        Somatic score
    -1.86 ( 3.48 )
    -2.08 ( 3.40 )
        Vasomotor score
    -1.23 ( 1.95 )
    -1.50 ( 2.05 )
        Sexual Dysfunction score
    -0.08 ( 0.96 )
    -0.40 ( 1.15 )
        Total score
    -6.56 ( 9.27 )
    -6.71 ( 9.28 )
    No statistical analyses for this end point

    Secondary: Greene Climacteric Scale - multilevel models

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    End point title
    		 Greene Climacteric Scale - multilevel models
    End point description
    End point type
    Secondary
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    81
    81
    Units: integer
    81
    81
    Statistical analysis title
    		 Psychological score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.679
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.55
         upper limit
    		 3.92
    Statistical analysis title
    		 Psychological (anxiety) score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.413
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.76
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.06
         upper limit
    		 2.58
    Statistical analysis title
    		 Psychological (depression) score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.943
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.96
         upper limit
    		 1.83
    Statistical analysis title
    		 Somatic score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.619
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.54
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.68
         upper limit
    		 1.59
    Statistical analysis title
    		 Vasomotor score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.537
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.86
         upper limit
    		 1.64
    Statistical analysis title
    		 Sexual Dysfunction score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.165
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.51
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.23
         upper limit
    		 0.21
    Statistical analysis title
    		 Total score
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    162
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.988
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.09
         upper limit
    		 5.16

    Other pre-specified: Change in serum folate level at week 12 from baseline

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    End point title
    		 Change in serum folate level at week 12 from baseline
    End point description
    End point type
    Other pre-specified
    End point timeframe
    between randomisation and week 12
    End point values
    		 Folic Acid Placebo
    Number of subjects analysed
    67
    66
    Units: value
        arithmetic mean (standard deviation)
    11.06 ( 3.86 )
    0.66 ( 3.15 )
    Statistical analysis title
    		 t-test
    Comparison groups
    Folic Acid v Placebo
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.001
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    10.39
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 9.18
         upper limit
    		 11.61
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.61

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse event reporting was from commencement of treatment to 30 days after completion of trial treatment.
    Adverse event reporting additional description
    The collection and reporting of AEs were in accordance with the Medicines for Human Use Clinical Trials Regulations 2004 and its subsequent amendments. Details of all SAEs were documented and reported from the date of informed consent until 30 days after the administration of last dose of trial medication.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Folic Acid
    Reporting group description
    		 Each patient received folic acid (5mg) once daily by mouth for 12 weeks.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received a folic acid-matched-tablet once daily by mouth for 12 weeks.

    Serious adverse events
    		 Folic Acid Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 83 (1.20%)
    2 / 81 (2.47%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    General disorders and administration site conditions
    Pain
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 81 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Renal Calculi
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 81 (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
    		 Folic Acid Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 83 (14.46%)
    7 / 81 (8.64%)
    Nervous system disorders
    Paraesthesia
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    General disorders and administration site conditions
    Night sweats
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Palpitations
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    2 / 83 (2.41%)
    3 / 81 (3.70%)
         occurrences all number
    2
    6
    Flatulence
         subjects affected / exposed
    4 / 83 (4.82%)
    4 / 81 (4.94%)
         occurrences all number
    5
    7
    Abdominal discomfort
         subjects affected / exposed
    1 / 83 (1.20%)
    1 / 81 (1.23%)
         occurrences all number
    1
    2
    Nausea
         subjects affected / exposed
    5 / 83 (6.02%)
    1 / 81 (1.23%)
         occurrences all number
    5
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 81 (0.00%)
         occurrences all number
    2
    0
    Urticaria
         subjects affected / exposed
    2 / 83 (2.41%)
    0 / 81 (0.00%)
         occurrences all number
    3
    0
    Pruritus
         subjects affected / exposed
    0 / 83 (0.00%)
    1 / 81 (1.23%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Renal colic
    Additional description: Renal Calculi
         subjects affected / exposed
    1 / 83 (1.20%)
    0 / 81 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Nov 2014
    Change in IMP supplier and formulation from capsules to tablets
    27 Feb 2015
    MHRA requested changes to SAE reporting period, unblinding procedure and removal of additional definition of postmenopausal women (requiring FSH testing)
    02 Sep 2015
    Changes to exclusion criteria (introduction of drug washout periods), use of Patient Advertisement and Patient Invitation Letter
    24 Nov 2015
    Inclusion of Patient Identification Centres, optional telephone visits at weeks 4 and/or 8, Patient Booklet.
    29 Mar 2017
    -Sample size re-evaluated due to slower than anticipated recruitment rate. In accordance with guidance from the DMC, TSC, TMG and Trial Statisticians, the power has been reduced from 90% to 80% and the expected dropout rate has been reduced from 30% to 10%. This has resulted in a reduction in the sample size required from 236 patients to 162 patients - Study duration extended to allow the sample size to be recruited -Contraindicated medication list clarified - Contact details updated including the randomisation telephone number
    06 Aug 2018
    Temporary Halt due to lack of IMP and restart to trial

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    10 Feb 2017
    Recruitment delays led to IMP expiry and the trial required halting so funding for a further batch of IMP could be secured which was produced and released to sites following approval of the updated Simplified IMPD submitted as part of substantial amendment AM08.
    20 Jun 2017
    11 May 2018
    The IMP stock at them was due to expire on 04th August 2018. On the FOAM trial, each patient is dispensed one bottle of IMP following randomisation containing their entire 12 week supply of folic acid. This means that randomisation of patients after 11th May 2018 couldn't take place as the IMP expiry date would not cover an extended treatment window. Due to the slower than anticipated recruitment and the relatively short IMP expiration dates, much of the IMP that was packaged towards the beginning of the study expired prior to use. This resulted in a lack of funds to produce an additional batch of IMP required to recruit the trial to target. Subsequent funding for a further batch of IMP was secured which was produced and released to sites following approval of the updated Simplified IMPD submitted as part of substantial amendment AM08. Further funds were acquired for this final batch of IMP and as per former advice received from the MHRA helpline on 06-Apr-2017, the trial halted and the team advised to automatically restart the study and resume recruitment as soon as this new IMP was ready to be dispatched.
    26 Sep 2018

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This study failed to identify a statistically significant benefit for folic acid (over placebo). Therefore, the use of folic acid would not be recommended as an alternative therapy for HRT in symptomatic postmenopausal women based on the findings.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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