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    Clinical Trial Results:
    How common are mood and sexual side-effects from combined oral contraceptives?

    Summary
    EudraCT number
    		 2013-000925-30
    Trial protocol
    		 SE  
    Global end of trial date
    29 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Mar 2020
    First version publication date
    22 Mar 2020
    Other versions
    Summary report(s)
    		 COCs and Mood, article published in Psychoneuroendocrinology

    Trial information

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    Trial identification
    Sponsor protocol code
    10
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Uppsala University
    Sponsor organisation address
    Uppsala University Hospital, Uppsala, Sweden,
    Public contact
    Inger Sundström Poromaa, Uppsala University, 46 186115764, inger.sundstrom@kbh.uu.se
    Scientific contact
    Inger Sundström Poromaa, Uppsala University, 46 186115764, inger.sundstrom@kbh.uu.se
    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
    01 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Sep 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    to prospectively estimate the prevalence of mood and sexual side effects in combined oral contraceptives users to compare the severity of mood and sexual side effects between combined oral contraceptives users and placebo users
    Protection of trial subjects
    The study participants underwent pregnancy tests on the screening visit, and then before the start of each treatment cycle. At the visits during ongoing treatment as well as at the follow-up, the study participants were asked for any adverse events.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Sep 2013
    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
    Sweden: 202
    Worldwide total number of subjects
    202
    EEA total number of subjects
    202
    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)
    202
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited by advertisements in local newspapers, on local notice boards and students websites. Recruitment started in September 2013 and ended in May 2015. Participants were recruited from six cities in Sweden.

    Pre-assignment
    Screening details
    		 A total of 224 subjects were screened for the study. Following a screening visit, women kept daily symptom diaries for one menstrual cycle (baseline cycle. After the baseline cycle, women started taking a combined oral contraceptive or placebo tablets once daily during three treatment cycles.

    Period 1
    Period 1 title
    Overall study (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
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    After the baseline cycle was completed, women started taking active treatment (COC) or placebo capsules once daily on the first day of menses and continued treatment for 24 days, followed by four pill-free days.

    Arm title
    		 1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Combined oral contraceptive
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    After the baseline cycle, women started taking active treatment (COC) or placebo once daily on the first day of menses and continued treatment for 24 days, followed by 4 pill-free days, repeated in three treatment cycles.

    Number of subjects in period 1
    		Placebo 1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Started
    100
    102
    Completed
    94
    84
    Not completed
    6
    18
         Consent withdrawn by subject
    4
    7
         Adverse event, non-fatal
    -
    5
         Pregnancy
    1
    -
         Unknown
    -
    3
         Lost to follow-up
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Reporting group description
    		 -

    Reporting group values
    		 Placebo 1.5 mg oestradiol/2.5 mg nomegestrolacetate Total
    Number of subjects
    		 100 102 202
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 100 102 202
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 24.8 ( 4.2 ) 23.8 ( 4.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 100 102 202
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Reporting group description
    		 -

    Primary: Change in mood scores

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    End point title
    		 Change in mood scores
    End point description
    Mood was scored on Daily Rating of Severity of Symptoms (DRSP) daily during baseline (hormonal free) and the third treatment cycle and any change and compared after end of trial. The DRSP consists of 21 items that reflect symptoms such as irritability, mood swings and fatigue. Each item is scored on 6-pinot Likert scale, with 6 representing maximum severity and 1 representing complete abscence of a particular symptom.
    End point type
    Primary
    End point timeframe
    3 months
    End point values
    		 Placebo 1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Number of subjects analysed
    94
    84
    Units: 1-6
    94
    84
    Statistical analysis title
    		 Change in MFSQ
    Statistical analysis description
    Delta scores were calculated for the MFSQ domains as difference between the final treatment cycle and baseline, meaning that negative delta scores indicate worsening and positive delta scores indicated improvement. Baseline and delta scores were compared between treatment groups by Mann-Whitney U-test.
    Comparison groups
    Placebo v 1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Confidence interval
    Statistical analysis title
    		 Change in mood scores
    Comparison groups
    Placebo v 1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 ANOVA
    Confidence interval

    Primary: Change in MFSQ scores

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    End point title
    		 Change in MFSQ scores
    End point description
    Change in McCoy Female Sexuality Questionnaire during last treatment cycle compared to baseline. The questionnaire consists of 19 questions, answered using a 7-point Likert scale where 1 represents negative answers such as "not at all enjoyable" and 7 represents positive answers such as "very enjoyable".
    End point type
    Primary
    End point timeframe
    3 months
    End point values
    		 Placebo 1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Number of subjects analysed
    94
    84
    Units: 1-7
    94
    84
    Statistical analysis title
    		 Change in sexual function
    Comparison groups
    Placebo v 1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Number of subjects included in analysis
    178
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 ≤ 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Four months
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    12.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo 1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 100 (0.00%)
    0 / 102 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo 1.5 mg oestradiol/2.5 mg nomegestrolacetate
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 100 (21.00%)
    34 / 102 (33.33%)
    Reproductive system and breast disorders
    Bleeding disturbances
         subjects affected / exposed
    11 / 100 (11.00%)
    26 / 102 (25.49%)
         occurrences all number
    11
    26
    Sexual function decrease
         subjects affected / exposed
    3 / 100 (3.00%)
    13 / 102 (12.75%)
         occurrences all number
    3
    13
    Breast swelling
         subjects affected / exposed
    5 / 100 (5.00%)
    8 / 102 (7.84%)
         occurrences all number
    5
    8
    Dysmenorrhea
         subjects affected / exposed
    6 / 100 (6.00%)
    2 / 102 (1.96%)
         occurrences all number
    6
    6
    Gastrointestinal disorders
    Change in appetite
         subjects affected / exposed
    6 / 100 (6.00%)
    7 / 102 (6.86%)
         occurrences all number
    6
    7
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    9 / 100 (9.00%)
    9 / 102 (8.82%)
         occurrences all number
    9
    9
    Psychiatric disorders
    Mood symptoms
    Additional description: Any report of depressed mood, anxiety, irritability, mood swings, difficulties concentrating, or affect lability
         subjects affected / exposed
    21 / 100 (21.00%)
    34 / 102 (33.33%)
         occurrences all number
    21
    34
    Fatigue
         subjects affected / exposed
    7 / 100 (7.00%)
    7 / 102 (6.86%)
         occurrences all number
    7
    7

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/27923181
    http://www.ncbi.nlm.nih.gov/pubmed/30352399
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