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    Clinical Trial Results:
    Neurokinin 3 Receptor Antagonism as a Novel Treatment for Menopausal Hot Flushes

    Summary
    EudraCT number
    		 2015-001553-32
    Trial protocol
    		 GB  
    Global end of trial date
    30 Apr 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Aug 2019
    First version publication date
    31 Aug 2019
    Other versions
    Summary report(s)
    		 End of Study Report

    Trial information

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    Trial identification
    Sponsor protocol code
    MR/M024954/1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    JRCO, Charing Cross Hospital, Fulham Palace Road, London, United Kingdom,
    Public contact
    Research Governance Manager, Imperial College London, 44 2033110205, becky.ward@imperial.ac.uk
    Scientific contact
    Research Governance Manager, Imperial College London, 44 2033110205, becky.ward@imperial.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
    30 Apr 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate if AZD4901 is effective in reducing the frequency of menopausal hot flushes by mean Hot Flush (HF) frequency per day (HF/day).
    Protection of trial subjects
    Trial subjects undergo regular blood test monitoring and clinical reviews with the investigators to ensure adequate protection of trial subjects. The independent data monitoring committee provides oversight for ensuring any deviation from the protocol is reported and that the protocol is complied with.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 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: 37
    Worldwide total number of subjects
    37
    EEA total number of subjects
    37
    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)
    37
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants will be recruited from the UK and will be screened for inclusion commencing in February 2016, until sufficient numbers of participants have been recruited.

    Pre-assignment
    Screening details
    		 Study participants will be menopausal women aged 40-62 years with >7HF/day some of which are reported as severe or bothersome who have not been on treatment for menopausal symptoms for the preceding 8 weeks. Eligibility will be determined after a visit with a doctor who will perform a health check including history, examination and blood tests.

    Period 1
    Period 1 title
    1st Intervention
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    All authors, participants, and trial staff were masked until completion of the study. Unmasking only occurred once all participants had completed the study, and all data had been entered into the electronic case record forms. To ensure safety in the case of a medical emergency, code break packs with individual scratch off panels were held but were never required.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active drug
    Arm description
    		 NK3R antagonist - AZD4901 - 40mg bd - for 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD4901
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg BD

    Arm title
    		 Placebo
    Arm description
    		 Placebo - 40mg bd - for 4 weeks
    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
    40mg twice daily.

    Number of subjects in period 1
    		Active drug Placebo
    Started
    20
    17
    Completed
    17
    15
    Not completed
    3
    2
         Physician decision
    1
    -
         Consent withdrawn by subject
    1
    2
         Adverse event, non-fatal
    1
    -
    Period 2
    Period 2 title
    2nd Intervention
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    All authors, participants, and trial staff were masked until completion of the study. Unmasking only occurred once all participants had completed the study, and all data had been entered into the electronic case record forms. To ensure safety in the case of a medical emergency, code break packs with individual scratch off panels were held but were never required.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active drug
    Arm description
    		 NK3R antagonist - AZD4901 - 40mg bd - for 4 weeks
    Arm type
    		 Experimental

    Investigational medicinal product name
    AZD4901
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    40mg BD

    Arm title
    		 Placebo
    Arm description
    		 Placebo - 40mg bd - for 4 weeks
    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
    40mg twice daily.

    Number of subjects in period 2
    		Active drug Placebo
    Started
    17
    15
    Completed
    16
    12
    Not completed
    1
    3
         Physician decision
    1
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Active drug
    Reporting group description
    		 NK3R antagonist - AZD4901 - 40mg bd - for 4 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo - 40mg bd - for 4 weeks

    Reporting group values
    		 Active drug Placebo Total
    Number of subjects
    		 20 17 37
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
        Age 40-62 years
    		 20 17 37
    Gender categorical
    Units: Subjects
        Female
    		 20 17 37
        Male
    		 0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Active drug
    Reporting group description
    		 NK3R antagonist - AZD4901 - 40mg bd - for 4 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo - 40mg bd - for 4 weeks
    Reporting group title
    Active drug
    Reporting group description
    		 NK3R antagonist - AZD4901 - 40mg bd - for 4 weeks

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo - 40mg bd - for 4 weeks

    Primary: Total Number of Hot Flushes During the Final Week of Both Treatment Periods.

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    End point title
    		 Total Number of Hot Flushes During the Final Week of Both Treatment Periods.
    End point description
    To ensure accurate records, participants recorded their flushes in real time using either a tally chart on a piece of paper (n=34) or an application on their smartphone such as Tally Counter (Pixel Research Labs, Minneapolis-Saint Paul, MN, USA; n=3), and then collated their total number of flushes twice daily on waking to record previous overnight symptoms and before bed to record daytime symptoms.
    End point type
    Primary
    End point timeframe
    4 weeks
    End point values
    		 Active drug Placebo
    Number of subjects analysed
    20
    17
    Units: Number
        arithmetic mean (confidence interval 95%)
    19.35 (15.99 to 23.42)
    49.01 (40.81 to 58.56)
    Statistical analysis title
    		 Statistical Analysis 1 - Active drug vs Placebo
    Statistical analysis description
    Whole group ITT analysis irrespective of treatment assignment order using adjusted means from crossover analysis with 95% CIs: percentage change in total no. hot flush frequency during final week of 4 week treatment period with MLE4901 and placebo compared with total no. hot flush frequency during the final week of the 2 week baseline period.
    Comparison groups
    Active drug v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 generalised linear mixed model with a Po
    Confidence interval

    Secondary: Hot Flush Severity

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    End point title
    		 Hot Flush Severity
    End point description
    HF severity (rated as 1-nil, 2-mild, 3-moderate, 4-severe, as per Joffe 2014) will be recorded twice daily (day/night as described above for HF frequency). The data will be analysed as detailed above for the HF frequency
    End point type
    Secondary
    End point timeframe
    14 weeks.
    End point values
    		 Active drug Placebo
    Number of subjects analysed
    20
    17
    Units: numerical rating of severity by particip
        arithmetic mean (confidence interval 95%)
    3.27 (2.92 to 3.66)
    5.70 (5.09 to 6.38)
    Statistical analysis title
    		 Statistical Analysis 1 - Active drug vs Placebo
    Comparison groups
    Active drug v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Hot Flush Bother

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    End point title
    		 Hot Flush Bother
    End point description
    HF bother (rated as 1-none, 2-a little, 3-moderate, 4-a lot, as per Joffe 2014) will be recorded twice daily (day/night as described above for HF frequency). The data will be analysed as detailed above for the HF frequency.
    End point type
    Secondary
    End point timeframe
    14 weeks
    End point values
    		 Active drug Placebo
    Number of subjects analysed
    20
    17
    Units: Bother score on a scale recorded by part
        arithmetic mean (confidence interval 95%)
    2.92 (2.61 to 3.27)
    5.56 (4.96 to 6.27)
    Statistical analysis title
    		 Statistical Analysis 1 - Active Drug vs Placebo
    Comparison groups
    Placebo v Active drug
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Hot Flush Interference

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    End point title
    		 Hot Flush Interference
    End point description
    HF interference (Hot Flash Related Daily Interference Scale, as per Carpenter 2001) will be recorded daily at bedtime. The data will be analysed as detailed above for the HF frequency.
    End point type
    Secondary
    End point timeframe
    14 weeks
    End point values
    		 Active drug Placebo
    Number of subjects analysed
    20
    17
    Units: Score by participant on 'interference sc
        arithmetic mean (confidence interval 95%)
    7.94 (5.76 to 10.95)
    26.48 (20.02 to 35.03)
    Statistical analysis title
    		 Statistical Analysis 1 - Active Drug vs Placebo
    Comparison groups
    Active drug v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Skin Conductance Monitor Data.

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    End point title
    		 Skin Conductance Monitor Data.
    End point description
    End point type
    Secondary
    End point timeframe
    14 weeks
    End point values
    		 Active drug Placebo
    Number of subjects analysed
    20
    17
    Units: Number hot flushes detected by monitor
        arithmetic mean (confidence interval 95%)
    16.22 (13.99 to 18.8)
    26.91 (23.16 to 31.27)
    Statistical analysis title
    		 Statistical Analysis 1 - Active Drug vs Placebo
    Comparison groups
    Active drug v Placebo
    Number of subjects included in analysis
    37
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Mixed models analysis
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    10 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Subjects affected vs at risk
    Reporting group description
    		 -

    Serious adverse events
    		 Subjects affected vs at risk
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 37 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Subjects affected vs at risk
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 37 (8.11%)
    Hepatobiliary disorders
    transaminase elevations by treatment and CTCAE grade
    Additional description: Transient transaminase rise (alanine aminotransferase [ALT] greater than aspartate aminotransferase [AST]) with a normal bilirubin following treatment with AZD4901
         subjects affected / exposed
    3 / 37 (8.11%)
         occurrences all number
    3

    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.
    The number of participants was small, short treatment duration, and higher than anticipated dropout rate. A larger and longer trial is needed to establish whether the treatment effect is long lasting in a greater number of individual

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/29533369
    http://www.ncbi.nlm.nih.gov/pubmed/28385352
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