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    Clinical Trial Results:
    A 46-week, Double-blind, Placebo-controlled, Phase 3 Study with a 6-week Randomized-withdrawal Period to Evaluate the Safety and Efficacy of Relamorelin in Patients with Diabetic Gastroparesis

    Summary
    EudraCT number
    2017-002143-15
    Trial protocol
    GB   DE   LV   HU   FR   BE   DK   BG   AT   ES   IT  
    Global end of trial date
    30 Oct 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Oct 2021
    First version publication date
    20 Oct 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RLM-MD-03
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03420781
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Allergan
    Sponsor organisation address
    1st Floor, Marlow International, The Parkway, Marlow Buckinghamshire, United Kingdom, SL7 1YL
    Public contact
    Therapeutic Area, Head, Allergan, 001 714-246-4500, IR-CTRegistration@Allergan.com
    Scientific contact
    Therapeutic Area, Head, Allergan, 001 714-246-4500, IR-CTRegistration@Allergan.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 Oct 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The main purpose of the study was to compare the efficacy of relamorelin with that of placebo in participants with diabetic gastroparesis (DG). Participants either continued on relamorelin or placebo for 6 additional weeks at the end of the 40-week Treatment Period.
    Protection of trial subjects
    All study participants were required to read and sign an Informed Consent Form.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    24 Jan 2018
    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
    Bulgaria: 3
    Country: Number of subjects enrolled
    Hungary: 3
    Country: Number of subjects enrolled
    Latvia: 6
    Country: Number of subjects enrolled
    Poland: 6
    Country: Number of subjects enrolled
    United Kingdom: 1
    Country: Number of subjects enrolled
    Argentina: 7
    Country: Number of subjects enrolled
    Brazil: 5
    Country: Number of subjects enrolled
    Canada: 4
    Country: Number of subjects enrolled
    Colombia: 5
    Country: Number of subjects enrolled
    India: 33
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Mexico: 29
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    South Africa: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Ukraine: 30
    Country: Number of subjects enrolled
    United States: 316
    Worldwide total number of subjects
    467
    EEA total number of subjects
    18
    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)
    355
    From 65 to 84 years
    111
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants who completed RLM-MD-01 [NCT03285308] or RLM-MD-02 [NCT03426345] were eligible for enrollment.

    Period 1
    Period 1 title
    Treatment Period (40 weeks)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment Period: Placebo
    Arm description
    Placebo-matching relamorelin injected subcutaneously twice daily for up to 40 weeks.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo injected twice daily

    Arm title
    Treatment Period: Relamorelin 10 μg
    Arm description
    Relamorelin 10 micrograms (μg) injected subcutaneously twice daily for up to 40 weeks.
    Arm type
    Experimental

    Investigational medicinal product name
    Relamorelin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Relamorelin 10 μg injected twice daily

    Number of subjects in period 1
    Treatment Period: Placebo Treatment Period: Relamorelin 10 μg
    Started
    236
    231
    Safety Population
    235
    231
    Completed
    92
    105
    Not completed
    144
    126
         Physician decision
    3
    4
         Site Terminated by the Sponsor
    1
    -
         Adverse Event
    1
    6
         Protocol Deviation
    -
    2
         Death
    2
    2
         Reason Not Specified
    3
    -
         Withdrawal by Subject
    22
    16
         Study Terminated by the Sponsor
    101
    89
         Lost to follow-up
    10
    6
         Lack of efficacy
    1
    1
    Period 2
    Period 2 title
    RW Period: 6 weeks (Week 41 to Week 46)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    RW Period: Placebo then Relamorelin 10 μg
    Arm description
    Participants who received placebo-matching relamorelin injected subcutaneously twice daily for 40 weeks, followed by relamorelin 10 μg injected twice daily for up to 6 weeks in the Randomized Withdrawal (RW) Period.
    Arm type
    Experimental

    Investigational medicinal product name
    Relamorelin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Relamorelin 10 μg injected twice daily

    Arm title
    RW Period: Relamorelin 10 μg then Relamorelin 10 μg
    Arm description
    Participants who received relamorelin 10 μg injected subcutaneously twice daily for 40 weeks, followed by relamorelin injected twice daily for up to 6 weeks in the RW Period.
    Arm type
    Experimental

    Investigational medicinal product name
    Relamorelin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Relamorelin 10 μg injected twice daily

    Arm title
    RW Period: Relamorelin 10 μg then Placebo
    Arm description
    Participants who received relamorelin 10 μg injected subcutaneously twice daily for 40 weeks, followed by placebo-matching relamorelin injected twice daily for up to 6 weeks in the RW Period.
    Arm type
    Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Placebo injected twice daily

    Number of subjects in period 2 [1]
    RW Period: Placebo then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Placebo
    Started
    91
    59
    43
    Completed
    85
    54
    38
    Not completed
    6
    5
    5
         Adverse Event
    -
    2
    -
         Withdrawal by Subject
    -
    -
    2
         Study Terminated by the Sponsor
    6
    3
    3
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 4 participants who completed the Treatment Period did not participate in the RW Period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Period: Placebo
    Reporting group description
    Placebo-matching relamorelin injected subcutaneously twice daily for up to 40 weeks.

    Reporting group title
    Treatment Period: Relamorelin 10 μg
    Reporting group description
    Relamorelin 10 micrograms (μg) injected subcutaneously twice daily for up to 40 weeks.

    Reporting group values
    Treatment Period: Placebo Treatment Period: Relamorelin 10 μg Total
    Number of subjects
    236 231 467
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    180 175 355
        From 65-84 years
    56 55 111
        >= 85 years
    0 1 1
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    55.5 ± 11.11 56.2 ± 11.51 -
    Sex: Female, Male
    Units: participants
        Female
    162 166 328
        Male
    74 65 139
    Race
    Units: Subjects
        American Indian or Alaska Native
    3 8 11
        Asian
    21 18 39
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    37 21 58
        White
    175 183 358
        More than one race
    0 1 1
        Unknown or Not Reported
    0 0 0
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    83 82 165
        Not Hispanic or Latino
    153 149 302
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Treatment Period: Placebo
    Reporting group description
    Placebo-matching relamorelin injected subcutaneously twice daily for up to 40 weeks.

    Reporting group title
    Treatment Period: Relamorelin 10 μg
    Reporting group description
    Relamorelin 10 micrograms (μg) injected subcutaneously twice daily for up to 40 weeks.
    Reporting group title
    RW Period: Placebo then Relamorelin 10 μg
    Reporting group description
    Participants who received placebo-matching relamorelin injected subcutaneously twice daily for 40 weeks, followed by relamorelin 10 μg injected twice daily for up to 6 weeks in the Randomized Withdrawal (RW) Period.

    Reporting group title
    RW Period: Relamorelin 10 μg then Relamorelin 10 μg
    Reporting group description
    Participants who received relamorelin 10 μg injected subcutaneously twice daily for 40 weeks, followed by relamorelin injected twice daily for up to 6 weeks in the RW Period.

    Reporting group title
    RW Period: Relamorelin 10 μg then Placebo
    Reporting group description
    Participants who received relamorelin 10 μg injected subcutaneously twice daily for 40 weeks, followed by placebo-matching relamorelin injected twice daily for up to 6 weeks in the RW Period.

    Primary: Change from Baseline to Week 12 in the Weekly Diabetic Gastroparesis Symptom Severity Score (DGSSS) of the Treatment Period

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    End point title
    Change from Baseline to Week 12 in the Weekly Diabetic Gastroparesis Symptom Severity Score (DGSSS) of the Treatment Period [1]
    End point description
    Participants assessed the severity of diabetic gastroparesis symptoms daily using the Diabetic Gastroparesis Symptom Severity Diary (DGSSD), recorded in an electronic diary (e-diary). The DGSSS was derived as the sum of the weekly averages of the 4 DGSSD items: nausea, abdominal pain, postprandial fullness and bloating. Each symptom was scored using an 11-point ordinal scale where: 0=no or not at all uncomfortable to 10=worst possible or most uncomfortable for a total possible DGSSS of 0 (best) to 40 (worst). A negative change from Baseline indicates improvement. Baseline was defined as the average of the 2 weekly DGSSS from the run-in period in the previous studies. Modified-intent-to-treat (mITT) Population included all participants in the ITT population with ≥1 postbaseline assessment of DGSSD. 'n' indicates number analysed is the number of participants with data available at the given time-point.
    End point type
    Primary
    End point timeframe
    Baseline (14-day Run-in Period of the previous relamorelin study RLM-MD-01 or RLM-MD-02) to Week 12 of this study
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    Treatment Period: Placebo Treatment Period: Relamorelin 10 μg
    Number of subjects analysed
    235
    229
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=235, 229)
    24.9 ± 5.65
    24.8 ± 6.28
        Change from Baseline to Week 12 (n=205, 202)
    -11.9 ± 9.43
    -11.2 ± 9.00
    No statistical analyses for this end point

    Primary: Percentage of Participants Meeting the Vomiting Responder Criterion During Each of the Last 6 Weeks of the First 12-weeks of the Treatment Period

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    End point title
    Percentage of Participants Meeting the Vomiting Responder Criterion During Each of the Last 6 Weeks of the First 12-weeks of the Treatment Period [2]
    End point description
    The number of vomiting episodes in the previous 24 hours were assessed daily by the participant using the DGSSD and were recorded in the e-diary. A Vomiting Responder was defined as a participant with zero weekly vomiting episodes during each of the last 6 weeks of the first 12-weeks of the 40-week Treatment Period. mITT Population included all participants in the ITT population with ≥1 postbaseline assessment of DGSSD.
    End point type
    Primary
    End point timeframe
    Week 6 to Week 12
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses are reported for this endpoint.
    End point values
    Treatment Period: Placebo Treatment Period: Relamorelin 10 μg
    Number of subjects analysed
    235
    229
    Units: percentage of participants
        number (not applicable)
    29.4
    21.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants Meeting the Nausea Responder Criterion During Each of the Last 6 Weeks of the First 12-weeks of the Treatment Period

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    End point title
    Percentage of Participants Meeting the Nausea Responder Criterion During Each of the Last 6 Weeks of the First 12-weeks of the Treatment Period
    End point description
    A Nausea Responder was defined as a participant with improvement (decrease) of at least 2-points in the weekly symptom scores for nausea at each of the last 6 weeks of the first 12-weeks of the 40-week Treatment Period. Nausea was one of the items of the DGSSD assessed daily and recorded in the e-diary by the participant using an 11-point ordinal scale where: 0=no nausea to 10=worst possible nausea. Baseline was defined as the average of the 2 weekly DGSSS from the run-in period in the previous studies. mITT Population included all participants in the ITT population with ≥1 postbaseline assessment of DGSSD.
    End point type
    Secondary
    End point timeframe
    Baseline (14-day Run-in Period of the previous relamorelin study RLM-MD-01 or RLM-MD-02) to (Week 6 to Week 12)
    End point values
    Treatment Period: Placebo Treatment Period: Relamorelin 10 μg
    Number of subjects analysed
    235
    229
    Units: percentage of participants
        number (not applicable)
    46.0
    43.2
    No statistical analyses for this end point

    Secondary: Percentage of Participants Meeting the Abdominal Pain Responder Criterion During Each of the Last 6 Weeks of the First 12-weeks of the Treatment Period

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    End point title
    Percentage of Participants Meeting the Abdominal Pain Responder Criterion During Each of the Last 6 Weeks of the First 12-weeks of the Treatment Period
    End point description
    An Abdominal Pain Responder was defined as a participant with an improvement (decrease) of at least 2-points in the weekly symptom scores for abdominal pain at each of the last 6 weeks of the first 12-weeks of the 40-week Treatment Period. Abdominal pain was one of the items of the DGSSD assessed daily and recorded in the e-diary by the participant using an 11-point ordinal scale where: 0=no abdominal pain to 10=the worst possible abdominal pain and was recorded in an e-diary. Baseline was defined as the average of the 2 weekly DGSSS from the run-in period in the previous studies. mITT Population included all participants in the ITT population with ≥1 postbaseline assessment of DGSSD.
    End point type
    Secondary
    End point timeframe
    Baseline (14-day Run-in Period of the previous relamorelin study RLM-MD-01 or RLM-MD-02) to (Week 6 to Week 12)
    End point values
    Treatment Period: Placebo Treatment Period: Relamorelin 10 μg
    Number of subjects analysed
    235
    229
    Units: percentage of participants
        number (not applicable)
    40.4
    39.7
    No statistical analyses for this end point

    Secondary: Percentage of Participants Meeting the Bloating Responder Criterion During Each of the Last 6 Weeks of the First 12-weeks of the Treatment Period

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    End point title
    Percentage of Participants Meeting the Bloating Responder Criterion During Each of the Last 6 Weeks of the First 12-weeks of the Treatment Period
    End point description
    A Bloating Responder was defined as a participant with an improvement (decrease) of at least 2-points in the weekly symptom scores for bloating at each of the last 6 weeks of the first 12-weeks of the 40-week Treatment Period. Bloating was one of the items of the DGSSD assessed daily and recorded by the participant in the e-diary using an 11-point ordinal scale where: 0=no bloating and 10=the worst possible bloating and was recorded in the e-diary. Baseline was defined as the average of the 2 weekly DGSSS from the run-in period in the previous studies. mITT Population included all participants in the ITT population with ≥1 postbaseline assessment of DGSSD.
    End point type
    Secondary
    End point timeframe
    Baseline (14-day Run-in Period of the previous relamorelin study RLM-MD-01 or RLM-MD-02) to (Week 6 to Week 12)
    End point values
    Treatment Period: Placebo Treatment Period: Relamorelin 10 μg
    Number of subjects analysed
    235
    229
    Units: percentage of participants
        number (not applicable)
    38.3
    38.4
    No statistical analyses for this end point

    Secondary: Percentage of Participants Meeting the Postprandial Fullness Responder Criterion During Each of the Last 6 Weeks of the First 12-weeks of the Treatment Period

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    End point title
    Percentage of Participants Meeting the Postprandial Fullness Responder Criterion During Each of the Last 6 Weeks of the First 12-weeks of the Treatment Period
    End point description
    A Postprandial Fullness Responder was defined as a participant with an improvement (decrease) of at least 2-points in the weekly symptom scores for Postprandial Fullness at each of the last 6 weeks of the first 12-weeks of the 40-week Treatment Period. Postprandial Fullness was one of the items of the DGSSD assessed daily and recorded by the participant in the e-diary using an 11-point ordinal scale where: 0=no feeling of fullness until finishing a meal (best) to 10=feeling full after only a few bites (worst). Baseline was defined as the average of the 2 weekly DGSSS from the run-in period in the previous studies. mITT Population included all participants in the ITT population with ≥1 postbaseline assessment of DGSSD.
    End point type
    Secondary
    End point timeframe
    Baseline (14-day Run-in Period of the previous relamorelin study RLM-MD-01 or RLM-MD-02) to (Week 6 to Week 12)
    End point values
    Treatment Period: Placebo Treatment Period: Relamorelin 10 μg
    Number of subjects analysed
    235
    229
    Units: percentage of participants
        number (not applicable)
    36.6
    36.2
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 40 in the Average Weekly DGSSS of the Treatment Period

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    End point title
    Change from Baseline to Week 40 in the Average Weekly DGSSS of the Treatment Period
    End point description
    Participants assessed the severity of diabetic gastroparesis symptoms daily using the DGSSD, recorded in an e-diary. The DGSSS was derived as the sum of the weekly averages (Week 37 to Week 40) of the 4 DGSSD items: nausea, abdominal pain, postprandial fullness and bloating. Each symptom was scored using an 11-point ordinal scale where: 0=no or not at all uncomfortable to 10=worst possible or most uncomfortable for a total possible DGSSS of 0 (best) to 40 (worst). A negative change from Baseline indicates improvement. Baseline was defined as the average of the 2 weekly DGSSS from the run-in period of the previous studies. mITT Population included all participants in the ITT population with ≥1 postbaseline assessment of DGSSD. 'n' indicates number analysed is the number of participants with data available at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline (14-day Run-in Period of the previous relamorelin study RLM-MD-01 or RLM-MD-02) to (Week 37 to Week 40)
    End point values
    Treatment Period: Placebo Treatment Period: Relamorelin 10 μg
    Number of subjects analysed
    235
    229
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=235, 229)
    24.9 ± 5.65
    24.8 ± 6.28
        Change from Baseline to Week 40 (n=112, 123)
    -13.3 ± 10.22
    -12.3 ± 9.20
    No statistical analyses for this end point

    Secondary: Percentage of Participants Meeting the Vomiting Responder Criterion at Week 40 of the Treatment Period

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    End point title
    Percentage of Participants Meeting the Vomiting Responder Criterion at Week 40 of the Treatment Period
    End point description
    The number of vomiting episodes in the previous 24 hours were assessed daily by the participant using the DGSSD and were recorded in the e-diary. A Vomiting Responder was defined as a participant with zero weekly vomiting episodes during the last 4 weeks of the 40-week Treatment Period. mITT Population included all participants in the ITT population with ≥1 postbaseline assessment of DGSSD.
    End point type
    Secondary
    End point timeframe
    Week 37 to Week 40
    End point values
    Treatment Period: Placebo Treatment Period: Relamorelin 10 μg
    Number of subjects analysed
    235
    229
    Units: percentage of participants
        number (not applicable)
    19.1
    18.8
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 40 in the Average Weekly Number of Vomiting Episodes of the Treatment Period

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    End point title
    Change from Baseline to Week 40 in the Average Weekly Number of Vomiting Episodes of the Treatment Period
    End point description
    The number of vomiting episodes in the previous 24 hours were assessed daily by the participant using the DGSSD and were recorded in the e-diary. The average weekly number of vomiting episodes were derived as the average of the weekly number of vomiting episodes in the last 4 weeks of the 40-week Treatment Period. A negative change from Baseline indicates improvement. Baseline was defined as the average of the 2 weekly DGSSS from the run-in period in the previous studies. mITT Population included all participants in the ITT population with ≥1 postbaseline assessment of DGSSD. 'n' indicates number analysed is the number of participants with data available at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline (14-day Run-in Period of the previous relamorelin study RLM-MD-01 or RLM-MD-02) to (Week 37 to Week 40)
    End point values
    Treatment Period: Placebo Treatment Period: Relamorelin 10 μg
    Number of subjects analysed
    235
    229
    Units: vomiting episodes per week
    arithmetic mean (standard deviation)
        Baseline (n=235, 229)
    6.8 ± 11.09
    7.3 ± 11.52
        Change from Baseline to Week 40 (n=112, 123)
    -1.8 ± 17.51
    -5.4 ± 11.87
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 46 in the Average Weekly DGSSS of the RW Period

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    End point title
    Change from Baseline to Week 46 in the Average Weekly DGSSS of the RW Period
    End point description
    Participants assessed the severity of diabetic gastroparesis symptoms daily using the DGSSD, recorded in an e-diary. The DGSSS was derived as the sum of the weekly averages of the 4 DGSSD items: nausea, abdominal pain, postprandial fullness and bloating. Each symptom was scored using an 11-point ordinal scale where: 0=no or not at all uncomfortable to 10=worst possible or most uncomfortable for a total possible DGSSS of 0 (best) to 40 (worst). Average weekly scores are derived as the average of the weekly scores from the 6 weeks of the RW Period. A negative change from Baseline indicates improvement. Baseline was defined as the average of the 2 weekly DGSSS from the run-in period in the previous studies. RW Population included all participants who were re-randomised or assigned to a treatment of RW Period and received ≥1 administration of study treatment during the RW Period. 'n' indicates number analysed is the number of participants with data available at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline (14-day Run-in Period of the previous relamorelin study RLM-MD-01 or RLM-MD-02) to (Week 41 to Week 46)
    End point values
    RW Period: Placebo then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Placebo
    Number of subjects analysed
    91
    58
    43
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=91, 58, 43)
    25.7 ± 5.65
    25.7 ± 6.25
    24.4 ± 5.47
        Change from Baseline to Week 46 (n=86, 56, 39)
    -13.4 ± 10.45
    -12.5 ± 9.71
    -12.5 ± 9.35
    No statistical analyses for this end point

    Secondary: Change from Baseline to Week 46 in the Average Weekly Number of Vomiting Episodes of the RW Period

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    End point title
    Change from Baseline to Week 46 in the Average Weekly Number of Vomiting Episodes of the RW Period
    End point description
    The number of vomiting episodes in the previous 24 hours were assessed daily by the participant using the DGSSD and were recorded in the e-diary. Average weekly number of vomiting episodes are derived as the average of the weekly number of vomiting episodes from the six weeks of the RW Period. A negative change from Baseline indicates improvement. Baseline was defined as the average of the 2 weekly DGSSS from the run-in period in the previous studies. RW Population included all participants who were re-randomised or assigned to a treatment of RW Period and received ≥1 administration of study treatment during the RW Period. 'n' indicates number analysed is the number of participants with data available at the given time-point.
    End point type
    Secondary
    End point timeframe
    Baseline (14-day Run-in Period of the previous relamorelin study RLM-MD-01 or RLM-MD-02) to (Week 41 to Week 46)
    End point values
    RW Period: Placebo then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Placebo
    Number of subjects analysed
    91
    58
    43
    Units: vomiting episodes per week
    arithmetic mean (standard deviation)
        Baseline (n=91, 58, 43)
    6.1 ± 7.01
    9.9 ± 11.92
    4.2 ± 4.73
        Change from Baseline to Week 46 (n=86, 56, 39)
    -1.8 ± 18.40
    -7.3 ± 10.23
    -1.8 ± 6.12
    No statistical analyses for this end point

    Secondary: Number of Participants who Experienced One or More Treatment-Emergent Adverse Events (TEAE)

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    End point title
    Number of Participants who Experienced One or More Treatment-Emergent Adverse Events (TEAE)
    End point description
    An adverse event (AE) is any untoward medical occurrence in a patient or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of study treatment. A TEAE is an AE that begins or worsens after receiving study drug. Safety Population included all participants in the ITT population who received ≥1 administration of study treatment in Treatment Period. RW Population included all participants who were re-randomised or assigned to a treatment of RW population and received ≥1 administration of study treatment during the RW Period.
    End point type
    Secondary
    End point timeframe
    First dose of study drug to within 30 days of the last dose of study drug (Up to approximately 50 weeks)
    End point values
    Treatment Period: Placebo RW Period: Placebo then Relamorelin 10 μg Treatment Period: Relamorelin 10 μg RW Period: Relamorelin 10 μg then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Placebo
    Number of subjects analysed
    235
    91
    231
    59
    43
    Units: participants
    129
    18
    131
    12
    8
    No statistical analyses for this end point

    Secondary: Number of Participants with Potential Clinically Significant (PCS) Clinical Laboratory Results

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    End point title
    Number of Participants with Potential Clinically Significant (PCS) Clinical Laboratory Results
    End point description
    Clinical Laboratory values:Hematology,Chemistry,Urinalysis tests. The investigator determined if results were clinically significant. Only those categories where at least 1 person had a non-PCS value at Baseline and met PCS criterion at least once during postbaseline are reported. Safety Population:all participants in ITT population who received ≥1 administration of study treatment in Treatment Period. RW Population:all participants who were re-randomised or assigned to a treatment of RW population and received ≥1 administration of study treatment during RW Period. 'n'=number analysed is the number of participants with non-PCS Baseline values and at least one post-baseline assessment. ACC=AbsoluteCellCount,ULN=upper limit of normal value,LLN=lower limit of normal value,L=liter,MCV=MeanCorpuscularVolume,fL=femtoliter,PC=PlateletCount,RBC=RedBloodCell,WBC=WhiteBloodCell,BUN=BloodUreaNitrogen,TF=TotalFasting,Hb=Glycohemoglobin,AT=aminotransferase,U=unit,mmol=millimoles,μmol=micromoles.
    End point type
    Secondary
    End point timeframe
    Up to 46 weeks
    End point values
    Treatment Period: Placebo RW Period: Placebo then Relamorelin 10 μg Treatment Period: Relamorelin 10 μg RW Period: Relamorelin 10 μg then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Placebo
    Number of subjects analysed
    235
    91
    231
    59
    43
    Units: participants
        Eosinophils ACC[10^9/L]:>3×ULN(n=227,225,91,59,43)
    2
    0
    1
    1
    1
        Hematocrit (RATIO): >1.1×ULN (n=214,224,86,59,42)
    1
    2
    2
    1
    0
        Hematocrit (RATIO): <0.9×LLN (n=214,224,86,59,42)
    7
    4
    7
    0
    2
        Hemoglobin [g/L]: <0.9×LLN (n=214,220,86,58,42)
    13
    5
    14
    1
    4
        LymphocytesACC(10^9/L):<0.8×LLN;n=226,221,90,57,42
    1
    0
    4
    0
    0
        MCV [fL]: >1.1×ULN (n=222,224,89,59,43)
    2
    1
    3
    0
    0
        MCV [fL]: <0.9×LLN (n=222,224,89,59,43)
    4
    1
    0
    0
    0
        NeutrophilsACC(10^9/L):>1.5×ULN;n=224,221,90,57,41
    0
    2
    2
    0
    0
        NeutrophilsACC(10^9/L):<0.8×LLN;n=224,221,90,57,41
    6
    2
    4
    0
    0
        PC,Thrombocytes;10^9/L:>1.5×ULN;n=227,224,91,59,42
    0
    0
    1
    0
    0
        PC,Thrombocytes;10^9/L:<0.5×LLN;n=227,224,91,59,42
    1
    0
    0
    0
    0
        RBC Count (10^12/L): >1.1×ULN (n=223,224,90,58,42)
    1
    0
    0
    0
    0
        RBC Count (10^12/L): <0.9×LLN (n=223,224,90,58,42)
    4
    4
    8
    1
    0
        WBC Count (10^9/L): <0.7×LLN (n=227,225,91,59,42)
    2
    0
    0
    0
    0
        Alanine AT [U/L]: >=3×ULN (n=227,225,91,59,43)
    2
    0
    2
    2
    1
        Albumin (g/L): <0.9×LLN (n=225,226,90,59,43)
    1
    1
    1
    0
    1
        AlkalinePhosphatase;U/L:>=3×ULN;n=227,226,91,59,43
    0
    0
    3
    0
    0
        Aspartate AT (U/L): >=3×ULN (n=227,225,91,59,42)
    3
    0
    2
    0
    0
        Bicarbonate [mmol/L]:>1.1×ULN (n=223,218,91,58,41)
    3
    1
    2
    1
    0
        Bicarbonate (mmol)/L:>0.9×LLN (n=223,218,91,58,41)
    6
    2
    9
    4
    1
        Bilirubin,Total;μmol/L:>1.5×ULN;n=227,226,91,59,43
    1
    0
    0
    0
    0
        BUN (mmol/L): >1.2×ULN (n=207,207,84,52,39)
    29
    8
    20
    4
    4
        Calcium (mmol/L): >1.1×ULN (n=225,221,90,57,42)
    1
    1
    0
    0
    0
        Calcium (mmol/L): <0.9×LLN (n=225,221,90,57,42)
    1
    0
    0
    0
    1
        Chloride (mmol/L): <0.9×LLN (n=227,226,91,59,43)
    2
    1
    1
    0
    1
        CholesterolTF(mmol/L):>1.6×ULN(n=221,222,90,59,43)
    4
    0
    1
    1
    0
        Creatinine (μmol/L): >1.3×ULN (n=211,213,84,51,41)
    22
    5
    16
    2
    3
        Glucose Fasting,mmol/L:>2.5×ULN;n=206,201,84,56,41
    41
    9
    33
    9
    4
        Glucose Fasting,mmol/L:<0.9×LLN;n=206,201,84,56,41
    14
    4
    9
    2
    2
        HbA1C: Increase of >=0.5% (n=224,223,91,59,43)
    134
    62
    138
    26
    28
        HbA1C: Increase of >=1% (n=224,223,91,59,43)
    134
    62
    138
    26
    28
        Phosphorus (mmol/L):>1.1×ULN (n=221,219,88,56,43)
    10
    4
    12
    4
    4
        Phosphorus (mmol/L):<0.9×LLN (n=221,219,88,56,43)
    4
    0
    3
    0
    0
        Potassium (mmol/L): <0.9×LLN (n=227,226,91,59,43)
    0
    2
    0
    0
    0
        Protein, Total (g/L):>1.1×ULN (n=225,226,90,59,43)
    0
    0
    1
    0
    0
        Protein, Total (g/L):<0.9×LLN (n=225,226,90,59,43)
    0
    0
    1
    0
    1
        Triglycerides,mmol/L: >=3×ULN(n=217,216,87,58,42)
    9
    4
    11
    4
    2
        Uric Acid,Urate;μmol/L:>1.1×ULN;n=192,181,77,44,35
    31
    5
    31
    3
    1
        Uric Acid,Urate;μmol/L:<0.9×LLN;n=192,181,77,44,35
    3
    1
    4
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Meaningful Trends for Vital Signs

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    End point title
    Number of Participants with Clinically Meaningful Trends for Vital Signs
    End point description
    Vital Signs included assessments of heart rate, respiratory rate, systolic and diastolic blood pressure, and body temperature. The investigator determined if the results were clinically significant. Safety Population included all participants in the ITT population who received ≥1 administration of study treatment in Treatment Period. RW Population included all participants who were re-randomised or assigned to a treatment of RW population and received ≥1 administration of study treatment during the RW Period.
    End point type
    Secondary
    End point timeframe
    Up to 46 weeks
    End point values
    Treatment Period: Placebo RW Period: Placebo then Relamorelin 10 μg Treatment Period: Relamorelin 10 μg RW Period: Relamorelin 10 μg then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Placebo
    Number of subjects analysed
    235
    91
    231
    59
    43
    Units: participants
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with Clinically Significant Abnormal Electrocardiogram (ECG) Results

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    End point title
    Number of Participants with Clinically Significant Abnormal Electrocardiogram (ECG) Results
    End point description
    A standard 12-lead ECG was performed. The investigator determined if the abnormal results were clinically significant. Safety Population included all participants in the ITT population who received ≥1 administration of study treatment in Treatment Period. RW Population included all participants who were re-randomised or assigned to a treatment of RW population and received ≥1 administration of study treatment during the RW Period.
    End point type
    Secondary
    End point timeframe
    Up to 46 weeks
    End point values
    Treatment Period: Placebo RW Period: Placebo then Relamorelin 10 μg Treatment Period: Relamorelin 10 μg RW Period: Relamorelin 10 μg then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Placebo
    Number of subjects analysed
    235
    91
    231
    59
    43
    Units: participants
    3
    0
    2
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Participants with a ≥1% Increase in Glycosylated Hemoglobin A1c (HBA1c)

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    End point title
    Number of Participants with a ≥1% Increase in Glycosylated Hemoglobin A1c (HBA1c)
    End point description
    Safety Population included all participants in the ITT population who received ≥1 administration of study treatment in Treatment Period. RW Population included all participants who were re-randomised or assigned to a treatment of RW population and received ≥1 administration of study treatment during the RW Period. Overall number analysed is the number of participants with non-PCS Baseline values and at least one postbaseline assessment.
    End point type
    Secondary
    End point timeframe
    Up to 46 weeks
    End point values
    Treatment Period: Placebo RW Period: Placebo then Relamorelin 10 μg Treatment Period: Relamorelin 10 μg RW Period: Relamorelin 10 μg then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Placebo
    Number of subjects analysed
    224
    91
    223
    59
    43
    Units: participants
    134
    62
    138
    26
    28
    No statistical analyses for this end point

    Secondary: Number of Participants with Anti-relamorelin Antibody Testing Results

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    End point title
    Number of Participants with Anti-relamorelin Antibody Testing Results [3]
    End point description
    A blood sample was collected that was sent to a laboratory for an anti-relamorelin antibody screening test. A positive screening test was confirmed by an immunodepletion assay. Safety Population included all participants who received ≥ 1 administration of double-blind study treatment (N=231 in the Relamorelin 10 μg arm). Anti-relamorelin antibody testing was only done for those participants who received treatment with relamorelin. No data was transferred to the sponsor. The one batch that was analysed, failed and was not repeated.
    End point type
    Secondary
    End point timeframe
    Up to 46 weeks
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Not all Baseline arms are applicable to this endpoint.
    End point values
    Treatment Period: Relamorelin 10 μg
    Number of subjects analysed
    0 [4]
    Units: participants
    Notes
    [4] - No data was transferred to the sponsor. One batch that was analysed, failed and was not repeated.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose of study drug to within 30 days of the last dose of study drug (Up to approximately 50 weeks)
    Adverse event reporting additional description
    All-Cause Mortality:all randomised participants. Adverse Events:Safety Population-all participants in ITT who received ≥1 administration of study treatment in Treatment Period; RW Population:all participants who were re-randomised or assigned to a treatment of RW population and received ≥1 administration of study treatment during the RW Period.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Treatment Period: Relamorelin 10 μg
    Reporting group description
    Relamorelin 10 μg injected subcutaneously twice daily for up to 40 weeks.

    Reporting group title
    Treatment Period: Placebo‌
    Reporting group description
    Placebo-matching relamorelin injected subcutaneously twice daily for up to 40 weeks.

    Reporting group title
    RW Period: Relamorelin 10 μg then Relamorelin 10 μg
    Reporting group description
    Participants who received relamorelin 10 μg injected subcutaneously twice daily for 40 weeks, followed by relamorelin injected twice daily for up to 6 weeks in the RW Period.

    Reporting group title
    RW Period: Relamorelin 10 μg then Placebo
    Reporting group description
    Participants who received relamorelin 10 μg injected subcutaneously twice daily for 40 weeks, followed by placebo-matching relamorelin injected twice daily for up to 6 weeks in the RW Period.

    Reporting group title
    RW Period: Placebo then Relamorelin 10 μg
    Reporting group description
    Participants who received placebo-matching relamorelin injected subcutaneously twice daily for 40 weeks, followed by relamorelin 10 μg injected twice daily for up to 6 weeks in the RW Period.

    Serious adverse events
    Treatment Period: Relamorelin 10 μg Treatment Period: Placebo‌ RW Period: Relamorelin 10 μg then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Placebo RW Period: Placebo then Relamorelin 10 μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    20 / 231 (8.66%)
    24 / 235 (10.21%)
    2 / 59 (3.39%)
    1 / 43 (2.33%)
    3 / 91 (3.30%)
         number of deaths (all causes)
    2
    3
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder transitional cell carcinoma metastatic
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral vascular disorder
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Accelerated hypertension
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    1 / 43 (2.33%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory distress syndrome
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory distress
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Confusional state
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychogenic tremor
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Chemical poisoning
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rib fracture
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    1 / 43 (2.33%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Coronary artery disease
         subjects affected / exposed
    1 / 231 (0.43%)
    3 / 235 (1.28%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Supraventricular extrasystoles
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 235 (0.85%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atrial tachycardia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 235 (0.00%)
    1 / 59 (1.69%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Postinfarction angina
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 235 (0.00%)
    1 / 59 (1.69%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoaesthesia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    1 / 59 (1.69%)
    1 / 43 (2.33%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive encephalopathy
         subjects affected / exposed
    0 / 231 (0.00%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    1 / 43 (2.33%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Pancreatitis
         subjects affected / exposed
    2 / 231 (0.87%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hiatus hernia
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Duodenitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intestinal ischaemia
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    0 / 231 (0.00%)
    2 / 235 (0.85%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dermatitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    3 / 231 (1.30%)
    4 / 235 (1.70%)
    0 / 59 (0.00%)
    1 / 43 (2.33%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 4
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal chest pain
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    1 / 43 (2.33%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Osteomyelitis
         subjects affected / exposed
    1 / 231 (0.43%)
    2 / 235 (0.85%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abscess limb
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Atypical pneumonia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    1 / 91 (1.10%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis gangrenous
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Localised infection
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal bacteraemia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Staphylococcal infection
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis viral
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infected dermal cyst
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal abscess
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    3 / 231 (1.30%)
    2 / 235 (0.85%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypoglycaemia
         subjects affected / exposed
    1 / 231 (0.43%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertriglyceridaemia
         subjects affected / exposed
    1 / 231 (0.43%)
    0 / 235 (0.00%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolic acidosis
         subjects affected / exposed
    0 / 231 (0.00%)
    1 / 235 (0.43%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment Period: Relamorelin 10 μg Treatment Period: Placebo‌ RW Period: Relamorelin 10 μg then Relamorelin 10 μg RW Period: Relamorelin 10 μg then Placebo RW Period: Placebo then Relamorelin 10 μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 231 (11.69%)
    18 / 235 (7.66%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    16 / 231 (6.93%)
    13 / 235 (5.53%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    22
    13
    0
    0
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    12 / 231 (5.19%)
    7 / 235 (2.98%)
    0 / 59 (0.00%)
    0 / 43 (0.00%)
    0 / 91 (0.00%)
         occurrences all number
    21
    7
    0
    0
    0

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    29 Mar 2018
    The following changes were implemented with Amendment 1: -Increased the number of study sites from 300 to 400 -Added anti-relamorelin antibodies as a secondary endpoint –Indicated that the Early Termination Visit was performed as soon as possible after the decision has been made -Included inspection of injection sites -Indicated that pregnancy testing was performed if required by local regulations -Indicated that a clinically significant injection site reaction should be reported as an adverse event (AE) -Added exclusion criterion regarding exclusion of participants involved in the conduct of administration of the study, or enrolled at another site -Provided an exception to the opioid prohibition -Indicated that the Early Termination Visit was performed as soon as possible after the decision to discontinue was made -Revised the time Period for AE/serious adverse event (SAE) collection to include “until 30 days after” the final visit -Amended the major adverse cardiovascular events (MACE) text for clarity and to describe the planned adjudication process -Amended physical examinations to add text about injection site inspection and clinically significant injection site reactions -Revised the contraception guidance and added recommendations for acceptable birth control methods.
    04 Mar 2019
    The following changes were implemented with Amendment 2: -Modified primary endpoint to specify “change from Baseline (CFB) at Week 12”; defined Vomiting Week 12 Responder for primary endpoint; deleted diabetic gastroparesis symptom severity diary (DGSSS) Week 40 Responder as a secondary endpoint -Increased the number of sites from approximately 400 to approximately 700 -Added electrocardiogram (ECG) assessment at Visit 4 -Modified clinical hypotheses -Added a cross reference to inclusion criterion -Deleted option for investigator to contact sponsor if the participant could not inject study treatment into abdomen -Unblinding procedures modified -Provided more specific guidelines for prohibiting anti-emetics; added 5-Hydroxytryptamine receptor 4 (5HT4) agonists; added tramadol as an opioid example -Removed antihistamines as an example of an anti-emetic drug -Removed “non-compliance with study treatment” -Added requirement for the investigator to contact the sponsor under specific conditions -Added the phrase “Inadequate Control of Diabetes” to section title -Specified 10 micrograms (μg) twice a day (BID) or 20 μg/day as maximum recommended dose and deleted statement referencing a dose of greater than 150 μg BID to be considered an overdose -Added CFB mixed model for repeated measures (MMRM) methodology and description, defined MMRM -Updated DGSSS key endpoint, along with description, timing, and methodology; deleted DGSSS Week 40 Responder as a secondary endpoint -Updated language with regards to the key endpoints -Replaced language about specific analyses and how they were described in statistical analysis plan (SAP).
    04 Mar 2019
    -Added a requirement for a Data Safety Monitoring Board (DSMB) to review interim safety data at defined intervals throughout the study -Additional criteria added for informed consent (IC) process for written documentation to be obtained in accordance with relevant country and local privacy requirements -Replaced requirement for records and documents to be retained for 15 years after study completion to requirement for them to be retained as per the clinical trial agreement -Added bullet about relevant country requirements -Revised procedures for reporting AE of special interest (AESIs); specified that specific diabetic gastroparesis (DG) manifestations were captured in the DGSSS -Identified specific AESIs -Added more options to highly effective methods that are user independent; added example of bilateral tubal occlusion; moved list of “Acceptable Methods” to table from text; specified that 2 acceptable methods of contraception should be used during treatment; female participants who become pregnant: deleted text that an elective termination is an AE or SAE; provided examples and details for abnormal pregnancy outcomes, including genetic abnormalities; deleted hormonal contraception’s susceptible interaction with study intervention -Corrected trial length from 52 to 46 weeks.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Oct 2020
    The study was prematurely terminated on 30 October 2020 as the sponsor decided not to develop the investigational product further. The study termination was not due to any safety concerns. As a result, only descriptive primary and secondary efficacy analyses and selected key safety analyses were conducted.
    -

    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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