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    Clinical Trial Results:
    A 12-week, Randomized, Double-blind, Placebo-controlled, Phase 3 Study to Evaluate the Safety and Efficacy of Relamorelin in Patients with Diabetic Gastroparesis

    Summary
    EudraCT number
    2017-002136-16
    Trial protocol
    FR   BG   ES   IT  
    Global end of trial date
    08 Jul 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    26 Jul 2021
    First version publication date
    26 Jul 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RLM-MD-01
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03285308
    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
    08 Jul 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main purpose of the study was to evaluate the safety and efficacy of relamorelin compared to placebo in participants with diabetic gastroparesis. Participants will report daily severity scores of their diabetic gastroparesis symptoms.
    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
    29 Sep 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Bulgaria: 3
    Country: Number of subjects enrolled
    Australia: 1
    Country: Number of subjects enrolled
    India: 46
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Malaysia: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Ukraine: 36
    Country: Number of subjects enrolled
    United States: 236
    Worldwide total number of subjects
    336
    EEA total number of subjects
    12
    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)
    259
    From 65 to 84 years
    77
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    Participants with a diagnosis of diabetic gastroparesis entered a screening period of up to 4 weeks, a 2-week run-in period, and a 12-week treatment period. The participants were randomised in 1:1 ratio to blinded treatment period with relamorelin 10 μg or placebo.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Following a 2-week placebo run-in, participants received placebo-matching relamorelin injected subcutaneously twice daily for up to 12 weeks.
    Arm type
    Placebo

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

    Arm title
    Relamorelin 10 μg
    Arm description
    Following a 2-week placebo run-in, participants received relamorelin 10 μg injected subcutaneously twice daily for up to 12 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 micrograms (μg) injected subcutaneously twice daily.

    Number of subjects in period 1
    Placebo Relamorelin 10 μg
    Started
    167
    169
    Safety Population
    163
    163
    Completed
    147
    146
    Not completed
    20
    23
         Consent withdrawn by subject
    8
    9
         Adverse event, non-fatal
    3
    7
         Protocol Deviation
    6
    5
         Lost to follow-up
    3
    1
         Reason not Specified
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Following a 2-week placebo run-in, participants received placebo-matching relamorelin injected subcutaneously twice daily for up to 12 weeks.

    Reporting group title
    Relamorelin 10 μg
    Reporting group description
    Following a 2-week placebo run-in, participants received relamorelin 10 μg injected subcutaneously twice daily for up to 12 weeks.

    Reporting group values
    Placebo Relamorelin 10 μg Total
    Number of subjects
    167 169 336
    Age categorical
    Units: Subjects
        Adults (<65 years)
    130 129 259
        From >= 65 years
    37 40 77
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    55.4 ± 10.78 56.3 ± 11.47 -
    Sex: Female, Male
    Units: participants
        Female
    107 115 222
        Male
    60 54 114
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 1 1
        Asian
    26 24 50
        Native Hawaiian or Other Pacific Islander
    0 0 0
        Black or African American
    25 19 44
        White
    116 125 241
        More than one race
    0 0 0
        Unknown or Not Reported
    0 0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    51 53 104
        Not Hispanic or Latino
    116 116 232
        Unknown or Not Reported
    0 0 0

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Following a 2-week placebo run-in, participants received placebo-matching relamorelin injected subcutaneously twice daily for up to 12 weeks.

    Reporting group title
    Relamorelin 10 μg
    Reporting group description
    Following a 2-week placebo run-in, participants received relamorelin 10 μg injected subcutaneously twice daily for up to 12 weeks.

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

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    End point title
    Change from Baseline to Week 12 in the Weekly Diabetic Gastroparesis Symptom Severity Score (DGSSS) [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. Modified Intent-to-treat (mITT) Population included all randomised participants 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 (Day-14 to Day-1) to Week 12
    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: Due to early termination of the trial, only a descriptive analyses for the primary and secondary efficacy endpoints were performed.
    End point values
    Placebo Relamorelin 10 μg
    Number of subjects analysed
    163
    165
    Units: score on a scale
    arithmetic mean (standard deviation)
        Baseline (n=163, 165)
    25.1 ± 5.53
    24.5 ± 5.99
        Change from Baseline to Week 12 (n=142, 141)
    -10.0 ± 8.89
    -9.3 ± 8.17
    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 12-week 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 12-week 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 12-week Treatment Period. mITT Population included all randomised participants 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: Due to early termination of the trial, only a descriptive analyses for the primary and secondary efficacy endpoints were performed.
    End point values
    Placebo Relamorelin 10 μg
    Number of subjects analysed
    164
    165
    Units: percentage of participants
        number (not applicable)
    19.5
    21.8
    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 12-week 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 12-week 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 12-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. mITT Population included all randomised participants with ≥1 postbaseline assessment of DGSSD.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-14 to Day-1) to (Week 6 to Week 12)
    End point values
    Placebo Relamorelin 10 μg
    Number of subjects analysed
    164
    165
    Units: percentage of participants
        number (not applicable)
    34.1
    29.7
    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 12-week 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 12-week 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 12-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. mITT Population included all randomised participants with ≥1 postbaseline assessment of DGSSD.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-14 to Day-1) to (Week 6 to Week 12)
    End point values
    Placebo Relamorelin 10 μg
    Number of subjects analysed
    164
    165
    Units: percentage of participants
        number (not applicable)
    28.0
    27.9
    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 12-week 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 12-week 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 12-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. mITT Population included all randomised participants with ≥1 postbaseline assessment of DGSSD.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-14 to Day-1) to (Week 6 to Week 12)
    End point values
    Placebo Relamorelin 10 μg
    Number of subjects analysed
    164
    165
    Units: percentage of participants
        number (not applicable)
    26.2
    27.9
    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 12-week 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 12-week 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 12-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). mITT Population included all randomised participants with ≥1 postbaseline assessment of DGSSD.
    End point type
    Secondary
    End point timeframe
    Baseline (Day-14 to Day-1) to (Week 6 to Week 12)
    End point values
    Placebo Relamorelin 10 μg
    Number of subjects analysed
    164
    165
    Units: percentage of participants
        number (not applicable)
    22.6
    25.5
    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 participant 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 who received ≥1 administration of double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Up approximately to 16 weeks
    End point values
    Placebo Relamorelin 10 μg
    Number of subjects analysed
    163
    163
    Units: participants
    68
    70
    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 tests included Hematology, Chemistry and Urinalysis tests. The investigator determined if the results were clinically significant. Only those categories where at least 1 person had a non-PCS value at Baseline and met the PCS criterion at least once during postbaseline are reported. Safety Population included all participants who received ≥1 administration of double-blind study treatment. 'n' indicates number analysed is the number of participants with non-PCS baseline values and at least one post-baseline assessment. Upper limit of normal value (ULN), lower limit of normal value (LLN), liter(L), femtoliter (fL), millimoles(mmol/L), micromoles(μmol/L), absolute cell count (ACC), platelet count (Thrombocytes), red blood cell (RBC), white blood cell (WBC), non-fasting (NF), fasting (F), glycohemoglobin A1C (HbA1c).
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    Placebo Relamorelin 10 μg
    Number of subjects analysed
    163
    163
    Units: participants
        Eosinophils ACC [10^9/L]: >3×ULN (n=152,158)
    0
    1
        Hematocrit (RATIO): <0.9×LLN (n=145,157)
    2
    2
        Hemoglobin (g/L): <0.9×LLN (n=147,153)
    10
    4
        Lymphocytes ACC (10^9/L): >1.5×ULN (n=151,158)
    1
    0
        Lymphocytes ACC (10^9/L): <0.8×LLN (n=151,158)
    2
    1
        Mean Corpuscular Volume (fL): >1.1×ULN (n=151,158)
    2
    0
        Neutrophils ACC (10^9/L): >1.5×ULN (n=150,156)
    0
    1
        Neutrophils ACC (10^9/L): <0.8×LLN (n=150,156)
    2
    3
        Thrombocytes (10^9/L): >1.5×ULN (n=152,158)
    0
    1
        RBC Count (10^12/L): >1.1×ULN (n=151,159)
    0
    1
        RBC Count (10^12/L): <0.9×LLN (n=151,159)
    1
    1
        WBC Count (10^9/L): >1.5×ULN (n=152,159)
    1
    1
        Bicarbonate (HCO3) (mmol/L): >1.1×ULN (n=152,156)
    3
    1
        Bicarbonate (HCO3) (mmol/L): >0.9×LLN (n=152,156)
    3
    1
        Blood Urea Nitrogen (mmol/L): >1.2×ULN (n=137,153)
    11
    11
        Calcium (mmol/L): <0.9×LLN (n=153,160)
    0
    1
        Cholesterol, Total, NF (mmol/L) (n=151,158)
    0
    1
        Creatinine [μmol/L]: >1.3×ULN (n=141,149)
    7
    8
        Glucose-Chemistry, F (mmol/L): >2.5×ULN(n=141,148)
    10
    21
        Glucose-Chemistry, F (mmol/L):<0.9×LLN(n=141,148)
    3
    1
        HbA1C: Increase of >=0.5% (n=155,160)
    91
    125
        HbA1C: Increase of >=1% (n=155,160)
    91
    124
        Phosphorus (mmol/L): >1.1×ULN (n=147,156)
    2
    5
        Phosphorus (mmol/L): <0.9×LLN (n=147,156)
    0
    1
        Triglycerides, F (mmol/L): >=3×ULN (n=149,154)
    5
    5
        Uric Acid (Urate) (μmol/L): >1.1×ULN (n=123,130)
    10
    18
        Uric Acid (Urate) (μmol/L): <0.9×LLN (n=123,130)
    1
    3
    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 who received ≥1 administration of double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    Placebo Relamorelin 10 μg
    Number of subjects analysed
    163
    163
    Units: participants
    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 who received ≥1 administration of double-blind study treatment.
    End point type
    Secondary
    End point timeframe
    Up to 12 weeks
    End point values
    Placebo Relamorelin 10 μg
    Number of subjects analysed
    163
    163
    Units: participants
    4
    3
    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
    HbA1c is also known as glycosylated hemoglobin. It is the concentration of glucose bound to hemoglobin as a percentage of the absolute maximum that can be bound. Safety Population included all participants who received ≥1 administration of double-blind study treatment. 'n' indicates number analysed is the number of participants with non-PCS Baseline values and at least one post-baseline assessment.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1) up to 12 weeks
    End point values
    Placebo Relamorelin 10 μg
    Number of subjects analysed
    163
    163
    Units: participants
        Glycohemoglobin A1C: Increase of >=0.5%(n=155,160)
    91
    125
        Glycohemoglobin A1C: Increase of >=1% (n=155,160)
    91
    124
    No statistical analyses for this end point

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

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    End point title
    Number of Participants with Anti-relamorelin Antibody Testing Results by Visit [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. The number of participants in each of the following categories are reported: Negative Screening Test, Positive Screening Test and Positive Confirmatory Test at each time point. Safety Population included all participants who received ≥ 1 administration of double-blind study treatment (N=163 in the Relamorelin 10 μg arm). Anti-relamorelin antibody testing was only done for those participants who received treatment with relamorelin. 'n' indicates number analysed is the number of participants with data available at the given timepoint. Due to a laboratory issue not all positive screening tests were confirmed.
    End point type
    Secondary
    End point timeframe
    Baseline (Day 1), Day 14, Day 28, Day 84, and End of Treatment (Up to Day 84)
    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: Due to early termination of the trial, only a descriptive analyses for the primary and secondary efficacy endpoints were performed.
    End point values
    Relamorelin 10 μg
    Number of subjects analysed
    163
    Units: participants
        Screening Test (Baseline) Negative (n=149)
    133
        Screening Test (Baseline) Positive (n=149)
    16
        Confirmatory Test (Baseline) Negative (n=15)
    13
        Confirmatory Test (Baseline) Positive (n=15)
    2
        Screening Test (Day 14) Negative (n=137)
    124
        Screening Test (Day 14) Positive (n=137)
    13
        Confirmatory Test (Day 14) Negative (n=13)
    13
        Confirmatory Test (Day 14) Positive (n=13)
    0
        Screening Test (Day 28) Negative (n=131)
    115
        Screening Test (Day 28) Positive (n=131)
    16
        Confirmatory Test (Day 28) Negative (n=16)
    15
        Confirmatory Test (Day 28) Positive (n=16)
    1
        Screening Test (Day 84) Negative (n=111)
    95
        Screening Test (Day 84) Positive (n=111)
    16
        Confirmatory Test (Day 84) Negative (n=15)
    14
        Confirmatory Test (Day 84) Positive (n=15)
    1
        Screening Test (End of Treatment) Negative (n=15)
    13
        Screening Test (End of Treatment) Positive (n=15)
    2
        Confirmatory Test (EOT) Negative (n=2)
    2
        Confirmatory Test (EOT) Positive (n=2)
    0
        Screening Test (Unscheduled) Negative (n=4)
    2
        Screening Test (Unscheduled) Positive (n=4)
    2
        Confirmatory Test (Unscheduled) Negative (n=2)
    1
        Confirmatory Test (Unscheduled) Positive (n=2)
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to approximately 16 weeks
    Adverse event reporting additional description
    All-Cause Mortality is based on the Intent-to-treat (ITT) Population. Safety Population, all participants who received ≥1 administration of double-blind study treatment, was used to determine the number of participants at risk for Serious Adverse Events and Other Adverse Events.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Following a 2-week placebo run-in, participants received placebo-matching relamorelin injected subcutaneously twice daily for up to 12 weeks.

    Reporting group title
    Relamorelin 10 μg
    Reporting group description
    Following a 2-week placebo run-in, participants received relamorelin 10 μg injected subcutaneously twice daily for up to 12 weeks.

    Serious adverse events
    Placebo Relamorelin 10 μg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    15 / 163 (9.20%)
    16 / 163 (9.82%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Investigations
    Anticoagulation drug level above therapeutic
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 163 (1.23%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ankle fracture
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 163 (0.61%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypovolaemic shock
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    1 / 163 (0.61%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Syncope
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Leukopenia
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 163 (0.61%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Impaired gastric emptying
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic gastroparesis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    2 / 163 (1.23%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Asthma
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypercapnia
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory failure
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    2 / 163 (1.23%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetic nephropathy
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nephrolithiasis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vertebral wedging
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    3 / 163 (1.84%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 163 (0.00%)
    2 / 163 (1.23%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    2 / 163 (1.23%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Acute sinusitis
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 163 (1.23%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cystitis
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis acute
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 163 (0.00%)
    1 / 163 (0.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dehydration
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diabetes mellitus
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperglycaemic hyperosmolar nonketotic syndrome
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 163 (0.61%)
    0 / 163 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Placebo Relamorelin 10 μg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 163 (5.52%)
    9 / 163 (5.52%)
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    9 / 163 (5.52%)
    9 / 163 (5.52%)
         occurrences all number
    10
    22

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Sep 2017
    The following changes were implemented with Amendment 1: -Changed the definition of the diabetic gastroparesis symptom severity diary (DGSSS) score for responder (the primary endpoint) from ≥8 point improvement to a ≥10 point improvement -Added GE by gastric emptying breath test (GEBTs) to Visit 7 and the early termination Visit, and to adjust the schedule of assessment (SoA) footnote l to add GEBT to assessments performed on a subset of participants at a subset of sites -Revised the wording of inclusion criteria -Revised the order of the inclusion and exclusion criteria -Added an exclusion criterion for hepatic disease -Removed the exclusion for treatment with a sodium-glucose co-transporter 2 (SGLT-2) -Reordered the objectives and endpoints -Corrected the maximum volumes of blood drawn for the scheduled labs and for the pharmacokinetic (PK) and hormone subset -Moved the questions for Patient Global Impression of Status and Impression of Change -Added information on the GEBT analysis -Revised the washout requirements for SGLT-2 inhibitors from 2 weeks prior to the start of the Run-in Period to 3 days prior to the GEBT done at the start of Run-in Period -Revised the sample size determination -Updated the definition of the PK population -Updated the statistical methodology to remove unused methodologies and descriptions -Removed the Multiple Comparisons Procedures for the United States and European Union, and added sections on multiple comparisons procedure and missing data -Added a new section on major adverse cardiovascular events -Clarified Hy’s Law and adverse events of special interest (AESI) reporting.
    18 Jan 2018
    The following changes were implemented with Amendment 2: -Removed glycated albumin from the safety endpoints and objectives and endpoints, and in the safety analyses -Increased the number of sites and participants screened -Moved no use of promotility agents and anti-emetics to after Run-in Period -Updated the SoA to add a new footnote (o) to PK samples at end of treatment (ET), to add fasting fingerstick glucose testing at Visit 7 and ET -Updated the SoA footnotes (f), (i). and (q) for clarity -Updated the SoA to add a new footnote (x) to inspect injection sites -Revised exclusion criterion -Inserted 2 new exclusion criteria -Revised treatments administered for clarity -Revised treatment compliance for clarity -Added text to concomitant therapy for clarity -Updated prohibited medications to clarify the use of anti-emetics, and to add an exception from the opioid prohibition -Updated rescue medicine to clarify the use of anti-emetics -Updated Patient Global Impression of Change-Diabetic Gastroparesis (PGIS-DG) for clarity -Updated major adverse cardiovascular events to define the required timing for reporting major adverse cardiovascular events (MACE) -Revised treatment of overdose for accuracy -Revise physical examinations for clarity -Updated PK to clarify PK draws at ET -Updated "Hommel test" was changed to "Holm test" -Updated clinical laboratory tests -Corrected the study title.
    25 Mar 2018
    The following changes were implemented with Amendment 3: -Revised SoA footnote (a) to indicate early termination visit must be performed as soon as possible after decision has been made -Revised SoA footnote (i) to clarify details of urine drug screen results -Revised SoA footnote (m) to indicate pregnancy testing can be performed if required by local regulations -Revised inclusion criterion 3 to remove treatment requirement “for at least 3 months” for participants being treated with medications for diabetes mellitus type I (T1DM) or diabetes mellitus type II (T2DM) -Revised inclusion criterion to remove upper limit for body mass index (BMI) -Revised exclusion criterion to clarify that celiac disease even if well-controlled on gluten-free diet is exclusionary, and to add history of non-celiac gluten sensitivity as exclusionary -Revised Exclusion Criterion 5 to remove functional dyspepsia -Deleted exclusion criterion which addresses anemia, replacing it with a new exclusion criterion for gastric or duodenal ulcer within 3 months of screening -Revised exclusion criterion 9 to reduce history of malignancy from 5 to 3 years -Revised exclusion criterion to shorten exclusion period for promotility agents from 2 weeks to 10 days -Revised exclusion criterion to clarify details of urine drug screen results -Revised exclusion criterion to extend exclusion for use of glucagon-like peptide-1 (GLP-1) agonists to 6 weeks, and remove pramlintide.
    25 Mar 2018
    -Revised exclusion criterion to remove the allowance for gluten-free crackers -Added exclusion criterion for functional dyspepsia diagnosed before diagnosis of diabetes mellitus -Revised screen failures to disallow rescreening after greater than 6 months -Revised Table 7-2 to shorten wash-out period for pro-motility agents, anticholinergics, anti-emetics, amylin analogue, and opioids from 2 weeks to 10 days prior to the start of Run-in Period; to extend exclusion for use of GLP-1 agonists from 2 to 6 weeks -Revised withdrawal from study to indicate ET Visit must be performed as soon as possible after the decision to discontinue has been made -Amended MACE text for clarity and to describe planned adjudication process -Added anti-relamorelin antibodies to other laboratory assessments in protocol-required safety laboratory assessments -Revised contraception guidance to add recommendations for acceptable birth control methods.
    08 Feb 2019
    The following changes were implemented with Amendment 4: - Modified definition of primary endpoints - Increased number of sites from approximately 200 to approximately 350 Increased number of participants screened from 2000 to 2500 -Added requirement for study population at screening to have had a history of at least 2 vomiting episodes and to have had at least 1 vomiting episode during Run-in Period - Removed body mass index (BMI) information - Start of screening period was revised from Day -28 to Day -42 -Increased duration of Screening Visit from 14 days to 28 days. Updated study schematic to reflect change in length of Screening Visit -Increased duration of study from 16 weeks to 18 weeks and increased screening period from 2 weeks to up to 4 weeks -Added footnote (a) for screening Visit -Added electrocardiogram (ECG) obtained at Visit 4 -Amended footnote (j) -Removed assessment of glycated albumin from SOA and all related text -Added footnote for fasting blood glucose: Serum for all visits except for Visit 4 and 6 (plasma) -Removed year in all references to the relamorelin investigator brochure -Amended clinical hypotheses -Amended inclusion #6 to allow for a GI series with contrast as an assessment tool for documenting absence of an obstructing lesion and adjust timing of assessments from some time before screening (Visit 1) to sometime before the Run-in Period (Visit 2) -Removed BMI criterion #9 -Inclusion #10: added a reference to Appendix 3 -Amended exclusion #3 to specify that participants with active eating disorders at the time of screening are to be excluded, as opposed to those with a history of eating disorders -exclusion #11: Added 5HT agonists as exclusionary drug -Amended exclusion #12 to allow a participant with a positive urine drug screen at Screening to continue in study while confirmatory testing is done on an aliquot of original sample; specified that opioids are not drugs for which investigator may choose not to consider exclusionary.
    08 Feb 2019
    -Added exclusion criteria for hypersensitivity to the study treatments and their excipients (Exclusion #25) and for specific corrected ECG results (Exclusion #26) -Added option for the sponsor to permit a participant with a positive urine drug screen at Screening to continue in the Screening Period while confirmatory urine drug screen testing by a more specific method is carried on an aliquot of the original sample -Clarified that the first dose of study treatment is to be administered within approximately 30 minutes before the morning meal and the second daily dose is to be administered within approximately 30 minutes before the evening meal -Deleted option for investigator to contact sponsor if the participant could not inject study treatment into abdomen -Unblinding procedures modified; requirement of investigator to notify sponsor prior to unblinding modified to encouraging the investigator to notify the sponsor prior to unblinding but requiring notification within 24 hours after breaking the blind -Removed: “non-compliance with study treatment” -Defined zero and 10 scores of the DG assessments -Changed Section 9.1.1.1 from diabetic gastroparesis symptom severity score (DGSSS) responder definition to Change from Baseline to Week 12 in the Weekly DGSSS -Revised assessment of DGSSS Weekly Scores -More assessments added in order to evaluate the additional endpoints -More assessments added in order to evaluate the additional endpoints -Added a row to describe Change from Baseline (CFB) -Updated primary endpoint and its description -Clarifications made to Hypothesis H1; reference made to SAP for other efficacy analyses -Added a requirement for a DSMB to review interim safety data at defined intervals throughout the study -Revised procedures for reporting AESIs; specified that specific DG manifestations will be captured in the DGSSS and not in the eCRF as a complication of the disease, as originally specified -Provided AESIs that have been identified for relamorelin.

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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