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    Clinical Trial Results:
    A Phase 3, Multicenter, Open-label Study to Determine the Efficacy, Safety, and Pharmacokinetics of Buccally Administered MHOS/SHP615 in Pediatric Subjects With Status Epilepticus (Convulsive) in the Hospital or Emergency Room

    Summary
    EudraCT number
    2020-000226-26
    Trial protocol
    Outside EU/EEA  
    Global end of trial date
    19 Aug 2019

    Results information
    Results version number
    v2(current)
    This version publication date
    25 Nov 2021
    First version publication date
    01 Mar 2020
    Other versions
    v1
    Version creation reason
    • Correction of full data set
    Information on paediatric regulatory details corrected

    Trial information

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    Trial identification
    Sponsor protocol code
    SHP615-301
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03336645
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Shire
    Sponsor organisation address
    300 Shire Way, Lexington, United States, MA 02421
    Public contact
    Study Director, Shire, 1 866-8425335, ClinicalTransparency@shire.com
    Scientific contact
    Study Director, Shire, 1 866-8425335, ClinicalTransparency@shire.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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    19 Aug 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Aug 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of this study was to assess the efficacy of midazolam hydrochloride oromucosal solution (MHOS/SHP615) administered buccally in pediatric subjects with convulsive status epilepticus (CSE).
    Protection of trial subjects
    The study was conducted in accordance with current applicable industry regulations, International Council for Harmonisation (ICH) Good Clinical Practice (GCP) Guideline E6 (1996) and any updates, European Union (EU) Directive 2001/20/EC and its updates, the ethical principles in the Declaration of Helsinki, and local ethical and legal requirements.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    23 Oct 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
    Japan: 25
    Worldwide total number of subjects
    25
    EEA total number of subjects
    0
    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)
    5
    Children (2-11 years)
    18
    Adolescents (12-17 years)
    2
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted at 28 study centers in the Japan between 23 October 2017 (first subject first visit) and 19 August 2019 (last subject last visit).

    Pre-assignment
    Screening details
    A total of 25 subjects were enrolled, received treatment and completed the study.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    SHP615
    Arm description
    Subjects received an oromucosal single fixed age-specific dose (2.5 mg: 3 months to less than [<] 1 year, 5 mg: 1 to <5 years, 7.5 mg: 5 to <10 years and 10 mg: 10 to <18 years) of MHOS/SHP615 solution on Day 1.
    Arm type
    Experimental

    Investigational medicinal product name
    Midazolam Hydrochloride Oromucosal Solution
    Investigational medicinal product code
    SHP615
    Other name
    Pharmaceutical forms
    Oromucosal solution
    Routes of administration
    Buccal use
    Dosage and administration details
    Subjects received MHOS/SHP615 oromucosal solution through buccal route.

    Number of subjects in period 1
    SHP615
    Started
    25
    Completed
    25

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    SHP615
    Reporting group description
    Subjects received an oromucosal single fixed age-specific dose (2.5 mg: 3 months to less than [<] 1 year, 5 mg: 1 to <5 years, 7.5 mg: 5 to <10 years and 10 mg: 10 to <18 years) of MHOS/SHP615 solution on Day 1.

    Reporting group values
    SHP615 Total
    Number of subjects
    25
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    4.63 ± 4.033 -
    Gender categorical
    Units: Subjects
        Female
    16 16
        Male
    9 9
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 0
        Asian
    25 25
        Native Hawaiian or Other Pacific Islander
    0 0
        Black or African American
    0 0
        White
    0 0
        More than one race
    0 0
        Unknown or Not Reported
    0 0
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    0 0
        Not Hispanic or Latino
    25 25
        Unknown or Not Reported
    0 0

    End points

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    End points reporting groups
    Reporting group title
    SHP615
    Reporting group description
    Subjects received an oromucosal single fixed age-specific dose (2.5 mg: 3 months to less than [<] 1 year, 5 mg: 1 to <5 years, 7.5 mg: 5 to <10 years and 10 mg: 10 to <18 years) of MHOS/SHP615 solution on Day 1.

    Primary: Percentage of Subjects with Response Rate

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    End point title
    Percentage of Subjects with Response Rate [1]
    End point description
    Response rate was defined as the percentage of subjects with therapeutic success. Therapeutic success was defined as the cessation of visible seizure activity within 10 minutes (mins) with a sustained absence of visible seizure activity for 30 minutes following a single dose of MHOS/SHP615 without the need for additional rescue medication. Percentage of subjects with response rate were reported. Full Analysis Set (FAS) consisted of all subjects in the safety set who had at least 1 assessment for determination of therapeutic success (date and time of the investigational product [IP] administration and seizure cessation for the initial seizure; subjects with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.
    End point type
    Primary
    End point timeframe
    From start of study drug administration up to 30 minutes post-dose
    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 and comparision analysis were performed for this endpoint.
    End point values
    SHP615
    Number of subjects analysed
    25
    Units: Percentage of subjects
        number (not applicable)
    80.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who had Sustained Absence of Seizure Activity for at Least 1, 4 and 6 Hours

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    End point title
    Percentage of Subjects Who had Sustained Absence of Seizure Activity for at Least 1, 4 and 6 Hours
    End point description
    Percentage of subject whose seizure event stopped within 10 mins of a single dose administration of SHP615 and who had sustained absence of seizure activity for at least 1, 4, and 6 hours were reported. FAS consisted of all subjects in the safety set who had at least 1 assessment for determination of therapeutic success (date and time of the IP administration and seizure cessation for the initial seizure; subjects with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration up to 1, 4 and 6 hours post-dose
    End point values
    SHP615
    Number of subjects analysed
    25
    Units: Percentage of subjects
    number (not applicable)
        At least 1 hour
    68.0
        At least 4 hours
    36.0
        At least 6 hours
    32.0
    No statistical analyses for this end point

    Secondary: Number of Subjects with Time to Resolution of Seizures (Convulsions)

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    End point title
    Number of Subjects with Time to Resolution of Seizures (Convulsions)
    End point description
    Time to resolution of seizures (convulsions) was calculated as time from IP administration to the end of the initial seizure or administration of rescue anticonvulsant medication, whichever occurs first,the initial seizure referred to the seizure that triggered the use of the IP and that was captured. Number of subjects with time to resolution of seizures (convulsions) was reported. FAS consisted of all subjects in the safety set who had at least 1 assessment for determination of therapeutic success (date and time of the IP administration and seizure cessation for the initial seizure; subjects with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration to follow-up (8 days)
    End point values
    SHP615
    Number of subjects analysed
    25
    Units: subjects
    21
    No statistical analyses for this end point

    Secondary: Number of Subjects with Time to Recovery of Consciousness

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    End point title
    Number of Subjects with Time to Recovery of Consciousness
    End point description
    Time to recovery of consciousness (in minutes) was calculated only for subjects who lost consciousness pre-dose as time from IP administration to recovery of consciousness post-dose or administration of rescue anticonvulsant medication, whichever occurs first. Number of subjects with time to recovery of consciousness was reported. FAS consisted of all subjects in the safety set who had at least 1 assessment for determination of therapeutic success (date and time of the IP administration and seizure cessation for the initial seizure; subjects with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration to follow-up (8 days)
    End point values
    SHP615
    Number of subjects analysed
    25
    Units: subjects
    19
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Required Additional Anticonvulsant Medication for Ongoing Status Epilepticus (SE)

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    End point title
    Percentage of Subjects Who Required Additional Anticonvulsant Medication for Ongoing Status Epilepticus (SE)
    End point description
    Percentage of subjects who required additional anticonvulsant medication for ongoing SE 10 minutes after a single dose of SHP615 were reported. FAS consisted of all subjects in the safety set who had at least 1 assessment for determination of therapeutic success (date and time of the IP administration and seizure cessation for the initial seizure; subjects with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.
    End point type
    Secondary
    End point timeframe
    10 minutes post-dose
    End point values
    SHP615
    Number of subjects analysed
    25
    Units: Percentage of Subjects
        number (not applicable)
    16.0
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Who Failed to Respond to the Treatment with SHP615

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    End point title
    Percentage of Subjects Who Failed to Respond to the Treatment with SHP615
    End point description
    Treatment failure/non-responder was defined as subjects with continuing seizure activity and/or the need for any additional rescue medication according to the participating healthcare setting protocol or guideline, for 10 minutes or more after a single dose of the IP. FAS consisted of all subjects in the safety set who had at least 1 assessment for determination of therapeutic success (date and time of the IP administration and seizure cessation for the initial seizure; subjects with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.
    End point type
    Secondary
    End point timeframe
    10 minutes post-dose
    End point values
    SHP615
    Number of subjects analysed
    25
    Units: Percentage of subjects
        number (not applicable)
    16.0
    No statistical analyses for this end point

    Secondary: Concentration of SHP615 in Plasma at 10 Minutes (C10)

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    End point title
    Concentration of SHP615 in Plasma at 10 Minutes (C10)
    End point description
    Concentration of SHP615 in plasma at 10 minutes was reported. Pharmacokinetic (PK) set consisted of all subjects who received a single dose of the IP and for whom at least 1 PK blood sample was collected post-dose. Here the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    10 minutes post-dose
    End point values
    SHP615
    Number of subjects analysed
    16
    Units: nanogram per milliliter (ng/mL)
        arithmetic mean (standard deviation)
    45.2 ± 21.3
    No statistical analyses for this end point

    Secondary: Maximum Plasma Concentration (Cmax) of SHP615

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    End point title
    Maximum Plasma Concentration (Cmax) of SHP615
    End point description
    Cmax of SHP615 in plasma was reported. PK set consisted of all subjects who received a single dose of the IP and for whom at least 1 PK blood sample was collected post-dose. Here the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    1, 3, 6 hours post-dose
    End point values
    SHP615
    Number of subjects analysed
    16
    Units: ng/mL
        arithmetic mean (standard deviation)
    78.0 ± 16.4
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve From Time Zero to 10 Minutes (AUC0-10) of SHP615 in Plasma

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    End point title
    Area Under the Concentration-time Curve From Time Zero to 10 Minutes (AUC0-10) of SHP615 in Plasma
    End point description
    AUC0-10 of SHP615 in plasma was reported. Here min ng/mL is minutes nanogram per milliliter. PK set consisted of all subjects who received a single dose of the IP and for whom at least 1 PK blood sample was collected post-dose. Here the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 10 minutes post-dose
    End point values
    SHP615
    Number of subjects analysed
    16
    Units: min ng/mL
        arithmetic mean (standard deviation)
    304 ± 149
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve From Time Zero to 60 Minutes (AUC0-60) of SHP615 in Plasma

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    End point title
    Area Under the Concentration-time Curve From Time Zero to 60 Minutes (AUC0-60) of SHP615 in Plasma
    End point description
    AUC0-60 of SHP615 in plasma was reported. PK set consisted of all subjects who received a single dose of the IP and for whom at least 1 PK blood sample was collected post-dose. Here the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 60 minutes post-dose
    End point values
    SHP615
    Number of subjects analysed
    16
    Units: min ng/mL
        arithmetic mean (standard deviation)
    2965 ± 592
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve From Time Zero to 180 Minutes (AUC0-180) of SHP615 in Plasma

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    End point title
    Area Under the Concentration-time Curve From Time Zero to 180 Minutes (AUC0-180) of SHP615 in Plasma
    End point description
    AUC0-180 of SHP615 in plasma was reported. PK set consisted of all subjects who received a single dose of the IP and for whom at least 1 PK blood sample was collected post-dose. Here the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 180 minutes post-dose
    End point values
    SHP615
    Number of subjects analysed
    16
    Units: min ng/mL
        arithmetic mean (standard deviation)
    4411 ± 1140
    No statistical analyses for this end point

    Secondary: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of SHP615 in Plasma

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    End point title
    Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of SHP615 in Plasma
    End point description
    AUC(0-infinity) of SHP615 in plasma was reported. PK set consisted of all subjects who received a single dose of the IP and for whom at least 1 PK blood sample was collected post-dose. Here the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Pre-dose, 1, 3, and 6 hours post-dose
    End point values
    SHP615
    Number of subjects analysed
    16
    Units: min ng/mL
        arithmetic mean (standard deviation)
    5847 ± 2599
    No statistical analyses for this end point

    Secondary: Time at Maximum Concentration (Tmax) of SHP615 in Plasma

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    End point title
    Time at Maximum Concentration (Tmax) of SHP615 in Plasma
    End point description
    Tmax of SHP615 in plasma was reported. PK set consisted of all subjects who received a single dose of the IP and for whom at least 1 PK blood sample was collected post-dose. Here the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    1, 3, and 6 hours post-dose
    End point values
    SHP615
    Number of subjects analysed
    16
    Units: minutes
        median (full range (min-max))
    20.5 (15.5 to 28.0)
    No statistical analyses for this end point

    Secondary: Elimination Half-life (t1/2) of SHP615 in Plasma

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    End point title
    Elimination Half-life (t1/2) of SHP615 in Plasma
    End point description
    t1/2 of SHP615 in plasma was reported. PK set consisted of all subjects who received a single dose of the IP and for whom at least 1 PK blood sample was collected post-dose. Here the number of subjects analyzed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    1, 3, and 6 hours post-dose
    End point values
    SHP615
    Number of subjects analysed
    16
    Units: minutes
        median (full range (min-max))
    115 (90.6 to 303)
    No statistical analyses for this end point

    Secondary: Number of Subjects with Respiratory Depression

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    End point title
    Number of Subjects with Respiratory Depression
    End point description
    Persistent decrease in oxygen saturation to <92 percent (%) measured at 10 minutes, 30 minutes, and 4, 6, and 24 hours post-dose (ie, <92% on room air for 2 minutes or more after dosing while monitoring [per healthcare setting protocol and/or the clinical judgment of the physician]) and increase in respiratory effort such that assisted ventilation is used (bag-valve-mask ventilation or endotracheal intubation). Safety set consisted of all subjects who had received a single dose of the IP, regardless of whether IP administration was documented to be complete or not on the IP administration page of the electronic case report form (eCRF).
    End point type
    Secondary
    End point timeframe
    From start of study drug administration to follow-up (8 days)
    End point values
    SHP615
    Number of subjects analysed
    25
    Units: subjects
        Persistent Decrease in Oxygen Saturation
    0
        Increase in Respiratory Effort
    1
    No statistical analyses for this end point

    Secondary: Number of Subjects With Aspiration Pneumonia Reported as Treatment Emergent Adverse Events (TEAEs)

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    End point title
    Number of Subjects With Aspiration Pneumonia Reported as Treatment Emergent Adverse Events (TEAEs)
    End point description
    Number of subjects with aspiration pneumonia were reported as TEAEs. Safety set consisted of all subjects who had received a single dose of the IP, regardless of whether IP administration was documented to be complete or not on the IP administration page of the eCRF.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration to follow-up (8 days)
    End point values
    SHP615
    Number of subjects analysed
    25
    Units: subjects
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in Riker Sedation-Agitation Scale at 24 Hours Post-dose

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    End point title
    Change From Baseline in Riker Sedation-Agitation Scale at 24 Hours Post-dose
    End point description
    Sedation - Agitation was assessed using the Riker Sedation-Agitation Scale (SAS) by the following 7-point scale: 7=dangerous agitation; 6=very agitated; 5=agitated; 4=calm, cooperative; 3=sedated; 2=very sedated; 1=unarousable. Change from baseline in riker sedation-agition scale at 24 hours post-dose was reported. Safety set consisted of all subjects who had received a single dose of the IP, regardless of whether IP administration was documented to be complete or not on the IP administration page of the eCRF. Here the number of subjects analysed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, 24 hours post-dose
    End point values
    SHP615
    Number of subjects analysed
    23
    Units: Score on the scale
        arithmetic mean (standard deviation)
    2.2 ± 1.23
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)

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    End point title
    Number of Subjects With Treatment-Emergent Adverse Events (TEAEs)
    End point description
    An adverse event (AE) was any untoward medical occurrence in a clinical investigation subjects administered a pharmaceutical product and that does not necessarily had a causal relationship with this treatment. TEAEs are defined as AEs that start or deteriorate on or after the date of the first dose of IP and no later than 3 days following the last dose of IP. Safety set consisted of all subjects who had received a single dose of the IP, regardless of whether IP administration was documented to be complete or not on the IP administration page of the eCRF.
    End point type
    Secondary
    End point timeframe
    From start of study drug administration to follow-up (8 days)
    End point values
    SHP615
    Number of subjects analysed
    25
    Units: subjects
    9
    No statistical analyses for this end point

    Secondary: Change From Baseline in Oxygen Saturation at 24 Hours Post-dose

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    End point title
    Change From Baseline in Oxygen Saturation at 24 Hours Post-dose
    End point description
    Oxygen saturation at baseline was measured and recorded on room air. The investigator had recorded the oxygen saturation, oxygen delivery system and amount of oxygen administered during the study. Change from baseline in oxygen saturation at 24 hours post-dose was reported. Safety set consisted of all subjects who had received a single dose of the IP, regardless of whether IP administration was documented to be complete or not on the IP administration page of the eCRF. Here the number of subjects analysed signifies subjects who were evaluable for this measure.
    End point type
    Secondary
    End point timeframe
    Baseline, 24 hours post-dose
    End point values
    SHP615
    Number of subjects analysed
    14
    Units: Percentage of oxygen saturation
        arithmetic mean (standard deviation)
    3.7 ± 10.21
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From start of study drug administration to follow up (8 days)
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    SHP615
    Reporting group description
    Subjects received an oromucosal single fixed age-specific dose (2.5 mg: 3 months to less than [<] 1 year, 5 mg: 1 to <5 years, 7.5 mg: 5 to <10 years and 10 mg: 10 to <18 years) of MHOS/SHP615 solution on Day 1.

    Serious adverse events
    SHP615
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 25 (12.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Respiratory, thoracic and mediastinal disorders
    Respiratory depression
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Seizure cluster
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Status epilepticus
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    SHP615
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 25 (8.00%)
    Respiratory, thoracic and mediastinal disorders
    Respiratory depression
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jul 2017
    Amendment 1 - To clarify that a subject should be excluded if their exact age is not known at the time of IP administration. - To replace “drugs that inhibit or induce CYP3A” with “concomitant drugs determined by the investigator to have a contraindication to the use of benzodiazepines” in Exclusion Criterion 6. - To change the schedule of assessments for oxygen saturation, 12-lead ECG, and hematology assessments. - To add details on requirement for oxygen saturation to be measured on room air. - To clarify responsibilities of investigator/sub-investigator versus qualified staff members. - To add requirement for laboratory blood samples to be repeated every 6 months if no seizure occurred that resulted in IP administration. - To add time windows for buccal cavity assessment. - To add requirement to re-sign ICF at time of admission if more than 3 months have elapsed between initial informed consent and seizure. - To update blood volume to be drawn. - To change creatinine clearance calculation method from Cockcroft and Gault to Schwartz.
    28 Aug 2017
    Amendment 2 - To clarify duration of condom use for 7 days after IP administration. - To update footnotes for schedules of assessments and recommended prescreening procedures and assessments. - To remove amylase from the clinical laboratory assessments
    18 Dec 2017
    Amendment 3 - To include an additional exclusion criterion to omit subjects with seizures due to severe cases of encephalitis or meningitis, as determined by the investigator. - To remove assessment of Riker SAS and 12-lead ECG at 10 minutes after IP administration, and add collection of 12-lead ECG at 1 hour after IP administration. - To remove AE monitoring at screening/baseline.

    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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