Study of Midazolam Hydrochloride Oromucosal Solution (MHOS/SHP615) in Pediatric Patients With Status Epilepticus (Convulsive) in the Community Setting

• Sponsor: Shire (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03336450
• Collaborator: Takeda Development Center Americas, Inc. (Industry)
• Enrollment: 3
• Locations: 23
• Arm: 1
• Actual Duration (Months): 29.7
• Patients Per Site: 0.1
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if the investigational treatment, MHOS/SHP615, is safe and effective in children with status epilepticus (SE) (convulsive) in the community setting. This study is open-label extension for patients who completed the SHP615-301 study and who tolerated and responded to MHOS/SHP615 treatment in the hospital setting.

Condition or Disease	Intervention/Treatment	Phase
Nervous System Diseases	Drug: SHP615; Drug: MHOS/SHP615	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 3 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 3, Multicenter, Open-label Extension Study of Buccally Administered MHOS/SHP615 in Pediatric Patients With Status Epilepticus (Convulsive) in Community Settings
• Actual Study Start Date: Apr 23, 2018
• Actual Primary Completion Date: Oct 13, 2020
• Actual Study Completion Date: Oct 13, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: SHP615 Participants will receive a single age-specific dose (approximately 0.25 to 0.5 milligram per kilogram [mg/kg] as midazolam) of SHP615 oromucosal solution through buccal route upon onset of seizures.	Drug: SHP615; SHP615 oromucosal solution will be administered as a single age-specific dose (2.5, 5, 7.5 and 10 mg).; Other Names: MHOS Midazolam hydrochloride oromucosal solution ; Drug: MHOS/SHP615; MHOS/SHP615

Outcome Measures

Primary Outcome Measures

1. Efficacy: Number of Participants With Therapeutic Success [From start of study drug administration up to 30 minutes post-dose]

   Therapeutic success was defined as cessation of visible seizure activity within 10 minutes and sustained absence of visible seizure activity for 30 minutes following a single dose of SHP615 without the need for additional rescue medication. Number of participants with therapeutic success were reported.

2. Safety: Number of Participants With Respiratory Depression [Up to 24 hours post-dose]

   Respiratory depression, included the following measures within 24 hours after administration of the IP: i) Persistent decrease in oxygen saturation to <92 percent (%) measured up to 24 hours post-dose (i.e., <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]. ii) Increase in respiratory effort such that assisted ventilation is used (bag-valve-mask ventilation or endotracheal intubation). Number of participants with respiratory depression were reported.

Secondary Outcome Measures

1. Efficacy: Number of Participants Who Had Sustained Absence of Seizure Activity for at Least 1, 4, and 6 Hours [From start of study drug administration up to 1, 4, and 6 hours post-dose]

   Number of participants whose seizure event stopped within 10 minutes of single dose administration of SHP615 and who had sustained absence of seizure activity for at least 1, 4, and 6 hours were reported.

2. Efficacy: Time to Resolution of Seizures (Convulsions) [From start of study drug administration up to follow-up (Day 8)]

   Time to resolution of seizures (convulsions) was calculated as time from SHP615 administration to the end of the initial seizure or administration of rescue anticonvulsant medication, whichever occurs first. The initial seizure refers to the seizure which triggered the use of the IP. Participant wise data was reported for this outcome.

3. Efficacy: Time to Recovery of Consciousness [From start of study drug administration up to follow-up (Day 8)]

   Time to recovery of consciousness in minutes was calculated only for participants who lost consciousness pre-dose as time from SHP615 administration to recovery of consciousness post-dose or administration of rescue anticonvulsant medication, whichever occurs first. Participant wise data was reported for this outcome.

4. Efficacy: Percentage of Participants Who Required Additional Anticonvulsant Medication for Ongoing Status Epilepticus (SE) 10 Minutes After Administration of SHP615 [10 minutes post-dose]

   Percentage of participants who required additional anticonvulsant medication for ongoing SE according to the participating hospital protocol or guideline, 10 minutes after the administration of SHP615 were reported.

5. Efficacy: Percentage of Participants Who Failed to Respond to Treatment With SHP615 [10 minutes post-dose]

   Treatment failure/non-responder was defined as continuing seizure activity and/or the need for any additional rescue medication according to the participating healthcare setting protocol or guideline 10 minutes after administration of SHP615 was reported.

6. Safety: Number of Participants With Aspiration Pneumonia Reported as Treatment Emergent Adverse Events (TEAEs) [From start of study drug administration up to follow-up (Day 8)]

   TEAEs was defined as adverse events (AEs) whose onset occurs, severity worsens or intensity increases on or after the date of SHP615 administration. Number of participants with aspiration pneumonia identified as TEAEs were reported.

7. Safety: Number of Participants Analyzed for Sedation or Agitation Measured by the Riker Sedation-Agitation Scale [1, 4, 6, and 24 hours post-dose]

   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. Number of participants analyzed for sedation or agitation measured by the riker sedation-agitation scale were reported.

8. Safety: Number of Participants With Buccal Irritation Reported as Treatment Emergent Adverse Events (TEAEs) [Up to 6 hours post-dose]

   TEAEs was defined as AEs whose onset occurs, severity worsens or intensity increases on or after the date of IP administration. Buccal cavity was examined for redness, inflammation and ulceration. Number of participants with buccal irritation reported as TEAEs were reported.

9. Safety: Number of Participants With Treatment-emergent Adverse Events (TEAEs) [From start of study drug administration up to follow-up (Day 8)]

   An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs was defined as AEs whose onset occurs, severity worsens or intensity increases on or after the date of IP administration. Number of participants with TEAEs were reported.

10. Safety: Number of Participants With Clinically Significant Change in Vital Signs Reported as TEAEs [From start of study drug administration up to 24 hours post-dose]

    Vital sign assessments included blood pressure, pulse, respiratory rate and body temperature. Any change in vital signs which were deemed clinically significant by the investigator were recorded as TEAEs.

11. Safety: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as TEAEs [From start of study drug administration up to 24 hours post-dose]

    Clinical laboratory evaluations included biochemistry, endocrinology, hematology and urinalysis. Any change in clinical laboratory abnormalities which were deemed clinically significant by the investigator were recorded as TEAEs.

12. Safety: Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Reported as TEAEs [From start of study drug administration up to 24 hours post-dose]

    12-lead ECG were evaluated. Any change in ECG assessments which are deemed clinically significant by the investigator were reported as TEAEs.

13. Safety: Percentage of Participants With Normal Oxygen Saturation Values Collected During Hospital Setting [0.5, 1, 4, 6 and 24 hours post-dose]

    Oxygen saturation is the amount of oxygen that is in bloodstream and is measured as the percentage of blood hemoglobin that is carrying oxygen. Normal oxygen saturation levels are considered to be 95-100 percent; low oxygen saturation values indicate worse disease. Oxygen saturation was measured and recorded on room air. The investigator recorded the oxygen saturation as well as the oxygen delivery system and amount of oxygen administered during hospital setting. Percentage of participants with normal oxygen saturation values collected during hospital setting were reported.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 6 Months to 216 Months
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects who completed the SHP615-301 study and who tolerated and responded to treatment with MHOS/SHP615 in the hospital and/or emergency room, and are considered stable for discharge from the hospital.

• Subjects who are greater than (>) 6 months and less than (<) 18 years of age at the time of investigational product administration. If the subject's exact age is not known, the subject should be excluded.

• Parent, guardian, or legally authorized representative of the child who provides informed consent and assent (when applicable) to participate in the study after initial stabilization of the subject with SE in hospital or emergency room during the SHP615-301 study. The subject also provides informed consent prior to participation, where applicable.

• Parent, guardian, or legally authorized representative who have received appropriate training/education and are deemed qualified by the investigator and are willing to:

1. Properly administer MHOS/SHP615.

2. Record seizure information and dosing of MHOS/SHP615 in a subject diary (including time of seizure onset, type of seizure, time necessary to administer MHOS/SHP615, time between MHOS/SHP615 administration to seizure cessation, etc.)

3. Follow the necessary instructions to secure the safety of the subject.

• Subjects who experience generalized tonic-clonic SE with seizures accompanied by loss of consciousness with any of the following characteristics persistent at the time of study drug administration:

1. Currently presenting with seizure (convulsive) activity and 3 or more convulsions within the preceding hour

2. Currently presenting with seizure (convulsive) and 2 or more convulsions in succession without recovery of consciousness.

3. Currently presenting with a single seizure (convulsive) persisting greater than or equal to (>=) 5 minutes.

Exclusion Criteria:

• Female subjects who are pregnant, suspected to be pregnant, or nursing.

• Subjects with major trauma, not necessarily restricted to the head, as the cause of the seizure.

• Subjects with known or suspected recurrent seizures due to illegal drug or alcohol withdrawal.

• Subjects with seizures due to illegal drug or acute alcoholic intoxication.

• Subjects with seizures of psychogenic origin.

• Subjects with seizures due to severe encephalitis or meningitis, as determined by the PI

• Subjects with known history of hypersensitivities, nonresponsiveness or contraindications to benzodiazepines (that is (ie), clinically significant respiratory depression, severe acute hepatic failure, myasthenia gravis, syndrome of sleep apnea, glaucoma with closed angle, or use of concomitant drugs determined by the investigator to have a contraindication to the use of benzodiazepines.)

• Subjects with a known history of benzodiazepine abuse.

• Subjects who have not responded to previous administrations of midazolam systemic therapies, including MIDAFRESA and/or DORMICUM.

• Subjects who need emergent surgical intervention and general anesthesia/intubation.

• Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors or HIV reverse transcriptase inhibitors.

• Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the healthcare provider.

• Have used an investigational product or been enrolled in a clinical study (including vaccine studies) that, in the investigator's opinion, may impact this Shire-sponsored study.

• Subject has prior placement of a vagus nerve stimulator.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Yamanashi Prefectural Central Hospital	Kofu	Fujimi	Japan	400-8506
2	Hokkaido University Hospital	Sapporo	Hokkaido	Japan	060-8648
3	NHO Minami-Okayama Medical Center	Okayama	Okayama Prefecture	Japan	701-0304
4	Tokyo Women's Medical University Yachiyo Medical Center	Yachiyo	Owada Shinden	Japan	276-8524
5	Shizuoka Institute of Epilepsy and Neurological Disorders	Shizuoka	Shizuoka Prefecture	Japan	420-8688
6	Fukuoka Children's Hospital(NW)	Fukuoka		Japan	813-0017
7	Gifu Prefectural General Medical Center	Gifu		Japan	500-8717
8	NHO Hokkaido Medical Center	Hokkaidō		Japan	063-0005
9	Kumamoto Saishunso National Hospital	Kumamoto		Japan	861-1196
10	NHO Nagasaki Medical Center	Nagasaki		Japan	856-8562
11	NHO Nishi Niigata Chuo National Hospital	Niigata		Japan	950-2085
12	Aichi Children's Health and Medical Center(NW)	Obu		Japan	474-8710
13	Okayama University Hospital	Okayama		Japan	700-0914
14	Nakano Children's Hospital	Osaka		Japan	535-0022
15	Osaka Women's and Children's Hospital(NW)	Osaka		Japan	594-1101
16	Jichi Children's Medical Center Tochigi	Saitama-shi		Japan	330-8503
17	Saitama Children's Medical Center(NW)	Saitama		Japan	330-8777
18	Osaka University Hospital	Suita		Japan	565-0871
19	Tokyo Women's Medical University Hospital	Tokyo		Japan	162-8666
20	National Center Hospital, NCNP	Tokyo		Japan	187-0031
21	Tottori University Hospital	Tottori		Japan	683-8504
22	Osaka University Hospital	Yamadaoka		Japan	565-0871
23	Kanagawa Children's Medical Center(NW)	Yokohama		Japan	232-0066

Sponsors and Collaborators

• Shire
• Takeda Development Center Americas, Inc.

Investigators

• Study Director: Study Director, Takeda Development Center Americas

Study Documents (Full-Text)

• Study Protocol - Dec 18, 2017
• Statistical Analysis Plan - Sep 12, 2019

More Information

Publications

None provided.

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT03336450
• Other Study ID Numbers: SHP615-302
• First Posted: Nov 8, 2017
• Last Update Posted: Sep 14, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Nervous System Diseases; Status Epilepticus; Midazolam

Study Results

Participant Flow

Recruitment Details	The study was conducted at 27 centers in Japan between 23 April 2018 (first participant first visit) and 13 October 2020 (last participant last visit).
Pre-assignment Detail	A total of 12 participants were screened, of which 9 participants were screen failures and withdrawn prior to randomization. Only 3 participants were enrolled to receive treatment and completed the study.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Period Title: Overall Study
STARTED	3
COMPLETED	3
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Overall Participants	3
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	5.07 (1.570)
Sex: Female, Male (Count of Participants)
Female	1 33.3%
Male	2 66.7%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	3 100%
Unknown or Not Reported	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	3 100%
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%

Outcome Measures

1. Primary Outcome

Title	Efficacy: Number of Participants With Therapeutic Success
Description	Therapeutic success was defined as cessation of visible seizure activity within 10 minutes and sustained absence of visible seizure activity for 30 minutes following a single dose of SHP615 without the need for additional rescue medication. Number of participants with therapeutic success were reported.
Time Frame	From start of study drug administration up to 30 minutes post-dose

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) consisted of all participants in the safety set who had at least 1 assessment for determination of therapeutic success (cessation of seizure within 10 minutes with sustained absence of seizure for 30 minutes) performed after the administration of IP.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Count of Participants [Participants]	3 100%

2. Secondary Outcome

Title	Efficacy: Number of Participants Who Had Sustained Absence of Seizure Activity for at Least 1, 4, and 6 Hours
Description	Number of participants whose seizure event stopped within 10 minutes of single dose administration of SHP615 and who had sustained absence of seizure activity for at least 1, 4, and 6 hours were reported.
Time Frame	From start of study drug administration up to 1, 4, and 6 hours post-dose

Outcome Measure Data

Analysis Population Description

FAS consisted of all participants in the safety set who had at least 1 assessment for determination of therapeutic success (cessation of seizure within 10 minutes with sustained absence of seizure for 30 minutes) performed after the administration of IP.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Sustained absence for at least 1 hour	3 100%
Sustained absence for at least 4 hour	0 0%
Sustained absence for at least 6 hour	1 33.3%

3. Secondary Outcome

Title	Efficacy: Time to Resolution of Seizures (Convulsions)
Description	Time to resolution of seizures (convulsions) was calculated as time from SHP615 administration to the end of the initial seizure or administration of rescue anticonvulsant medication, whichever occurs first. The initial seizure refers to the seizure which triggered the use of the IP. Participant wise data was reported for this outcome.
Time Frame	From start of study drug administration up to follow-up (Day 8)

Outcome Measure Data

Analysis Population Description

FAS consisted of all participants in the safety set who had at least 1 assessment for determination of therapeutic success (cessation of seizure within 10 minutes with sustained absence of seizure for 30 minutes) performed after the administration of IP. Here, number analyzed signifies participants who were evaluable for this specific category.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Participant 1	1
Participant 2	2
Participant 3	5

4. Secondary Outcome

Title	Efficacy: Time to Recovery of Consciousness
Description	Time to recovery of consciousness in minutes was calculated only for participants who lost consciousness pre-dose as time from SHP615 administration to recovery of consciousness post-dose or administration of rescue anticonvulsant medication, whichever occurs first. Participant wise data was reported for this outcome.
Time Frame	From start of study drug administration up to follow-up (Day 8)

Outcome Measure Data

Analysis Population Description

FAS consisted of all participants in the safety set who had at least 1 assessment for determination of therapeutic success (cessation of seizure within 10 minutes with sustained absence of seizure for 30 minutes) performed after the administration of IP. Here, number analyzed signifies participants who were evaluable for this specific category.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Participant 1	4
Participant 2	143
Participant 3	5

5. Secondary Outcome

Title	Efficacy: Percentage of Participants Who Required Additional Anticonvulsant Medication for Ongoing Status Epilepticus (SE) 10 Minutes After Administration of SHP615
Description	Percentage of participants who required additional anticonvulsant medication for ongoing SE according to the participating hospital protocol or guideline, 10 minutes after the administration of SHP615 were reported.
Time Frame	10 minutes post-dose

Outcome Measure Data

Analysis Population Description

FAS consisted of all participants in the safety set who had at least 1 assessment for determination of therapeutic success (cessation of seizure within 10 minutes with sustained absence of seizure for 30 minutes) performed after the administration of IP.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Number [Percentage of participants]	0 0%

6. Secondary Outcome

Title	Efficacy: Percentage of Participants Who Failed to Respond to Treatment With SHP615
Description	Treatment failure/non-responder was defined as continuing seizure activity and/or the need for any additional rescue medication according to the participating healthcare setting protocol or guideline 10 minutes after administration of SHP615 was reported.
Time Frame	10 minutes post-dose

Outcome Measure Data

Analysis Population Description

FAS consisted of all participants in the safety set who had at least 1 assessment for determination of therapeutic success (cessation of seizure within 10 minutes with sustained absence of seizure for 30 minutes) performed after the administration of IP.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Number [Percentage of participants]	0 0%

7. Primary Outcome

Title	Safety: Number of Participants With Respiratory Depression
Description	Respiratory depression, included the following measures within 24 hours after administration of the IP: i) Persistent decrease in oxygen saturation to <92 percent (%) measured up to 24 hours post-dose (i.e., <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]. ii) Increase in respiratory effort such that assisted ventilation is used (bag-valve-mask ventilation or endotracheal intubation). Number of participants with respiratory depression were reported.
Time Frame	Up to 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Safety set consisted of all participants who had received a single dose of IP, regardless of whether the study drug administration was documented to be complete or not on the study drug administration eCRF.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Count of Participants [Participants]	0 0%

8. Secondary Outcome

Title	Safety: Number of Participants With Aspiration Pneumonia Reported as Treatment Emergent Adverse Events (TEAEs)
Description	TEAEs was defined as adverse events (AEs) whose onset occurs, severity worsens or intensity increases on or after the date of SHP615 administration. Number of participants with aspiration pneumonia identified as TEAEs were reported.
Time Frame	From start of study drug administration up to follow-up (Day 8)

Outcome Measure Data

Analysis Population Description

Safety set consisted of all participants who had received a single dose of IP, regardless of whether the study drug administration was documented to be complete or not on the study drug administration eCRF.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Count of Participants [Participants]	0 0%

9. Secondary Outcome

Title	Safety: Number of Participants Analyzed for Sedation or Agitation Measured by the Riker Sedation-Agitation Scale
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. Number of participants analyzed for sedation or agitation measured by the riker sedation-agitation scale were reported.
Time Frame	1, 4, 6, and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Safety set consisted of all participants who had received a single dose of IP, regardless of whether the study drug administration was documented to be complete or not on the study drug administration eCRF.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Participant with unarousable	0 0%
Participant with very sedated	1 33.3%
Participant with sedated	1 33.3%
Participant with calm and cooperative	3 100%
Participant with agitated	1 33.3%
Participant with very agitated	0 0%
Participant with dangerous agitation	0 0%

10. Secondary Outcome

Title	Safety: Number of Participants With Buccal Irritation Reported as Treatment Emergent Adverse Events (TEAEs)
Description	TEAEs was defined as AEs whose onset occurs, severity worsens or intensity increases on or after the date of IP administration. Buccal cavity was examined for redness, inflammation and ulceration. Number of participants with buccal irritation reported as TEAEs were reported.
Time Frame	Up to 6 hours post-dose

Outcome Measure Data

Analysis Population Description

Safety set consisted of all participants who had received a single dose of IP, regardless of whether the study drug administration was documented to be complete or not on the study drug administration eCRF.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Count of Participants [Participants]	0 0%

11. Secondary Outcome

Title	Safety: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
Description	An AE was any untoward medical occurrence in a clinical investigation participant administered a pharmaceutical product and that does not necessarily have a causal relationship with this treatment. TEAEs was defined as AEs whose onset occurs, severity worsens or intensity increases on or after the date of IP administration. Number of participants with TEAEs were reported.
Time Frame	From start of study drug administration up to follow-up (Day 8)

Outcome Measure Data

Analysis Population Description

Safety set consisted of all participants who had received a single dose of IP, regardless of whether the study drug administration was documented to be complete or not on the study drug administration eCRF.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Count of Participants [Participants]	2 66.7%

12. Secondary Outcome

Title	Safety: Number of Participants With Clinically Significant Change in Vital Signs Reported as TEAEs
Description	Vital sign assessments included blood pressure, pulse, respiratory rate and body temperature. Any change in vital signs which were deemed clinically significant by the investigator were recorded as TEAEs.
Time Frame	From start of study drug administration up to 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Safety set consisted of all participants who had received a single dose of IP, regardless of whether the study drug administration was documented to be complete or not on the study drug administration eCRF.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Count of Participants [Participants]	0 0%

13. Secondary Outcome

Title	Safety: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as TEAEs
Description	Clinical laboratory evaluations included biochemistry, endocrinology, hematology and urinalysis. Any change in clinical laboratory abnormalities which were deemed clinically significant by the investigator were recorded as TEAEs.
Time Frame	From start of study drug administration up to 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Safety set consisted of all participants who had received a single dose of IP, regardless of whether the study drug administration was documented to be complete or not on the study drug administration eCRF.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Count of Participants [Participants]	0 0%

14. Secondary Outcome

Title	Safety: Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Reported as TEAEs
Description	12-lead ECG were evaluated. Any change in ECG assessments which are deemed clinically significant by the investigator were reported as TEAEs.
Time Frame	From start of study drug administration up to 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Safety set consisted of all participants who had received a single dose of IP, regardless of whether the study drug administration was documented to be complete or not on the study drug administration eCRF.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Count of Participants [Participants]	0 0%

15. Secondary Outcome

Title	Safety: Percentage of Participants With Normal Oxygen Saturation Values Collected During Hospital Setting
Description	Oxygen saturation is the amount of oxygen that is in bloodstream and is measured as the percentage of blood hemoglobin that is carrying oxygen. Normal oxygen saturation levels are considered to be 95-100 percent; low oxygen saturation values indicate worse disease. Oxygen saturation was measured and recorded on room air. The investigator recorded the oxygen saturation as well as the oxygen delivery system and amount of oxygen administered during hospital setting. Percentage of participants with normal oxygen saturation values collected during hospital setting were reported.
Time Frame	0.5, 1, 4, 6 and 24 hours post-dose

Outcome Measure Data

Analysis Population Description

Safety set consisted of all participants who had received a single dose of IP, regardless of whether the study drug administration was documented to be complete or not on the study drug administration eCRF.

Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
Measure Participants	3
Number [Percentage of participants]	100 3333.3%

Adverse Events

Time Frame	From start of study drug administration up to follow-up (Day 8)
Arm/Group Title	SHP615
Arm/Group Description	Participants received single fixed age-specific dose (6 months to less than [<] 1 year received 2.5 milligrams [mg]; 1 to < 5 years received 5 mg; 5 to <10 years received 7.5 mg and 10 to < 18 years received 10 mg) of midazolam hydrochloride oromucosal solution (MHOS)/SHP615 buccally by caregivers on Day 1.
All Cause Mortality
	SHP615
	Affected / at Risk (%)	# Events
Total	0/3 (0%)
Serious Adverse Events
	SHP615
	Affected / at Risk (%)	# Events
Total	1/3 (33.3%)
Nervous system disorders
Febrile convulsion	1/3 (33.3%)	1
Other (Not Including Serious) Adverse Events
	SHP615
	Affected / at Risk (%)	# Events
Total	2/3 (66.7%)
Gastrointestinal disorders
Nausea	1/3 (33.3%)	1
Vomiting	1/3 (33.3%)	1
Infections and infestations
Upper respiratory tract infection	1/3 (33.3%)	1
Nervous system disorders
Somnolence	1/3 (33.3%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

If a multicenter publication is not submitted within twelve (12) months after conclusion, abandonment or termination of the Study at all sites, or after Sponsor confirms there shall be no multicenter Study publication, the Institution and/or such Principal Investigator may publish the results from the Institution site individually.