Trial Outcomes & Findings for Study of Midazolam Hydrochloride Oromucosal Solution (MHOS/SHP615) in Pediatric Patients With Status Epilepticus (Convulsive) in the Community Setting (NCT NCT03336450)

NCT ID: NCT03336450

Last Updated: 2021-09-14

Results Overview

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.

• Recruitment status: COMPLETED
• Study phase: PHASE3
• Target enrollment: 3 participants
• Primary outcome timeframe: From start of study drug administration up to 30 minutes post-dose
• Results posted on: 2021-09-14

Participant Flow

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).

A total of 12 participants were screened, of which 9 participants were screen failures and withdrawn prior to randomization.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.

Participant milestones

Measure	SHP615 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 Study STARTED	3
Overall Study COMPLETED	3
Overall Study NOT COMPLETED	0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	SHP615 n=3 Participants 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.
Age, Continuous	5.07 Years STANDARD_DEVIATION 1.570 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants
Sex: Female, Male Male	2 Participants n=5 Participants
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants n=5 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	3 Participants n=5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	0 Participants n=5 Participants
Race (NIH/OMB) White	0 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants n=5 Participants

PRIMARY outcome

Timeframe: From start of study drug administration up to 30 minutes post-dose

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Efficacy: Number of Participants With Therapeutic Success	3 Participants

PRIMARY outcome

Timeframe: Up to 24 hours post-dose

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Safety: Number of Participants With Respiratory Depression	0 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to 1, 4, and 6 hours post-dose

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Efficacy: Number of Participants Who Had Sustained Absence of Seizure Activity for at Least 1, 4, and 6 Hours Sustained absence for at least 1 hour	3 Participants
Efficacy: Number of Participants Who Had Sustained Absence of Seizure Activity for at Least 1, 4, and 6 Hours Sustained absence for at least 4 hour	0 Participants
Efficacy: Number of Participants Who Had Sustained Absence of Seizure Activity for at Least 1, 4, and 6 Hours Sustained absence for at least 6 hour	1 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to follow-up (Day 8)

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Efficacy: Time to Resolution of Seizures (Convulsions) Participant 1	1 Minutes
Efficacy: Time to Resolution of Seizures (Convulsions) Participant 2	2 Minutes
Efficacy: Time to Resolution of Seizures (Convulsions) Participant 3	5 Minutes

SECONDARY outcome

Timeframe: From start of study drug administration up to follow-up (Day 8)

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Efficacy: Time to Recovery of Consciousness Participant 1	4 Minutes
Efficacy: Time to Recovery of Consciousness Participant 2	143 Minutes
Efficacy: Time to Recovery of Consciousness Participant 3	5 Minutes

SECONDARY outcome

Timeframe: 10 minutes post-dose

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Efficacy: Percentage of Participants Who Required Additional Anticonvulsant Medication for Ongoing Status Epilepticus (SE) 10 Minutes After Administration of SHP615	0 Percentage of participants

SECONDARY outcome

Timeframe: 10 minutes post-dose

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Efficacy: Percentage of Participants Who Failed to Respond to Treatment With SHP615	0 Percentage of participants

SECONDARY outcome

Timeframe: From start of study drug administration up to follow-up (Day 8)

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Safety: Number of Participants With Aspiration Pneumonia Reported as Treatment Emergent Adverse Events (TEAEs)	0 Participants

SECONDARY outcome

Timeframe: 1, 4, 6, and 24 hours post-dose

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Safety: Number of Participants Analyzed for Sedation or Agitation Measured by the Riker Sedation-Agitation Scale Participant with unarousable	0 Participants
Safety: Number of Participants Analyzed for Sedation or Agitation Measured by the Riker Sedation-Agitation Scale Participant with very sedated	1 Participants
Safety: Number of Participants Analyzed for Sedation or Agitation Measured by the Riker Sedation-Agitation Scale Participant with sedated	1 Participants
Safety: Number of Participants Analyzed for Sedation or Agitation Measured by the Riker Sedation-Agitation Scale Participant with calm and cooperative	3 Participants
Safety: Number of Participants Analyzed for Sedation or Agitation Measured by the Riker Sedation-Agitation Scale Participant with agitated	1 Participants
Safety: Number of Participants Analyzed for Sedation or Agitation Measured by the Riker Sedation-Agitation Scale Participant with very agitated	0 Participants
Safety: Number of Participants Analyzed for Sedation or Agitation Measured by the Riker Sedation-Agitation Scale Participant with dangerous agitation	0 Participants

SECONDARY outcome

Timeframe: Up to 6 hours post-dose

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Safety: Number of Participants With Buccal Irritation Reported as Treatment Emergent Adverse Events (TEAEs)	0 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to follow-up (Day 8)

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Safety: Number of Participants With Treatment-emergent Adverse Events (TEAEs)	2 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to 24 hours post-dose

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Safety: Number of Participants With Clinically Significant Change in Vital Signs Reported as TEAEs	0 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to 24 hours post-dose

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Safety: Number of Participants With Clinically Significant Abnormalities in Laboratory Parameters Reported as TEAEs	0 Participants

SECONDARY outcome

Timeframe: From start of study drug administration up to 24 hours post-dose

Population: 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.

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

Outcome measures

Measure	SHP615 n=3 Participants 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.
Safety: Number of Participants With Clinically Significant Change in Electrocardiogram (ECG) Reported as TEAEs	0 Participants

SECONDARY outcome

Timeframe: 0.5, 1, 4, 6 and 24 hours post-dose

Population: 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.

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.

Outcome measures

Measure	SHP615 n=3 Participants 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.
Safety: Percentage of Participants With Normal Oxygen Saturation Values Collected During Hospital Setting	100 Percentage of participants

Adverse Events

SHP615

Serious events: 1 serious events

Other events: 2 other events

Deaths: 0 deaths

Serious adverse events

Measure	SHP615 n=3 participants at risk 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.
Nervous system disorders Febrile convulsion	33.3% 1/3 • Number of events 1 • From start of study drug administration up to follow-up (Day 8)

Other adverse events

Measure	SHP615 n=3 participants at risk 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.
Nervous system disorders Somnolence	33.3% 1/3 • Number of events 1 • From start of study drug administration up to follow-up (Day 8)
Gastrointestinal disorders Nausea	33.3% 1/3 • Number of events 1 • From start of study drug administration up to follow-up (Day 8)
Gastrointestinal disorders Vomiting	33.3% 1/3 • Number of events 1 • From start of study drug administration up to follow-up (Day 8)
Infections and infestations Upper respiratory tract infection	33.3% 1/3 • Number of events 1 • From start of study drug administration up to follow-up (Day 8)

Additional Information

Study Director

Shire

Phone: +1 866 842 5335

Email: ClinicalTransparency@shire.com

Results disclosure agreements

• Principal investigator is a sponsor employee 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.
• Publication restrictions are in place

Restriction type: OTHER