Trial Outcomes & Findings for Open-label Study of Midazolam Hydrochloride Oromucosal Solution (MHOS/SHP615) in Children With Status Epilepticus (Convulsive) in a Healthcare Setting in Japan (NCT NCT03336645)

NCT ID: NCT03336645

Last Updated: 2020-07-31

Results Overview

Response rate was defined as the percentage of participants with therapeutic success. Therapeutic success was defined as the cessation of visible seizure activity within 10 minutes 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.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

25 participants

Primary outcome timeframe

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

Results posted on

2020-07-31

Participant Flow

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

A total of 25 participants were enrolled, received treatment and completed the study.

Participant milestones

Participant milestones
Measure
SHP615
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Overall Study
STARTED
25
Overall Study
COMPLETED
25
Overall Study
NOT COMPLETED
0

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Open-label Study of Midazolam Hydrochloride Oromucosal Solution (MHOS/SHP615) in Children With Status Epilepticus (Convulsive) in a Healthcare Setting in Japan

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure
SHP615
n=25 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Age, Continuous
4.63 Years
STANDARD_DEVIATION 4.033 • n=39 Participants
Sex: Female, Male
Female
16 Participants
n=39 Participants
Sex: Female, Male
Male
9 Participants
n=39 Participants
Ethnicity (NIH/OMB)
Hispanic or Latino
0 Participants
n=39 Participants
Ethnicity (NIH/OMB)
Not Hispanic or Latino
25 Participants
n=39 Participants
Ethnicity (NIH/OMB)
Unknown or Not Reported
0 Participants
n=39 Participants
Race (NIH/OMB)
American Indian or Alaska Native
0 Participants
n=39 Participants
Race (NIH/OMB)
Asian
25 Participants
n=39 Participants
Race (NIH/OMB)
Native Hawaiian or Other Pacific Islander
0 Participants
n=39 Participants
Race (NIH/OMB)
Black or African American
0 Participants
n=39 Participants
Race (NIH/OMB)
White
0 Participants
n=39 Participants
Race (NIH/OMB)
More than one race
0 Participants
n=39 Participants
Race (NIH/OMB)
Unknown or Not Reported
0 Participants
n=39 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 (date and time of the IP administration and seizure cessation for the initial seizure; participants with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.

Response rate was defined as the percentage of participants with therapeutic success. Therapeutic success was defined as the cessation of visible seizure activity within 10 minutes 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.

Outcome measures

Outcome measures
Measure
SHP615
n=25 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Percentage of Participants With Response Rate
80.0 Percentage of 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 (date and time of the IP administration and seizure cessation for the initial seizure; participants with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.

Percentage 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

Outcome measures
Measure
SHP615
n=25 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Percentage of Participants Who Had Sustained Absence of Seizure Activity for at Least 1, 4 and 6 Hours
Sustained Absence for at least 1 hour
68.0 Percentage of participants
Percentage of Participants Who Had Sustained Absence of Seizure Activity for at Least 1, 4 and 6 Hours
Sustained Absence for at least 4 hours
36.0 Percentage of participants
Percentage of Participants Who Had Sustained Absence of Seizure Activity for at Least 1, 4 and 6 Hours
Sustained Absence for at least 6 hours
32.0 Percentage of 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 (date and time of the IP administration and seizure cessation for the initial seizure; participants with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.

Time to resolution of seizures (convulsions) was calculated as time from IP administration to the end of the initial seizure or administration of rescue anti-convulsant medication, whichever occurs first. Initial seizure referred to the seizure that triggered the use of the IP. Number of participants with time to resolution of seizures (convulsions) from the administration of SHP615 were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=25 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Number of Participants With Time to Resolution of Seizures (Convulsions)
21 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 (date and time of the IP administration and seizure cessation for the initial seizure; participants with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.

Time to recovery of consciousness (in minutes) was calculated only for participants who lost consciousness pre-dose at time from investigational product administration to recovery of consciousness post-dose or administration of rescue anticonvulsant medication, whichever occurs first. Number of participants with time to recovery of consciousness were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=25 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Number of Participants With Time to Recovery of Consciousness
19 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 (date and time of the IP administration and seizure cessation for the initial seizure; participants with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.

Percentage of participants who required additional anticonvulsant medication for ongoing SE, 10 minutes after a single dose of SHP615 were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=25 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Percentage of Participants Who Required Additional Anticonvulsant Medication for Ongoing Status Epilepticus (SE)
16.0 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 (date and time of the IP administration and seizure cessation for the initial seizure; participants with no recurrence of seizure within 30 minutes post-dose) performed after the administration of the IP.

Treatment failure/non-responder was defined as participants with continuing seizure activity and/or the need for any additional rescue medication according to the participating healthcare setting protocol or guideline, for 10 mins or more after a single dose of the IP.

Outcome measures

Outcome measures
Measure
SHP615
n=25 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Percentage of Participants Who Failed to Respond to the Treatment With SHP615
16.0 Percentage of participants

SECONDARY outcome

Timeframe: 10 minutes post-dose

Population: Pharmacokinetic (PK) set consisted of all participants 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 participants analyzed refer to the participants evaluable for this outcome.

Concentration of SHP615 in plasma at 10 minutes were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=16 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Concentration of SHP615 in Plasma at 10 Minutes (C10)
45.2 nanogram per milliliter (ng/mL)
Standard Deviation 21.3

SECONDARY outcome

Timeframe: 1, 3, 6 hours post-dose

Population: PK set consisted of all participants 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 participants analyzed refer to the participants evaluable for this outcome.

Cmax of SHP615 in plasma were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=16 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Maximum Plasma Concentration (Cmax) of SHP615
78.0 ng/mL
Standard Deviation 16.4

SECONDARY outcome

Timeframe: Pre-dose, 10 minutes post-dose

Population: PK set consisted of all participants 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 participants analyzed refer to the participants evaluable for this outcome.

AUC0-10 of SHP615 in plasma were reported. Here "min ng/mL" was minutes nanogram per milliliter.

Outcome measures

Outcome measures
Measure
SHP615
n=16 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Area Under the Concentration-time Curve From Time Zero to 10 Minutes (AUC0-10) of SHP615 in Plasma
304 min ng/mL
Standard Deviation 149

SECONDARY outcome

Timeframe: Pre-dose, 60 minutes post-dose

Population: PK set consisted of all participants 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 participants analyzed refer to the participants evaluable for this outcome.

AUC0-60 of SHP615 in plasma were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=16 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Area Under the Concentration-time Curve From Time Zero to 60 Minutes (AUC0-60) of SHP615 in Plasma
2965 min ng/mL
Standard Deviation 592

SECONDARY outcome

Timeframe: Pre-dose, 180 minutes post-dose

Population: PK set consisted of all participants 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 participants analyzed refer to the participants evaluable for this outcome.

AUC0-180 of SHP615 in plasma were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=16 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Area Under the Concentration-time Curve From Time Zero to 180 Minutes (AUC0-180) of SHP615 in Plasma
4411 min ng/mL
Standard Deviation 1140

SECONDARY outcome

Timeframe: Pre-dose, 1, 3, and 6 hours post-dose

Population: PK set consisted of all participants 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 participants analyzed refer to the participants evaluable for this outcome.

AUC(0-infinity) of SHP615 in plasma were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=16 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of SHP615 in Plasma
5847 min ng/mL
Standard Deviation 2599

SECONDARY outcome

Timeframe: 1, 3, and 6 hours post-dose

Population: PK set consisted of all participants 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 participants analyzed refer to the participants evaluable for this outcome.

Tmax of SHP615 in plasma were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=16 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Time at Maximum Concentration (Tmax) of SHP615 in Plasma
20.5 minutes
Interval 15.5 to 28.0

SECONDARY outcome

Timeframe: 1, 3, and 6 hours post-dose

Population: PK set consisted of all participants 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 participants analyzed refer to the participants evaluable for this outcome.

T1/2 of SHP615 in plasma were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=16 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Elimination Half-life (T1/2) of SHP615 in Plasma
115 minutes
Interval 90.6 to 303.0

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 the IP, regardless of whether IP administration was documented to be complete or not on the IP administration page of the 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 at 10, 30 minutes, and 4, 6, and 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

Outcome measures
Measure
SHP615
n=25 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Number of Participants With Respiratory Depression
Persistent Decrease in Oxygen Saturation
0 Participants
Number of Participants With Respiratory Depression
Increase in Respiratory Effort
1 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 the IP, regardless of whether IP administration was documented to be complete or not on the IP administration page of the eCRF.

TEAEs was defined as AEs that start or deteriorate on or after the date of the first dose of investigational product and no later than 3 days following the last dose of IP. Number of participants with aspiration pneumonia identified as TEAEs were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=25 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Number of Participants With Aspiration Pneumonia Reported as Treatment Emergent Adverse Events (TEAEs)
0 Participants

SECONDARY outcome

Timeframe: Baseline, 24 hours post-dose

Population: Safety set consisted of all participants 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 participants analyzed refer to the participants evaluable for this outcome.

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 were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=23 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Change From Baseline in Riker Sedation-Agitation Scale at 24 Hours Post-dose
2.2 Score on the scale
Standard Deviation 1.23

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 the IP, regardless of whether IP administration was documented to be complete or not on the IP administration page of the eCRF.

An adverse event (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 that start or deteriorate on or after the date of the first dose of investigational product and no later than 3 days following the last dose of IP. Number of participants with TEAEs were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=25 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
9 Participants

SECONDARY outcome

Timeframe: Baseline, 24 hours post-dose

Population: Safety set consisted of all participants 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 participants analyzed refer to the participants evaluable for this outcome.

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 percentage at 24 hours post-dose were reported.

Outcome measures

Outcome measures
Measure
SHP615
n=14 Participants
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Change From Baseline in Oxygen Saturation Percentage at 24 Hours Post-dose
3.7 Percentage of oxygen saturation
Standard Deviation 10.21

Adverse Events

SHP615

Serious events: 3 serious events
Other events: 2 other events
Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure
SHP615
n=25 participants at risk
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Nervous system disorders
Seizure cluster
4.0%
1/25 • Number of events 1 • From start of study drug administration to follow-up (8 days).
Nervous system disorders
Status epilepticus
4.0%
1/25 • Number of events 1 • From start of study drug administration to follow-up (8 days).
Respiratory, thoracic and mediastinal disorders
Respiratory depression
4.0%
1/25 • Number of events 1 • From start of study drug administration to follow-up (8 days).

Other adverse events

Other adverse events
Measure
SHP615
n=25 participants at risk
Participants received single fixed age-specific dose (3 months to less than \[\<\] 1 year received 2.4 milligram \[mg\]; 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 on Day 1.
Respiratory, thoracic and mediastinal disorders
Respiratory depression
8.0%
2/25 • Number of events 2 • From start of study drug administration to follow-up (8 days).

Additional Information

Study Physician

Shire

Phone: 1 866-842-5335

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