Clinical trial NCT03336645: Open-label Study of Midazolam Hydrochloride Oromucosal Solution (MHOS/SHP615) in Children With Status Epilepticus (Convulsive) in a Healthcare Setting in Japan
Official title: A Phase 3, Multicenter, Open-label Study to Determine the Efficacy, Safety, and Pharmacokinetics of Buccally Administered MHOS/SHP615 in Pediatric Patients With Status Epilepticus (Convulsive) in the Hospital or Emergency Room
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Nervous System Diseases
Keywords: Seizure
Midazolam hydrochloride
Convulsive
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2017-11-08
Enrollment: 25
Sex: ALL
Minimum age (years): 3
Maximum age (years): 216
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the efficacy, safety and pharmacokinetics of MHOS/SHP615 administered buccally in children with status epilepticus (convulsive) in a healthcare setting.


Eligibility criteria: Inclusion Criteria:

* Male and female participants whose corrected gestational age is greater than or equal to (\>=) 52 weeks (gestational weeks plus the number of weeks after birth) and less than (\<) 18 years (and weight greater than \[\>\] 5 kilogram \[kg\]), at the time of investigational product administration. If the participant's exact age is not known, the participant should be excluded.
* Parent, guardian, or legally authorized representative (LAR) of the child provides informed consent (and assent, when applicable per Shire policy and country regulations) to participate in the study prior to participation in any protocol specific procedures. The participant may be prescreened by the investigator in their clinical practice and the parent, guardian, or LAR may sign informed consent before the participant presents to the healthcare setting for treatment of the seizure.
* Participant with 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) lasting \>=5 mins

Exclusion Criteria:

* Female participants 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 seizures due to illegal drug or acute alcoholic intoxication.
* Subjects with known or suspected recurrent seizures due to illegal drug or alcohol withdrawal.
* Subjects with history of seizures of psychogenic origin.
* Subjects with seizures due to severe encephalitis or meningitis, as determined by the PI
* Subjects with known history of hypersensitivities, non-responsiveness or contraindications to benzodiazepines (ie, clinically significant respiratory depression, severe acute hepatic failure, myasthenia gravis, syndrome of sleep apnea, glaucoma with closed angle, 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, in the judgment of the healthcare provider, 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 with significant hypotension and cardiac dysrhythmia (example \[eg\], atrioventricular \[AV\] block of second or third degree, VT \[ventricular tachycardia\]).
* Subjects who have been receiving human immunodeficiency virus (HIV) protease inhibitors or HIV reverse transcriptase inhibitors.
* Subjects with current hypoglycemia (glucose \<60 milligram per deciliter \[mg/dL\]) upon presentation at the hospital or healthcare setting.
* Subjects with severe cerebral anoxia (except cerebral palsy), in the judgment of the healthcare provider.
* Subjects 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.
* Subjects has received antiseizure medication prior to arrival in the healthcare setting.
* Subjects has prior placement of a vagus nerve stimulator.

Primary outcomes:
measure: Percentage of Participants With Response Rate
timeFrame: From start of study drug administration up to 30 minutes post-dose
Secondary outcomes:
measure: Percentage of Participants Who Had Sustained Absence of Seizure Activity for at Least 1, 4 and 6 Hours
timeFrame: From start of study drug administration up to 1, 4 and 6 hours post-dose
measure: Number of Participants With Time to Resolution of Seizures (Convulsions)
timeFrame: From start of study drug administration up to follow-up (Day 8)
measure: Number of Participants With Time to Recovery of Consciousness
timeFrame: From start of study drug administration up to follow-up (Day 8)
measure: Percentage of Participants Who Required Additional Anticonvulsant Medication for Ongoing Status Epilepticus (SE)
timeFrame: 10 minutes post-dose
measure: Percentage of Participants Who Failed to Respond to the Treatment With SHP615
timeFrame: 10 minutes post-dose
measure: Concentration of SHP615 in Plasma at 10 Minutes (C10)
timeFrame: 10 minutes post-dose
measure: Maximum Plasma Concentration (Cmax) of SHP615
timeFrame: 1, 3, 6 hours post-dose
measure: Area Under the Concentration-time Curve From Time Zero to 10 Minutes (AUC0-10) of SHP615 in Plasma
timeFrame: Pre-dose, 10 minutes post-dose
measure: Area Under the Concentration-time Curve From Time Zero to 60 Minutes (AUC0-60) of SHP615 in Plasma
timeFrame: Pre-dose, 60 minutes post-dose
measure: Area Under the Concentration-time Curve From Time Zero to 180 Minutes (AUC0-180) of SHP615 in Plasma
timeFrame: Pre-dose, 180 minutes post-dose
measure: Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of SHP615 in Plasma
timeFrame: Pre-dose, 1, 3, and 6 hours post-dose
measure: Time at Maximum Concentration (Tmax) of SHP615 in Plasma
timeFrame: 1, 3, and 6 hours post-dose
measure: Elimination Half-life (T1/2) of SHP615 in Plasma
timeFrame: 1, 3, and 6 hours post-dose
measure: Number of Participants With Respiratory Depression
timeFrame: From start of study drug administration up to follow-up (Day 8)
measure: Number of Participants With Aspiration Pneumonia Reported as Treatment Emergent Adverse Events (TEAEs)
timeFrame: From start of study drug administration up to follow-up (Day 8)
measure: Change From Baseline in Riker Sedation-Agitation Scale at 24 Hours Post-dose
timeFrame: Baseline, 24 hours post-dose
measure: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)
timeFrame: From start of study drug administration up to follow-up (Day 8)
measure: Change From Baseline in Oxygen Saturation Percentage at 24 Hours Post-dose
timeFrame: Baseline, 24 hours post-dose
Other outcomes:
Locations:
city: Kofu
country: Japan
facility: Yamanashi Prefectural Central Hospital
state: Fujimi
city: Gifu
country: Japan
facility: Gifu Prefectural General Medical Center
state: Gifu Prefecture
city: Sapporo
country: Japan
facility: Hokkaido University Hospital
state: Hokkaido
city: Tokyo
country: Japan
facility: Tokyo Women's Medical University Hospital
state: Kawadacho
city: Okayama
country: Japan
facility: NHO Minami-Okayama Medical Center
state: Okayama Prefecture
city: Yachiyo
country: Japan
facility: Tokyo Women's Medical University Yachiyo Medical Center
state: Owada Shinden
city: Saitama-shi
country: Japan
facility: Jichi Children's Medical Center Tochigi
state: Saitama-ken
city: Shizuoka
country: Japan
facility: Shizuoka Institute of Epilepsy and Neurological Disorders
state: Shizuoka Prefecture
city: Fukuoka
country: Japan
facility: Fukuoka Children's Hospital(NW)
city: Hokkaidō
country: Japan
facility: NHO Hokkaido Medical Center
city: Kumamoto
country: Japan
facility: Kumamoto Saishunso National Hospital
city: Nagasaki
country: Japan
facility: NHO Nagasaki Medical Center
city: Niigata
country: Japan
facility: NHO Nishi Niigata Chuo National Hospital
city: Obu
country: Japan
facility: Aichi Children's Health and Medical Center(NW)
city: Okayama
country: Japan
facility: Okayama University Hospital
city: Osaka
country: Japan
facility: Nakano Children's Hospital
city: Osaka
country: Japan
facility: Osaka Women's and Children's Hospital(NW)
city: Saitama
country: Japan
facility: Saitama Children's Medical Center(NW)
city: Suita
country: Japan
facility: Osaka University Hospital
city: Tokyo
country: Japan
facility: National Center Hospital, NCNP
city: Tottori
country: Japan
facility: Tottori University Hospital
city: Yamadaoka
country: Japan
facility: Osaka University Hospital
city: Yokohama
country: Japan
facility: Kanagawa Children's Medical Center(NW)
Study officials:
affiliation: Shire
name: Shire Study Physician
role: STUDY_DIRECTOR
References: