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

• ClinicalTrials.gov Identifier: NCT03336645
• Recruitment Status: Completed
• First Posted: November 8, 2017
• Results First Posted: July 31, 2020
• Last Update Posted: July 31, 2020
• Sponsor: Shire
• Information provided by (Responsible Party): Takeda ( Shire )

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Nervous System Diseases	Drug: SHP615	Phase 3

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 25 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: October 23, 2017
• Actual Primary Completion Date: August 19, 2019
• Actual Study Completion Date: August 19, 2019

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: Midazolam hydrochloride oromucosal solution; MHOS

Outcome Measures

Primary Outcome Measures :

1. Percentage of Participants With Response Rate [ Time Frame: From start of study drug administration up to 30 minutes post-dose ]
   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.

Secondary Outcome Measures :

1. Percentage of Participants Who Had Sustained Absence of Seizure Activity for at Least 1, 4 and 6 Hours [ Time Frame: From start of study drug administration up to 1, 4 and 6 hours post-dose ]
   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.
2. Number of Participants With Time to Resolution of Seizures (Convulsions) [ Time Frame: From start of study drug administration up to follow-up (Day 8) ]
   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.
3. Number of Participants With Time to Recovery of Consciousness [ Time Frame: 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 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.
4. Percentage of Participants Who Required Additional Anticonvulsant Medication for Ongoing Status Epilepticus (SE) [ Time Frame: 10 minutes post-dose ]
   Percentage of participants who required additional anticonvulsant medication for ongoing SE, 10 minutes after a single dose of SHP615 were reported.
5. Percentage of Participants Who Failed to Respond to the Treatment With SHP615 [ Time Frame: 10 minutes post-dose ]
   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.
6. Concentration of SHP615 in Plasma at 10 Minutes (C10) [ Time Frame: 10 minutes post-dose ]
   Concentration of SHP615 in plasma at 10 minutes were reported.
7. Maximum Plasma Concentration (Cmax) of SHP615 [ Time Frame: 1, 3, 6 hours post-dose ]
   Cmax of SHP615 in plasma were reported.
8. Area Under the Concentration-time Curve From Time Zero to 10 Minutes (AUC0-10) of SHP615 in Plasma [ Time Frame: Pre-dose, 10 minutes post-dose ]
   AUC0-10 of SHP615 in plasma were reported. Here "min ng/mL" was minutes nanogram per milliliter.
9. Area Under the Concentration-time Curve From Time Zero to 60 Minutes (AUC0-60) of SHP615 in Plasma [ Time Frame: Pre-dose, 60 minutes post-dose ]
   AUC0-60 of SHP615 in plasma were reported.
10. Area Under the Concentration-time Curve From Time Zero to 180 Minutes (AUC0-180) of SHP615 in Plasma [ Time Frame: Pre-dose, 180 minutes post-dose ]
    AUC0-180 of SHP615 in plasma were reported.
11. Area Under the Concentration-time Curve From Time Zero to Infinity (AUC0-inf) of SHP615 in Plasma [ Time Frame: Pre-dose, 1, 3, and 6 hours post-dose ]
    AUC(0-infinity) of SHP615 in plasma were reported.
12. Time at Maximum Concentration (Tmax) of SHP615 in Plasma [ Time Frame: 1, 3, and 6 hours post-dose ]
    Tmax of SHP615 in plasma were reported.
13. Elimination Half-life (T1/2) of SHP615 in Plasma [ Time Frame: 1, 3, and 6 hours post-dose ]
    T1/2 of SHP615 in plasma were reported.
14. Number of Participants With Respiratory Depression [ Time Frame: From start of study drug administration up to follow-up (Day 8) ]
    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.
15. Number of Participants With Aspiration Pneumonia Reported as Treatment Emergent Adverse Events (TEAEs) [ Time Frame: From start of study drug administration up to follow-up (Day 8) ]
    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.
16. Change From Baseline in Riker Sedation-Agitation Scale at 24 Hours Post-dose [ Time Frame: Baseline, 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. Change from baseline in riker sedation-agition scale at 24 hours post-dose were reported.
17. Number of Participants With Treatment-Emergent Adverse Events (TEAEs) [ Time Frame: From start of study drug administration up to follow-up (Day 8) ]
    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.
18. Change From Baseline in Oxygen Saturation Percentage at 24 Hours Post-dose [ Time Frame: Baseline, 24 hours post-dose ]
    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.

Eligibility Criteria

• Ages Eligible for Study: 3 Months to 216 Months (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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.

Contacts and Locations

Locations

Japan

Yamanashi Prefectural Central Hospital

Kofu, Fujimi, Japan, 400-8506

Gifu Prefectural General Medical Center

Gifu, Gifu Prefecture, Japan, 500-8717

Hokkaido University Hospital

Sapporo, Hokkaido, Japan, 060-8648

Tokyo Women's Medical University Hospital

Tokyo, Kawadacho, Japan, 162-8666

NHO Minami-Okayama Medical Center

Okayama, Okayama Prefecture, Japan, 701-0304

Tokyo Women's Medical University Yachiyo Medical Center

Yachiyo, Owada Shinden, Japan, 276-8524

Jichi Children's Medical Center Tochigi

Saitama-shi, Saitama-ken, Japan, 330-8503

Shizuoka Institute of Epilepsy and Neurological Disorders

Shizuoka, Shizuoka Prefecture, Japan, 420-8688

Fukuoka Children's Hospital(NW)

Fukuoka, Japan, 813-0017

NHO Hokkaido Medical Center

Hokkaidō, Japan, 063-0005

Kumamoto Saishunso National Hospital

Kumamoto, Japan, 861-1196

NHO Nagasaki Medical Center

Nagasaki, Japan, 856-8562

NHO Nishi Niigata Chuo National Hospital

Niigata, Japan, 950-2085

Aichi Children's Health and Medical Center(NW)

Obu, Japan, 474-8710

Okayama University Hospital

Okayama, Japan, 700-0914

Nakano Children's Hospital

Osaka, Japan, 535-0022

Osaka Women's and Children's Hospital(NW)

Osaka, Japan, 594-1101

Saitama Children's Medical Center(NW)

Saitama, Japan, 330-8777

Osaka University Hospital

Suita, Japan, 565-0871

National Center Hospital, NCNP

Tokyo, Japan, 187-0031

Tottori University Hospital

Tottori, Japan, 683-8504

Osaka University Hospital

Yamadaoka, Japan, 565-0871

Kanagawa Children's Medical Center(NW)

Yokohama, Japan, 232-0066

Sponsors and Collaborators

Shire

Investigators

• Study Director: Shire Study Physician; Shire

  Study Documents (Full-Text)

Documents provided by Takeda ( Shire ):

Statistical Analysis Plan  [PDF] September 11, 2019

Study Protocol: Protocol  [PDF] March 20, 2017

Study Protocol: Amendment 1  [PDF] July 8, 2017

Study Protocol: Amendment 2  [PDF] August 28, 2017

Study Protocol: Amendment 3  [PDF] December 18, 2017

More Information

• Responsible Party: Shire
• ClinicalTrials.gov Identifier: NCT03336645
• Other Study ID Numbers: SHP615-301
• First Posted: November 8, 2017
• Results First Posted: July 31, 2020
• Last Update Posted: July 31, 2020
• Last Verified: June 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Shire provides access to the de-identified individual participant data for eligible studies to aid qualified researchers in addressing legitimate scientific objectives. These IPDs will be provided following approval of a data sharing request, and under the terms of a data sharing agreement.
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Access Criteria: IPD from eligible studies will be shared with qualified researchers according to the criteria and process described in the Data Sharing section of the www.shiretrials.com website. For approved requests, the researchers will be provided access to anonymized data (to respect patient privacy in line with applicable laws and regulations) and with information necessary to address the research objectives under the terms of a data sharing agreement.
• URL: https://www.shiretrials.com/en/our-commitment-to-transparency/data-sharing-with-researchers

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Takeda ( Shire ):

Seizure; Midazolam hydrochloride; Convulsive

Additional relevant MeSH terms:

Nervous System Diseases; Status Epilepticus; Seizures; Neurologic Manifestations; Midazolam; Adjuvants, Anesthesia; Hypnotics and Sedatives; Central Nervous System Depressants; Physiological Effects of Drugs; Anti-Anxiety Agents; Tranquilizing Agents; Psychotropic Drugs; Anesthetics, Intravenous; Anesthetics, General; Anesthetics; GABA Modulators; GABA Agents; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action