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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT03336450
Recruitment Status : Completed
First Posted : November 8, 2017
Results First Posted : September 14, 2021
Last Update Posted : September 14, 2021
Sponsor:
Collaborator:
Takeda Development Center Americas, Inc.
Information provided by (Responsible Party):
Takeda ( Shire )

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

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Study Type : Interventional  (Clinical Trial)
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 : April 23, 2018
Actual Primary Completion Date : October 13, 2020
Actual Study Completion Date : October 13, 2020


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




Primary Outcome Measures :
  1. Efficacy: Number of Participants With Therapeutic Success [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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) [ 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 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 [ 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 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 [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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) [ Time Frame: 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) [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: 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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   6 Months to 216 Months   (Child, Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03336450


Locations
Show Show 23 study locations
Sponsors and Collaborators
Shire
Takeda Development Center Americas, Inc.
Investigators
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Study Director: Study Director Takeda Development Center Americas
  Study Documents (Full-Text)

Documents provided by Takeda ( Shire ):
Study Protocol  [PDF] December 18, 2017
Statistical Analysis Plan  [PDF] September 12, 2019

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Responsible Party: Shire
ClinicalTrials.gov Identifier: NCT03336450    
Other Study ID Numbers: SHP615-302
First Posted: November 8, 2017    Key Record Dates
Results First Posted: September 14, 2021
Last Update Posted: September 14, 2021
Last Verified: August 2021
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

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Status Epilepticus
Midazolam
Nervous System Diseases
Seizures
Neurologic Manifestations
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