Age-Based Seizure Protocol for Pediatric Seizures

(PediDOSE Trial)

Recruiting at 19 trial locations

Overseen By Leonard Basobas, MS

Age: < 18

Sex: Any

Trial Phase: Phase 3

Sponsor: Stanford University

Disqualifiers: Benzodiazepine allergy, Pregnancy, Growth restriction

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: Unknown

6000 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial information does not specify whether participants need to stop taking their current medications.

What data supports the effectiveness of the drug for pediatric seizures?

Research shows that midazolam, especially in nasal spray form like Nayzilam, is effective and safe for treating seizures in children, offering quick relief and easy administration compared to traditional methods. Buccal midazolam is also proven to be effective and well-accepted for rapid seizure control in children. ^{1 2 3 4 5}

Is the Age-Based Seizure Protocol for Pediatric Seizures safe for children?

Midazolam, used in various forms like nasal spray and buccal (inside the cheek) administration, has been shown to be safe for treating seizures in children. Studies indicate it is well-tolerated and effective in quickly stopping seizures, making it a reliable option for both hospital and community settings. ^{1 2 5 6 7}

What makes the drug used in the Age-Based Seizure Protocol for Pediatric Seizures unique?

The drug used in this protocol, midazolam, is unique because it can be administered intranasally, making it easy for non-medical personnel to use during a seizure. This method is quicker and more accessible than the traditional rectal diazepam, providing a fast and effective way to stop seizures outside of a hospital setting. ^{1 2 8 9 10}

What is the purpose of this trial?

The Pediatric Dose Optimization for Seizures in Emergency Medical Services (PediDOSE) study is designed to improve how paramedics treat seizures in children on ambulances. Seizures are one of the most common reasons why people call an ambulance for a child, and paramedics typically administer midazolam to stop the seizure. One-third of children with active seizures on ambulances arrive at emergency departments still seizing. Prior research suggests that seizures on ambulances continue due to under-dosing and delayed delivery of medication. Under-dosing happens when calculation errors occur, and delayed medication delivery occurs due to the time required for dose calculation and placement of an intravenous line to give the medication. Seizures stop quickly when standardized medication doses are given as a muscular injection or a nasal spray. This research has primarily been done in adults, and evidence is needed to determine if this is effective and safe in children. PediDOSE optimizes how paramedics choose the midazolam dose by eliminating calculations and making the dose age-based. This study involves changing the seizure treatment protocols for ambulance services in 20 different cities, in a staggered and randomly-assigned manner. One aim of PediDOSE is to determine if using age to select one of four standardized doses of midazolam and giving it as a muscular injection or nasal spray is more effective than the current calculation-based method, as measured by the number of children arriving at emergency departments still seizing. The investigators believe that a standardized seizure protocol with age-based doses is more effective than current practice. Another aim of PediDOSE is to determine if a standardized seizure protocol with age-based doses is just as safe as current practice, since either ongoing seizures or receiving too much midazolam can interfere with breathing. The investigators believe that a standardized seizure protocol with age-based doses is just as safe as current practice, since the seizures may stop faster and these doses are safely used in children in other healthcare settings. If this study demonstrates that standardized, age-based midazolam dosing is equally safe and more effective in comparison to current practice, the potential impact of this study is a shift in the treatment of pediatric seizures that can be easily implemented in ambulance services across the United States and in other parts of the world.

Research Team

Manish I Shah, MD, MS

Principal Investigator

Stanford University

Eligibility Criteria

The PediDOSE trial is for children actively seizing when paramedics arrive, under their care, and transported by an EMS agency in the study. It excludes kids with known pregnancy, benzodiazepine allergy, or severe growth restriction as judged by the paramedic.

Inclusion Criteria

You were brought to the study location by an ambulance service that is involved in the study.

A paramedic saw you having a seizure, no matter how long it lasted or what type it was.

Currently being treated by a paramedic.

Exclusion Criteria

Known or presumed pregnancy

The paramedic believes that the person's growth is severely restricted.

You have had an allergic reaction to benzodiazepine before.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Intervention

Paramedics administer age-based standardized doses of midazolam to treat seizures in children on ambulances

Up to 1 hour

On-scene and during transport

Emergency Department Assessment

Participants are assessed for seizure cessation and other outcomes upon arrival at the emergency department

Up to 24 hours

Emergency department visit

Follow-up

Participants are monitored for safety and effectiveness after treatment

24 hours

Treatment Details

Interventions

• Conventional seizure protocol
• Standardized seizure protocol

Trial Overview PediDOSE tests if age-based doses of midazolam given via muscle injection or nasal spray are more effective than current calculation-based methods at stopping seizures before reaching the hospital. The study changes protocols across 20 cities to compare outcomes.

Participant Groups

Group I: Intervention Experimental Treatment 1 Intervention

This arm will be exposed to the study intervention: a standardized seizure protocol.

Group II: Control Active Control 1 Intervention

This arm will be exposed to the emergency medical services (EMS) agency's existing seizure protocol; this is the control arm

Conventional seizure protocol is already approved in European Union, United States, Canada for the following indications:

Approved in European Union as Midazolam for:

• Seizures
• Anesthesia
• Anxiety disorders

Approved in United States as Midazolam for:

• Seizures
• Anesthesia
• Anxiety disorders

Approved in Canada as Midazolam for:

• Seizures
• Anesthesia
• Anxiety disorders

Who Is Running the Clinical Trial?

Stanford University

Lead Sponsor

Trials

2,527

Recruited

17,430,000+

Baylor College of Medicine

Collaborator

Trials

1,044

Recruited

6,031,000+

National Institute of Neurological Disorders and Stroke (NINDS)

Collaborator

Trials

1,403

Recruited

655,000+

University of Utah

Collaborator

Trials

1,169

Recruited

1,623,000+

Findings from Research

In a study of 128 children with seizure disorders, a midazolam-based protocol effectively terminated seizures in 67.6% of cases, with 86.3% of those treated successfully responding to one or two doses.

The protocol demonstrated safety, with only a small number of complications, including a few cases requiring advanced airway management, indicating it can be a reliable option for managing impending status epilepticus in children.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Quality assurance evaluation of a simple linear protocol for the treatment of impending status epilepticus in a pediatric emergency department 2 years postimplementation. Tourigny-Ruel, G., Diksic, D., Mok, E., et al.[2019]

Nayzilam, an intranasal formulation of midazolam, is FDA-approved for treating intermittent seizures and is user-friendly, allowing non-medical personnel to administer it quickly during a seizure episode.

Studies show that Nayzilam effectively stops seizures faster than the traditional rectal diazepam, making it a safe and revolutionary option for treating acute seizures, especially in children when intravenous access is not available.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Midazolam nasal spray to treat intermittent, stereotypic episodes of frequent seizure activity: pharmacology and clinical role, a comprehensive review. Cornett, EM., Nemomsa, MA., Turbeville, B., et al.[2022]

In a study of 2,034 pediatric patients, intranasal (IN) midazolam was found to require redosing in 25% of cases, compared to only 14% for intravenous (IV) or intramuscular (IM) routes, indicating that the IN route may be less effective at the standard dose of 0.1 mg/kg.

The results suggest that the current dose for IN midazolam may be too low for effective seizure termination in children, as it was associated with a higher likelihood of needing additional doses compared to other administration methods.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Effectiveness of Intranasal Midazolam for the Treatment of Prehospital Pediatric Seizures: A Non-inferiority Study. Whitfield, D., Bosson, N., Kaji, AH., et al.[2022]

Three approved rescue therapies for treating seizure clusters in the U.S. are diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray, with diazepam rectal gel being effective but potentially socially uncomfortable for adults and adolescents.

Midazolam and diazepam nasal sprays offer a rapid and socially acceptable alternative to rectal administration, allowing for easier self-administration during seizure clusters.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rescue Treatments for Seizure Clusters. Kotloski, RJ., Gidal, BE.[2022]

Midazolam, when delivered through the buccal mucosa, has been shown to be an effective and safe treatment for prolonged seizures and status epilepticus in children, addressing the challenges of intravenous access.

A new formulation of buccal midazolam has been licensed for use in Europe, highlighting its acceptability to both children and caregivers in emergency situations.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Buccal midazolam for pediatric convulsive seizures: efficacy, safety, and patient acceptability. Anderson, M.[2021]

In a study involving 175 patients with seizure clusters, the nasal spray formulation of midazolam (MDZ-NS) was effective, achieving seizure termination in 55% of episodes after a single dose and 80.2% after a second dose, indicating strong efficacy in an outpatient setting.

The treatment was generally well tolerated, with 40.4% of patients experiencing treatment-emergent adverse events, primarily nasal discomfort and somnolence, but no serious safety concerns like respiratory depression or signs of drug dependence were reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters: An open-label extension trial. Wheless, JW., Meng, TC., Van Ess, PJ., et al.[2020]

Midazolam nasal spray (MDZ-NS) has been shown to be effective in treating seizure clusters, with a significant success rate in terminating seizures within 10 minutes and maintaining seizure-free status for at least six hours, compared to placebo.

The 5 mg dose of MDZ-NS was found to be as safe as a placebo, indicating that it is a well-tolerated option for patients aged 12 years and older experiencing seizures.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Evaluation of the Efficacy and Safety of Midazolam Nasal Spray in Patients With Seizure Clusters: A Systematic Review and Meta-Analysis. Niraj, N., Mahajan, S., Prakash, A., et al.[2023]

Buccolam(®), a licensed midazolam oromucosal solution, is more cost-effective than both rectal diazepam and unlicensed buccal midazolam for treating prolonged, acute convulsive seizures in children, showing a cost reduction of £2,939 compared to standard care.

The use of Buccolam(®) not only saves costs but also improves quality-adjusted life-years (QALYs) by 0.025 to 0.082, indicating it is a beneficial treatment option for children with epilepsy in the community setting.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The cost effectiveness of licensed oromucosal midazolam (Buccolam(®)) for the treatment of children experiencing acute epileptic seizures: an approach when trial evidence is limited. Lee, D., Gladwell, D., Batty, AJ., et al.[2021]

In a study involving 34 children with status epilepticus unresponsive to diazepam, intravenous midazolam showed an impressive seizure cessation rate of 88% after an initial bolus dose, indicating its efficacy as a first-line treatment.

The treatment was generally safe, with only mild adverse events reported, including one case of respiratory depression, suggesting that midazolam can be administered with careful monitoring in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, safety, and pharmacokinetics of intravenous midazolam in Japanese children with status epilepticus. Hamano, SI., Sugai, K., Miki, M., et al.[2019]

In a study of 124 pediatric patients experiencing seizures, those treated with intranasal midazolam using a Mucosal Atomization Device (MAD) had significantly shorter seizure durations (11 minutes) compared to those treated with rectal diazepam (30 minutes).

Patients receiving rectal diazepam were more likely to experience severe outcomes, including ongoing seizures in the emergency department, intubation, and higher rates of hospital admissions, indicating that IN-MAD midazolam is a more effective and safer option for prehospital seizure management.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Prehospital intranasal midazolam for the treatment of pediatric seizures. Holsti, M., Sill, BL., Firth, SD., et al.[2013]

References

1. England pubmed.ncbi.nlm.nih.gov

Quality assurance evaluation of a simple linear protocol for the treatment of impending status epilepticus in a pediatric emergency department 2 years postimplementation. [2019]

2. United States pubmed.ncbi.nlm.nih.gov

Midazolam nasal spray to treat intermittent, stereotypic episodes of frequent seizure activity: pharmacology and clinical role, a comprehensive review. [2022]

3. England pubmed.ncbi.nlm.nih.gov

The Effectiveness of Intranasal Midazolam for the Treatment of Prehospital Pediatric Seizures: A Non-inferiority Study. [2022]

4. United States pubmed.ncbi.nlm.nih.gov

Rescue Treatments for Seizure Clusters. [2022]

5. New Zealand pubmed.ncbi.nlm.nih.gov

Buccal midazolam for pediatric convulsive seizures: efficacy, safety, and patient acceptability. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Safety and efficacy of midazolam nasal spray in the outpatient treatment of patients with seizure clusters: An open-label extension trial. [2020]

7. United States pubmed.ncbi.nlm.nih.gov

The Evaluation of the Efficacy and Safety of Midazolam Nasal Spray in Patients With Seizure Clusters: A Systematic Review and Meta-Analysis. [2023]

8. Switzerland pubmed.ncbi.nlm.nih.gov

The cost effectiveness of licensed oromucosal midazolam (Buccolam(®)) for the treatment of children experiencing acute epileptic seizures: an approach when trial evidence is limited. [2021]

9. Netherlands pubmed.ncbi.nlm.nih.gov

Efficacy, safety, and pharmacokinetics of intravenous midazolam in Japanese children with status epilepticus. [2019]

10. United States pubmed.ncbi.nlm.nih.gov

Prehospital intranasal midazolam for the treatment of pediatric seizures. [2013]