Seizure Rescue Medication for Epilepsy

Overseen By Study Research Coordinator

Age: 18+

Sex: Any

Trial Phase: Phase 4

Sponsor: Martha Sajatovic

Must be taking: Anti-epileptic

Must not be taking: Opioids, Benzodiazepines

Disqualifiers: Glaucoma, Dementia, Suicidal, others

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

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

Approved in 4 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 10

43 Participants Needed

Trial Summary

Will I have to stop taking my current medications?

The trial does not specify if you need to stop your current medications. However, it mentions that participants should still be experiencing seizures while on anti-epileptic medication, suggesting you may continue your current regimen.

What data supports the effectiveness of the drug SMART RM, Diazepam, Midazolam, Lorazepam, Clonazepam, Valtoco Nasal Product, Valtoco, Diazepam Nasal Spray for treating seizure clusters in epilepsy?

Research shows that diazepam rectal gel and diazepam nasal spray are effective in stopping seizure clusters, with diazepam rectal gel stopping seizures in 90% of patients in one study. Midazolam nasal spray is also highlighted as a promising alternative due to its easy and rapid administration. ^{1 2 3 4 5}

Is the seizure rescue medication generally safe for humans?

The seizure rescue medications, including diazepam, midazolam, lorazepam, and clonazepam, are generally considered safe for humans, but they can cause side effects like drowsiness, ataxia (loss of control of body movements), and behavior changes. These side effects are often dose-related and may decrease over time. Midazolam nasal spray has been evaluated for safety in treating seizure clusters, and clonazepam has been used safely in various types of epilepsy, though it may cause drowsiness and other side effects. ^{3 6 7 8 9}

How is the drug SMART RM different from other epilepsy treatments?

SMART RM, which includes diazepam, midazolam, lorazepam, and clonazepam, is unique because it offers multiple administration routes like nasal sprays and rectal gels, making it more socially acceptable and easier to use quickly during seizure clusters compared to traditional methods. ^{1 2 4 5 10}

What is the purpose of this trial?

This study will be done in two phases. Using stakeholder input (community advisory board (CAB)), the study team will adapt the SMART program to incorporate education and self-management support for use of Rescue Medication (RM) to manage seizure occurrence among Persons With Epilepsy (PWE) who have repetitive seizures. Additional content/support materials, pending input stakeholder might include posters/hand-outs that present information on the use of RM in a way that is engaging and salient to PWE. It is expected that participants will be in Phase 1 for about 3 months and participate in the CAB 2 or 3 times via zoom for 60-90 minutes/meeting. The advisory board will provide input on needed refinement of an adapted version of SMART based on their individual experiences. It is anticipate the total time commitment to be no more than 6 hours over 3 months, spread out over 2-3 meetings with review of materials possible in between meetings. Phase 2: The investigators will use a 6-month prospective trial design to test engagement with and effects of SMART-RM among approximately 35 adult (≥ 18 years) PWE who have repetitive seizures.

Research Team

Martha Sajatovic, MD

Principal Investigator

University Hospitals

Eligibility Criteria

This trial is for adults with epilepsy who experience repetitive seizures. Participants should be willing to engage in a comprehensive self-management program, which includes education on using rescue medication (RM) effectively. They must commit to attending several virtual meetings and providing feedback.

Inclusion Criteria

Inclusion criteria for participants who will receive SMART-RM: Have received a previous diagnosis of epilepsy, Be adults ≥ age 18, While on a regimen of anti-epileptic medication, still be experiencing bouts of seizures (e.g. frequent break through or acute repetitive seizures) distinct from their usual seizure pattern, and, in the opinion of the study epilepsy clinician, may need benzodiazepine intervention for seizure control, Have experienced at least 5 seizures but not more than 100 seizures in the previous 6 months, Be able to speak and understand English, Be able to provide written, informed consent to study participation

Exclusion Criteria

Exclusion criteria for participants who will receive SMART-RM: Individuals who have had allergic reaction to diazepam or who have medical/psychiatric conditions that are contraindications to the use of diazepam, Individuals prescribed opioid medications, Individuals with acute narrow angle glaucoma, Individuals with known dependence on benzodiazepines or current benzodiazepine abuse, Actively suicidal/homicidal, Individuals with a diagnosis of dementia, Individuals who are unable to provide written informed consent to participate in study and who do not have a legally authorized representative or individuals who are unable to participate in study procedures, Pregnant women

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Phase 1: Adaptation and Stakeholder Input

Participants engage with the community advisory board (CAB) to adapt the SMART program for Rescue Medication (RM) use, involving 2-3 Zoom meetings over 3 months.

12 weeks

2-3 visits (virtual)

Phase 2: Treatment and Engagement

Participants engage in 8 group-format sessions of SMART-RM, followed by 3 monthly maintenance sessions.

24 weeks

8 group sessions (virtual), 3 maintenance sessions (telephone)

Follow-up

Participants are monitored for changes in epilepsy self-management, self-efficacy, social support, stigma, quality of life, functional status, and depressive symptoms.

4 weeks

Treatment Details

Interventions

• SMART RM
• Valtoco Nasal Product

Trial Overview The study tests the SMART RM program, adapted to include rescue medication use for seizure management. Phase 1 involves adapting the program with participant input. In Phase 2, the effectiveness of this tailored SMART-RM will be tested over six months.

Participant Groups

Group I: SMART RM Experimental Treatment 2 Interventions

The SMART-RM will consist of 8 group-format, 45-60 minute sessions (up to 11 participants per group), which will be collaboratively delivered by a Nurse Educator (NE) and a Peer Educator (PE). The intervention will be remotely delivered in a web-based format using a secure web teleconferencing system (such as Zoom) that will allow us to set up a virtual meeting room. Following the group-session series, participants will have 3 monthly telephone maintenance sessions lasting around 15 minutes. Maintenance session web/telephone calls will be made to study participants by a NE with experience in epilepsy and/or chronic health condition management.

SMART RM is already approved in United States, European Union, Canada, Japan for the following indications:

Approved in United States as Diazepam for:

• Acute treatment of seizures
• Status epilepticus

Approved in European Union as Midazolam for:

• Acute treatment of seizures
• Status epilepticus

Approved in Canada as Lorazepam for:

• Acute treatment of seizures
• Status epilepticus

Approved in Japan as Clonazepam for:

• Acute treatment of seizures
• Status epilepticus

Who Is Running the Clinical Trial?

Martha Sajatovic

Lead Sponsor

Trials

3

Recruited

110+

University Hospitals Cleveland Medical Center

Lead Sponsor

Trials

348

Recruited

394,000+

Findings from Research

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]

Rescue therapies like diazepam rectal gel, midazolam nasal spray, and diazepam nasal spray are crucial for stopping seizure clusters and preventing progression to more severe conditions, with benzodiazepines acting as positive allosteric modulators of GABAA receptors to reduce neuronal excitation.

Midazolam and diazepam in nasal spray form provide a socially acceptable and rapid alternative to rectal administration, making them more convenient for adults and adolescents who may have reservations about rectal treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Rescue therapies for seizure clusters: Pharmacology and target of treatments. Gidal, B., Detyniecki, K.[2022]

Clonazepam is an FDA-approved benzodiazepine anticonvulsant effective for various types of seizures, with a biological half-life of 22 to 32 hours, allowing for sustained therapeutic effects.

While it is effective, clonazepam can cause side effects like drowsiness and ataxia, which are often dose-related and may improve over time; therefore, it is recommended to start with a low dose and gradually increase.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Clonazepam. A review of a new anticonvulsant drug. Browne, TR.[2019]

Intranasal rescue medications for seizure clusters, such as midazolam nasal spray, are easier and faster to administer than rectal or intravenous options, leading to shorter seizure durations.

Despite their effectiveness and safety, rescue medications are underutilized due to patient and caregiver perceptions, highlighting the need for better education and seizure action plans to improve their use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Overcoming barriers to the management of seizure clusters: ease of use and time to administration of rescue medications. O'Hara, K., Dewar, S., Bougher, G., et al.[2023]

In a study of 50 adults with epilepsy, rectal diazepam was effective in stopping breakthrough seizures in 90% of cases, indicating its strong efficacy as a rescue medication.

While most patients experienced somnolence (drowsiness) as a side effect, no serious adverse events were reported, suggesting that diazepam rectal gel is generally well-tolerated and could enhance the quality of life for those with epilepsy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effectiveness of diazepam rectal gel in adults with acute repetitive seizures and prolonged seizures: a single-center experience. Fakhoury, T., Chumley, A., Bensalem-Owen, M.[2013]

Clobazam, a 1,5-benzodiazepine, has been shown to significantly reduce seizure frequency by 65% in patients with refractory epilepsy, making it an effective adjunctive therapy.

While clobazam is generally well tolerated with minimal cognitive impairment, it can cause sedation in some patients, and about 36% may develop tolerance over time, necessitating careful management of dosage and withdrawal.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Current status of the 1,4- and 1,5-benzodiazepines in the treatment of epilepsy: the place of clobazam. Robertson, MM.[2022]

In a study of 32 epileptic patients, clonazepam showed substantial improvement in seizure control for 22 patients, particularly effective for myoclonus, petit mal absences, and partial complex epilepsy.

While clonazepam is considered the drug of choice for generalized infantile organic epilepsy, its effectiveness may decrease over time, and drowsiness is the primary side effect reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of epileptic seizures with clonazepam. A reappraisal. Fazio, C., Manfredi, M., Piccinelli, A.[2019]

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]

Clonazepam is effective for treating childhood minor motor seizures and petit mal seizures that do not respond to other medications, but it is less effective for infantile spasms, although it may help if steroids fail.

While clonazepam can cause side effects like lethargy and ataxia, these are often temporary; however, some children may experience increased aggressiveness or hyperactivity, which could require stopping the medication.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The utility of clonazepam in epilepsy of various types. Observations with 22 childhood cases. Nogen, AG.[2017]

Seizure clusters, which are acute repetitive seizures, affect about 1.2% of the U.S. population and require prompt treatment to prevent serious complications; however, up to 80% of adult patients do not use rescue medications like benzodiazepines, which are the standard treatment.

Long-term clinical trials have shown that intranasal benzodiazepines, such as midazolam and diazepam nasal spray, are effective and well-tolerated for treating seizure clusters, with mild to moderate adverse events and no reports of respiratory depression, highlighting their safety and ease of use for patients and caregivers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Treatment of Seizure Clusters in Epilepsy: A Narrative Review on Rescue Therapies. Becker, DA., Wheless, JW., Sirven, J., et al.[2023]

References

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

Rescue Treatments for Seizure Clusters. [2022]

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

Rescue therapies for seizure clusters: Pharmacology and target of treatments. [2022]

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

Clonazepam. A review of a new anticonvulsant drug. [2019]

4. England pubmed.ncbi.nlm.nih.gov

Overcoming barriers to the management of seizure clusters: ease of use and time to administration of rescue medications. [2023]

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

Effectiveness of diazepam rectal gel in adults with acute repetitive seizures and prolonged seizures: a single-center experience. [2013]

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

Current status of the 1,4- and 1,5-benzodiazepines in the treatment of epilepsy: the place of clobazam. [2022]

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

Treatment of epileptic seizures with clonazepam. A reappraisal. [2019]

8. 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]

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

The utility of clonazepam in epilepsy of various types. Observations with 22 childhood cases. [2017]

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

Treatment of Seizure Clusters in Epilepsy: A Narrative Review on Rescue Therapies. [2023]