Pharmacodynamics of Nasal and Buccal Midazolam Using EEG

NCT01316445 | Terminated Phase 1

• 1 other identifier: AAAF3704
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

Approximately 3 million individuals suffer from epilepsy in America alone and about 200,000 new cases of epilepsy in America are diagnosed each year (Epilepsy Foundation, 2005). Epilepsy can be defined as a condition in which a person has recurrent, unprovoked seizures. Prolonged or back-to-back repetitive seizures, known as "acute repetitive seizures" (ARS), are medical emergencies. ARS can occur unexpectedly, a circumstance for which quick and efficient antiepileptic drugs are needed for household and prehospital use. Currently, benzodiazepines are the antiepileptic drug of choice when dealing with ARS because they are proven to be efficient and take little time to work. Benzodiazepines can be administered by mouth, by vein via a needle (intravenously; IV), rectally, between the cheek and gum (buccally), or in the nose (intranasally; IN). The nasal formulation is not yet FDA-approved. The rectal treatment route has been commonly used for acute seizure treatment in past years, but recent studies propose that the nasal route for benzodiazepines may be better overall for home treatment and easier to administer (see Wermeling, 2009). For many "out of hospital" situations, nasal benzodiazepines can be more convenient and more comfortable than rectal treatment. In addition to the above benefits, nasal benzodiazepines are rapidly absorbed by the blood vessels in the nose and the time of drug administration and cessation of seizures may thus be reduced using nasal routes. This study sets out to characterize how fast buccal and nasal treatments begin to work on the brain by monitoring brain waves during administration of the drug, and to determine whether nasal or buccal administration is best.

Conditions

Epilepsy

Keywords

Electroencephalography; Benzodiazepines; Midazolam

Outcome Measures

Primary Outcomes (1)

• 25% increase in total beta power for at least 1 minute at 10-30Hz

  Quantitative and qualitative visual EEG analysis for benzodiazepine-induced beta activity, total power of \~10-30 Hz activity

  for 30 mins after administration of drug

Secondary Outcomes (4)

• beta activity at 10-12 Hz

  for 30 minutes after drug administration

• beta activity at 30-40Hz

  for 30 minutes after drug administration

• sedation

  for 30 minues after drug administration

• pain/discomfort

  for 30 minutes after drug administration

Study Arms (1)

nasal Midazolam

EXPERIMENTAL

3 mg of the standard IV solution of midazolam (5 mg/mL) was given via a metered-dose nasal sprayer (6 sprays × 0.1 ml/spray, or 6 × 0.5 mg/spray) divided between the two nostrils within 1-2 min. During the EEG, vital signs (blood oxygen saturation, blood pressure, pulse and respiratory rate) were monitored and a nurse and a physician were available at all times. Subjects were monitored for 2 hours after administration of midazolam to ensure adequate recovery from sedation.

Drug: nasal Midazolam

Interventions

nasal Midazolam DRUG

Intranasal and buccal administration of the standard IV formulation of midazolam (5mg/mL), administered via a metered dose sprayer at 0.1mL/spray (i.e. 0.5mg/spray). Administration will be via three sprays in each nostril (for nasal) or three sprays between the cheek and the gum per side (for buccal).

Also known as: Versed

nasal Midazolam

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• adults undergoing extracranial EEG in an Epilepsy Monitoring Unit
• adults undergoing intracranial EEG in an Epilepsy Monitoring Unit
• adults with chronically implanted intracranial neurostimulators with the capacity for continuous intracranial EEG monitoring

You may not qualify if:

• any patient on additional sedative medications (narcotics, other central nervous system depressants)
• any patient with documented sensitivity or adverse reaction to any benzodiazepine

Sponsors & Collaborators

• Columbia University: lead
• Upsher-Smith Laboratories: collaborator

Study Sites (1)

Columbia University Medical Center, Milstein Hospital

New York, New York, 10032, United States

Location

Related Publications (5)

• Loftsson T, Gudmundsdottir H, Sigurjonsdottir JF, Sigurdsson HH, Sigfusson SD, Masson M, Stefansson E. Cyclodextrin solubilization of benzodiazepines: formulation of midazolam nasal spray. Int J Pharm. 2001 Jan 5;212(1):29-40. doi: 10.1016/s0378-5173(00)00580-9.

  PMID: 11165818 BACKGROUND

• Knoester PD, Jonker DM, Van Der Hoeven RT, Vermeij TA, Edelbroek PM, Brekelmans GJ, de Haan GJ. Pharmacokinetics and pharmacodynamics of midazolam administered as a concentrated intranasal spray. A study in healthy volunteers. Br J Clin Pharmacol. 2002 May;53(5):501-7. doi: 10.1046/j.1365-2125.2002.01588.x.

  PMID: 11994056 BACKGROUND

• Wermeling DP, Record KA, Kelly TH, Archer SM, Clinch T, Rudy AC. Pharmacokinetics and pharmacodynamics of a new intranasal midazolam formulation in healthy volunteers. Anesth Analg. 2006 Aug;103(2):344-9, table of contents. doi: 10.1213/01.ane.0000226150.90317.16.

  PMID: 16861415 BACKGROUND

• Wermeling DP, Record KA, Archer SM, Rudy AC. A pharmacokinetic and pharmacodynamic study, in healthy volunteers, of a rapidly absorbed intranasal midazolam formulation. Epilepsy Res. 2009 Feb;83(2-3):124-32. doi: 10.1016/j.eplepsyres.2008.10.005. Epub 2008 Nov 29.

  PMID: 19046855 BACKGROUND

• Dale O, Nilsen T, Loftsson T, Hjorth Tonnesen H, Klepstad P, Kaasa S, Holand T, Djupesland PG. Intranasal midazolam: a comparison of two delivery devices in human volunteers. J Pharm Pharmacol. 2006 Oct;58(10):1311-8. doi: 10.1211/jpp.58.10.0003.

  PMID: 17034653 BACKGROUND

MeSH Terms

Conditions

Epilepsy

Interventions

Midazolam

Condition Hierarchy (Ancestors)

Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Intervention Hierarchy (Ancestors)

Benzodiazepines; Benzazepines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Derek Chong, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Research Scientist

Study Record Dates

• First Submitted: March 15, 2011
• First Posted: March 16, 2011
• Study Start: July 1, 2011
• Primary Completion: February 1, 2014
• Study Completion: February 1, 2014
• Last Updated: February 4, 2015

Record last verified: 2015-02

Locations

US (1)