Clinical Trial to evaluate the efficacy, safety and tolerability of Midazolam Intranasal Spray compared with a placebo administered through the nose (intranasal) for the treatment of intermittent bouts of increased seizure in a site that monitors epilepsy.

• Register: EUCTR
• Last refreshed on: 14 November 2016
• Main ID: EUCTR2014-003961-49-CZ
• Date of registration: 27/11/2014
• Prospective Registration: Yes
• Primary sponsor: Upsher-Smith Laboratories, Inc.
• Public title: Clinical Trial to evaluate the efficacy, safety and tolerability of Midazolam Intranasal Spray compared with a placebo administered through the nose (intranasal) for the treatment of intermittent bouts of increased seizure in a site that monitors epilepsy.
• Scientific title: A Randomized, Double-Blind, Placebo Controlled Trial Examining the Safety and Efficacy of Midazolam Intranasal Spray (USL261) for the Treatment of Intermittent Bouts of Increased Seizure Activity in the Epilepsy Monitoring Unit (EMU) - ARTEMIS EMU
• Date of first enrolment: 09/02/2015
• Target sample size: 62
• Recruitment status: Not Recruiting
• URL: https://www.clinicaltrialsregister.eu/ctr-search/search?query=eudract_number:2014-003961-49
• Study type: Interventional clinical trial of medicinal product
• Study design: Controlled: yes Randomised: yes Open: no Single blind: no Double blind: yes Parallel group: yes Cross over: no Other: no If controlled, specify comparator, Other Medicinial Product: no Placebo: yes Other: no Number of treatment arms in the trial: 2
• Phase: Human pharmacology (Phase I): no Therapeutic exploratory (Phase II): no Therapeutic confirmatory - (Phase III): yes Therapeutic use (Phase IV): no

Countries of recruitment

Australia, Austria, Belgium, Czech Republic, France, Germany, Italy, Lithuania, Spain, United States

Contacts

• Name: Associate Direct Clinical Research
• Affiliation: Upsher-Smith Laboratories, Inc.

• Name: Associate Direct Clinical Research
• Affiliation: Upsher-Smith Laboratories, Inc.

Key inclusion & exclusion criteria

Inclusion criteria:
A subject will be eligible for enrollment in the study if all of the following criteria apply:
1.The subject or the subject’s legally acceptable representative (LAR) has provided written informed consent, and subject has provided written assent where required by local law or Institutional Review Board (IRB)/Independent Ethics Committee (IEC) policy
2.Subject has been admitted to the institution’s EMU for seizure characterization or pre-surgical evaluation, or such admission is planned within 28 days
3.Subject body weight is = 40 kg to = 125 kg (inclusive)
4.Subject is = 12 years of age at Screening
5.Subject has an established diagnosis of partial or generalized epilepsy
Are the trial subjects under 18? no
Number of subjects for this age range:
F.1.2 Adults (18-64 years) yes
F.1.2.1 Number of subjects for this age range 50
F.1.3 Elderly (>=65 years) yes
F.1.3.1 Number of subjects for this age range 2

Exclusion criteria:
1.Subject has a medical condition that could interfere with the absorption or pharmacokinetics of USL261
2.Subject has history of status epilepticus in the 6 months prior to screening
3.Subject has a progressive neurological disorder such as brain tumor, demyelinating disease, or degenerative central nervous system (CNS) disease that is likely to progress in the next 12 months
4.Subject has a positive alcohol test or a positive urine drug screen (UDS) not associated with documented legitimate medical use. Individuals with cognitive disability that precludes the collection of a urine sample by conventional means are exempt from the screening UDS requirement provided that the subject is deemed unlikely to have been recently exposed to drugs of abuse based on the opinion of the investigator and the reason the urine could not be obtained is documented
5.Subject has respiratory failure (or is at risk for respiratory failure) or other severe cardio-respiratory disease with New York Heart Association Class III or IV functional status, or requires supplemental oxygen
6.Subject has acute narrow-angle glaucoma
7.Subject (females only) has a positive pregnancy test during the Screening Phase or is currently pregnant or breastfeeding at time of Screening or time of admission to the EMU
8.Subject has a prior history of any significant adverse reactions (including rash) to benzodiazepines or known allergies to midazolam or formulation components
9.Subject requires concomitant treatment with any of the prohibited substances listed in this protocol (including strong CYP3A4 inhibitors or respiratory depressants), or cannot safely discontinue prohibited substances with sufficient washout prior to the Treatment Phase (See Appendix 1)
10.Subject is receiving chronic benzodiazepine treatment (defined as an average of = 4 administrations per week) and cannot safely withdraw from such treatment within the washout period prior to the Treatment Phase. The management of safe withdrawal of benzodiazepine therapy is left to the discretion of the investigator. Benzodiazepines that are used for rescue therapy of seizures or for non-epilepsy indications are allowed provided they are typically used = 3 times in a 7-day period
11.Subject has any clinically significant laboratory abnormality as determined by the investigator at Screening
12.Subject has any clinically significant 12-lead electrocardiogram (ECG) findings as determined by the investigator at Screening
13.Subject has any clinically significant abnormal vital sign values as determined by the investigator at Screening
14.Subject is currently using an investigational drug or device or has used such within the 60 days prior to the Screening Phase. The use of experimental non-interventional devices such as seizure detection devices is not considered exclusionary.
15.Subject has previously participated in a study of USL261
16.Subject has any condition that may interfere with subject safety/safety monitoring, or preclude the safe administration of a benzodiazepine, or is not appropriate for the study for any other reason as determined by the investigator.


Age minimum:
Age maximum:
Gender:
Female: yes
Male: yes

Health Condition(s) or Problem(s) studied

Therapeutic area: Diseases [C] - Nervous System Diseases [C10]

Epilepsy
MedDRA version: 18.0 Level: LLT Classification code 10015052 Term: Epileptic seizure System Organ Class: 100000004852

Intervention(s)

Product Name: Intranasal midazolam
Product Code: USL261
Pharmaceutical Form: Nasal spray, solution in single-dose container
INN or Proposed INN: MIDAZOLAM
CAS Number: 59467-70-8
Current Sponsor code: USL261
Concentration unit: mg/ml milligram(s)/millilitre
Concentration type: equal
Concentration number: 50-
Pharmaceutical form of the placebo: Nasal spray, solution in single-dose container
Route of administration of the placebo: Intranasal use (Noncurrent)

Primary Outcome(s)

Main Objective: To evaluate the efficacy, safety, and tolerability of USL261 compared with that of intranasal (IN) placebo for the treatment of intermittent bouts of increased seizure activity in the Epilepsy Monitoring Unit.

Primary end point(s): The primary efficacy endpoint is the difference between the USL261- and placebo-treated groups in the proportion of subjects that are seizure-free (no clinically observable seizures) during the Treatment Phase. The proportion of seizure-free subjects will be determined by the number of subjects who complete 6 hours of the Treatment Phase without a seizure. The difference in proportion of seizure-free subjects by treatments will be evaluated using two-sided standard Wald asymptotic 95% confidence intervals.

Timepoint(s) of evaluation of this end point: The proportion of seizure-free subjects will be determined by the number of subjects who complete 6 hours of the Treatment Phase without a seizure.

Secondary Objective: Not applicable

Secondary Outcome(s)

Secondary end point(s): Time to first seizure following treatment (TFSFT) – TFSFT will be defined as time from treatment with study drug to the onset of the next seizure or 6 hours, whichever comes first. Comparison of TFSFT between the USL261- and placebo-treated groups will be analyzed by a log-rank test, with right censoring for subjects who complete 6 hours without a seizure, and presented with Kaplan-Meier estimates of median and two-sided 95% Confidence Intervals for time to event. Those subjects who discontinue prior to 6 hours without a seizure will be analyzed at the time they discontinued.

Timepoint(s) of evaluation of this end point: TFSFT will be defined as time from treatment with study drug to the onset of the next seizure or 6 hours, whichever comes first.

Secondary ID(s)

2014-003961-49-BE

P261-301

Source(s) of Monetary Support

Upsher-Smith Laboratories, Inc.