Lorazepam for the Treatment of Status Epilepticus or Repetitive Status Epilepticus in Japan

• Sponsor: Pfizer (Industry)
• Overall Status: Completed
• CT.gov ID: NCT02239380
• Collaborator: (none)
• Enrollment: 26
• Locations: 20
• Arm: 1
• Actual Duration (Months): 21
• Patients Per Site: 1.3
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the efficacy, safety and pharmacokinetics of Lorazepam on Japanese patients with Status Epilepticus or Repetitive Status Eplilepticus.

Condition or Disease	Intervention/Treatment	Phase
Status Epilepticus	Drug: Lorazepam	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 26 participants
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multi-center, Open-label, Non-controlled Study To Evaluate The Efficacy And Safety Of Lorazepam Intravenously Administered In Subjects With Status Epilepticus Or Repetitive Status Epilepticus
• Actual Study Start Date: Nov 1, 2014
• Actual Primary Completion Date: Aug 1, 2016
• Actual Study Completion Date: Aug 1, 2016

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Lorazepam Lorazepam intravenous formulation

Drug: Lorazepam; intravenous administration. Dosage for adult subjects (16 years aged and over): 4 mg Dosage for pediatric subjects (3 months to < 16 years): 0.05 mg/kg (but not exceeding 4 mg) Frequency: Intravenous administration of lorazepam. Subjects whose seizure does not stop or recurs within 10 minutes after the initial dose may receive the same amount of lorazepam injection no earlier than 10 minutes following the initial dose. Also, subjects whose seizure stops within 10 minutes after the initial dose, but recurs thereafter (within 12 hours) may receive the same amount of lorazepam injection; a total of 2 doses will be permitted in this study.

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants Who Achieved Seizure Free Interval of At Least 30 Minutes After Initial Dose (Dose 1) of Study Drug [30 minutes post Dose 1]

   Participants with clinical benefit were defined as participants whose initial seizure stopped within 10 minutes after initial dose (Dose 1) and who continued seizure-free for at least 30 minutes after the completion of initial dose (Dose 1).

Secondary Outcome Measures

1. Percentage of Participants Who Achieved Seizure Free Interval of At Least 30 Minutes After Any Dose of Study Drug [30 minutes post Dose 1 or 2]

   Percentage of participants whose initial seizure stopped within 10 minutes after the administration of study drug (either Dose 1 or 2 [in 10 to 30 minutes from the initial dose]) and who continued seizure-free for at least 30 minutes were analyzed and reported in this outcome measure.

2. Percentage of Participants Who Achieved Seizure Free Interval of At Least 12 Hours After Administration (Either Initial or Any Dose) of Study Drug [12 hour post Dose 1; 12 hour post Dose 1 or 2]

   Percentage of participants whose seizures stopped within 10 minutes after the administration of initial dose (Dose 1) of study drug and after any study drug dose (either Dose 1 or Dose 2 [in 10 to 30 minutes from the initial dose]), who continued to be seizure-free for at least 12 hours post-dose were analyzed and reported in this outcome measure.

3. Percentage of Participants Who Achieved Seizure Free Interval of At Least 24 Hours After Administration (Either Initial or Any Dose) of Study Drug [24 hour post Dose 1; 24 hour post Dose 1 or 2]

   Percentage of participants whose seizures stopped within 10 minutes after the administration of initial dose (Dose 1) of study drug and after any study drug dose (either Dose 1 or Dose 2 [in 10 to 30 minutes from the initial dose]), who continued to be seizure-free for at least 24 hours post-dose were analyzed and reported in this outcome measure.

4. Time to Resolution of Seizures From The Administration (Either Initial or Any Dose) of Study Drug [10 minutes post Dose 1; 10 minutes post Dose 1 or 2]

   Time to resolution (in minutes) was defined as the duration between the administration of study drug until the seizure resolved without receiving the prohibited medications.

5. Time to Relapse Following The Administration (Either Initial or Any Dose) of Study Drug [24 hour post Dose 1; 24 hour post Dose 1 or 2]

   Time to relapse (in minutes) was defined as duration from the time of study drug administration to the time of relapse, as determined by investigator. Participants whose seizure stops within 10 minutes without receiving the prohibited medications were analyzed in this outcome measure.

6. Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs) [Baseline up to 7 days after last dose of study drug administration (up to 12 days)]

   An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug to the end of study (Day 12), that were absent before treatment or that worsened relative to pre-treatment state. AEs include both serious and non-serious adverse events.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 3 Months and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Subjects with status epilepticus or repetitive status epilepticus / cluster seizure who have seizures that can be evaluated by investigator's visual observations based on motor symptoms or who have seizures that can be evaluated by EEG.

• Subjects with status epilepticus accompanied by generalized seizure, partial seizure or secondarily generalized seizure lasting 5 minutes or longer

• Subjects with repetitive status epilepticus / cluster seizure accompanied by not less than 3 consecutive episodes of generalized seizure, partial seizure or secondarily generalized seizure in 1 hour.

• Subjects not younger than 3 months (either gender is eligible for the study)

Exclusion Criteria:

• Subjects with known or suspected recurrent seizures due to illegal drug or alcohol withdrawal

• Subjects with known history of hypersensitivity to lorazepam or benzodiazepine

• Subjects with a known history of benzodiazepine abuse.

• Subjects currently receiving lorazepam

• Subjects with angle-closure glaucoma

• Subjects with myasthenia gravis

• Subjects with either of aspartate transaminase, alanine transaminase, total bilirubin, blood urea nitrogen, or creatinine at screening visit exceeding 2x the upper limit of normal of the institutional reference value (if the data is available)

• Subjects with white blood cell count less than 3000/mm3 or neutrophil count less than 1500/mm3 at screening visit (if the data is available)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Aichi Children's Health and Medical Center	Obu-shi	Aichi	Japan	474-8710
2	National Hospital Organization Fukuoka-Higashi Medical Center	Koga	Fukuoka	Japan	811-3195
3	Hokkaido Medical Center for Child Health and Rehabilitation	Sapporo	Hokkaido	Japan	006-0041
4	Nakamura Memorial Hospital	Sapporo	Hokkaido	Japan	060-8570
5	National Hospital Organization Hokkaido Medical Center	Sapporo	Hokkaido	Japan	063-0005
6	Hyogo Prefectural Kobe Children's Hospital	Kobe	Hyogo	Japan	650-0047
7	Tohoku University Hospital	Sendai	Miyagi	Japan	980-8574
8	National Hospital Organization Nagasaki Medical Center	Ohmura	Nagasaki	Japan	856-8562
9	National Nishi-Niigata Central Hospital / Pediatrics	Niigata-shi	Niigata	Japan	950-2085
10	Okayama University Hospital / Child Neurology	Okayama-shi	Okayama	Japan	700-8558
11	Osaka Medical Center and Research Institute for Maternal and Child Health	Izumi	Osaka	Japan	594-1101
12	Osaka City General Hospital Pediatric Neurology	Miyakojima-ku	Osaka	Japan	534-0021
13	NHO Shizuoka Institute of Epilepsy and Neurological Disorders	Shizuoka-city	Shizuoka	Japan	420-8688
14	National Center of Neurology and Psychiatry	Kodaira	Tokyo	Japan	187-8551
15	Yamanashi Prefectural Central Hospital	Kofu	Yamanashi	Japan	400-8506
16	Fukuoka Children's Hospital	Fukuoka		Japan	813-0017
17	Fukuoka Sanno Hospital	Fukuoka		Japan	814-0001
18	Fukuoka University Hospital	Fukuoka		Japan	814-0180
19	Gifu Prefectural General Medical Center	Gifu		Japan	500-8717
20	Saitama Children's Medical Center	Saitama		Japan	339-8551

Sponsors and Collaborators

• Pfizer

Investigators

• Study Director: Pfizer CT.gov Call Center, Pfizer

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• To obtain contact information for a study center near you, click here.

Publications

None provided.

• Responsible Party: Pfizer
• ClinicalTrials.gov Identifier: NCT02239380
• Other Study ID Numbers: B3541002; 2017-000125-13
• First Posted: Sep 12, 2014
• Last Update Posted: Feb 18, 2019
• Last Verified: Oct 1, 2018

• Keywords provided by Pfizer: Lorazepam; Status Epilepticus
• Additional relevant MeSH terms: Status Epilepticus; Lorazepam

Study Results

Participant Flow

Arm/Group Title	Lorazepam
Arm/Group Description	Participants aged between 3 months to below 16 years received single intravenous dose (Dose 1) of 0.05 milligram per kilogram (mg/kg) of Lorazepam (up to a maximum dose of 4 mg) on Day 1. Participants aged above 16 years received single intravenous dose of 4 mg of Lorazepam. Participants whose seizures continued or recurred within 10 minutes following the initial dose, an additional dose (Dose 2) of 4 mg (for participants above 16 years of age) or 0.05 mg/kg dose (for participants between 3 months to below 16 years of age) was administered accordingly. Participants were followed up to 7 days after last dose of study drug administration.
Period Title: Overall Study
STARTED	26
COMPLETED	26
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Lorazepam
Arm/Group Description	Participants aged between 3 months to below 16 years received single intravenous dose (Dose 1) of 0.05 milligram per kilogram (mg/kg) of Lorazepam (up to a maximum dose of 4 mg) on Day 1. Participants aged above 16 years received single intravenous dose of 4 mg of Lorazepam. Participants whose seizures continued or recurred within 10 minutes following the initial dose, an additional dose (Dose 2) of 4 mg (for participants above 16 years of age) or 0.05 mg/kg dose (for participants between 3 months to below 16 years of age) was administered accordingly. Participants were followed up to 7 days after last dose of study drug administration.
Overall Participants	26
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	14.0 (12.9)
Sex: Female, Male (Count of Participants)
Female	10 38.5%
Male	16 61.5%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants Who Achieved Seizure Free Interval of At Least 30 Minutes After Initial Dose (Dose 1) of Study Drug
Description	Participants with clinical benefit were defined as participants whose initial seizure stopped within 10 minutes after initial dose (Dose 1) and who continued seizure-free for at least 30 minutes after the completion of initial dose (Dose 1).
Time Frame	30 minutes post Dose 1

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) included all participants who received at least 1 dose of study drug, excluded those participants whose status epilepticus (SE) or repetitive SE/cluster seizure was determined on the electroencephalography (EEG).

Arm/Group Title	Lorazepam
Arm/Group Description	Participants aged between 3 months to below 16 years received single intravenous dose (Dose 1) of 0.05 milligram per kilogram (mg/kg) of Lorazepam (up to a maximum dose of 4 mg) on Day 1. Participants aged above 16 years received single intravenous dose of 4 mg of Lorazepam. Participants whose seizures continued or recurred within 10 minutes following the initial dose, an additional dose (Dose 2) of 4 mg (for participants above 16 years of age) or 0.05 mg/kg dose (for participants between 3 months to below 16 years of age) was administered accordingly. Participants were followed up to 7 days after last dose of study drug administration.
Measure Participants	25
Number (95% Confidence Interval) [percentage of participants]	48.0 184.6%

2. Secondary Outcome

Title	Percentage of Participants Who Achieved Seizure Free Interval of At Least 30 Minutes After Any Dose of Study Drug
Description	Percentage of participants whose initial seizure stopped within 10 minutes after the administration of study drug (either Dose 1 or 2 [in 10 to 30 minutes from the initial dose]) and who continued seizure-free for at least 30 minutes were analyzed and reported in this outcome measure.
Time Frame	30 minutes post Dose 1 or 2

Outcome Measure Data

Analysis Population Description

FAS included all participants who received at least 1 dose of study drug, excluded those participants whose SE or repetitive SE/cluster seizure was determined on the EEG.

Arm/Group Title	Lorazepam
Arm/Group Description	Participants aged between 3 months to below 16 years received single intravenous dose (Dose 1) of 0.05 milligram per kilogram (mg/kg) of Lorazepam (up to a maximum dose of 4 mg) on Day 1. Participants aged above 16 years received single intravenous dose of 4 mg of Lorazepam. Participants whose seizures continued or recurred within 10 minutes following the initial dose, an additional dose (Dose 2) of 4 mg (for participants above 16 years of age) or 0.05 mg/kg dose (for participants between 3 months to below 16 years of age) was administered accordingly. Participants were followed up to 7 days after last dose of study drug administration.
Measure Participants	25
Number (95% Confidence Interval) [percentage of participants]	64.0 246.2%

3. Secondary Outcome

Title	Percentage of Participants Who Achieved Seizure Free Interval of At Least 12 Hours After Administration (Either Initial or Any Dose) of Study Drug
Description	Percentage of participants whose seizures stopped within 10 minutes after the administration of initial dose (Dose 1) of study drug and after any study drug dose (either Dose 1 or Dose 2 [in 10 to 30 minutes from the initial dose]), who continued to be seizure-free for at least 12 hours post-dose were analyzed and reported in this outcome measure.
Time Frame	12 hour post Dose 1; 12 hour post Dose 1 or 2

Outcome Measure Data

Analysis Population Description

FAS included all participants who received at least 1 dose of study drug, excluded those participants whose SE or repetitive SE/cluster seizure was determined on the EEG.

Arm/Group Title	Lorazepam
Arm/Group Description	Participants aged between 3 months to below 16 years received single intravenous dose (Dose 1) of 0.05 milligram per kilogram (mg/kg) of Lorazepam (up to a maximum dose of 4 mg) on Day 1. Participants aged above 16 years received single intravenous dose of 4 mg of Lorazepam. Participants whose seizures continued or recurred within 10 minutes following the initial dose, an additional dose (Dose 2) of 4 mg (for participants above 16 years of age) or 0.05 mg/kg dose (for participants between 3 months to below 16 years of age) was administered accordingly. Participants were followed up to 7 days after last dose of study drug administration.
Measure Participants	25
Post Dose 1	32.0 123.1%
Post Dose 1 or 2	44.0 169.2%

4. Secondary Outcome

Title	Percentage of Participants Who Achieved Seizure Free Interval of At Least 24 Hours After Administration (Either Initial or Any Dose) of Study Drug
Description	Percentage of participants whose seizures stopped within 10 minutes after the administration of initial dose (Dose 1) of study drug and after any study drug dose (either Dose 1 or Dose 2 [in 10 to 30 minutes from the initial dose]), who continued to be seizure-free for at least 24 hours post-dose were analyzed and reported in this outcome measure.
Time Frame	24 hour post Dose 1; 24 hour post Dose 1 or 2

Outcome Measure Data

Analysis Population Description

FAS included all participants who received at least 1 dose of study drug, excluded those participants whose SE or repetitive SE/cluster seizure was determined on the EEG.

Arm/Group Title	Lorazepam
Arm/Group Description	Participants aged between 3 months to below 16 years received single intravenous dose (Dose 1) of 0.05 milligram per kilogram (mg/kg) of Lorazepam (up to a maximum dose of 4 mg) on Day 1. Participants aged above 16 years received single intravenous dose of 4 mg of Lorazepam. Participants whose seizures continued or recurred within 10 minutes following the initial dose, an additional dose (Dose 2) of 4 mg (for participants above 16 years of age) or 0.05 mg/kg dose (for participants between 3 months to below 16 years of age) was administered accordingly. Participants were followed up to 7 days after last dose of study drug administration.
Measure Participants	25
Post Dose 1	24.0 92.3%
Post Dose 1 or 2	32.0 123.1%

5. Secondary Outcome

Title	Time to Resolution of Seizures From The Administration (Either Initial or Any Dose) of Study Drug
Description	Time to resolution (in minutes) was defined as the duration between the administration of study drug until the seizure resolved without receiving the prohibited medications.
Time Frame	10 minutes post Dose 1; 10 minutes post Dose 1 or 2

Outcome Measure Data

Analysis Population Description

FAS included all participants who received at least 1 dose of study drug, excluded those participants whose SE or repetitive SE/cluster seizure was determined on the EEG. Here, 'n' signifies those participants who were evaluable for specific category.

Arm/Group Title	Lorazepam
Arm/Group Description	Participants aged between 3 months to below 16 years received single intravenous dose (Dose 1) of 0.05 milligram per kilogram (mg/kg) of Lorazepam (up to a maximum dose of 4 mg) on Day 1. Participants aged above 16 years received single intravenous dose of 4 mg of Lorazepam. Participants whose seizures continued or recurred within 10 minutes following the initial dose, an additional dose (Dose 2) of 4 mg (for participants above 16 years of age) or 0.05 mg/kg dose (for participants between 3 months to below 16 years of age) was administered accordingly. Participants were followed up to 7 days after last dose of study drug administration.
Measure Participants	25
Post Dose 1	1.0
Post Dose 1 or 2	1.0

6. Secondary Outcome

Title	Time to Relapse Following The Administration (Either Initial or Any Dose) of Study Drug
Description	Time to relapse (in minutes) was defined as duration from the time of study drug administration to the time of relapse, as determined by investigator. Participants whose seizure stops within 10 minutes without receiving the prohibited medications were analyzed in this outcome measure.
Time Frame	24 hour post Dose 1; 24 hour post Dose 1 or 2

Outcome Measure Data

Analysis Population Description

FAS included all participants who received at least 1 dose of study drug, excluded those participants whose SE or repetitive SE/cluster seizure was determined on the EEG. Here, number of participants analyzed (N) signifies those participants who were evaluable for this outcome measure.

Arm/Group Title	Lorazepam
Arm/Group Description	Participants aged between 3 months to below 16 years received single intravenous dose (Dose 1) of 0.05 milligram per kilogram (mg/kg) of Lorazepam (up to a maximum dose of 4 mg) on Day 1. Participants aged above 16 years received single intravenous dose of 4 mg of Lorazepam. Participants whose seizures continued or recurred within 10 minutes following the initial dose, an additional dose (Dose 2) of 4 mg (for participants above 16 years of age) or 0.05 mg/kg dose (for participants between 3 months to below 16 years of age) was administered accordingly. Participants were followed up to 7 days after last dose of study drug administration.
Measure Participants	9
Post Dose 1	62.0
Post Dose 1 or 2	103.0

7. Secondary Outcome

Title	Number of Participants With Treatment-Emergent Adverse Events (AEs) and Serious Adverse Events (SAEs)
Description	An AE was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. An SAE was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Treatment-emergent were events between first dose of study drug to the end of study (Day 12), that were absent before treatment or that worsened relative to pre-treatment state. AEs include both serious and non-serious adverse events.
Time Frame	Baseline up to 7 days after last dose of study drug administration (up to 12 days)

Outcome Measure Data

Analysis Population Description

Safety analysis set included all participants who received at least 1 dose of study drug.

Arm/Group Title	Lorazepam
Arm/Group Description	Participants aged between 3 months to below 16 years received single intravenous dose (Dose 1) of 0.05 milligram per kilogram (mg/kg) of Lorazepam (up to a maximum dose of 4 mg) on Day 1. Participants aged above 16 years received single intravenous dose of 4 mg of Lorazepam. Participants whose seizures continued or recurred within 10 minutes following the initial dose, an additional dose (Dose 2) of 4 mg (for participants above 16 years of age) or 0.05 mg/kg dose (for participants between 3 months to below 16 years of age) was administered accordingly. Participants were followed up to 7 days after last dose of study drug administration.
Measure Participants	26
AEs	12 46.2%
SAEs	1 3.8%

Adverse Events

Time Frame	Baseline up to 7 days after last dose of study drug administration (up to 12 days)
Adverse Event Reporting Description	The same event may appear as both an AE and SAE. However, what is presented are distinct events. An event may be categorized as serious in one event and as nonserious in another participant, or one participant may have experienced both a serious and nonserious event during the study.
Arm/Group Title	Lorazepam
Arm/Group Description	Participants aged between 3 months to below 16 years received single intravenous dose (Dose 1) of 0.05 milligram per kilogram (mg/kg) of Lorazepam (up to a maximum dose of 4 mg) on Day 1. Participants aged above 16 years received single intravenous dose of 4 mg of Lorazepam. Participants whose seizures continued or recurred within 10 minutes following the initial dose, an additional dose (Dose 2) of 4 mg (for participants above 16 years of age) or 0.05 mg/kg dose (for participants between 3 months to below 16 years of age) was administered accordingly. Participants were followed up to 7 days after last dose of study drug administration.
All Cause Mortality
	Lorazepam
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	Lorazepam
	Affected / at Risk (%)	# Events
Total	1/26 (3.8%)
Respiratory, thoracic and mediastinal disorders
Pneumonia aspiration	1/26 (3.8%)
Other (Not Including Serious) Adverse Events
	Lorazepam
	Affected / at Risk (%)	# Events
Total	12/26 (46.2%)
Gastrointestinal disorders
Vomiting	1/26 (3.8%)
General disorders
Pyrexia	1/26 (3.8%)
Infections and infestations
Pneumonia	1/26 (3.8%)
Urinary tract infection	1/26 (3.8%)
Injury, poisoning and procedural complications
Fall	1/26 (3.8%)
Laceration	1/26 (3.8%)
Investigations
Blood creatine phosphokinase increased	1/26 (3.8%)
Nervous system disorders
Ataxia	1/26 (3.8%)
Balance disorder	1/26 (3.8%)
Somnolence	2/26 (7.7%)
Psychiatric disorders
Insomnia	2/26 (7.7%)
Renal and urinary disorders
Pollakiuria	1/26 (3.8%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/26 (3.8%)
Skin and subcutaneous tissue disorders
Erythema	1/26 (3.8%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Pfizer has the right to review disclosures, requesting a delay of less than 60 days. Investigator will postpone single center publications until after disclosure of pooled data (all sites), less than 12 months from study completion/termination at all participating sites. Investigator may not disclose previously undisclosed confidential information other than study results.