Trial Outcomes & Findings for Intravenous Lacosamide Compared With Fosphenytoin in the Treatment of Patients With Frequent Nonconvulsive Seizures (NCT NCT01458522)

Last Updated: 2018-06-11

Results Overview

Percentage of subjects who experience no nonconvulsive seizures (NCS) for 24 hours (after the 2-hour observation-only period) following treatment with LCM vs. fPHT, as measured by continuous electroencephalography (cEEG) monitoring with blinded review.

Recruitment status

COMPLETED

Study phase

PHASE2

Target enrollment

74 participants

Primary outcome timeframe

24 hours

Results posted on

2018-06-11

Participant Flow

173 participants consented. 74 participants were randomized.

37 participants randomized to LCM, however 2 participants did not receive drug. 37 participants were randomized to fPHT and everyone received drug.

Participant milestones

Participant milestones
Measure	LCM First, Then fPHT LCM bolus of 400 mg administered over 30 minutes. If further bolus is required, 200 mg is administered. Regardless of whether the subject received a rebolus, they will begin receiving a maintenance dose 12 hrs after initial dose. Daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached end of 1st treatment arm and will crossover and receive the other drug. If any of the following did not occur the subject will be considered completed. Subject has another seizure within 24 hrs following the 2-hr post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hrs following 2-hr post bolus observation-only period. Subject experiences an AE that precludes further use of the 1st study drug. If crossover occurs, the subject will start over with the second drug, going through the same observation-only period.	fPHT First, Then LCM fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. If any of the following did NOT occur the subject will be considered completed. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Overall Study STARTED	37	37
Overall Study Received First Drug	35	35
Overall Study Crossover to Second Drug	15	10
Overall Study COMPLETED	34	26
Overall Study NOT COMPLETED	3	11

Reasons for withdrawal

Reasons for withdrawal
Measure	LCM First, Then fPHT LCM bolus of 400 mg administered over 30 minutes. If further bolus is required, 200 mg is administered. Regardless of whether the subject received a rebolus, they will begin receiving a maintenance dose 12 hrs after initial dose. Daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached end of 1st treatment arm and will crossover and receive the other drug. If any of the following did not occur the subject will be considered completed. Subject has another seizure within 24 hrs following the 2-hr post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hrs following 2-hr post bolus observation-only period. Subject experiences an AE that precludes further use of the 1st study drug. If crossover occurs, the subject will start over with the second drug, going through the same observation-only period.	fPHT First, Then LCM fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. If any of the following did NOT occur the subject will be considered completed. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Overall Study Withdrawal by Subject	2	2
Overall Study Physician Decision	1	9

Baseline Characteristics

Intravenous Lacosamide Compared With Fosphenytoin in the Treatment of Patients With Frequent Nonconvulsive Seizures

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	LCM First, Then fPHT n=37 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=37 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).	Total n=74 Participants Total of all reporting groups
Age, Continuous	63.8 years STANDARD_DEVIATION 12.1 • n=5 Participants	63.4 years STANDARD_DEVIATION 20.4 • n=7 Participants	63.6 years STANDARD_DEVIATION 16.6 • n=5 Participants
Sex: Female, Male Female	17 Participants n=5 Participants	21 Participants n=7 Participants	38 Participants n=5 Participants
Sex: Female, Male Male	20 Participants n=5 Participants	16 Participants n=7 Participants	36 Participants n=5 Participants
Race/Ethnicity, Customized White	26 Participants n=5 Participants	32 Participants n=7 Participants	58 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	9 Participants n=5 Participants	3 Participants n=7 Participants	12 Participants n=5 Participants
Race/Ethnicity, Customized Asian	2 Participants n=5 Participants	2 Participants n=7 Participants	4 Participants n=5 Participants
Region of Enrollment United States	37 Participants n=5 Participants	37 Participants n=7 Participants	74 Participants n=5 Participants

PRIMARY outcome

Timeframe: 24 hours

Population: Data are reported for the percentage of participants without a nonconvulsive seizure event in the period prior to crossover.

Outcome measures

Outcome measures
Measure	LCM First, Then fPHT n=35 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=35 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Percentage of Subjects Who Experience no Nonconvulsive Seizures (NCS) for 24 Hours Following Treatment With LCM vs. fPHT, as Measured by Continuous Electroencephalography (cEEG) Monitoring.	19 Participants	22 Participants

SECONDARY outcome

Timeframe: 24 hours

Population: Data are reported for the percentage of participants who require a rebolus of the initial antiepileptic drugs (AED) to control nonconvulsive seizures (NCS) in the LCM vs fPHT arms in the period prior to crossover.

The percentage of subjects who require a rebolus of the initial antiepileptic drug (AED) to control nonconvulsive seizures (NCS) in the LCM vs fPHT arms.

Outcome measures

Outcome measures
Measure	LCM First, Then fPHT n=35 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=35 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Percentage of Subjects Who Require a Rebolus of the Initial Antiepileptic Drugs (AED) to Control Nonconvulsive Seizures (NCS) in the LCM vs fPHT Arms.	16 Participants	13 Participants

SECONDARY outcome

Timeframe: 24-26 hours

Population: Participants who crossed over to second drug

Number of subjects who required a second antiepileptic drug (AED) to control nonconvulsive seizures (NCS)

Outcome measures

Outcome measures
Measure	LCM First, Then fPHT n=35 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=35 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Number of Subjects Who Required a Second Antiepileptic Drug (AED) to Control Nonconvulsive Seizures (NCS)	15 Participants	10 Participants

SECONDARY outcome

Timeframe: Baseline, 24 hours

Population: Participants who had satisfactory EEG data (sometimes EEG leads would come off)

Absolute change in seizure time (defined as the number of minutes of electrographic seizure (ESz) activity per hour) before treatment and at the end of the first treatment arm. If less than 1 hour of recording time is available, seizure time will be extrapolated to 1 hour. The maximum amount of time that can be used to determine baseline seizure time is 6 hours.

Outcome measures

Outcome measures
Measure	LCM First, Then fPHT n=32 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=29 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Seizure Burden Change From Baseline to End of Initial Treatment	-0.58 min/hour Standard Deviation 0.950	-0.54 min/hour Standard Deviation 0.828

SECONDARY outcome

Timeframe: baseline, 26-68 hours

Population: participants who had satisfactory EEG data (sometimes EEG leads would come off)

Absolute change defined as the number of minutes of ESz activity per hour before treatment and at the end of the second treatment arm. This measure does not evaluate seizure activity in the first treatment arm. If less than 1 hour of recording time is available, seizure time will be extrapolated to 1 hour.

Outcome measures

Outcome measures
Measure	LCM First, Then fPHT n=11 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=9 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Seizure Burden Change From Baseline to End of Crossover, Excluding Initial Treatment Arm	-0.78 min/hour Standard Deviation 0.486	-0.83 min/hour Standard Deviation 0.346

SECONDARY outcome

Timeframe: time of first bolus to end of seizures after initial treatment arm, time from crossover to end of seizures in crossover treatment arm

Population: participants who had satisfactory EEG data (sometimes EEG leads would come off)

Time of first bolus to end of seizures after initial treatment arm, time from crossover to end of seizures in crossover treatment arm

Outcome measures

Outcome measures
Measure	LCM First, Then fPHT n=35 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=34 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Time of First Bolus to End of Seizures After Initial Treatment Arm, Time From Crossover to End of Seizures in Crossover Treatment Arm Initial Treatment	8.4 hours Standard Deviation 13.08	9.8 hours Standard Deviation 11.84
Time of First Bolus to End of Seizures After Initial Treatment Arm, Time From Crossover to End of Seizures in Crossover Treatment Arm Crossover Treatment	8.2 hours Standard Deviation 11.05	1.7 hours Standard Deviation 3.46

SECONDARY outcome

Timeframe: 24 hours

Population: Patients who received treatment arm 1

Number of predefined adverse events (AE) after treatment arm 1 administration. These predefined adverse events include Patients with at least one AE of interest, Cardiac disorders, investigations, suspected hypersensitivity reactions, vascular disorders, and hypotension.

Outcome measures

Outcome measures
Measure	LCM First, Then fPHT n=35 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=35 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Number of Predefined Adverse Events (AE) After Treatment Arm 1 Administration	4 Number of predefined AEs	5 Number of predefined AEs

SECONDARY outcome

Timeframe: baseline to end of treatment arm 1

Percentage of subjects in whom study drug is withdrawn early after treatment with treatment arm 1

Outcome measures

Outcome measures
Measure	LCM First, Then fPHT n=35 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=35 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Percentage of Subjects in Whom Study Drug is Withdrawn Early After Treatment With Treatment Arm 1	2 Participants	3 Participants

SECONDARY outcome

Timeframe: initial bolus to end of study

Data was acquired in a manner consistent with determining if one treatment arm (LCM first, then fPHT versus fPHT first, then LCM) resulted in more days of hospitalization than the other over the course of the study.

Outcome measures

Outcome measures
Measure	LCM First, Then fPHT n=37 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=37 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Days in the Intensive Care Unit/Hospital Days in ICU	7.4 days Standard Deviation 8.36	6.5 days Standard Deviation 8.73
Days in the Intensive Care Unit/Hospital Days in hospital	12.7 days Standard Deviation 7.63	12.5 days Standard Deviation 10.03

SECONDARY outcome

Timeframe: Baseline to day 7-9, baseline to day 30

Population: participants who completed the Functional Disability Scale

Change in functional status as measured by the Functional Disability Scale, using a 0-29 rating (0=w/o disability; 29=extreme vegetative state) at Day 7 to 9 postrandomization and Day 30 post-randomization in the LCM first, then fPHT versus fPHT first, then LCM arms. Data was analyzed in a manner consistent with determining if one treatment arm resulted in a greater change in functional status than the other.

Outcome measures

Outcome measures
Measure	LCM First, Then fPHT n=20 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=28 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Change in Functional Status as Measured by the Functional Disability Scale at Day 7 to 9 Postrandomization and Day 30 Post-randomization in the LCM vs fPHT Arms. Change from baseline to day 7-9	-4.1 units on a scale Standard Deviation 7.64	0.3 units on a scale Standard Deviation 4.52
Change in Functional Status as Measured by the Functional Disability Scale at Day 7 to 9 Postrandomization and Day 30 Post-randomization in the LCM vs fPHT Arms. Change from baseline to day 30	-8.5 units on a scale Standard Deviation 11.73	-3.7 units on a scale Standard Deviation 5.01

SECONDARY outcome

Timeframe: both acute treatment periods to 30 days

Percentage of all subjects who have had a seizure, are on antiepileptic drug (AED) therapy, and are alive and dead at day 30. Data was acquired in a manner consistent with determining if one treatment arm (LCM first, then fPHT versus fPHT first, then LCM) resulted in a greater effect on seizures, antiepileptic drug (AED) use, and survival at day 30 after the acute treatment period. The acute treatment period could range from 6 to 30 hours.

Outcome measures

Outcome measures
Measure	LCM First, Then fPHT n=45 Participants LCM treatment arm, a bolus of 400 mg will be administered over 30 minutes. If a further bolus is required, 200 mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400 mg or 600 mg) divided into 2 doses. If after initial treatment and any of the following occurs, subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period.	fPHT First, Then LCM n=50 Participants fPHT treatment arm, a bolus of 20 mg PE/kg will be administered at a rate of no greater than 75 mg PE/minute. If a further bolus is required, 5 mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5 mg PE/kg divided into 2 doses. If after initial treatment and any of the following occurs, the subject will have reached the end of the first treatment arm and will "cross over" and begin receiving the other drug. Subject has another seizure within 24 hours following the 2-hour post-rebolus observation-only period. Subject dose not receive a rebolus but has a seizure within 24 hours following 2-hour post bolus observation-only period. Subject experiences an AE that precludes further use of the first study drug. If crossover occurs, the subject will "start over" with the second drug, going through the same observation-only period, rebolusing (if necessary).
Percentage of All Subjects Who Have Had a Seizure, Are on Antiepileptic Drug (AED) Therapy, and Are Alive/Dead at Day 30 any seizure within 30 days after acute tx period	27.4 percentage of participants	38.9 percentage of participants
Percentage of All Subjects Who Have Had a Seizure, Are on Antiepileptic Drug (AED) Therapy, and Are Alive/Dead at Day 30 AED use within 30 days after acute tx period	82.2 percentage of participants	74.0 percentage of participants
Percentage of All Subjects Who Have Had a Seizure, Are on Antiepileptic Drug (AED) Therapy, and Are Alive/Dead at Day 30 Died within 30 days after randomization	15.5 percentage of participants	16.0 percentage of participants

Adverse Events

All Participants Receiving LCM 400mg

Serious events: 10 serious events

Other events: 22 other events

Deaths: 7 deaths

All Participants Receiving fPHT 20mg PE/kg

Serious events: 13 serious events

Other events: 27 other events

Deaths: 8 deaths

Serious adverse events

Other adverse events

Additional Information

Aatif M. Husain, M.D.

Duke University

Phone: 919-668-8700

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Measure	All Participants Receiving LCM 400mg n=45 participants at risk Participants who receive a bolus of 400mg administered over 30 minutes. If a further bolus is required, 200mg will be administered. Regardless of whether the subject received a rebolus, he or she will begin receiving a maintenance dose 12 hours after the initial dose. The daily maintenance dose will be the same as the total bolus (400mg or 600mg) divided into 2 doses.	All Participants Receiving fPHT 20mg PE/kg n=50 participants at risk Participants who receive a bolus of 20mg PE/kg administered at a rate no greater than 75mg PE/minute. If a further bolus is required, 5mg PE/kg will be administered. The daily maintenance dose for fPHT will be 5mg PE/kg divided into 2 doses.
Cardiac disorders Bradycardia	2.2% 1/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	0.00% 0/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Infections and infestations Herpes simplex encephalitis	0.00% 0/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Infections and infestations Sepsis	0.00% 0/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Infections and infestations Septic shock	0.00% 0/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Injury, poisoning and procedural complications Subdural haematoma	4.4% 2/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Cardiac disorders Atrial tachycardia	0.00% 0/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Injury, poisoning and procedural complications Toxicity to various agents	0.00% 0/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	4.0% 2/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Nervous system disorders Cerebral hemorrhage	4.4% 2/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Nervous system disorders Neurological decompensation	2.2% 1/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	0.00% 0/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Renal and urinary disorders Renal failure	0.00% 0/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	4.4% 2/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Vascular disorders Hypotension	4.4% 2/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	4.0% 2/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Infections and infestations Encephalitis viral	0.00% 0/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Nervous system disorders Grand mal convulsion	0.00% 0/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Nervous system disorders Haemorrhage intracranial	0.00% 0/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Nervous system disorders Haemorrhagic stroke	0.00% 0/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Nervous system disorders Intracranial pressure increased	0.00% 0/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	2.0% 1/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)
Respiratory, thoracic and mediastinal disorders respiratory failure	2.2% 1/45 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)	0.00% 0/50 • Adverse event data was collected for 30 days after last dose of study drug (approximately 30-32 days)