This was an open label, single arm, multicentric clinical trial conducted in adult patients with FOS enrolled from nine sites across India. All investigational sites were approved by respective Independent Ethics Committees, or Institutional Review Boards (IRBs), before the enrolment of any patient in the trial.

This trial followed the principles outlined in the Declaration of Helsinki and the trial protocol was approved by the Institutional Ethics Committees and the Drug Controller General of India, the head of the department of the Central Drugs Standard Control Organization of the Government of India (BR/DCGI/LACO-INJ/10/648-I), which is a national body that provides authorization to conduct studies and approve products for marketing in India. The trial was registered on 14 ^th July 2011 with the Clinical Trial Registry of India (Registry identifier: CTRI/2011/07/001888).

This trial was conducted from ^{July 2011 to January 2012. The study was conducted according to the finalized protocol and no changes were done during the entire study period.}

All male and female patients, ≥18 years of age with a confirmed diagnosis of FOS, on a stable dose of oral lacosamide (Torrent Pharmaceuticals Limited, India (batch no. IT11003)) and willing to sign informed consent were enrolled. Patients were excluded if they had abnormal platelet count, high liver enzymes, bilirubin and/or serum creatinine, seizures occurring in clusters, status epilepticus within three months of enrolment, history of non-epileptic seizures, allergy to the study drugs/excipients, cardiac conduction defects and on drugs that can prolong P-R interval, clinically significant ECG abnormalities, structural lesions in the central nervous system (CNS), progressive neurological disorders or psychiatric disorders, use of neuroleptics, monoamine oxidase (MOA) inhibitors, barbiturates, or narcotic analgesics within 28 days before screening. Pregnant or lactating women were also excluded from the study.

We conducted an open-label, single-arm, multi-centric safety and tolerability study across multiple sites in India between July 2011 and January 2012. Patients with stable FOS were enrolled after obtaining their written informed consent and a baseline evaluation was performed.

During this phase, a thorough clinical history including the presence of concomitant disease, treatment with current AED regime, medical and surgical history, or allergies were noted. Laboratory investigations—ECG, hematology and biochemistry, urine examination, urine pregnancy test for women of childbearing potential—were done to exclude ineligible patients. Enrolled patients were given i.v. lacosamide and outcomes were assessed as per study protocol. A detailed flowchart of the study protocol is given in Figure 1.

Enrolled patients were switched from oral to i.v. lacosamide (10 mg/ml). The study medication was supplied by Torrent Pharmaceuticals Ltd., India in a single use vial i.e., lacosamide injection 200 mg/20 ml. The total daily intravenous dosage of lacosamide was optimized per patient and made equivalent to the total daily dosage and frequency of oral lacosamide. Lacosamide was infused intravenously for 30 to 60 minutes in 250 ml normal saline twice a day (morning dose, MD and evening dose, ED) for five consecutive days at 12-hr intervals.

Medications other than the study drug that were considered necessary for the patients were allowed at the discretion of the investigator and an appropriate record was maintained in the “Concomitant medication Record Sheet” of CRF.

The individual patient’s observation period was 12 days, which included five days of treatment period with follow-up after seven days of the last injection.

The number of patients included in the study was on the basis of the first trial conducted with i.v. lacosamide. ¹⁵ So, data of the 60 patients who completed the trial was deemed appropriate to meet the safety and tolerability objectives of the trial. Since, no sample size was determined in the study no statistical analysis was performed.

Safety evaluation

Vital parameters

Vital signs (blood pressure, pulse rate, and temperature) were measured at baseline, day 1 to day 5 (end of treatment), and on day 12 (follow-up).

Laboratory parameters

Hematology, biochemistry, and urine analysis were performed at the time of screening and day 5 (end-of-treatment).

Changes in ECG

ECG was done at screening, day 3, day 5, and follow-up (day 12).

Adverse events (AEs) assessment

AEs were monitored for the entire study duration and the record was maintained.

Efficacy evaluation

A detailed history of seizures (frequency of seizure/week) was recorded during screening and after enrolment i.e., from day 1 to day 5 and also during follow-up to evaluate any change from baseline during treatment and also when patients were switched back to oral lacosamide.

Continuous variables were summarized using mean, standard deviation (SD), and median. AEs and local AEs at the injection site were reported by frequency analysis with respect to incidence, severity, and seriousness. Seizures were calculated in terms of frequency. Maintenance of seizure frequency was calculated from baseline to follow-up. All statistical analysis were performed by using SAS ^® (RRID:SCR_008567) Version 9.1.3 (SAS Institute Inc., North Carolina, Cary, USA) (free alternative, R (programming language)).

A total of 74 patients were screened for the study across all participating centers between July 2011 and January 2012. A total of 14 patients were ineligible for participation in the trial. Overall, 60 patients; 45 male and 15 female with a mean age of 29±9.5 years old were enrolled and completed the study ( Table 1). ³⁶ No patient withdraw from the study during the entire study duration.

All enrolled patients were switched from oral lacosamide to i.v. lacosamide. The total daily intravenous dosage of lacosamide was equivalent to the total daily dosage and frequency of oral lacosamide. Intravenous treatment was administered for five consecutive days at 12-hr intervals. The dose range of i.v. lacosamide was 100-400 mg/day and majority of the patients were administered with a daily dose of 200 mg/day. Out of 60 patients, two patients were taking oral lacosamide three times a day and both received i.v. lacosamide twice a day for five days. However, the total daily dose of lacosamide injection in both patients was the same. Out of 60 patients, 49 patients received i.v. lacosamide as 30 min infusion and 11 received as 60 min infusion. Lacosamide dose and duration of the infusion for all patients are described in Table 2.

Concurrent medications of all patients were recorded. The commonly used concomitant drugs were AEDs such as carbamazepine, clobazam, oxcarbazepine, phenytoin, sodium valproate, valproic acid, and levetiracetam.

Vital parameters

The comparison of vital signs—blood pressure (systolic and diastolic), pulse rate, and temperature—during baseline to follow-up visit is shown in Figure 2. No significant change in the blood pressure, pulse rate, and temperature were seen between days 1-5 or at follow–up.

Laboratory parameters

Minimal changes were observed in the laboratory parameters from baseline to end of treatment i.e., day 5. Urine analysis & microscopy showed no abnormality in any patient. Urine pregnancy test was done in 14 female patients at screening and day 5; all tests were negative. There were no alterations in hematology, clinical biochemistry, and urine analysis in patients after study drug administration ( Table 3).

Changes in ECG findings

ECG was done at screening day 3, day 5, and follow-up (day: 12). The frequency analysis was within the normal limit for all the visits.

Adverse events (AEs) assessment

There were no serious AEs reported in this study. Among all patients (n=60), 26.66% (n=16) patients reported a few AEs. A total of 24 AEs were reported; 16 systemic and 8 due to reaction at the local injection site. All AEs were mild to moderate and did not result in patient’s withdrawal from the study. The more commonly reported systemic AEs were upper abdominal pain upper (n=3), and nausea (n=3; 5% of the total population), whereas dizziness, insomnia, thrombophlebitis, upper respiratory tract infection (n=1; 1.7% of the total population) were less commonly observed ( Table 4). All AEs were reported during lacosamide injection (days 1-5) except one that was reported during follow-up. A total of eight local AEs (pain, pruritus, erythema, thrombophlebitis and rash erythematous) were reported at the injection site out of 600 lacosamide infusions administered to 60 patients over a period of five days ( Table 5). There was good tolerability with i.v. lacosamide as all the patients completed the study without a single withdrawal due to AEs.

The frequency of seizures in patients at baseline (screening), day 1 to day 5 (end of treatment), and from day 1 to day 12 (follow-up) is described in Figure 3.

It was observed that oral to i.v. switch of lacosamide either reduced or maintained the seizure frequency in patients with FOS. As compared to only 13 subjects who did not show seizures during baseline evaluation, 40 and 37 patients remained seizure free between days 1 to 5 and day 12, respectively.

Our study had a few limitations. Seizure control and seizure freedom could not be assessed due to the short duration of the study. Long-term follow-up with observation for seizure frequency and seizure freedom at 4 to 12 weeks with better-matched safety assessment for QTc prolongation could be explored in further randomized controlled clinical trials in this line.