Keywords
Efficacy, Epilepsy, Focal onset seizures, Intravenous Lacosamide, Safety, Switch
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Kakkad A, Keshava BS, Ahmadi B et al. Multi-centric Phase III, single-arm, open-label clinical study to assess clinical safety, tolerability, and efficacy of intravenous lacosamide in focal onset seizures [version 1; peer review: 2 approved with reservations]. F1000Research 2023, 12:1037 (https://doi.org/10.12688/f1000research.125607.1)
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Clinical trial
Multi-centric Phase III, single-arm, open-label clinical study to assess clinical safety, tolerability, and efficacy of intravenous lacosamide in focal onset seizures
[version 1; peer review: 2 approved with reservations]
PUBLISHED 24 Aug 2023
OPEN PEER REVIEW
REVIEWER STATUS
Abstract
Corresponding author:
Ashutosh Kakkad
Competing interests:
Site investigators received study honorarium for the conduct of the study with no other financial or scientific obligations towards or by the sponsor. Ashutosh Kakkad, Krishnaprasad Korukonda, Ram Gupta, Hitesh Raval, Dhaval Rathod, and Shohini Ghosh declare being employees of Torrent Pharmaceuticals Ltd. These listed authors are paid employees of Torrent Pharmaceuticals Ltd. The authors report no other potential conflicts of interest in this work.
Grant information:
This research was funded by Torrent Pharmaceuticals Limited, India.
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Copyright:
© 2023 Kakkad A et al.
This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
How to cite: Kakkad A, Keshava BS, Ahmadi B et al. Multi-centric Phase III, single-arm, open-label clinical study to assess clinical safety, tolerability, and efficacy of intravenous lacosamide in focal onset seizures [version 1; peer review: 2 approved with reservations]. F1000Research 2023, 12:1037 (https://doi.org/10.12688/f1000research.125607.1)
First published: 24 Aug 2023, 12:1037 (https://doi.org/10.12688/f1000research.125607.1)
Latest published: 24 Aug 2023, 12:1037 (https://doi.org/10.12688/f1000research.125607.1)
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Introduction
Focal onset seizures (FOS) are defined as seizures that originate within networks limited to one hemisphere of the brain that is often associated with increased morbidity and impaired quality of life (QoL), especially with associated or primary generalized tonic-clonic seizures.1 Epilepsy accounts for 0.5% of the global disease burden. In India, the overall prevalence of epilepsy ranges between 1.3 and 11.9 per 1,000 population, and the incidence varies from 0.2 to 0.6/1,000/year2 with a standardized mortality ratio of 2.56-7.6%.3–6 As per recent epidemiological studies conducted in India between 2018-2019, 17-47% of patients with epilepsy were suffering from FOS with or without focal to bilateral tonic-clonic seizures.7–9 Increased incidence of FOS was more predominant with advanced age.
Acute seizures and/or status epilepticus cases often require an infusion strategy during the ictal phase to prevent neurologic damage that is likely to happen within the first 15 to 20 mins of uncontrolled seizures. In most of these cases, a switch to oral strategy is often recommended to prevent recurrence while improving patient compliance and adherence to therapy.
Lacosamide is an amino acid derivative from the novel class of anti-epileptic drugs (AEDs), termed functionalized amino acids. It is licensed for use as an adjunctive and monotherapy for FOS and associated focal to bilateral and primary generalized tonic-clonic seizures in the US as well as many European countries.10,11 The complementary action on slow voltage-gated sodium channels and collapsin response mediator protein 2 (CRMP2) results in stabilization of hyper-excitable neuronal membranes and inhibition of repetitive neuronal firing.10,12
The favorable pharmacokinetic/pharmacodynamic (PK/PD) profile includes high solubility (≈25 mg/ml), improved bioavailability and bioequivalence to intravenous infusion, minimal drug-drug interaction, low plasma protein binding (<15%), and it can be easily converted from oral to intravenous (i.v.) formulation without the need for dose modification.13,14 This is especially beneficial in conditions when oral administration of the drug is temporarily not feasible such as when patients undergo surgery, are hospitalized, have swallowing difficulties, or experience acute gastrointestinal disorders. Also, in case of a seizure emergency, such as refractory convulsive status epilepticus, where the quick onset of action is required, intravenous administration is essential for immediate seizure control.
To assess the clinical safety, tolerability, and efficacy of i.v. lacosamide when prescribed in real-world settings for patients with FOS, this clinical study was a single arm, ‘Switch’ study from oral to i.v. lacosamide therapy.
Methods
Standard protocol approvals, ethical conduct, and patient consent
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 14th 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.
Patients
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.
Study design and plan
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.
Figure 1. Study plan flowchart.
AED, antiepileptic therapy; ECG, electrocardiogram; AE, adverse event.
Treatment and duration
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.
Endpoints – Safety and efficacy assessment
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.
Statistical analysis
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)).
Results
Patients
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.
Table 1. Baseline demographics.
Treatment
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.
Table 2. Patient disposition chart for lacosamide injection (dose and infusion time).
| Lacosamide injection dose | Lacosamide infusion duration | Total (n=60) | |
|---|---|---|---|
| 30 min | 60 min | ||
| 100 mg/day | 21 | 03 | 24 |
| 150 mg/day | 04 | 00 | 04 |
| 200 mg/day | 21 | 04 | 25 |
| 300 mg/day | 02 | 00 | 02 |
| 400 mg/day | 01 | 04 | 05 |
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.
Safety evaluation
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.
Figure 2. Mean change in vitals.
BP, blood pressure; MD, morning dose; ED, evening dose.
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).
Table 3. Laboratory parameters at baseline and end of treatment (Day 5).
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.
Table 4. Incidence (N) and frequency analysis (%) of adverse events reported during the treatment with lacosamide injection.
Table 5. Incidence (N) and frequency (%) of local adverse events at injection site reported during treatment with lacosamide injection.
| Local adverse events at the injection site | N (%) |
|---|---|
| Injection site pain | 2(3.3) |
| Injection site erythema | 1(1.7) |
| Injection site pruritus | 3(5) |
| Rash erythematous | 1(1.7) |
| Thrombophlebitis | 1(1.7) |
Efficacy evaluation
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.
Figure 3. Frequency of seizures.
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.
Discussion
The purpose of this study was to evaluate the safety and tolerability of short-term i.v. lacosamide in patients with FOS.
Ethnic variability is an important factor that may influence both the pharmacokinetics and pharmacodynamics of a drug resulting in varied responses to drug therapy.16,17 Therefore, while similar studies were conducted in Western countries,15–20 this study was performed to establish the safety and efficacy of i.v. lacosamide in the Indian cohort. The findings reported herein showed that the patients on the established dose of oral lacosamide can be safely switched to i.v. lacosamide for up to five days across a broad range of doses (100-400 mg/day) without compromising the efficacy.
The primary assessment of safety and tolerability showed no alteration from baseline, in laboratory parameters (hematology, biochemistry, and urine analysis), vitals (blood pressure, pulse rate, and temperature), and ECG, after i.v. lacosamide administration and at follow-up. The AEs reported were mild to moderate in nature and mostly limited to upper abdominal pain, headache, nausea, vomiting, and pyrexia; none of the AEs resulted in patient withdrawal. The nature and frequency of these AEs were consistent with other similar studies conducted in the past.15,18,21 No events of bradycardia, hypotension or post-dose sedation were observed except for dizziness that was reported in one patient. Similarly, other studies reported no deleterious cardiovascular effect or QR/PT prolongation in patients treated with i.v. lacosamide,22,23 which suggests cardiovascular safety. This study also reported a few local reactions at the injection site (pain, pruritus, pain pruritus, erythema, thrombophlebitis, and rash erythematous) occurring in only 1.3% of the total infusions administered. These local AEs were mild and consistent with those found in other similar studies, suggesting no new safety signals with the use of parenteral lacosamide.15,18,21
The secondary outcome of the study evaluating the efficacy, in terms of seizure frequency, during i.v. lacosamide treatment did not show any negative change in the pattern of seizures over for 12 days. The majority of the patients remained seizure-free while others showed either a reduction in seizure frequency or were stable during the treatment period and even at follow-up after 12 days indicating no seizure deterioration with i.v. lacosamide. Similar efficacy was reported in other studies in patients with FOS.15,18 Besides FOS, the efficacy of i.v. lacosamide was also reported in status epilepticus and seizure clusters in some studies24–26 suggesting its use as a potential alternative to standard AEDs in seizure emergencies.
Combination therapy is a common practice in the treatment of epilepsy. In the current study, many patients were on two or more AEDs such as carbamazepine, clobazam, oxcarbazepine, phenytoin, sodium valproate, valproic acid, and levetiracetam including lacosamide. However, no drug interaction was reported. This can be attributed to the low or no potential of lacosamide to inhibit or induce Cytochrome (CYP) 450 isoforms indicating that lacosamide can be safely co-administered with other AEDs. The finding was supported by two other studies, which showed no pharmacokinetic interaction with the use of lacosamide with other AEDs.27,28 Similarly, Baulac et al. (2017), also demonstrated the safety as well as the efficacy of i.v. lacosamide, in combination with levetiracetam in patients with FOS, is not adequately controlled by the combination of levetiracetam and sodium channel blockers AEDs (e.g., lamotrigine, carbamazepine, oxcarbazepine).29 Overall, the study suggests that i.v. lacosamide can be used as a suitable alternative in FOS and is devoid of severe AEs like respiratory depression, hypotonia, or cardiac arrhythmia, often associated with the use of conventional AEDs such as phenytoin, phenobarbital, benzodiazepines and valproate,30 or post-dose sedation (somnolence) commonly reported with newer AEDs such as levetiracetam and brivaracetam.31–35
Limitations
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.
Conclusions
Intravenous injection or infusion is essential to control seizures in an emergency or when oral administration is not feasible, to prevent neurological complications that may occur due to seizure cluster or status epilepticus. In such conditions, switching to an i.v. formulation of an already established oral AED regime is the safest and most convenient option but requires dose titration. With a favorable pharmacokinetic profile, minimal drug interaction, and dual mechanism of action, lacosamide is an ideal drug that can be safely switched to its i.v. form without dose modification to prevent seizure deterioration and to avoid unexpected side effects of using an alternative AED. The study showed that patients with FOS and on a stable oral dose of lacosamide can be safely switched to i.v. lacosamide for up to five days, alone or in combination with other AEDs without compromising the efficacy.
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how to cite this article
Kakkad A, Keshava BS, Ahmadi B et al. Multi-centric Phase III, single-arm, open-label clinical study to assess clinical safety, tolerability, and efficacy of intravenous lacosamide in focal onset seizures [version 1; peer review: 2 approved with reservations]. F1000Research 2023, 12:1037 (https://doi.org/10.12688/f1000research.125607.1)
NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Version 1
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PUBLISHED 24 Aug 2023
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How to cite this report:
Shah S and Trivedi S. Reviewer Report For: Multi-centric Phase III, single-arm, open-label clinical study to assess clinical safety, tolerability, and efficacy of intravenous lacosamide in focal onset seizures [version 1; peer review: 2 approved with reservations]. F1000Research 2023, 12:1037 (https://doi.org/10.5256/f1000research.137934.r203888)
The direct URL for this report is:
https://f1000research.com/articles/12-1037/v1#referee-response-203888
https://f1000research.com/articles/12-1037/v1#referee-response-203888
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 26 Apr 2024
Sudhir Shah,
Professor and Head Department of Neurology at NHL Municipal College and V. S. General Hospital, Ahmedabad Director of Neurosciences at Sterling Hospital, Ahmedabad, India
Approved with Reservations
VIEWS 13
The manuscript “Multi-centric Phase III, single-arm, open-label clinical study to assess clinical safety, tolerability, and efficacy of intravenous lacosamide in focal onset seizures” by Dr Ashutosh Kakkad et al, authors have described the results of safety efficacy and tolerability of
... Continue reading
CITE
HOW TO CITE THIS REPORT
Shah S and Trivedi S. Reviewer Report For: Multi-centric Phase III, single-arm, open-label clinical study to assess clinical safety, tolerability, and efficacy of intravenous lacosamide in focal onset seizures [version 1; peer review: 2 approved with reservations]. F1000Research 2023, 12:1037 (https://doi.org/10.5256/f1000research.137934.r203888)
The direct URL for this report is:
https://f1000research.com/articles/12-1037/v1#referee-response-203888
https://f1000research.com/articles/12-1037/v1#referee-response-203888
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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How to cite this report:
Ishikawa N. Reviewer Report For: Multi-centric Phase III, single-arm, open-label clinical study to assess clinical safety, tolerability, and efficacy of intravenous lacosamide in focal onset seizures [version 1; peer review: 2 approved with reservations]. F1000Research 2023, 12:1037 (https://doi.org/10.5256/f1000research.137934.r208170)
The direct URL for this report is:
https://f1000research.com/articles/12-1037/v1#referee-response-208170
https://f1000research.com/articles/12-1037/v1#referee-response-208170
NOTE: it is important to ensure the information in square brackets after the title is included in this citation.
Reviewer Report 11 Feb 2024
Approved with Reservations
VIEWS 15
The authors describe that i.v. lacosamide is a safe and effective strategy in adult patients with FOS and can be co-administered with other anti-epileptic drugs based on 12 days-period phase III study in India. This is an overall well organized
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CITE
HOW TO CITE THIS REPORT
Ishikawa N. Reviewer Report For: Multi-centric Phase III, single-arm, open-label clinical study to assess clinical safety, tolerability, and efficacy of intravenous lacosamide in focal onset seizures [version 1; peer review: 2 approved with reservations]. F1000Research 2023, 12:1037 (https://doi.org/10.5256/f1000research.137934.r208170)
The direct URL for this report is:
https://f1000research.com/articles/12-1037/v1#referee-response-208170
https://f1000research.com/articles/12-1037/v1#referee-response-208170
NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article.
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Author Response 13 Apr 2024Ashutosh Kakkad, Medical Services, Torrent Pharmaceuticals Limited, Ahmedabad, 380009, India13 Apr 2024Author ResponseThere are some points which can potentially improve this manuscript as follows:
- How did the authors confirm seizure types of participants? The authors should clarify it because this
COMMENTS ON THIS REPORT
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Author Response 13 Apr 2024Ashutosh Kakkad, Medical Services, Torrent Pharmaceuticals Limited, Ahmedabad, 380009, India13 Apr 2024Author ResponseThere are some points which can potentially improve this manuscript as follows:
- How did the authors confirm seizure types of participants? The authors should clarify it because this
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