Pharmacokinetics in Neonates Exposed to Lacosamide

Rationale and background:

Seizures are one of the most common neurologic emergencies in neonates, arising in ~3/1000term live births and are associated with significant mortality and neuro-developmental disability (Soul et al, 2018). In contrast to seizures in older children, most neonatal seizures result from acute symptomatic etiologies rather than epilepsy. The most common etiologies include neonatal encephalopathy caused by hypoxic-ischemia (HIE), focal ischemia affecting one or more vascular territories (stroke), intracranial hemorrhage, infection, cerebral dysgenesis, and metabolic disturbances. (Soul et al, 2018, Venkatesan et al, 2016). Treatment is largely guided by physician preference and tradition, due to a lack of data from well-designed clinical studies. Globally, phenobarbital (PB) is standard of care as first-line therapy in neonatal seizures. Phenobarbital has shown efficacy (response usually defined as 80% to 100% reduction in seizure burden in sec/h) of between 50% and 80% in several small studies. Several other antiepileptic drugs (AEDs) have shown some efficacy as first-line treatment (eg, levetiracetam [LEV]vs. PB as first-line [Rao et al, 2018]) or as adjunct treatment, but gold standard evidence of efficacy or effectiveness is lacking for all compounds, and all AED-based treatments are currently off-label (Soul et al, 2018).

Lacosamide(LCM, VIMPAT®), is indicated for the treatment of partial-onset seizures (POS) in patients 4 years of age and older, and this indication is currently limited in the US to VIMPAT oral dosage forms (FilmCoated Tablets and Oral Solution). VIMPAT intravenous (iv) delivery is indicated for the treatment of POS in adults (17 years of age and older) in the US. Any AED use in neonates is off label and and the scant literature in the neonatal seizure population indicates variations in the care pathway with numerous AEDs utilized at varying doses according to underlying condition (Rennie et al, 2018; Glass et al, 2017; Venkatesan et al, 2016; Dizon et al, 2019).

Count data of LCM prescribing in neonates indicates scant usage: PEDSnet database n~27, PCORnet n ~ 13, Soul collaboration dataset n <50. A paper by Glass and colleagues indicates no usage (Glass et al, 2017), and an internal survey (Watson et al, 2019) shows no use in acute seizure and rarely in prophylaxis. These factors indicate the challenge in recruiting both physicians and parents for a clinical study, where to date no safety data exists in neonates.

Based on these factors, UCB has decided to set up an epidemiological neonatal seizure study evaluating pharmacokinetics (PK) and effectiveness outcome to support development of a clinical study and provide evidence for the clinical and patient community. The study will include all neonates initially exposed to iv LCM in PEDSnet and PCORnet. Patients can later be switched to oral LCMduring follow up.

Research question and objectives:

Aim: to evaluate PK and seizure outcomes in neonates exposed to any dose of iv LCM.

Primary objectives:

1.To obtain measurements of PK of LCM (plasma concentration) by obtaining drug dosing with time stamps and blood tests with time stamps at any time during the first observable episode of exposure to LCM and thereafter up to 30 days.

2.To assess effectiveness outcomes in a non-comparative design, evaluating-endpoints within 30 days of drug start. Any of the following can apply:

a. Electroencephalography(EEG)evidence of seizure cessation/SE cessation during continuous exposure* to LCM (without introduction of another drug post LCM initiation).

b. EEG evidence of seizure burden reduction during continuous exposure to LCM without introduction of another drug post LCM initiation (taken from EEG reports. Reduction will be defined as i) clinically meaningful reduction of 80%; ii) 50% reduction iii)<50%to 10%. All must be maintained throughout exposure.

c. Statement in notes of seizure cessation/SE cessation during continuous exposure to LCM (without introduction of another drug post LCM initiation) (or SNOMED code for seizure cessation/SE cessation if available).

d. Statement in notes of seizure burden reduction during continuous exposure to LCM without introduction of another drug post LCM initiation. Reduction will be defined as i)clinically meaningful reduction of 80%; ii) 50% reduction iii) <50% to 10%. All must be maintained throughout exposure.

e. Maintenance of LCM for >14 days in hospital without introduction of another drug post LCM initiation.

f. To quantify the numbers of neonate patients above, that transfer to pediatric unit or home on iv or oral LCM.

*Continuous exposure is defined initially as exposure to iv LCM without addition of another AED and breaks in administrations of less than 24 hours estimated using time stamps for drug administration. If LCM therapy has been switched to oral therapy, then the gap between drug administration must not be greater than 24 hours with no introduction of another AED.

Note: LCM can be used asmonotherapy or adjunct to a prior AED therapy during intensive care/in-hospital stay. This will be described.

Secondary Objectives:

Safety in ~13 patients from PCORnet only (the PEDSnet ~ 27 are already evaluated in the Loading study EP0147–a safety evaluation study comparing events in pediatrics loaded with LCM versus recommended dosing).

1. To estimate the incidence of the selected medical events for 6 System Organ Classes (SOC) namely: i) Cardiac disorders; ii) Skin and subcutaneous tissue disorders; iii) Nervous system disorders; iv) Metabolism and nutrition disorders; v) Administration site conditions and injury; vi) Blood and lymphatic system disorders.

2. Plus 2 Standardized MedDRA Queries (SMQs) namely: i) Drug rash -reaction with eosinophilia and systemic symptoms (DRESS) syndrome; ii) Severe cutaneous adverse reactions.