Pharmaco-TMS and qEEG in rare myclonic epilepsy condition

TMS-EDMs assess target engagement of novel ion channel positive modulator for rare genetic form of myoclonic epilepsy.

Challenge/Opportunity

Design and optimise the Pharmaco-TMS and Pharmaco-EEG measures to ensure sufficient data was acquired within the time constraints of the full study protocol.

Train on-site neuroscience research and clinical neurology teams on the protocols to capture the specific neurological measures.

Consider patient comfort and fatigue throughout.

Balance the above with the need to keep data collection as consistent as possible from one day and session to the next.

About MEAK

Myoclonus epilepsy and ataxia due to potassium channel mutation (MEAK) is an ultra-rare, genetic, progressive and life limiting condition that affects young people. Patients with this condition usually present with myoclonus (brief shock-like jerks of a muscle or a group of muscles) and/or ataxia (unsteadiness and difficulty in co-ordinating movements) in childhood, between the ages of 3 and 15 and get progressively worse over time. In some cases, patients also experience generalised tonic-clonic seizures. By the time patients are in their late teenage years they often need to use a wheelchair and other assistive devices. In many cases, patients have difficulty with daily activities and are mostly dependent, although in adulthood seizures are less frequent and the disease stabilises. There is currently no specific treatment for MEAK or the relief of myoclonus or ataxia in these patients. Therapy typically involves anti-seizure medications for the symptomatic relief of seizures.

Having established Proof of Concept in a related condition (Fragile X), our client hypothesised that their precision medicine candidate would reduce neuronal hyperexcitability caused by this genetic mutation and therefore improve the symptoms of these young patients as well as patients with other forms of progressive myoclonic epilepsy (PME)

About the Study

This Phase 1b clinical trial is a double-blind, randomised, placebo-controlled treatment designed to establish a Proof of Mechanism using a number of biomarkers in a small population of patients with MEAK.

Our Approach/Solution

Protocol Design

The Science Behind began with conducting background research to establish and understand prior scientific evidence of the drug candidate and MEAK. We then applied this knowledge to develop efficient protocols that accommodated time constraints related to other biomarker and PK assessments while ensuring sufficient data is collected to still be meaningful.

TMS-EDM – The Science Behind proposed a Threshold Tracking Paired Pulse TMS protocol. This protocol is more complex to design, and can take more time to deliver than fixed intensity methods as each measurement would be captured in a separate run but has shown better intra and interday reliability compared to fixed intensity TMS protocol.

qEEG and Auditory Habituation – Original protocol requirements suggested that these measures would require patients to be still and vigilant for up to 180mins in total. It was anticipated that Patients would be experiencing frequent episodes of myoclonic activity and may become easily fatigued. They also would have undertaken several other tasks prior to the qEEG and Auditory Habituation tasks. To accommodate this, The Science Behind adjusted the protocol to enable the minimum amount of data required to be able to make a useful assessment of the drugs effect.

Integrated Solution Design

Specification of neuroscience equipment require for effective and efficient collection of TMS-EDM and EEG data.

Once the protocols had been signed off and approved by the client, The Science Behind’s multi-disciplinary team of neuroscience researchers and equipment specialists set about identifying the individual systems that were required to deliver them.

For TMS-EDMs, we designed an integrated solution that incorporated neuronavigation to enable easy cortical navigation for the TMS measures, Paired Pulse TMS, programme codes to deliver Threshold Tracking protocols and EMG data capture.

The qEEG and Auditory Habituation protocol our solution included EEG, an auditory chirp and programmed software to deliver the chirp and trigger the EEG and a silent movie to ensure vigilance throughout the protocol.

Training

The Science Behind prepared a detailed user manual for trial site outlining every aspect, step-by-step, of the TMS-EDM and qEEG and Auditory Habituation protocols and delivered remotely and in person several training sessions for site staff until they were confident and competent with the requirements of the protocols.

Data Quality Control

Overnight turnaround of a quality control review of TMS and EEG data to ensure all data and parameters were collected effectively and to provide feedback to the study team of any adjustments and considerations they may need/should take to improve the following day’s data collection.

Data Analysis

The Science Behind prepared a plan for statistical analysis of TMS-EDM data as well as provided some interim indications of drug effect based on emerging data.