Clinical Trials in Epilepsy

Question 1

Epilepsy

Answer 1

CNS disorder affecting <1% of general population

Recurrent, spontaneous and uncontrolled abnormal neuronal discharges, lasting seconds to minutes

Prolonged seizures (status epilepticus) can be life-threatening

Seizures often preceded by aura and can be triggered

Question 2

Underlying Causes of Epilepsy

Answer 2

Idiopathic
- Majority of cases
- More common in very young children or later in life
- No well defined cause but can be caused by any brain disorder/injury

Symptomatic
- Known cause, includes: congenital, perinatal injury, metabolic disorder, trauma, tumours, cerebral vascular disease, neurodegenerative disease, infectious disease

Question 3

Seizure Classification

Answer 3

Partial Seizure
- discharge spreads locally from a focus of abnormal cells
- reduced threshold of neuronal excitability limited to a particular area of the brain

Primary Generalised Seizure
- discharge spreads symmetrically throughout brain
- entire brain is simultaneously discharging

Partial Seizure with Secondary Generalisation
- discharge starts locally then spreads to brainstem structures which spread widely throughout brain
- also known as partial complex epilepsy

Question 4

Further Classification of Seizures

Answer 4

Partial Seizures:
- Simple: no impairment of conscious
- Complex: consciousness is impaired -> most refractory to treatment

Generalised Seizures:
- consciousness is usually impaired
- Tonic-clonic: ‘grand mal’ epilepsy
- Absence: ‘petit mal’, usually brief but occur in clusters, child looks disengaged
- Myoclonic: sudden brief jerks
- Clonic: rhythmical rapid contraction and relaxation
- Tonic: sudden contraction causing rigidity
- Atonic: instantaneous complete loss of muscle tone

Question 5

Current Treatments for Epilepsy

Answer 5

Traditional AEDs are majority of first-line treatment:
- Partial seizures: carbamazepine, phenytoin
- Primary generalised seizures: valproate

• 60% monotherapy, combination for remaining, sometimes including surgery

Question 6

Diagnosis of Epilepsy

Answer 6

Made primarily on clinical grounds: description of seizure, eye-witness accounts, multiple episodes

Diagnostic tools include EEG and imaging to identify underlying structural/functional pathology
- Very specialised so not often used routinely

Question 7

Need for New AEDs

Answer 7

More than 20 seizure types exist

More than one AED is often needed, increasing likelihood of side effects and drug interactions

Up to 30% of patients have refractory epilepsy

Need for improved efficacy, safety (particularly women), compliance and agents with disease modifying activity

Question 8

Treatment Withdrawal

Answer 8

Drugs are gradually withdrawn one at a time as epilepsy can naturally improve over time

If seizures reoccur, treatment with the same drug is immediately reinstated
- unlikely to ever attempt withdrawal again

Question 9

Surrogate Markers in Epilepsy Trial

Answer 9

Interictal EEG (between seizures)

Photoconvulsive test (affects 5% of patients)

Imaging, but may not be sensitive enough to detect drug efficacy

Question 10

Clinical Trials in Epilepsy

Answer 10

As soon as a patient is diagnosed with epilepsy they must be given treatment

This treatment may require changing after a few weeks

Normal trial designs cannot be used in epilepsy as they cannot have their treatment washed out or be put on placebo

Question 11

Add-On Trial Design Epilepsy

Answer 11

A baseline observation is run prior to the trial with participants on their standard care to confirm how many attacks they have

At the end of the baseline, the group is randomised and split, with half receiving a new AED and half receiving placebo on top of their current care

This can determine if the group with the additional new AED have a better outcome than placebo

However, requires a huge amount of patients due to variability and it does not tell you if the drug is effective as a monotherapy or if ARs are due to drug interaction or the new AED

Question 12

Amery Design After Add-On

Answer 12

Also known as a stepping down trial

25% of standard therapy is removed at a time whilst the new AED remains

If positive, then remove another 25% until no standard therapy, just new AED and placebo

If patient is deteriorating, they go back on standard treatment and the trial is stopped

Determines if drug works as a monotherapy but does not tell the minimum effective dose

Question 13

Enriched Amery Design

Answer 13

Same design as Amery except the new AED is reduced, rather than the standard therapy

Removing more of the drug but seeing if the effect is maintained helps to determine the minimum effective dose