Effects of Marketed Antiepileptic Drugs and Placebo in the Human Photosensitivity Screening Protocol

Abstract

A study of epilepsy patients with a reproducible range of photoparoxysmal responses (PPR) (epileptiform discharges evoked by flashing lights) has been used as a "proofof-concept" trial to determine if novel potential antiepileptic drugs (AEDs) should proceed in development. The standard design for this trial requires a 3-day inpatient stay and is single-blind. We evaluated two marketed and effective AEDs-one narrow-spectrum [carbamazepine (CBZ)], and one broad-spectrum [levetiracetam (LEV)]-using a novel double-blinded, cross-over outpatient version of the trial to detect acute drug effects of the two marketed AEDs on photosensitivity. We tested 6 patients with a known stable photosensitivity response, using single oral doses of CBZ 400 mg and LEV 1000 mg, compared to 2 test days with single placebo doses. Patients who received LEV had the lowest mean PPR (compared with placebo and CBZ). The mixed effect model showed a significant effect of LEV in all eye closure conditions (p <0.001). There was no evidence of a significant change in PPR after CBZ or placebo treatment. In conclusion, LEV 1000 mg, but not CBZ 400 mg, was effective in suppressing photosensitivity within a 6-h period compared with placebo showing the ability of our novel photosensitivity trial design to demonstrate effects of broadspectrum AEDs. We cannot confirm the ability of the photosensitivity trial to detect the narrow-spectrum AED CBZ in our design. The novel outpatient study design is feasible and is expected to reduce costs compared with previous methodology.

Inhaled alprazolam rapidly suppresses epileptic activity in photosensitive participants

“…Several prior antiepileptic drugs (AEDs) have been developed using participants with a photoparoxysmal response (PPR) on electroencephalogram (EEG) to provide initial data on the drugs’ potential antiepileptic activity . Suppression of photic stimulation‐induced epileptiform activity in such individuals indicates an anticonvulsive effect of potential AEDs; trials using such participants have been conducted for lamotrigine, levetiracetam, and brivaracetam among others . As epileptic activity can be elicited at will and with precise timing in these participants, eliciting a PPR provides an ideal opportunity to explore time to onset of action of a drug.…”

Comment from Dorothée G.A. Kasteleijn-Nolst Trenité, Edouard Hirsch, Ronald C. Reed, Bassel Abou-Khalil, and Bernd Schmidt on: How predictive are photosensitive epilepsy models as proof of principle trials for epilepsy?

“…1 1. Apparent discrepancy in results of CBZ in the photosensitivity model-dose and formulation impact the effect of CBZ Binnie et al 2 found that CBZ produced a suppressive PPR (positive effect) in the photosensitivity model; yet recently, French et al 3 did not. The difference in conclusion reached likely can be explained by:…”

“…(a) the formulation of CBZ used (CBZ liquid solution 2 and tablets 3 ) and by (b) the total time of IPS EEG recording post-dose.…”

“…10 However, we do not believe that publication bias exists for the IPS model. In fact, two studies with negative results have been published-the above discussed retry of CBZ, 3 and a trial of ORG-6370 11 (increased photosensitivity and spontaneous myoclonic jerks was observed). The authors' statement 1 that ''a positive photosensitivity PoP will not necessarily guarantee future success in epilepsy efficacy trials'', based on assumption of publication bias of positive trials only, is thus not correct.…”

“…VPA and Lamotrigine have been much less effective in the model than LEV. 2,3 In summary, the three-day photosensitivity Phase IIa model in a limited number of patient volunteers, with its adaptive doseranging design, gives invaluable, fast and cost-effective information on potency, dose/concentration-effect relationship and sideeffects of a potential AED. It can even be performed before completion of long-term toxicity preclinical work.…”