Efficacy, safety, and tolerability of imepitoin in dogs with newly diagnosed epilepsy in a randomised controlled clinical study with long term follow up. Chris Rundfeldt, Andrea Tipold, Wolfgang Löscher. BioMed Central Veterinary Research (2015) 11:288
Summarised by Dr Liesel van der Merwe, BVSC MMedVet (Med)
Why they did it:
Canine epilepsy is seen in about 0.5 – 5% of the general canine population and is found in a wide range of breeds. Idiopathic epilepsy represents about 60 – 70% of all cases. Current therapy is unsatisfactory with only 15% of patients becoming seizure free and 30% of patients not experiencing significant seizure reduction with phenobarbitone or potassium bromide, the most commonly used anti-epileptic drugs (AEDs).
Imeptitoin, originally developed for epilepsy and anxiety in humans, was withdrawn from further development for humans due to inter-individual pharmacological variability. Initial studies showed the drug was well tolerated in dogs and had good effects as a monotherapy and add-on therapy. The aim of this study was to confirm the safety and efficacy of imepitoin in dogs with idiopathic epilepsy.
How they did it:
A multi-centre randomized double blind clinical field study was aimed at demonstrating the superiority of imepitoin at 30 mg/kg bid (HD) over 1mg/kg bid (LD), the lowest effective dose. In Phase 1, 120 dogs were randomly placed into the HD and LD groups and treated for 12 weeks. Dogs which completed Phase 1 or exited Phase 1 early due to poor response to medication were started on Phase 2, open label follow up at 30 mg/kg bid for another 12 weeks
The sample size was calculated at a minimum of 54 patients per group, which was necessary to pick up a difference of 1 seizure/28 days. Inclusion criteria required at least one of: 2-10 generalised seizures within 3 months, 1 cluster seizure event or status event within 7 days. Dogs were excluded if there was evidence of intracranial disease, more than 10 seizures or any other AEDs used within 3 months of randomisation.
What they found:
127 dogs were included in the study with 66 dogs in the high dose (HD) group and 61 in the low dose (LD) group. Dogs from 60 different breeds were included. 29 (45%) of dogs in the HD group and 30 (50%) dogs in the LD group completed the study (24 weeks). 100 animals continued to open label treatment in Phase 2. The HD group, despite randomisation, had a significantly higher starting baseline mean seizure frequency. Seizure frequency dropped in both groups, but was more pronounced and in the high dose group, 1.7±2.8 seizures per month, versus 0.8±2 seizures per month in the LD group. This was statistically significant. In the HD group 37.5% of animals became seizure free and 31.7% in the LD group.
There was no change in mean seizure frequency in Phase 2 of the trial – indicating continued efficacy of the drug. The increased dose in Phase 2 for some of the patients resulted in a slight reduction in seizures and an increased number of seizure free dogs. Of the 14 seizure free dogs in the LD group, an additional 8 became seizure free on the higher dose (from 30% in the former LD group to 46.8%). Imepitoin did not result in any significant reduction in cluster seizures. The HD group showed significantly higher numbers of CNS-related adverse events: ataxia, disorientation, hyperactivity and restlessness.
Imepitoin is an effective monotherapy AED in a clinical setting. The drug is suitable for long term use as tolerance was not shown and adverse effects were mild and transient, in the first weeks of treatment only. Imepitoin is less effective against cluster seizures. Approximately 39% of all animals in Phase 2 became seizure free.