Adult Antiepileptics for PGTC Seizures Effective in Children

Pauline Anderson

April 24, 2017

BOSTON — Preliminary results from a meta-analysis have shown that antiepileptic drugs (AEDs) approved for adults with primary generalized tonic-clonic (PGTC) seizures are also effective in children with the same condition.

The new information represents another step toward endorsing the concept of extrapolating adult data to children, said lead researcher, Douglas Nordli Jr, MD, chief of the Division of Pediatric Neurology at Children's Hospital Los Angeles and professor of clinical neurology at the Keck School of Medicine of the University of Southern California.

"This helps to make the argument that seizures in children with primary generalized tonic-clonic seizures are strikingly similar to those in adults, and that this idea of extrapolation is valid."

The concept of extrapolation of data from adults to children has already been accepted for focal (partial) seizures.

The results will be presented here April 27 at the American Academy of Neurology 2017 Annual Meeting (AAN).

Wasting Time?

As new AEDs are studied and get approved for adults by the US Food and Drug Administration (FDA) and by the European Medicines Agency (EMA), the aim should be to get important information into the hands of pediatricians and neurologists as fast as possible, instead of having to do similar studies all over again in children, said Dr Nordli.

In some ways, he said, "we're wasting our time doing these studies in children above about the age of 4 years because they always come up with similar results as in adults."

Explaining the current situation to Medscape Medical News, Jacqueline French, MD, professor, New York University, and Comprehensive Epilepsy Center, New York City, said FDA approval of drugs is often based on trials carried out first in adolescents and adults.

"After an AED is on the market, it can be very hard to do placebo-controlled trials in children, which are the kind of trials the FDA likes to see to grant approval. This means that approval for kids often lags very far behind adult approval."

To address this situation, academics and the FDA collaborated on the Pediatric Epilepsy Academic Consortium for Extrapolation (PEACE), said Dr French.

"This initiative demonstrated — based on analysis of  [pharmacokinetics/pharmacodynamics] relationships for adult and pediatric studies of the same drug — that for focal seizures, if trials showed that a drug worked in adolescents and adults, it would work similarly in children down to the age of 4."

As a result of this work, the FDA decided that once efficacy was proven in adolescents and adults, additional efficacy trials in children will no longer be necessary; only safety and pharmacokinetics trials will be required, said Dr French.

In an article published last fall in CNS Drugs , a group of experts proposed "a new paradigm" for the development of drugs for focal epilepsies. Under the new arrangement, adults and children aged 2 years and older would be simultaneously enrolled into phase 2 and phase 3 studies. Medications would be licensed upon a successful outcome of the phase 3 study, but pediatric licensure would be provisional until neurodevelopmental safety was verified by a phase 4 trial.

"Patients, clinicians and sponsors would all benefit from this new structure through cost reduction and earlier access to novel treatment," those authors, led by Ian Wadsworth, MRC North-West Hub for Trials Methodology Research, Department of Mathematics and Statistics, Fylde College, Lancaster University, United Kingdom, wrote.

However, this initiative does not include generalized seizures.

"For generalized seizures, there is still a need for efficacy studies in children," said Dr French. "This new abstract is suggesting that perhaps the same philosophy could be used for generalized seizures."

For their meta-analysis, the researchers searched databases for randomized placebo-controlled studies of AEDs as adjunctive treatment in adults and children with PGTC seizures (a previous analysis had already investigated partial-onset seizures).

Tonic-clonic is a fairly common seizure type beyond the first few years of life. However, if children haven't yet had video electroencephalography, it's sometimes difficult to tell what seizure type they have, said Dr Nordli.  PGTC seizures are associated with increased risk for injury and death.

The current meta-analysis included seven studies, dating from 1999 to 2015, that analyzed a total of 757 patients. Four studies were in adults, two in both adults and children (some as young as age 2 years), and one in children.

The AEDs tested in the studies included lamotrigine, perampanel, and topiramate.

The meta-analysis assessed the median percentage seizure reduction and the proportion of patients who had a 50% or greater reduction in seizures.

Strikingly Similar

"Looking at either of those outcomes, they're strikingly similar, whether it's involving pediatric patients or adult patients," said Dr Nordli.

The results are similar to those researchers previously showed with respect to partial or focal seizures, he said.

The new findings are a "validation of what we suspected — that for things like focal seizures or generalized seizures, drugs that tend to work in adults also work in children," said Dr Nordli.

"That's not earthshattering; it's common sense."

As it stands now, adult-approved AEDs are used routinely in children, said Dr Nordli. "I have heard that 70% of all the drugs that we use in pediatrics are not technically approved for use in pediatrics."

That's because "we are frequently desperate for alternatives" for children "and so will use these medications even though they don't technically have an FDA or EMA approval for children," added Dr Nordli.

He used the hypothetical example of a doctor treating a child with tonic-clonic seizures as a new AED comes on the market. The child has developed a rash while receiving lamotrigine, can't be prescribed valproate because of her age, and has not responded to one other drug.

"So we reach for that new drug, but we don't know anything about that new drug; we don't know anything about its dosing and we don't know anything about its safety profile other than anecdotal experience," said Dr Nordli.

"Rather than wait several years for complex, double-blind, placebo-controlled studies to be done looking at efficacy, let's frontline the studies and get that information to clinicians earlier."

For a comment on the new research, Medscape Medical News approached Juan G. Ochoa, MD, associate professor of neurology, director of USA SouthCEP, The Comprehensive Epilepsy Program, University of South Alabama College of Medicine, Mobile.

Although the study appears "well designed," it's not clear from the abstract the number of pediatric vs adult patients, said Dr Ochoa.

"If the number of pediatric and adult patients is comparable, the significance of this study is very important. New drugs that already have an indication for primary generalized epilepsy in adults would not need a separate trial in children." 

The study was supported by Eisai Inc.

American Academy of Neurology 2017 Annual Meeting (AAN). Abstract S37.004. To be presented April 27, 2017.

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