Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial.

Background: Infantile spasms constitutes a severe infantile epilepsy syndrome that is difficult to treat and has a high morbidity. Hormonal therapies or vigabatrin are the most commonly used treatments. We aimed to assess whether combining the treatments would be more effective than hormonal therapy alone.

Methods: In this multicentre, open-label randomised trial, 102 hospitals (Australia [three], Germany [11], New Zealand [two], Switzerland [three], and the UK [83]) enrolled infants who had a clinical diagnosis of infantile spasms and a hypsarrhythmic (or similar) EEG no more than 7 days before enrolment. Participants were randomly assigned (1:1) by a secure website to receive hormonal therapy with vigabatrin or hormonal therapy alone. If parents consented, there was an additional randomisation (1:1) of type of hormonal therapy used (prednisolone or tetracosactide depot). Block randomisation was stratified for hormonal treatment and risk of developmental impairment. Parents and clinicians were not masked to therapy, but investigators assessing electro-clinical outcome were masked to treatment allocation. Minimum doses were prednisolone 10 mg four times a day or intramuscular tetracosactide depot 0·5 mg (40 IU) on alternate days with or without vigabatrin 100 mg/kg per day. The primary outcome was cessation of spasms, which was defined as no witnessed spasms on and between day 14 and day 42 from trial entry, as recorded by parents and carers in a seizure diary. Analysis was by intention to treat. The trial is registered with The International Standard Randomised Controlled Trial Number (ISRCTN), number 54363174, and the European Union Drug Regulating Authorities Clinical Trials (EUDRACT), number 2006-000788-27.

Findings: Between March 7, 2007, and May 22, 2014, 766 infants were screened and, of those, 377 were randomly assigned to hormonal therapy with vigabatrin (186) or hormonal therapy alone (191). All 377 infants were assessed for the primary outcome. Between days 14 and 42 inclusive no spasms were witnessed in 133 (72%) of 186 patients on hormonal therapy with vigabatrin compared with 108 (57%) of 191 patients on hormonal therapy alone (difference 15·0%, 95% CI 5·1-24·9, p=0·002). Serious adverse reactions necessitating hospitalisation occurred in 33 infants (16 on hormonal therapy alone and 17 on hormonal therapy with vigabatrin). The most common serious adverse reaction was infection occurring in five infants on hormonal therapy alone and four on hormonal therapy with vigabatrin. There were no deaths attributable to treatment.

Interpretation: Hormonal therapy with vigabatrin is significantly more effective at stopping infantile spasms than hormonal therapy alone. The 4 week period of spasm cessation required to achieve a primary clinical response to treatment suggests that the effect seen might be sustained, but this needs to be confirmed at the 18 month follow-up.

Funding: The Castang Foundation, Bath Unit for Research in Paediatrics, National Institute of Health Research, the Royal United Hospitals Bath NHS Foundation Trust, the BRONNER-BENDUNG Stifung/Gernsbach, and University Children's Hospital Zurich.