The University of Southampton
University of Southampton Institutional Repository

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

Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial
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.
33-42
O'Callaghan, Finbar J.K.
2509fcd7-56d9-4f56-9e8b-aeaaccd86aea
Edwards, Stuart W.
e12d224c-059a-4da8-9ed8-0d4f13debc7a
Alber, Fabienne Dietrich
98c46b6f-616b-4dde-811a-c91f490f20c6
Hancock, Eleanor
0aac9197-3944-40b6-a4f4-b3f40bd3b602
Johnson, Anthony L.
f3bbadf1-d1a1-4b09-8d7f-2e9b86aa25dd
Kennedy, Colin
7c3aff62-0a86-4b44-b7d7-4bc01f23ec93
Likeman, Marcus
eeb18984-bee1-45b9-8df9-0a32f9dc77be
Lux, Andrew L.
8ce75001-3fbe-411d-8a78-31e1027508db
Mackay, Mark
8cd6fe6c-c61d-4a1f-bfca-de07629cc2c5
Mallick, Andrew A.
97c8dd33-55de-41e8-9c2f-07f0883ef56c
Newton, Richard W.
b307ba85-c13b-40f7-9c05-ba1b4bafd922
Nolan, Melinda
572272a2-0902-4c66-a5e7-e7d0ddc7b4ed
Pressler, Ronit
bd9e312f-6a0e-4530-a2f0-a36b358db213
Rating, Dietz
7bee9a60-ddd7-4bc8-aebb-098731fb09b6
Schmitt, Bernhard
37bf60fc-3dfa-4726-8964-c07a4b2c4887
Verity, Christopher M.
24c500a4-8efd-4195-b75a-34c49406ff87
Osborne, John P.
db90ab19-3de3-49a8-b82a-b050a1180e6f
O'Callaghan, Finbar J.K.
2509fcd7-56d9-4f56-9e8b-aeaaccd86aea
Edwards, Stuart W.
e12d224c-059a-4da8-9ed8-0d4f13debc7a
Alber, Fabienne Dietrich
98c46b6f-616b-4dde-811a-c91f490f20c6
Hancock, Eleanor
0aac9197-3944-40b6-a4f4-b3f40bd3b602
Johnson, Anthony L.
f3bbadf1-d1a1-4b09-8d7f-2e9b86aa25dd
Kennedy, Colin
7c3aff62-0a86-4b44-b7d7-4bc01f23ec93
Likeman, Marcus
eeb18984-bee1-45b9-8df9-0a32f9dc77be
Lux, Andrew L.
8ce75001-3fbe-411d-8a78-31e1027508db
Mackay, Mark
8cd6fe6c-c61d-4a1f-bfca-de07629cc2c5
Mallick, Andrew A.
97c8dd33-55de-41e8-9c2f-07f0883ef56c
Newton, Richard W.
b307ba85-c13b-40f7-9c05-ba1b4bafd922
Nolan, Melinda
572272a2-0902-4c66-a5e7-e7d0ddc7b4ed
Pressler, Ronit
bd9e312f-6a0e-4530-a2f0-a36b358db213
Rating, Dietz
7bee9a60-ddd7-4bc8-aebb-098731fb09b6
Schmitt, Bernhard
37bf60fc-3dfa-4726-8964-c07a4b2c4887
Verity, Christopher M.
24c500a4-8efd-4195-b75a-34c49406ff87
Osborne, John P.
db90ab19-3de3-49a8-b82a-b050a1180e6f

O'Callaghan, Finbar J.K., Edwards, Stuart W., Alber, Fabienne Dietrich, Hancock, Eleanor, Johnson, Anthony L., Kennedy, Colin, Likeman, Marcus, Lux, Andrew L., Mackay, Mark, Mallick, Andrew A., Newton, Richard W., Nolan, Melinda, Pressler, Ronit, Rating, Dietz, Schmitt, Bernhard, Verity, Christopher M. and Osborne, John P. (2017) Safety and effectiveness of hormonal treatment versus hormonal treatment with vigabatrin for infantile spasms (ICISS): a randomised, multicentre, open-label trial. The Lancet Neurology, 16 (1), 33-42. (doi:10.1016/S1474-4422(16)30294-0).

Record type: Article

Abstract

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.

Text
ICISS Nov 2015 draft (clean) prior to Lancet submission published Nov 2016.docx - Accepted Manuscript
Restricted to Repository staff only until 10 May 2017.
Request a copy

More information

Accepted/In Press date: 9 November 2016
e-pub ahead of print date: 10 November 2016
Published date: January 2017
Organisations: Clinical & Experimental Sciences

Identifiers

Local EPrints ID: 405159
URI: https://eprints.soton.ac.uk/id/eprint/405159
PURE UUID: a1967008-09e6-4832-91f0-d76d672f54dd

Catalogue record

Date deposited: 27 Jan 2017 15:01
Last modified: 09 Dec 2019 19:16

Export record

Altmetrics

Contributors

Author: Finbar J.K. O'Callaghan
Author: Stuart W. Edwards
Author: Fabienne Dietrich Alber
Author: Eleanor Hancock
Author: Anthony L. Johnson
Author: Colin Kennedy
Author: Marcus Likeman
Author: Andrew L. Lux
Author: Mark Mackay
Author: Andrew A. Mallick
Author: Richard W. Newton
Author: Melinda Nolan
Author: Ronit Pressler
Author: Dietz Rating
Author: Bernhard Schmitt
Author: Christopher M. Verity
Author: John P. Osborne

University divisions

Download statistics

Downloads from ePrints over the past year. Other digital versions may also be available to download e.g. from the publisher's website.

View more statistics

Atom RSS 1.0 RSS 2.0

Contact ePrints Soton: eprints@soton.ac.uk

ePrints Soton supports OAI 2.0 with a base URL of https://eprints.soton.ac.uk/cgi/oai2

This repository has been built using EPrints software, developed at the University of Southampton, but available to everyone to use.

We use cookies to ensure that we give you the best experience on our website. If you continue without changing your settings, we will assume that you are happy to receive cookies on the University of Southampton website.

×