Prednisolone Versus Vigabatrin in the First-line Treatment of Infantile Spasms

NCT02299115 | Withdrawn Phase 3

• 1 other identifier: 1000045463
• Study Type: interventional
• Target: N/A
• Locations: 1 country
• Sites: 1

Brief Summary

Infantile Spasms, is an rare age-specific epilepsy of early infancy. A 2012 American Academy Neurology/ Child Neurology Society practice parameter update on the medical treatment of infantile spasms concluded: adrenocorticotrophic hormone or vigabatrin may be offered for short-term treatment of infantile spasms. There was insufficient evidence to recommend the use of prednisolone, dexamethasone, and methylprednisolone. The cost of ACTH and the side effects of vigabatrin have led to the consideration of alternative medications to treat infantile spasms. The United Kingdom Infantile Spasms Study (UKISS) in 2004, comparing the efficacy of intramuscular synthetic ACTH to high dose oral prednisolone, showed a response rate of 74% for ACTH and 70% for prednisolone. Since the UKISS paper was published, many institutions in the United States and Australia have used oral prednisolone instead of ACTH, partly due to the exorbitant cost of intramuscular ACTH but also its ease of use and better adverse event profile compared to ACTH. Prednisolone and vigabatrin are both oral medications, which can be initiated promptly upon diagnosis of infantile spasms, expediting treatment and shortening treatment lag time. Because the UKISS trial is the only Class 3 study providing evidence for oral prednisolone in the first-line treatment of infantile spasms, further prospective studies are needed.

Conditions

Infantile Spasms

Keywords

Vigabatrin; Prednisolone

Outcome Measures

Primary Outcomes (1)

• Resolution of Infantile spasms and Hypsarrhythmia

  Clinical response: cessation of spasms: no reported spasms for at least 48 hours including day 14 of the trial. EEG response: complete resolution of hypsarrhythmia or modified hypsarrhythmia pattern, on follow up EEG at approximately 2 weeks of the trial.

  14 days

Secondary Outcomes (4)

• Clinical or EEG relapse of Infantile Spasms

  6 months

• Seizure outcome at final follow up (presence or absence of any seizure types at final follow up as assessed by seizure diary and on history at final follow up visit)

  6 months

• Time to cessation of Infantile spasms

  14 days

• Time to relapse

  6 months

Study Arms (2)

Prednisolone

EXPERIMENTAL

Single center, prospective, observational, open trial using high-dose oral prednisolone as first-line treatment for newly diagnosed Infantile Spasms (non-Tuberous Sclerosis)

Drug: Prednisolone

Vigabatrin

ACTIVE COMPARATOR

Retrospective controls composed of our cohort of non-Tuberous Sclerosis Infantile Spasms patients from January 2010- September 2013 who received Vigabatrin as first-line treatment.

Drug: Vigabatrin

Interventions

Prednisolone DRUG

Corticosteroid

Also known as: pms-prednisolone

Prednisolone

Vigabatrin DRUG

Antiepileptic

Also known as: Sabril

Vigabatrin

Eligibility Criteria

• Age: 2 Months - 24 Months
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• Age 2-24 months
• Clinical spasms
• Initial EEG with hypsarrhythmia or modified hypsarrhythmia

You may not qualify if:

• Age \<2months or older than 24 months
• Tuberous sclerosis (if known at the time of enrolment)
• Previous treatment (within 28 days) with VGB or hormonal treatments
• Contraindications to hormonal therapy: This includes untreated systemic fungal infections, known hypersensitivity to prednisolone or other corticosteroids, or to any of the non-medicinal ingredients present in the solution. Active or latent tuberculosis, ocular herpes simplex, hypothyroidism, hepatic cirrhosis, nonspecific ulcerative colitis, abscess or other pyogenic infection, fresh intestinal anastomoses, active or latent peptic ulcer, renal insufficiency, hypertension, osteoporosis, cardiac disease, thromboembolic disorders and diabetes mellitus. All patients with cardiac risk factors will receive an electrocardiogram (ECG), chest xray (CXR) and cardiology referral if indicated. Patients diagnosed with cardiac disorders will be excluded from the study since high dose steroids may exacerbate arrhythmias.
• Inability of parents or guardians to give consent
• Enrolment in a concurrent treatment trial that might affect outcome measures of this trial -

Sponsors & Collaborators

• The Hospital for Sick Children: lead

Study Sites (1)

Hospital for Sick Children

Toronto, Ontario, M5G1X8, Canada

Location

Related Publications (25)

• Riikonen R. Epidemiological data of West syndrome in Finland. Brain Dev. 2001 Nov;23(7):539-41. doi: 10.1016/s0387-7604(01)00263-7.

  PMID: 11701251 BACKGROUND

• Luthvigsson P, Olafsson E, Sigurthardottir S, Hauser WA. Epidemiologic features of infantile spasms in Iceland. Epilepsia. 1994 Jul-Aug;35(4):802-5. doi: 10.1111/j.1528-1157.1994.tb02514.x.

  PMID: 8082625 BACKGROUND

• Trevathan E, Murphy CC, Yeargin-Allsopp M. The descriptive epidemiology of infantile spasms among Atlanta children. Epilepsia. 1999 Jun;40(6):748-51. doi: 10.1111/j.1528-1157.1999.tb00773.x.

  PMID: 10368073 BACKGROUND

• Hattori H. Spontaneous remission of spasms in West syndrome--implications of viral infection. Brain Dev. 2001 Nov;23(7):705-7. doi: 10.1016/s0387-7604(01)00278-9.

  PMID: 11701282 BACKGROUND

• Hrachovy RA, Glaze DG, Frost JD Jr. A retrospective study of spontaneous remission and long-term outcome in patients with infantile spasms. Epilepsia. 1991 Mar-Apr;32(2):212-4. doi: 10.1111/j.1528-1157.1991.tb05246.x.

  PMID: 1848513 BACKGROUND

• O'Callaghan FJ, Lux AL, Darke K, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, Verity CM, Osborne JP. The effect of lead time to treatment and of age of onset on developmental outcome at 4 years in infantile spasms: evidence from the United Kingdom Infantile Spasms Study. Epilepsia. 2011 Jul;52(7):1359-64. doi: 10.1111/j.1528-1167.2011.03127.x. Epub 2011 Jun 10.

  PMID: 21668442 BACKGROUND

• Eisermann MM, DeLaRaillere A, Dellatolas G, Tozzi E, Nabbout R, Dulac O, Chiron C. Infantile spasms in Down syndrome--effects of delayed anticonvulsive treatment. Epilepsy Res. 2003 Jun-Jul;55(1-2):21-7. doi: 10.1016/s0920-1211(03)00088-3.

  PMID: 12948613 BACKGROUND

• Jambaque I, Chiron C, Dumas C, Mumford J, Dulac O. Mental and behavioural outcome of infantile epilepsy treated by vigabatrin in tuberous sclerosis patients. Epilepsy Res. 2000 Feb;38(2-3):151-60. doi: 10.1016/s0920-1211(99)00082-0.

  PMID: 10642043 BACKGROUND

• Pellock JM, Hrachovy R, Shinnar S, Baram TZ, Bettis D, Dlugos DJ, Gaillard WD, Gibson PA, Holmes GL, Nordl DR, O'Dell C, Shields WD, Trevathan E, Wheless JW. Infantile spasms: a U.S. consensus report. Epilepsia. 2010 Oct;51(10):2175-89. doi: 10.1111/j.1528-1167.2010.02657.x.

  PMID: 20608959 BACKGROUND

• Mytinger JR, Joshi S; Pediatric Epilepsy Research Consortium, Section on Infantile Spasms. The current evaluation and treatment of infantile spasms among members of the Child Neurology Society. J Child Neurol. 2012 Oct;27(10):1289-94. doi: 10.1177/0883073812455692. Epub 2012 Aug 21.

  PMID: 22914371 BACKGROUND

• Mackay MT, Weiss SK, Adams-Webber T, Ashwal S, Stephens D, Ballaban-Gill K, Baram TZ, Duchowny M, Hirtz D, Pellock JM, Shields WD, Shinnar S, Wyllie E, Snead OC 3rd; American Academy of Neurology; Child Neurology Society. Practice parameter: medical treatment of infantile spasms: report of the American Academy of Neurology and the Child Neurology Society. Neurology. 2004 May 25;62(10):1668-81. doi: 10.1212/01.wnl.0000127773.72699.c8.

  PMID: 15159460 BACKGROUND

• Go CY, Mackay MT, Weiss SK, Stephens D, Adams-Webber T, Ashwal S, Snead OC 3rd; Child Neurology Society; American Academy of Neurology. Evidence-based guideline update: medical treatment of infantile spasms [RETIRED]. Report of the Guideline Development Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2012 Jun 12;78(24):1974-80. doi: 10.1212/WNL.0b013e318259e2cf.

  PMID: 22689735 BACKGROUND

• Rho JM. Basic science behind the catastrophic epilepsies. Epilepsia. 2004;45 Suppl 5:5-11. doi: 10.1111/j.0013-9580.2004.05001.x.

  PMID: 15283705 BACKGROUND

• Arya R, Shinnar S, Glauser TA. Corticosteroids for the treatment of infantile spasms: a systematic review. J Child Neurol. 2012 Oct;27(10):1284-8. doi: 10.1177/0883073812453203. Epub 2012 Aug 1.

  PMID: 22859699 BACKGROUND

• Ben-Menachem E. Mechanism of action of vigabatrin: correcting misperceptions. Acta Neurol Scand Suppl. 2011;(192):5-15. doi: 10.1111/j.1600-0404.2011.01596.x.

  PMID: 22061176 BACKGROUND

• Zhang B, McDaniel SS, Rensing NR, Wong M. Vigabatrin inhibits seizures and mTOR pathway activation in a mouse model of tuberous sclerosis complex. PLoS One. 2013;8(2):e57445. doi: 10.1371/journal.pone.0057445. Epub 2013 Feb 20.

  PMID: 23437388 BACKGROUND

• Vanhatalo S, Nousiainen I, Eriksson K, Rantala H, Vainionpaa L, Mustonen K, Aarimaa T, Alen R, Aine MR, Byring R, Hirvasniemi A, Nuutila A, Walden T, Ritanen-Mohammed UM, Karttunen-Lewandowski P, Pohjola LM, Kaksonen S, Jurvelin P, Granstrom ML. Visual field constriction in 91 Finnish children treated with vigabatrin. Epilepsia. 2002 Jul;43(7):748-56. doi: 10.1046/j.1528-1157.2002.17801.x.

  PMID: 12102679 BACKGROUND

• Westall CA, Nobile R, Morong S, Buncic JR, Logan WJ, Panton CM. Changes in the electroretinogram resulting from discontinuation of vigabatrin in children. Doc Ophthalmol. 2003 Nov;107(3):299-309. doi: 10.1023/b:doop.0000005339.23258.8f.

  PMID: 14711162 BACKGROUND

• Simao GN, Zarei Mahmoodabadi S, Snead OC, Go C, Widjaja E. Abnormal axial diffusivity in the deep gray nuclei and dorsal brain stem in infantile spasm treated with vigabatrin. AJNR Am J Neuroradiol. 2011 Jan;32(1):199-203. doi: 10.3174/ajnr.A2224. Epub 2010 Aug 26.

  PMID: 20801762 BACKGROUND

• Wheless JW, Carmant L, Bebin M, Conry JA, Chiron C, Elterman RD, Frost M, Paolicchi JM, Donald Shields W, Thiele EA, Zupanc ML, Collins SD. Magnetic resonance imaging abnormalities associated with vigabatrin in patients with epilepsy. Epilepsia. 2009 Feb;50(2):195-205. doi: 10.1111/j.1528-1167.2008.01896.x. Epub 2008 Nov 17.

  PMID: 19054414 BACKGROUND

• Lux AL, Edwards SW, Hancock E, Johnson AL, Kennedy CR, Newton RW, O'Callaghan FJ, Verity CM, Osborne JP. The United Kingdom Infantile Spasms Study comparing vigabatrin with prednisolone or tetracosactide at 14 days: a multicentre, randomised controlled trial. Lancet. 2004 Nov 13-19;364(9447):1773-8. doi: 10.1016/S0140-6736(04)17400-X.

  PMID: 15541450 BACKGROUND

• Jones K, Snead OC 3rd, Boyd J, Go C. Adrenocorticotropic hormone versus prednisolone in the treatment of infantile spasms post vigabatrin failure. J Child Neurol. 2015 Apr;30(5):595-600. doi: 10.1177/0883073814533148. Epub 2014 Jun 25.

  PMID: 24965788 BACKGROUND

• Kossoff EH, Hartman AL, Rubenstein JE, Vining EP. High-dose oral prednisolone for infantile spasms: an effective and less expensive alternative to ACTH. Epilepsy Behav. 2009 Apr;14(4):674-6. doi: 10.1016/j.yebeh.2009.01.023. Epub 2009 Feb 4.

  PMID: 19435579 BACKGROUND

• Ware TL, Mackay MT, Harvey AS, Freeman JL. Epileptic spasms: experience with a high-dose oral corticosteroid protocol. J Paediatr Child Health. 2012 Nov;48(11):985-9. doi: 10.1111/j.1440-1754.2012.02582.x. Epub 2012 Oct 8.

  PMID: 23039949 BACKGROUND

• Hussain SA, Shinnar S, Kwong G, Lerner JT, Matsumoto JH, Wu JY, Shields WD, Sankar R. Treatment of infantile spasms with very high dose prednisolone before high dose adrenocorticotropic hormone. Epilepsia. 2014 Jan;55(1):103-7. doi: 10.1111/epi.12460. Epub 2013 Nov 8.

  PMID: 24446954 BACKGROUND

MeSH Terms

Conditions

Spasms, Infantile

Interventions

Prednisolone; Vigabatrin

Condition Hierarchy (Ancestors)

Epilepsy, Generalized; Epilepsy; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epileptic Syndromes

Intervention Hierarchy (Ancestors)

Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; gamma-Aminobutyric Acid; Aminobutyrates; Butyrates; Acids, Acyclic; Carboxylic Acids; Organic Chemicals; Amino Acids; Amino Acids, Peptides, and Proteins

Study Officials

• Carter Snead, MD

  The Hospital for Sick Children

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Staff Neurologist

Study Record Dates

• First Submitted: November 18, 2014
• First Posted: November 24, 2014
• Study Start: September 5, 2017
• Primary Completion: March 6, 2019
• Study Completion: March 6, 2019
• Last Updated: November 14, 2019

Record last verified: 2019-11

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)